HFA Position Papers 2019

COMPENDIUM OF
POSITION PAPERS
FROM 2019
From the Heart Failure

Association
PAPERS
FROM Heart Failure
Association Committees
Published in the European Journal of Heart Failure

European Journal of Heart Failure (2019) 21, 137–155 POSITION PAPER
doi:10.1002/ejhf.1369
The use of diuretics in heart failure with

congestion — a position statement from the
Heart Failure Association of the European
Society of Cardiology
Wilfried Mullens1,2*, Kevin Damman3, Veli-Pekka Harjola4, Alexandre Mebazaa5,
Hans-Peter Brunner-La Rocca6, Pieter Martens1,2, Jeffrey M. Testani7,
W.H. Wilson Tang8, Francesco Orso9, Patrick Rossignol10, Marco Metra11,
Gerasimos Filippatos12,13, Petar M. Seferovic14, Frank Ruschitzka15,
and Andrew J. Coats16
1 Ziekenhuis Oost Limburg, Genk, Belgium; 2 University of Hasselt, Hasselt, Belgium; 3 University of Groningen, University Medical Center Groningen, Groningen,
The Netherlands; 4 Emergency Medicine, University of Helsinki, Helsinki University Hospital, Helsinki, Finland; 5 University of Paris Diderot, Hôpitaux Universitaires Saint Louis
Lariboisière, APHP, U 942 Inserm, F-CRIN INI-CRCT, Paris, France; 6 Maastricht University Medical Center, Maastricht, The Netherlands; 7 Yale University, New Haven, CT, USA;
8 Cleveland Clinic, Cleveland, OH, USA; 9 University of Florence, Florence, Italy; 10 Université de Lorraine, Inserm, Centre d’Investigations Clinique 1433 and Inserm U1116;
CHRU Nancy; F-CRIN INI-CRCT, Nancy, France; 11 University of Brescia, Brescia, Italy; 12 National and Kapodistrian University of Athens, Athens, Greece; 13 University of Cyprus,
Nicosia, Cyprus; 14 University of Belgrade, Faculty of Medicine, Belgrade, Serbia; 15 UniversitätsSpital Zürich, Zürich, Switzerland; and 16 IRCCS, San Raffaele Pisana, Rome, Italy
Received 19 July 2018; revised 14 October 2018; accepted 27 October 2018 ; online publish-ahead-of-print 1 January 2019
The vast majority of acute heart failure episodes are characterized by increasing symptoms and signs of congestion with volume overload.
The goal of therapy in those patients is the relief of congestion through achieving a state of euvolaemia, mainly through the use of diuretic
therapy. The appropriate use of diuretics however remains challenging, especially when worsening renal function, diuretic resistance and
electrolyte disturbances occur. This position paper focuses on the use of diuretics in heart failure with congestion. The manuscript addresses
frequently encountered challenges, such as (i) evaluation of congestion and clinical euvolaemia, (ii) assessment of diuretic response/resistance
in the treatment of acute heart failure, (iii) an approach towards stepped pharmacologic diuretic strategies, based upon diuretic response,
and (iv) management of common electrolyte disturbances. Recommendations are made in line with available guidelines, evidence and expert
opinion.
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Keywords Diuretics • Heart failure • Acute heart failure • Pharmacotherapy • Loop diuretics
Introduction of this manuscript will refer to this setting as acute heart failure.
...........................
Only a minority of patients with acute heart failure present acutely

The natural history of heart failure is characterized by acute with signs and symptoms of low perfusion.4 Given the pivotal role
decompensation episodes, which are associated with increased of congestion in heart failure, diuretics are a cornerstone of therapy
morbidity and mortality and pose an economic burden on our in heart failure.6 Guidelines strongly recommend the use of loop
society .1,2 Increasing signs and symptoms of congestion are the diuretics to alleviate signs and symptoms of fluid overload (class
main reasons why patients with acute heart failure seek urgent I, level of evidence B).7 This paper discusses the practical use of
medical care.3 – 5 Even though congestion often develops over an diuretics in patients with acute and chronic heart failure, based on
extended period of time before acute presentation, the remainder contemporary evidence and expert opinion.
*Corresponding author. Department of Cardiology, Ziekenhuis Oost-Limburg, Schiepse Bos 6, 3600 Genk, Belgium. Tel: +32 89 327160, Fax: +32 89 327918, Email:
wilfried.mullens@zol.be
© 2018 The Authors

European Journal of Heart Failure © 2018 European Society of Cardiology
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138 W. Mullens et al.
Congestion in heart failure haemodynamics.23 The diagnostic accuracy of non-invasive clinical
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and technical assessments of congestion has been validated against
Definition and mechanisms of congestion invasive haemodynamic evaluation and shown a variable sensitivity
Congestion in heart failure is defined as signs and symptoms and specificity (Table 1).22 – 28 Physical signs and symptoms of con-
of extracellular fluid accumulation that result in increased car- gestion are based on detecting increased filling pressures and/or
diac filling pressures.8 Filling pressures are the integrated result the extravascular fluid build-up secondary to the increased filling
of the cardiac systolic and diastolic function, plasma volume, and pressures. As such, the jugular venous pulse is the most useful
venous capacitance/compliance.9 – 11 Heart failure with increased physical finding for determining a patient’s volume status. Not only
neurohumoral activation induces a state of increased renal sodium does an elevated jugular venous pulsation (JVP) detect systemic
and water avidity resulting in an increased plasma volume.11,12 congestion, but there is good sensitivity (70%) and specificity (79%)
Also, increased sympathetic output leads to splanchnic arterial between high JVP and elevated left-sided filling pressure. Changes in
and venous constriction resulting in blood redistribution from the JVP with therapy usually parallel changes in left-sided filling pressure
splanchnic capacitance vasculature to the circulatory volume. This although significant inter-observer variability regarding the extent
increases the effective circulating volume by redistribution, in a of JVP elevation exist.29 – 31 However, in a series of 50 patients with
state where volume expansion is already present.13 As a result, chronic heart failure it was shown that physical signs of congestion
(rales, oedema and JVP elevation) were absent in 42% of patients
with a PCWP ≥ 22 mmHg.32 Additionally, there is a waning of
venous return and cardiac filling pressures increase.11 Indeed, the
venous capacitance function becomes compromised during states
of longstanding venous congestion and/or increased sympathetic skills in performing physical examination in current practice.33
activation in acute heart failure.11,14,15 Importantly, the term vol- Also, while a chest X-ray can show signs of lung congestion and
ume overload and congestion are often used interchangeably. How- pleural fluid, 20% of patients with congestion exhibit a normal
ever, it has been demonstrated that 54% of patients hospitalized for chest X-ray.34 In comparison to chest X-ray, lung ultrasound is
acute heart failure gain ≤ 1 kg during the month prior to admission, better in ruling out interstitial oedema and pleural effusions. Lung
suggesting that volume overload incompletely characterizes the ultrasound detects B-lines originating from extravasated fluid into
pathophysiology of acute heart failure and redistribution of volume the interstitium and alveoli.35,36 More than three B-lines in more
may also contribute to the development of signs and symptoms than two intercostal spaces bilaterally are considered diagnostic
of congestion.16,17 Furthermore, heart failure is often associated for the detection of interstitial and alveolar oedema in acute heart
with cachexia which makes the interpretation of weight changes failure. Echocardiographic parameters (Table 1) can be used to
difficult. Additionally, cachexia might result in a loss of plasma pro- estimate right- and left-sided filling pressures, although with less
teins, reducing plasma oncotic pressure, hampering plasma refilling certainty in acute heart failure.25 Estimation of right atrial pres-
from the interstitium.18,19 Additionally, weight loss during hospi- sures can be performed by assessing the collapsibility and width of
talization is not necessarily associated with improved in-hospital the vena cava. Doppler imaging and tissue Doppler can be used to
or post-discharge morbidity or mortality, however weight gain has assess left-sided filling pressures. With rising filling pressures, an
been associated with poor outcome.20,21 Therefore, the European increase in early diastolic mitral inflow velocities (E wave) occurs.
Society of Cardiology (ESC) guidelines for the diagnosis and treat- This is indicative of increased filling pressures in the presence of a
ment of acute and chronic heart failure recommend to distinguish low e’, especially if E-wave deceleration time is short and A-wave
acute fluid redistribution from true volume overload in patients velocities are low.28 Nevertheless, the use of e’ might be limited in
presenting with congestion (no class recommendation).7 As diuret- advanced heart failure.25 Guidelines suggest the measurement of
ics are mainly used to relieve excessive volume, the remainder of natriuretic peptides (NPs) in all patients with acute heart failure,
this manuscript will focus on congestion with excessive volume especially to distinguish from non-cardiac causes of dyspnoea
overload. (class I recommendation, level of evidence A).7 NPs have a high
negative predictive value for ruling out acute heart failure with
congestion [thresholds for excluding acute heart failure; B-type
Detecting congestion in heart failure natriuretic peptide (BNP) < 100 pg/mL, N-terminal pro BNP
(NT-proBNP) < 300 ng/mL and mid-regional pro atrial natriuretic
Although the intravascular pressure–volume relationship may peptide < 120 pg/mL].7,37 In patients with history of heart failure
vary across individuals and clinical conditions, the gold standard or cardiac disease, the combination of signs and symptoms of
for diagnosing congestion in heart failure is cardiac catheterization congestion, an indicative chest X-ray and the measurement of
with direct measurement of right atrial pressure and pulmonary elevated NPs allows for the diagnosis of congestion.22,38 According
capillary wedge pressure (PCWP).22 However, the invasive to local availability, these tests can be supplemented with transtho-
nature of this technique limits its routine use in clinical practice. racic echocardiography or lung ultrasound. In line with the ESC
Furthermore, the use of pulmonary artery catheterization to guidelines, direct haemodynamic evaluation should be reserved for
guide decongestive therapy did not improve outcome in the patients with cardiogenic shock, refractory pulmonary oedema or
Evaluation Study of Congestive Heart Failure and Pulmonary suspected mismatch between left and right-sided filling pressures
Artery Catheterization Effectiveness (ESCAPE) study in compar- (class IIb recommendation, level of evidence C) or in cases of
ison to serial clinical assessment, despite significantly improving uncertainty of the haemodynamic status.7
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Diuretics in heart failure 139
Table 1 Sensitivity and specificity of different clinical and technical parameters to detect congestion
Parameter Sensitivity Specificity Comparator Comment

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Clinical evaluation
Right-sided
JVP > 8 cm 48% 78% RAP > 7 mmHg Difficult in obese patient
Jugular venous reflux 50% 75% RAP > 7 mmHg Difficult in obese patient
Hepatomegaly 51% 62% RAP > 7 mmHg Difficult in obese patient, non-HF causes
Bilateral leg oedema 94% 10% RAP > 7 mmHg Non-HF oedema gives false positive
Left-sided
Dyspnoea 50% 73% PCWP > 18 mmHg Multiple reasons for dyspnoea
Dyspnoea on exertion 66% 52% PCWP > 18 mmHg Multiple reasons for dyspnoea on exertion
Orthopnoea 66% 47% PCWP > 18 mmHg May be non-cardiac in origin or absent
S3 73% 42% PCWP > 18 mmHg Intra-observer variability
Rales 13% 90% PCWP > 18 mmHg May be non-cardiac in origin or absent
Echocardiographic evaluation
Right-sided
Collapse (< 50%) IVC 12% 27% RAP > 7 mmHg Difficult to use in positive pressure ventilated
patients
Inspiratory diameter IVC < 12 mm 67% 91% RAP > 7 mmHg Cannot be used in positive pressure ventilated
patients
Left-sided
Mitral inflow E-wave velocity > 50 (cm/s) 92% 28% PCWP > 18 mmHg Difficult when fusion of E and A wave
Lateral E/e’ > 12 66% 55% PCWP > 18 mmHg Less accurate in advanced heart failure and CRT
Deceleration time < 130 ms 81% 80% PCWP > 18 mmHg Difficult when fusion of E and A wave
Pulmonary vein S/D < 1 83% 72% PCWP > 18 mmHg Intra-observer variability in Doppler
measurements of the vein
Diffuse B-lines on lung ultrasounda 85.7% 40% PCWP > 18 mmHg B-lines might be present in non-cardiac
conditions
CRT, cardiac resynchronization therapy; HF, heart failure; IVC, inferior vena cava; JVP, jugular venous pulsation; PCWP, pulmonary capillary wedge pressure; RAP, right atrial
pressure; S/D, systolic diastolic velocity.
a More than three B-lines in more than two intercostal spaces bilaterally.
Adapted from Gheorghiade,22 Nagueh,24 Mullens,25 Parrinello26 and Volpicelli.27
Determination of euvolaemia detect congestion have been used as surrogates for the presence
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of increased filling pressures (right atrial pressure > 7 mmHg or

Many patients are discharged with residual clinical congestion.39 – 41
PCWP > 18 mmHg).48 However, their performance in detecting
For example, only 15% of patients were assessed to be euvolaemic
the euvolaemic point without residual haemodynamic congestion
by their treating physician in the Diuretic Optimization Strate-
is unclear. Increasing interest is being placed on biomarkers in
gies Evaluation (DOSE-AHF) study after decongestive therapy.42 detecting a state of decongestion, as they have the advantage of
Importantly, clinical congestion at discharge is a strong predictor being easy to measure. To serve as a biomarker for decongestion,
of poor outcome and readmission, especially in the setting of markers do not only need to be correlated with congestion
worsening of renal function.20,43,44 However, even in patients at a certain time point, but also need to respond to changes
with limited clinical signs and symptoms of congestion at dis- in congestion status rapidly and reliably. NPs are released in
charge, outcome can remain poor, pointing towards a role of response to increased myocardial wall stress, hereby reflecting
subclinical congestion.45 Relief of dyspnoea is a poor marker of intracardiac filling pressures. However, many additional factors
decongestion, as patients without dyspnoea frequently still have may influence the NP levels in addition to wall stress.37,49 To
significant clinical or haemodynamic congestion.39,46 The same date, no randomized controlled trial has demonstrated that
applies to attaining a similar body weight loss when the patient NP-guided decongestive therapy in acute heart failure improves
was stable.47 Determining euvolaemia or the optimal stopping clinical outcome.50 However, changes in NP concentrations over
point for decongestive therapy remains a major challenge in heart time may help to further stratify risk, as reductions in previously
failure. At the moment no reliable practical bedside test exists elevated NP levels, whether achieved spontaneously or through
to determine euvolaemia as it is not yet clear what euvolaemia application of appropriate medical therapy, appear to be associated
encompasses. Theoretically, it relates to an optimal fluid volume with an improvement in clinical outcomes50,51 Soluble CD146, car-
allowing the body to meet metabolic demands without excessive bohydrate antigen-125 and adrenomedulin are novel biomarkers
interstitial fluid or the development of a detrimental increase in more precisely reflecting vascular congestion. They could poten-
cardiac filling pressures. Indeed, most non-invasive clinical tests to tially offer incremental information in addition to the value of
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NPs reflecting cardiac congestion. However, their use is currently should not automatically stop further decongestive therapy, espe-
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restricted to the field of research and less embedded in clinical cially if congestion persists. Additionally, an increase in creatinine
practice.52 – 54 An increase in haemoglobin (haemoconcentration) during decongestion is not associated with intrinsic renal tubular
after decongestion has been proposed as a marker of the reduction damage.59,60 Clinical outcomes are extremely poor if patients are
of intravascular volume.55 – 57 However, haemoconcentration only discharged with ongoing congestion in the face of worsening of
provides a surrogate for a relative reduction in plasma volume renal function.20 In addition, an overemphasis on serial biomarker
between two time points and it therefore does not provide an indi- level assessment as a surrogate for changes in volume status
cation of the absolute plasma volume (which might be the target).58 might lead to inappropriate dose escalation of loop diuretics
Only late haemoconcentration (e.g. during the last days of hospital- among patients without significant residual congestion, potentially
ization) was associated with improved outcome, making it a poor increasing the rate of hypotension, renal dysfunction, and other
candidate to guide decongestive therapy.56 In addition, changes in adverse events. In contrast, improved biomarker levels may pro-
haematocrit are small, and can also relate to bleeding, phlebotomy, vide false reassurance that decongestion has been achieved. In line
splenic pooling of blood and postural changes. Importantly, an with a previous position paper, the use of a multi-parameter-based
increase in plasma creatinine is frequently interpreted in clinical evaluation of congestion pre-discharge, using clinical assessment
practice as a decrease in effective circulating volume, prompting at rest and during dynamic manoeuvres as well as biomarkers,
physicians to reduce decongestive therapy, based on the often false supplemented with technical assessments according to local
assumption that further decongestion might result in renal tubular expertise, is probably the best contemporary strategy (Figure 1),
damage. Indeed, during decongestion, an increase in creatinine but has never been prospectively evaluated.22,61,62
Figure 1 Integrative euvolaemia/congestion evaluation at discharge. 6MWT, 6-minute walk test; BNP, B-type natriuretic peptide; HJR,
hepato-jugular reflux; HR, heart rate; JVP, jugular venous pulsation; NP, natriuretic peptide; NT-proBNP, N-terminal pro B-type natriuretic
peptide; SBP, systolic blood pressure. ∘ The cut-off for NT-proBNP to exclude congestion as endorsed by the Heart Failure Association
position paper on grading congestion is higher than the cut-off endorsed by the European Society of Cardiology guidelines to exclude acute
heart failure. *Chest X-ray can be clear but presence of abnormalities suggests higher degree of congestion. Partially adapted from the Heart
Failure Association position paper on assessing and grading congestion in acute heart failure.22
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Figure 2 Sites and mode of action and effects on sodium reabsorption in the nephron of different diuretics. AQP2, aquaporin-2; AVP,
arginine vasopressin; cAMP, cyclic adenosine monophosphate; eNaC, epithelial sodium channel; HF, heart failure; PKA, protein kinase A; SGLT2,
sodium–glucose linked transporter-2.
Mechanisms of action of diuretics form the mainstay of diuretic therapy in heart failure, the terms
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diuretic resistance and loop diuretic resistance are often used

in heart failure interchangeably.65,67 – 69 To assess the response to an initiated
In the case of congestion with volume overload, chronic retention diuretic regimen, physicians need an indicator of the diuretic
of sodium and water further expands intravascular volume, result- response. Currently, net fluid output and changes in body weight
ing in excessive extravascular fluid build-up. Other than ultrafiltra- are frequently used. While assessment of weight might appear to be
tion, the only pathway to get rid of sodium and water is through a simple measurement, it is technically challenging and fluctuations
increased renal natriuresis and diuresis. Diuretics increase renal in weight might not represent changes in volume redistribution.47
sodium and water output. Thorough knowledge of their pharma- Furthermore, there is a poor correlation between weight loss and
cokinetics and pharmacodynamics are mandatory for their suc- fluid output.47
cessful employment.63 The site of action of cellular mechanisms As the objective of diuretic therapy is to get rid of excessive
of different diuretics are listed in Figure 2 and a synopsis of their sodium (and accompanying water), the measurement of urinary
pharmacologic properties is presented in Table 2.64 sodium content has recently experienced a renewed interest as
an indicator for diuretic response.70 – 73 In addition to measuring
sodium in a continuous urinary collection, a spot urine sample
Diuretic response and resistance 1–2 h following loop diuretic administration has recently demon-
strated an excellent correlation with total urine sodium output in
in heart failure a 6 h urine collection.73 This strategy might allow the clinician to
In achieving euvolaemia, the degree of volume overload and diuretic determine loop diuretic response in a systematic and timely fash-
response will determine the success of therapy.65 The capacity of ion, potentially allowing for more timely adjustments in therapy.
inducing natriuresis or diuresis following diuretic administration is However, during consecutive days of loop diuretic therapy in acute
defined as diuretic response. Diuretic resistance is defined as an heart failure, urinary sodium composition changes significantly.74
impaired sensitivity to diuretics resulting in reduced natriuresis and Despite persistent increased urinary volume output (diuresis),
diuresis limiting the possibility to achieve euvolaemia.66 Diuretic renal sodium output (natriuresis) diminishes over time. There-
response should always be interpreted in light of the dose and fore, increasingly hypotonic urine is produced during consecutive
type of the diuretic agent administered and the degree of volume days of loop diuretic therapy, which might relate to numerous fac-
overload, body composition and kidney function. As loop diuretics tors including altered renal haemodynamics, differential substrate
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142
Table 2 Pharmacology of diuretics
Acetazolamide Loop diuretics Thiazide-like diuretics MRAa Amiloride

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Site of action Proximal nephron Ascending loop of Henle Early distal convoluted tubule Late distal tubuie Late distal tubule
Starting dose/usual Oral: 250–375 mg Furosemide: 20–40/40–240 mgb HCTZ: 25/12.5–100 mgc Spironolactone: 25/25–50 mg 5/10 mg
chronic dose Intravenous: 500 mg Bumetanide: 0.5–1.0/1–5 mgb Metolazone: 2.5/2.5–10 mgc Eplerenone: 25/25–50 mg
Torsemide: 5–10/10–20 mgb Chlorthalidone: 25/25–200 mgc Potassium canrenoate:
Chlorothiazide: 500–1000 mg 25–200 mg/not for
(IV formulation available) chronic use
Maximum recommended Oral: 500 mg 3x/day Furosemide: 400–600 mg HCTZ: 200 mg 50–100 mg (doses up to 400 mg 20 mg
total daily dose Intravenous: 500 mg 3x/day Bumetanide: 10–15 mg Metolazone: 20 mg are used in hepatology)
Torsemide: 200–300 mg Chlorthalidone: 100 mg
Chlorothiazide: 1000 mg
Half-life 2.4–5.4 h Furosemide: 1.5–3.0 h HCTZ: 6–15 h Canrenone: 16.5 hd Normal GFR: 6–9 h
Bumetanide: 1–1.5 h Metolazone: 6–20 h Eplerenone: 3–6 h GFR < 50 mL/min: 21–144 h
Torsemide: 3–6 h Chlorthalidone: 45–60 h
Onset PO: 1 h PO: 0.5–1 he PO: 1–2.5 h PO: 48–72 hd PO: 2 h
IV: 15–60 min IV: 5–10 mine IV: Chlorothiazide is IV available, IV: potassium canrenoate; 2.5 h IV: not available
SC: 0.5 he onset action: 30 min
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Oral bioavailability Absorption is dose-dependent, Furosemide: 10–100% HCTZ: 65–75% Spironolactone: ∼90% 30–90%
dose >10 mg/kg exhibit Bumetanide: 80–100% Metolazone: 60–65%f Eplerenone: 69%
variable uptake Torsemide: 80–100% Chlorthalidone: unknown
Chlorothiazide: 9–56%
Enteral absorption May be taken with food. Food Furosemide: yes (slowed) HCTZ: unknown Spironolactone: bioavailability Unknown
affected by food decreases symptoms of GI Bumetanide: yes (slowed) Metolazone: unknown increase with high fat food
upset. Torsemide: no Chlorthalidone: unknown Eplerenone: unknown
Potency (FENa%)g 4% 20–25%e 5–8% 2% 2%
FENa, fractional excretion of sodium; GFR, glomerular filtration rate; GI, gastrointestinal; HCTZ, hydrochlorothiazide; HF, heart failure; IV, intravenous; MRA, mineralocorticoid receptor antagonist; PO, per oral; SC, subcutaneous.
Diuretic agents are reflected from the site of action; from proximal nephron to distal nephron.
a Minimal diuretic effect.
b Dose of intravenous and oral loop diuretics are similar.
c Only PO use in acute HF, thiazides are not recommended for daily ambulatory use in chronic stable HF.
d Canrenone is the active metabolite of spironolactone. Intravenous potassium canrenoate is the intravenous formulation and is metabolized to canrenone resulting in significant plasma levels after 2.5 h of administration.
e Generally similar for different loop diuretics.
f Variations between pharmaceutical brands of metolazone exist.
g Tested in non-HF patients. FENa is the percentage of the sodium filtered by the kidney, which is ultimately excreted in the urine. It is measured based on plasma and urinary sodium. In clinical use, FENa can be calculated as part of
the evaluation of diuretic effectiveness. The normal value depends primarily on the GFR of the patient but is commonly < 2% in patients with relatively intact renal function. Diuretic agents increase FeNa with loop diuretic agents to
be the most potent ones. FENa = 100 × (Na urine × creatinine plasma)/(Na plasma × creatinine urine).
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W. Mullens et al.

delivery (sodium and/or diuretics), neurohormonal factors and are heavily protein-bound (> 90%) and need to be secreted into
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structural kidney alterations. Although several studies have illus- the proximal convoluted tubule through several organic anion
trated the prognostic value of urinary sodium following a first transporters. Therefore, adequate dosing with sufficient plasma
administration of a loop diuretic, its prognostic value during con- levels is pivotal as renal perfusion is often reduced in heart failure,
secutive days remains unstudied. resulting in diminished secretion of loop diuretics. Additionally,
The pathophysiology of diuretic resistance is multi-factorial decreased plasma protein content can result in reduced secretion
and involves sympathetic nervous system activation, renin– of loop diuretics. Loop diuretics inhibit the Na-K-2Cl symporter
angiotensin–aldosterone system (RAAS) activation, nephron at the ascending loop of Henle, and have the most potent diuretic
remodelling, pre-existing renal function alterations, disrupted effect, promoting excretion of sodium and chloride (and potassium,
pharmacokinetics and dynamics of diuretics and intravascular albeit to a lesser extent than thiazides).64 The pharmacological
fluid depletion due to slow plasma refilling.65,75,76 Therefore, a properties of the different loop diuretics are presented in Table 2.
stepped pharmacologic approach focused on achieving successful The bioavailability of orally administered furosemide is highly
decongestion with alterations in diuretic therapy based on early variable (10–90%), and is determined by absorption from the
and repetitive treatment assessment is suggested to be superior gastrointestinal tract into the bloodstream.6 The oral bioavail-
to standard high-dose loop diuretics in patients with worsening ability for torsemide and bumetanide are consistently higher than
of renal function (serum creatinine increase of > 0.3 mg/dL within 80–90%. In addition, torsemide has a longer half-life in heart
previous 12 weeks before decompensation), as assessed in a failure patients when compared to furosemide or bumetanide.84
post-hoc analysis of the DOSE-AHF and the Renal Optimization Although some smaller studies suggested superior diuretic effect
Strategies Evaluation (ROSE-AHF) trials.77,78 of torsemide, no large randomized studies have compared the
difference between different loop diuretics.85 The Torsemide
Comparison with Furosemide for Management of Heart Failure
Practical use of diuretics in acute (TRANSFORM-HF) trial (NCT03296813) is planned to randomize
heart failure 6000 heart failure patients who are hospitalized. While heart
failure need not to be the reason for hospitalization, its objective
Goals of therapy in acute is to detect a difference between furosemide vs. torsemide for
decompensated heart failure the primary endpoint all-cause mortality. Given the wide range of
Before initiating decongestive therapies in acutely decompensated bioavailability of oral furosemide, variance exists in the conversion
patients, the distinction should be made if volume overload or vol- calculation. Therefore an oral dose of 40 mg of furosemide is
ume redistribution is contributing to congestion.79 The goals of generally equivalent to 10–20 mg of torsemide and 0.5–1 mg of
therapy in patients presenting with congestion and volume over- bumetanide. Importantly, loop diuretics may also lead to renin
load consists of (i) achieving thorough decongestion without resid- release by the macula densa by blocking chloride uptake, further
ual volume overload. Nevertheless, the optimal stopping point of stimulating RAAS. Furthermore, chronic use of loop diuretics
decongestive therapy is often difficult to determine, as alluded induces compensatory distal tubular sodium reabsorption through
to above. (ii) Ensuring adequate perfusion pressures to guarantee hypertrophy of tubular cells, leading to reduced natriuresis.8
organ perfusion. (iii) Maintaining guideline-directed medical ther- Guidelines recommend the use of intravenous loop diuretics in
apies as these medications may also increase diuretic response acute heart failure, as the uptake of oral diuretics (particularly
and improve long-term survival.80,81 When patients with heart fail- furosemide) can be diminished in the face of congestion due to
ure with reduced (HFrEF) or preserved ejection fraction (HFpEF) bowel oedema (class I, level of evidence B).7 Optimal dosing and
decompensate, they often can present with a similar profile of timing of intravenous loop diuretics are pertinent. Loop diuretics
congestion.82,83 Therefore, the goal of decongestive therapy is sim- exhibit a threshold concentration to invoke natriuresis, necessi-
ilar in terms of diuretic use in patients with HFrEF and HFpEF.7 A tating a minimal drug dose prior to exceeding the baseline rate of
practical stepped approach to diuretic treatment and assessment sodium excretion.6,86 Afterwards a log-linear increase in the dose
in acute heart failure is reflected in Figure 3. Once euvolaemia is necessary to achieve a ceiling in natriuretic response. Further
has been achieved, loop diuretic therapy should be continued increasing the loop diuretic dose beyond this ceiling will not result
at the lowest dose that can maintain euvolaemia.7,8 Additionally, in a greater rate of peak natriuresis, however it will lead to a
enrolment of patients in a detailed multi-disciplinary heart fail- longer period of loop diuretic over the threshold level and thus
ure care management programme, promoting medication adher- increases total natriuresis. Similarly, multiple administrations can
ence, up-titration of disease-modifying therapy, cardiac rehabilita- cause additional natriuresis, as it increases the duration of time
tion, treatment of underlying co-morbidities, timely follow-up with above a natriuretic threshold. These pharmacologic characteristics
the health care team, and screening for additive device-based and lead to the following recommendation in acute heart failure: (i)
medical interventions therapies is essential.7 diuretic naïve patients with acute heart failure should receive a
dose of intravenous furosemide of at least 20–40 mg furosemide
equivalent. The higher dose should be considered in patients with
Loop diuretics pre-existing kidney dysfunction as it is associated with a rightward
Loop diuretics form the backbone of diuretic therapy in acute shift in the dose–response curve.6,86 (ii) Patients on an ambulatory
heart failure, being used in over 90% of patients.3 Loop diuretics diuretic regimen should receive at least the pre-existing oral dose
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Figure 3 Flowchart to diuretic use in acute heart failure. (A) Congestion with volume overload. (B) Treatment algorithm after 24 h. Total
loop diuretic dose can be administered either as continuous infusion or bolus infusion. BP, blood pressure; HF, heart failure; IV, intravenous;
SGLT2-I, sodium–glucose linked transporter 2 inhibitor; UF, ultrafiltration; UO, urine output. & Higher dose should be considered in patients
with reduced glomerular filtration rate. *Consider other reasons for dyspnoea given the quick resolution of congestion. ∘ The maximal dose
for IV loop diuretics is generally considered furosemide 400–600 mg or 10–15 mg bumetanide. # In patients with good diuresis following a
single loop diuretic administration, once a day dosing can be considered.
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Figure 3 Continued.
© 2018 The Authors

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administered intravenously. The DOSE-AHF trial demonstrated I recommendation, level of evidence C), this Cardio-Renal Dys-
........................................................................................................................................................................
that high loop diuretic dose (2.5 times the usual home dose, with at function Study Group proposes the active evaluation of diuretic
least 80 mg/day furosemide equivalents) in comparison to low dose response early after start of therapy. Diuretic response may be eval-
(equal to home dose) resulted in a favourable effect on secondary uated using urinary volume output and post-diuretic (spot) urinary
endpoints of dyspnoea relief, change in weight and net fluid loss.42 sodium content as outlined in Figure 3. To allow for standardiza-
Worsening of renal function (defined as an increase in creatinine tion and reliable results, patients presenting with congestion need
by more than 0.3 mg/dL) occurred more in the high-dose group. to empty their bladder before the administration of diuretics. The
However, a post-hoc analysis of the DOSE-AHF trial illustrated degree of bladder emptying could potentially be checked using a
that this increase in creatinine did not portend a worse outcome.87 bladder scan. Afterwards, determination of urinary spot sodium
In addition, the high-dose group was associated with better out- content allows the clinician to interpret diuretic response, thereby
comes when adjusted for the total amount of loop diuretics generating the opportunity to intervene if sodium content is low. In
received, suggesting that adequacy of loop diuretic dosing to reach the face of congestion with volume overload, a spot urine sodium
the ‘ceiling’ threshold is key.88 Determining the individual ceiling content of < 50–70 mEq/L after 2 h, and/or an hourly urine output
dose in a patient is difficult and is influenced by numerous factors, < 100–150 mL during the first 6 h, generally identifies a patient
including previous treatment with loop diuretics, body composi- with an insufficient diuretic response.72,73,94 In patients who pro-
tion, degree of volume overload and kidney function. However, duce sufficient urinary volumes following a first intravenous loop
an intravenous dose ranging between 400–600 mg furosemide vs. diuretic administration, urinary sodium is almost universally high.
10–15 mg bumetanide is generally considered as the maximal total However, more recent data indicate that in patients with a low
daily dose above which limited additional natriuresis should be to medium volume output, spot urinary sodium content offers
expected but side effects will continue to increase. Generally, loop independent prognostic information on heart failure admissions on
diuretics are given in multiple doses (twice to three times daily). top of urinary volume output.71 Prompt doubling of loop diuretic
Intravenous loop diuretics should be administered as early as dose might allow the attainment of a loop diuretic ceiling dose ear-
possible, since early loop diuretic administration is associated with lier (as alluded to in the loop diuretic section). After these doses
lower in-hospital mortality.89 In the DOSE-AHF trial, no difference are achieved, addition of another diuretic agent should be consid-
was seen in the primary endpoint between continuous or bolus ered, as increasing the loop diuretic dose any further does not
infusion. However, continuous infusion was not preceded by a induces incremental diuresis/natriuresis. In the Cardiorenal Res-
bolus loading dose which might have resulted in not reaching the cue Study in Acute Decompensated Heart Failure (CARRESS-HF),
threshold dose in the continuous infusion group. If bolus infusion is a strategy of stepped pharmacologic therapy was compared with
given, doses should be split-up into doses with at least 6 h intervals, ultrafiltration in acute decompensated heart failure patients with
to maximize the time above the natriuretic threshold and to avoid worsened renal function and persistent congestion (online supple-
rebound sodium retention.90 Continuous infusion should be pre- mentary Figure S1). The pharmacologic care approach using early
ceded by a loading dose, which assures the prompt achievement assessment of urinary output with adjustment of loop diuretic dos-
of a steady-state of plasma loop diuretic concentration.6 ing and the addition of a thiazide-like diuretic, resulted in equal
decongestion compared to ultrafiltration, however with fewer seri-
ous adverse events.95 Post-hoc comparisons with the DOSE-AHF
Stepped pharmacologic care
and ROSE-AHF trials indicates that a stepped pharmacologic care
Early evaluation and loop diuretic intensification approach was also associated with greater net fluid and weight loss,
The majority of the diuretic effect of intravenous loop diuretics without compromising renal function.77,78 As urine sodium content
occurs within the first couple of hours with a return to base- rarely changes discordantly to urine output during the first day of
line sodium excretion by 6–8 h. Early evaluation of the diuretic decongestive therapy (in the absence of excessive fluid intake by
response is therefore warranted and will allow for the identification the patient), it seems reasonable to assess urinary sodium con-
of patients with a poor diuretic response.67,69,73,74 This will permit tent always together with urine volume to adjust diuretic intensity
early intensification of loop diuretic dose and/or using a strategy during the first day. Insufficient data are available to support the
of sequential nephron blockade (combining diuretics with a differ- use of urinary sodium during consecutive days of decongestion. In
ent mode of action). Although this concept has yet to be formally the CARRESS-HF trial, a urinary output of > 5 L per day allowed
tested in prospective trials, such a strategy is important in several the physicians to reduce diuretic intensity, however continuation of
aspects. Firstly, persisting congestion further compromises organ the diuretic regimen may be acceptable if renal function and blood
function.91 Secondly, the plasma refill rate (the rate at which fluid pressure remain stable.
is mobilized from the interstitium into the plasma compartment)
might drop during decongestion.92,93 Thirdly, patients are often
hospitalized in acute care units for the first days, where intensive Thiazide or thiazide-like co-administration
adaptation of therapy is more likely to occur than in a regular ward. Thiazide and thiazide-like diuretics encompass a large class
Additionally, faster decongestion might be especially valuable in of agents that block the sodium–chloride co-transporter (NCC)
health care systems where length of hospital stay needs to be short. in the distal convoluted tubule.96 Therefore, from a theoreti-
In addition to the evaluation of vital signs, daily weights, and cal point of view, they may partially overcome distal increased
signs/symptoms of congestion as endorsed by ESC guidelines (class sodium avidity accompanied with chronic loop diuretic use. Large
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geographical differences exist in the use of thiazide-like diuretics incremental diuretic effect of high-dose MRA therapy in addition
........................................................................................................................................................................
with metolazone being the most used thiazide-like diuretic in the to standard loop diuretic therapy has been tested in the Aldos-
United States.97 The different molecules have a similar blocking terone Targeted Neurohormonal Combined with Natriuresis
effect of NCC, however they differ in terms of half-lives and Therapy in Heart Failure (ATHENA-HF) trial.106 Therapy with
off-target effects (Table 2). In contrast with loop diuretics, meto- 100 mg of spironolactone per day was not superior to 25 mg per
lazone and chlorthalidone have a slow gastrointestinal absorption day in reducing NT-proBNP or increase urine output after 96 h.
(time to peak up to 8 h) and a very long half-life, therefore if low However, as illustrated in Table 2, spironolactone is a pro-drug
oral doses are started, they should be given hours before the with onset of action only 48–72 h after oral intake, which could
intravenous loop diuretic is administered as it will take a long account for the observed nil-effect. However, high-dose MRA
time until a steady state is achieved. However, chlorothiazide has was safe, as it did not result in hyperkalaemia or worsening of
a short half-life so it should be given closer to the loop diuretic. renal function. Furthermore, MRA therapy might be useful in
In healthy individuals, the maximal diuretic effect of a thiazide offsetting the hypokalaemic effect of potassium-wasting loop
is limited, generating a diuretic response of maximum 30–40% and thiazide diuretics.106 – 108 Importantly, data indicate marked
of a loop diuretic when used in monotherapy.96 Thiazides are under-utilization of MRAs as a disease-modifying drug class in
also protein bound requiring adequate renal blood flow to be HFrEF.109 It is the opinion of the expert panel that early initiation
secreted into the tubules. Furthermore, thiazides can induce of a MRA, in a regular dose (25 mg), might be useful in reducing
significant kaliuresis, as per sodium ion lost 2–3 ions of potas- treatment-induced hypokalaemia and may lead to higher chance of
sium are excreted.98 This potassium losing effect is especially HFrEF patients being discharged on an optimized disease-modifying
pronounced in high aldosterone states, such as heart failure.99 therapy regimen. However, the use of MRA in the acute settings
The rationale for using thiazides in acute heart failure is based needs to be individualized with temporarily discontinuation in case
on the finding of increased distal nephron sodium avidity in the of the development of hyperkalaemia.
case of (prolonged) loop diuretic administration.100 Indeed, animal
data indicate that distal nephron hypertrophy occurs following Acetazolamide
chronic loop diuretic administration, which might explain loop
Due to haemodynamic alterations in heart failure with a reduction
diuretic resistance to an extent.101 In contrast to conventional
in renal blood flow with a correspondingly increased filtration
teaching, more recent evidence does support the effectiveness
fraction, important increases in proximal nephron sodium avidity
of thiazides in patients with a reduced glomerular filtration rate
occur.9,63 From a pathophysiological point of view, targeting sodium
(< 30 mL/min).102 There are no randomized controlled trials
reabsorption in the proximal tubules has several potential benefits
published in heart failure testing the use of thiazide diuretics.
in heart failure. First, most sodium is reabsorbed in the proxi-
Currently, there is a study ongoing comparing Metolazone Versus
mal nephron, especially in decompensated heart failure. Second,
Chlorothiazide for Acute Decompensated Heart Failure With greater delivery of chloride to the macula densa cells decreases
Diuretic Resistance (NCT03574857). A meta-analysis of exist- renin production, reducing neurohumoral activation.9 Third,
ing observational data underscores the frequent occurrence of endogenous natriuretic peptides (acting in the distal nephron) will
hypokalaemia. In a propensity-matched analysis of real-world possibly regain their effects.110 The carbonic anhydrase inhibitor
use of thiazides (combined with lower-dose loop diuretics) and acetazolamide inhibits sodium reabsorption in the proximal
high-dose loop diuretics in heart failure patients, thiazides, but tubules. An observational study in patients with decompensated
not high-dose loop diuretics, were independent predictors of the heart failure and marked volume overload indicated that the
occurrence of hyponatraemia and hypokalaemia with an indica- addition of acetazolamide (500 mg intravenous bolus on top of
tion towards a higher risk for all-cause mortality.103 Given the loop diuretic) improved loop diuretic response with ∼100 mmol
relative safety of high-dose loop diuretics in the DOSE-AHF trial, Na + excreted per 40 mg of furosemide dose equivalents.69 Addi-
a preference might be given to initial intensification of the loop tionally, acetazolamide efficiently boosts the diuretic response
diuretic dose before adding a thiazide diuretic.42 However, in the in combination with loop diuretics, as illustrated by one small
CARRESS-HF-trial, the addition of metolazone was an intrinsic randomized trial including 24 patients with acute volume overload
part of the stepped pharmacologic algorithm, resulting in the refractory to loop diuretic therapy.110 A multicentre, randomized,
recommendation of thiazides as a second-line agent in the Heart double-blind, phase IV clinical trial of the diuretic effects of Aceta-
Failure Society of America practical guidelines.90 zolamide in Decompensated heart failure with Volume OveRload
(ADVOR, NCT03505788) will investigate if combination therapy
Mineralocorticoid receptor antagonists with acetazolamide improves loop diuretic response to increase
diuresis in decompensated heart failure patients.111 Observational
Mineralocorticoid receptor antagonists (MRAs) exhibit
studies have only assessed the role of intravenous acetazolamide,
pleiotropic effects, but their renal effects consist of modulat-
and no data are available supporting the role of oral acetazolamide.
ing the expression/activity of sodium and potassium channels
in the distal nephron. MRAs have a class I recommendation as a
disease-modifying therapeutic agent in symptomatic chronic HFrEF, Other potential agents
counteracting the aldosterone escape generated by neurohor- In addition, the new diabetic drug class of sodium–glucose linked
monal over-activation.104,105 Recently in acute heart failure, the transporter-2 (SGLT2 inhibitors) also inhibit proximal sodium
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absorption (Figure 2).9,112,113 Two trials in diabetic patients with pressures are low.122 Additionally, in the CARRESS-HF trial, the
........................................................................................................................................................................
mostly established cardiovascular disease, illustrated that SGLT2 proportion of patients with catheter-related access site bleeding
inhibitors reduced heart failure hospitalizations and resulted and infection was numerically higher in the ultrafiltration group.
in a less steep slope of glomerular filtration rate decline over
time.114,115 However, the potential of SGLT2 inhibitors in heart
failure with or without diabetes remains unknown. Several trials Diuretic use and electrolyte
are ongoing in testing the disease-modifying effect of SGLT2 abnormalities
inhibitors in the setting of both chronic and acute heart failure.
Electrolyte abnormalities resulting from neurohormonal activation,
Amiloride inhibits distal epithelial sodium channels (ENaC), and
kidney dysfunction, or iatrogenic due to the employed diuretic regi-
anecdotal evidence suggests that ENaC inhibition can result in
men occur frequently during episodes of acute heart failure, mostly
decongestion with a lowering of filling pressures.116 Furthermore,
affecting sodium and potassium handling.121,123,124 Recently, also
chronic over-expression of ENaC has been implicated in the
alterations in chloride metabolism have been recognized to inde-
thiazolidinedione-mediated volume retention witnessed in dia-
pendently predict adverse outcomes.125 Hyponatraemia, defined as
betics. Finally, vasopressin antagonists limit distal nephron free
a plasma sodium concentration < 135 mEq/L, is the main abnormal-
water re-uptake by counteracting arginine vasopressin, which
ity of sodium homeostasis occurring in acute heart failure whereas
results in a limited availability of luminal aquaporin water channels
hypernatraemia rarely occurs. A sub-analysis of the Organized Pro-
in the renal collecting ducts. This results in increased aquaresis
gram to Initiate Lifesaving Treatment in Hospitalized Patients with
without significantly impacting natriuretic response. The selective
Heart Failure (OPTIMIZE-HF) illustrated that 20% of patients had
V2 - receptor antagonist tolvaptan did not result in a reduction of
hyponatraemia at the time of admission.126 The incidence of hospi-
morbidity or mortality in the Efficacy of Vasopressin Antagonism
tal acquired hyponatraemia during decongestive therapy for acute
in Heart Failure Outcome Study With Tolvaptan (EVEREST)
heart failure ranges between 15–25%.127 The pathophysiology of
study in acute heart failure patients when added to standard
hyponatraemia in heart failure is either due to the inability to
therapy.117 This limits its use in heart failure with congestion,
excrete free water (dilution hyponatraemia) or either due to a
as extracellular volume expansion is mainly driven by sodium
depletion of sodium (depletion hyponatraemia),123 or a combina-
retention. However, in more advanced stages of heart failure
tion of these factors. A practical approach to hyponatraemia is
inappropriately high levels of arginine vasopressin contribute to
reflected in Table 3. After confirmation of a low serum osmo-
plasma expansion and dilutional hyponatraemia. More recently,
lality, the differentiation between dilution and depletion is made
early use of tolvaptan and use in patients with diuretic resistance,
on the basis of the clinical picture and urinary analysis. Abnor-
renal dysfunction or hyponatraemia, did result in more weight loss,
malities in the potassium homeostasis are typically the result of
but no significant improvement in dyspnoea relief.118,119 Currently,
the employed pharmacologic therapy in heart failure in combi-
vasopressin antagonists are only indicated in patients with severe
nation with pre-existing renal impairment. Hypokalaemia (plasma
hyponatraemia, and their widespread use might be limited by the
K < 3.5 mEq/L) occurs typically in acute heart failure secondary
high drug costs. In Europe, tolvaptan is available but not officially
to diuretic-induced diuresis with potassium wasting.110 In clin-
approved for heart failure by the European Medicines Agency.
ical practice, loop diuretic use is the most common reason
for hypokalaemia, however thiazide diuretics do exhibit an even
Ultrafiltration stronger kaliuretic effect.110 Treatment consists of adding upfront
MRA therapy during decongestion, increasing RAAS blockade and
Ultrafiltration removes plasma water across a semipermeable
supplementation of potassium (Table 3). In addition to potassium
membrane driven by a machine generated transmembrane pres-
wasting, diuretics often induce the loss of magnesium, poten-
sure gradient. There is limited compelling evidence to support
tially resulting in therapy-refractory hypokalaemia. Although not
ultrafiltration as first-line therapy over loop diuretics in patients
supported by strong evidence, magnesium supplementation could
with acute heart failure.95,120 Therefore, in most centres, ultra-
be considered during diuretic treatment. Although less common
filtration is reserved as a bail-out therapy to relieve congestion
than hypokalaemia during acute heart failure, hyperkalaemia (K
if stepped pharmacologic care fails.121 Of note, the Peripheral
> 5.0 mEq/L) can occur in patients on RAAS blockade, especially
Ultrafiltration for the RElief From Congestion in Heart Failure
(PURE-HF) trial (NCT03161158) is evaluating whether tailored, in the case of pre-existing renal impairment.128 A clinical approach
peripheral veno–venous ultrafiltration (CHIARA System) comple- to hyperkalaemia is reflected in Table 3.
mentary to low-dose diuretics is associated with a reduction in
cardiovascular mortality and heart failure hospitalization in 90 days
after randomization compared to usual care including stepped Diuretics in chronic heart failure
intravenous diuretics in acutely decompensated chronic heart fail-
The ambulatory loop diuretic dose is
ure with fluid overload (not fully responsive to diuretic therapy).
Renal replacement therapy allows for management of metabolic variable
complications of anuria/oliguria such as hyperkalaemia, acidosis and Loop diuretics are recommended in chronic heart failure to pre-
uraemia,95,121 although in a large proportion of cases such use vent signs and symptoms of congestion.7 This recommendation
has poor long-term prognosis, especially when systemic perfusion is valid across the entire spectrum of left ventricular ejection
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© 2018 The Authors
Diuretics in heart failure
Table 3 Approach to electrolyte disturbances in acute heart failure
Hyponatraemia Hypokalaemia Hyperkalaemia

.........................................................................................................................................................................................
Definition Na+ < 135 mEq/L K+ < 3.5 mEq/L K+ > 5 mEq/L
Diagnostic tests • Posm : should be <285 mOsm/L (else • ABG: confirm on ABG, check pH status • ABG: confirm on ABG, check pH status
pseudo-hyponatraemia) • ECG: check potential abnormalities • ECG: check potential abnormalities
• Physical examination: to differentiate between volume • Physical examination: usually normal, • Lab: check renal function, exclude haemolysis as cause
overload or volume depletion however muscle weakness or paralysis present of pseudo-hyperkalaemia
• Urinary analysis: Uosm and UNa in severe cases
• Lab: check for Mg deficit
Pathophysiology • Dilution: impaired free water excretion. Clinical picture • Diuretic use results in hypokalaemia Most likely due to combination of RAAS blocker agent and
of volume overload with inappropriate high Uosm • Predisposing factors in HF can play a role, for poor renal function with diminished renal potassium
(≥ 100 mOsm/L). Typical in the setting of ADHF instance: cachexia with low K+ intake and excretion capacity

• Depletion: true body deficit of Na+ . Typical in the setting chronic hypomagnesaemia
- 17 -
of chronic excessive diuretic use (and strict Na+ intake).
Clinical picture of volume depletion with low Uosm
(< 100 mOsm/L) and UNa (< 50 mEq/L)
Treatment • Dilution: temporarily stop distal acting diureticsa, limit • Consider discontinuation of thiazide diuretics • Acute hyperkalaemia: if ECG abnormalities present,
water intake, promote distal nephron flow (loop diuretics, • Upfront use of MRA during decongestion then prevent arrhythmias by IV calcium. Intermediate
hypertonic saline, acetazolamide/SGLT2 inhibitor) or • Increase dose of RAAS blocking agent strategies include: insulin/albuterol/sodium HCO3 IV.
vaptans, correction of K+ and Mg2+ deficiencies • IV substitution of K+ and Mg2+ : peripheral or Ultimately potassium must be removed from the body
• Depletion: stop distal acting diureticsa, calculate Na central depending on severity of K+ deficit. with either diuretics, potassium binding resins, or RRT.
deficit and administer IV Na+ correction of K+ and Mg2+ • Chronic hyperkalaemia: reduces dose RAAS
deficiencies blocker, increase loop diuretic, potassium binders
ABG, arterial blood gas analysis; ADHF, acute decompensated heart failure; AVP, arginine vasopressin; ECG, electrocardiogram; HCO3 , bicarbonate; HF, heart failure; IV, intravenous; MRA, mineralocorticoid receptor antagonist; Posm ,
plasma osmolality; RAAS, renin–angiotensin–aldosterone system; RRT, renal replacement therapy; SGLT2, sodium–glucose linked transporter-2; Uosm , urine osmolality; UNa , urine sodium.
a Distal acting diuretics included thiazide-like diuretics, MRA and amiloride.
149
fraction. Indeed, diuretics are the only group of drugs with a class of therapies that improve cardiac status (such as cardiac resyn-
........................................................................................................................................................................
I recommendation in patients with heart failure with reduced, chronization therapy or sacubitril/valsartan).112,135 A recent pilot
mid-range, or preserved ejection fraction.7 However, the effects study illustrated the potential of self-measuring urine chloride
of diuretics in chronic heart failure on morbidity and mortality content after loop diuretic intake using a dipstick to determine the
have not been studied in large prospective randomized controlled need for maintenance loop diuretics in stable ambulatory heart
trials. Several observational studies have linked loop diuretic use failure patients.136 Despite the guideline recommendation to use
to increased mortality, even after multivariate adjustment or the lowest possible dose of diuretics and discontinue loop diuret-
propensity matching.129 However, potential bias remains as sicker ics if possible, little information is available on discontinuing loop
patients are generally prescribed (higher doses of) loop diuretics. diuretics in contemporary treated heart failure patients.137,138
A Cochrane meta-analysis has shown that in patients with chronic A prospective interventional study in 50 stable ambulatory
heart failure, loop diuretics and thiazides might reduce the risk heart failure patients assessed the feasibility of loop diuretic
of death and worsening of heart failure in comparison to placebo down-titration and discontinuation.138 At 30 days, down-titration
and could lead to improved exercise capacity.86 However, this remained successful in 62% of patients, however baseline investi-
meta-analysis included only small studies with limited follow-up, gations including physical examination, echocardiography and NP
showing unrealistically large reductions in events. Moreover, this measurement were not capable to predict in which patients loop
analysis was not updated in 2016 as requested by the Cochrane diuretic down-titration would be successful or not.138
Institute and subsequently withdrawn. Therefore, the prognostic
effect of diuretic therapy is still unknown. Clearly, patients at risk
for congestion would benefit from maintenance therapy with a Heart failure disease management
loop diuretic. However, in patients at low risk for developing wors- strategy
ening of congestion, the use of loop diuretics might indeed result in The goals of heart failure care are dynamic and vary according
electrolyte disturbances, further neurohormonal activation, accel- to the stage of heart failure. In the ambulatory patient, care should
erated kidney function decline, and symptomatic hypotension.130 focus on up-titrating disease-modifying drugs, evaluating the need
The latter might especially be relevant in patients with HFrEF as for device-based therapies, enrolling patients in multidisciplinary
it could result in treatment with lower doses of neurohormonal disease-modifying programmes, focusing on self-management,
blockers.43 Therefore, it is generally advised to use to the lowest physical activity, and dietary interventions.7 Furthermore, efforts
possible dose of diuretics and the dose of the loop diuretic often should be made to reduce readmission and improve quality and
needs to be adjusted to the individual need.131,132 Importantly, the longevity of life. With average salt intake in the western world
individual diuretic need significantly changes over time. This was reaching up to 6–8 g, it has been recommended by the ESC guide-
clearly illustrated by a post-hoc analysis of the CardioMEMS Heart lines to avoid excessive high salt intake (>6 g NaCl = 2.4 g Na per
Sensor Allows Monitoring of Pressure to Improve Outcomes in day) and excessive fluid intake (no class recommendation).7 Salt
Class III Heart Failure (CHAMPION) trial, which indicated that and fluid restriction are often underscored in disease-modifying
mainly increases but also decreases in loop diuretic dose were programmes. Yet, animal and epidemiologic data suggest that an
the most common therapy changes made by treating physicians.133 excessively low sodium intake (<2 g Na+ per day) is associated
Nevertheless, uncertainty exists about the optimal dose of loop with cardiac remodelling and worse clinical outcome.139 Currently
diuretics following discharge. For patients who developed an acute four trials are evaluating the benefit of sodium restriction, including
heart failure episode while previously taking a loop diuretic before one trial assessing a hard clinical endpoint.140 A meta-analysis on
admission, a higher dose following discharge might need to be fluid restriction did not indicate benefit or harm when performed
used. Additionally, in case that this previous loop diuretic was in heart failure patients.141 Therefore, dietary restrictions should
furosemide, a switch to either bumetanide or torsemide might be be adapted according to the clinical context. In the case of acute
considered, as they have a more predictable absorption pattern heart failure with dilution hyponatraemia, more stringent fluid
and bioavailability, especially in the face of subclinical congestion. restriction is necessary.
However, defining the most appropriate outpatient dose of diuretic
can be difficult and requires careful follow-up, particularly early
in the post-discharge period. The chronic use of thiazides in the Gaps in knowledge and future
stable ambulatory setting (sequential nephron blocking) should be
avoided, if possible, as this practice often induces severe electrolyte
directions
disturbances that could go undetected in the ambulatory setting. Evidence-based medicine with respect to diuretic treatment
Additional research is needed to evaluate ambulatory metrics (in in heart failure remains difficult as only a limited number of small
addition to pulmonary pressures) of volume status, which might prospective studies have been performed. Ongoing research is
allow easier adaptation of loop diuretic therapy. Registry data necessary to determine the ideal diuretic strategy and to optimally
indicate that mildly symptomatic heart failure patients [New York evaluate full decongestion (euvolaemia) in heart failure. The role
Heart Association (NYHA) class I and II] are generally treated of urinary sodium to assess the adequacy of diuretic therapy
with similar doses of loop diuretics as more symptomatic heart in acute heart failure should be further assessed prospectively. The
failure patients (NYHA class III and IV).134 This underscores the role of hypertonic NaCl infusion in conjunction with high-dose
importance to re-assess loop diuretic need following the initiation loop diuretics in hyponatraemic volume overloaded patients needs
© 2018 The Authors

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to be studied as this concept is supported by several analyses, fees from Zoll, AstraZeneca, Sanofi, Amgen, BMS, Pfizer, Frese-
........................................................................................................................................................................
however suffering from methodologic restrains.142 Random- nius, Vifor, Roche, Cardiorentis, Boehringer Ingelheim, other from
ized controlled trials are necessary assessing the decongestive Heartware, grants from Mars, during the conduct of the study;
properties of diuretics other than loop diuretics or MRAs. Novel since 1st January 2018: no personal payments/all payments directly
effective and safe pharmacologic or mechanical methods to achieve to the University of Zurich. A.J.C. reports personal fees from
decongestion without inducing end-organ damage are needed. Fur- Respicardia, Vifor and Servier. The other authors have no conflicts
thermore, several upcoming studies will investigate the optimal use of interest to declare.
of current diuretic treatment options. The TRANSFORM-HF will
assess the superiority of torsemide in comparison to furosemide
in reducing all-cause mortality. Furthermore, ongoing studies are References
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© 2018 The Authors

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European Journal of Heart Failure (2019) 21, 272–285 HFA POSITION STATEMENT
doi:10.1002/ejhf.1406
Towards better definition, quantification

and treatment of fibrosis in heart failure.
A scientific roadmap by the Committee
of Translational Research of the Heart Failure
Association (HFA) of the European Society
of Cardiology
Rudolf A. de Boer1*, Gilles De Keulenaer2, Johann Bauersachs3, Dirk Brutsaert2,
John G. Cleland4, Javier Diez5, Xiao-Jun Du6, Paul Ford7, Frank R. Heinzel8,
Kenneth E. Lipson9, Theresa McDonagh10, Natalia Lopez-Andres11, Ida G. Lunde12,
Alexander R. Lyon13, Piero Pollesello14, Sanjay K. Prasad15, Carlo G. Tocchetti16,
Manuel Mayr17, Joost P.G. Sluijter18, Thomas Thum19,20,21, Carsten Tschöpe8,
Faiez Zannad22, Wolfram-Hubertus Zimmermann23,24, Frank Ruschitzka25,
Gerasimos Filippatos26, Merry L. Lindsey27, Christoph Maack28,
and Stephane Heymans29,30,31
1 University Medical Center Groningen, University of Groningen, Department of Cardiology, Groningen, The Netherlands; 2 Laboratory of Physiopharmacology, University of
Antwerp, Antwerp, Belgium; 3 Department of Cardiology and Angiology, Hannover Medical School, Hannover, Germany; 4 Robertson Centre for Biostatistics & Clinical Trials,
University of Glasgow, Glasgow, UK; 5 Program of Cardiovascular Diseases, Center for Applied Medical Research, Departments of Nephrology, and Cardiology and Cardiac
Surgery, University Clinic, University of Navarra, Pamplona, Spain; 6 Baker Heart and Diabetes Institute, Melbourne, Australia; 7 Galecto Biotech, Lund, Sweden; 8 Department of
Cardiology, Campus Virchow-Klinikum, Charite Universitaetsmedizin Berlin, Berlin, Germany; 9 FibroGen Inc., San Francisco, CA, USA; 10 King’s College Hospital, London, UK;
11 Cardiovascular Translational Research, Navarrabiomed, Complejo Hospitalario de Navarra, Universidad Publica de Navarra, Idisna, Spain; 12 Institute for Experimental Medical
Research, Oslo University Hospital and University of Oslo, Oslo, Norway; 13 Royal Brompton Hospital, and Imperial College London, London, UK; 14 Orion Pharma, Espoo,
Finland; 15 Royal Brompton and Harefield Hospital, London, UK; 16 Department of Translational Medical Sciences, Federico II University, Naples, Italy; 17 The James Black Centre,
King’s College, University of London, London, UK; 18 University Medical Centre Utrecht, Experimental Cardiology Laboratory, UMC Utrecht Regenerative Medicine Center,
University Utrecht, Utrecht, The Netherlands; 19 Institute of Molecular and Translational Therapeutic Strategies (IMTTS), Hannover Medical School, Hannover, Germany;
20 REBIRTH Excellence Cluster, Hannover Medical School, Hannover, Germany; 21 DZHK (German Center for Cardiovascular Research) partner site Berlin, Berlin, Germany;
22 Centre d’Investigation Clinique, CHU de Nancy, Nancy, France; 23 Institute of Pharmacology and Toxicology, University Medical Center Göttingen, Göttingen, Germany;
24 DZHK (German Center for Cardiovascular Research) partner site Göttingen, Göttingen, Germany; 25 Department of Cardiology, University Heart Center, University Hospital
Zurich, Zurich, Switzerland; 26 Heart Failure Unit, Department of Cardiology, School of Medicine, Athens University Hospital Attikon, National and Kapodistrian University of
Athens, Athens, Greece; 27 Department of Physiology and Biophysics, Mississippi Center for Heart Research, University of Mississippi Medical Center and Research Service, G.V.
(Sonny) Montgomery Veterans Affairs Medical Center, Jackson, MS, USA; 28 Comprehensive Heart Failure Centre, University and University Hospital Würzburg, Würzburg,
Germany; 29 Department of Cardiology, CARIM School for Cardiovascular Diseases Faculty of Health, Medicine and Life Sciences, Maastricht University, Maastricht, The
Netherlands; 30 Department of Cardiovascular Sciences, Centre for Molecular and Vascular Biology, KU Leuven,, Leuven, Belgium; and 31 The Netherlands Heart Institute, Nl-HI,
Utrecht, The Netherlands
Received 25 July 2018; revised 28 November 2018; accepted 3 December 2018 ; online publish-ahead-of-print 4 February 2019
Fibrosis is a pivotal player in heart failure development and progression. Measurements of (markers of) fibrosis in tissue and blood may help
to diagnose and risk stratify patients with heart failure, and its treatment may be effective in preventing heart failure and its progression.
A lack of pathophysiological insights and uniform definitions has hampered the research in fibrosis and heart failure. The Translational
Research Committee of the Heart Failure Association discussed several aspects of fibrosis in their workshop. Early insidious perturbations
such as subclinical hypertension or inflammation may trigger first fibrotic events, while more dramatic triggers such as myocardial infarction
*Corresponding author. University Medical Center Groningen, Department of Cardiology, Hanzeplein 1, 9700RB Groningen, The Netherlands. Tel: +31 50 3612355, Email:
r.a.de.boer@umcg.nl
© 2019 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.
This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and
reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.
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Definition, quantification and treatment of fibrosis in heart failure 273
and myocarditis give rise to full blown scar formation and ongoing fibrosis in diseased hearts. Aging itself is also associated with a cardiac
phenotype that includes fibrosis. Fibrosis is an extremely heterogeneous phenomenon, as several stages of the fibrotic process exist, each
with different fibrosis subtypes and a different composition of various cells and proteins — resulting in a very complex pathophysiology.
As a result, detection of fibrosis, e.g. using current cardiac imaging modalities or plasma biomarkers, will detect only specific subforms of
fibrosis, but cannot capture all aspects of the complex fibrotic process. Furthermore, several anti-fibrotic therapies are under investigation,
but such therapies generally target aspecific aspects of the fibrotic process and suffer from a lack of precision. This review discusses the
mechanisms and the caveats and proposes a roadmap for future research.
..........................................................................................................
Keywords Fibrosis • Heart failure • Biomarkers • Fibroblast • Matrix • Prognosis • Imaging
Introduction different pathological processes that underlie fibrosis formation, it
..................................................................................................................................
may not be a surprise that the outcomes of various studies are
Fibrosis is a fundamental process observed in cardiac remodelling often contradictory and can only be rarely translated from one
and considered to be a key contributor to heart failure and its clinical setting to another. Also, as a consequence, fibrosis has not
progression. Importantly, the presence and extent of myocardial yet emerged as a primary target for heart failure therapies.
fibrosis has also prognostic implications, as it causes contractile The Translational Research Committee of the Heart Failure
dysfunction and arrhythmias in structural heart disease of vari- Association (HFA) of the European Society of Cardiology (ESC)
ous aetiologies.1 – 6 Fibrosis is a direct and indirect target in the organized a workshop on myocardial fibrosis with the aim to
treatment of heart failure, either by established drug therapies discuss and recommend strategies to address knowledge gaps in
(e.g. angiotensin-converting enzyme inhibitors or mineralocorti- this field. This scientific roadmap paper summarizes the principal
coid receptor antagonists) or specific anti-fibrotic drugs (e.g. pir- knowledge gaps that were identified, including the need for (i)
fenidone). However, its resilience to therapy requires additional more specific definitions of processes underlying the formation of
major efforts to control (and ideally prevent or reverse) fibrotic fibrosis in heart failure under different pathological conditions, (ii)
remodelling, being identified as a major contributor to heart failure improved methods to detect fibrosis using imaging techniques and
progression.1 – 6 biomarkers associated with specific entities of fibrosis; and (iii) new
While fibrosis is a widely used term, the exact definition is therapies to directly target specific processes underlying cardiac
less precisely defined. Fibrosis in the broadest sense is defined as fibrosis. Here, we provide a framework to better define fibrosis
excessive accumulation of extracellular matrix (ECM). In simpli- during various stages, aetiologies, and severities of heart failure.
fied terms, fibrosis can be divided into (i) ‘reparative fibrosis’ and We propose a structured experimental scheme to assess fibrosis
(ii) ‘reactive fibrosis’. The development of an organized scar after quality as well as quantity, and to provide a work-up template that
myocardial infarction (MI) can be best described as reparative or can be used in both translational and clinical research. Our goal is to
replacement fibrosis, which is necessary to mechanically stabilize direct future research to the identification of individual mechanisms
the evolving (necrotic) tissue defect. In contrast, the fine interstitial of fibrosis formation, anticipating that this will provide insight into
‘reactive fibrosis’ encountered in non-ischaemic cardiomyopathies novel therapeutic targets and diagnostic tools for cardiac fibrosis
or in the surviving myocardium after MI appears to result from dif- stratification during heart failure progression.
ferent pathological processes resulting in unique structural quality,
ECM composition, and metabolic properties. Additionally, there is
also a time component to scar development that has to be con-
sidered. For example, reactive fibrosis in the setting of pressure
More specific definitions are
overload is initially characterized by perivascular fibrosis that later needed to describe the formation
progresses to interstitial fibrosis. Fibrosis is also highly dynamic of myocardial fibrosis in heart
as it typically entails recruitment of fibroblasts and their conver-
sion into myofibroblasts, excessive synthesis and secretion of ECM failure
and ECM-associated modulatory glycoproteins, posttranslational
Myocardial fibrosis in heart failure is not
modification and cross-linking of ECM proteins, and dysregulation
of ECM production and breakdown by matrix metalloproteinases a uniformly initiated process
(MMPs) and their endogenous inhibitors (TIMPs). These different Myocardial fibrosis is an endogenous, albeit suboptimal, repair
manifestations of fibrosis suggest that multiple targets or thera- response of the failing heart that can offer structural support
peutic opportunities may exist and that therapy may have to be while cardiomyocyte loss is occurring in the absence of appro-
personalized according to the diagnosis of specific remodelling propriate cardiomyocyte replacement. Several key events characterize
cesses and finally specific types of fibrosis. the fibrotic response to cardiac injury, which have been excellently
Because todays’ ‘one size fits all’ guideline approaches and broad reviewed elsewhere.1 – 5 Activation and conversion of fibroblasts
heart failure patient classifications do not properly consider the into myofibroblasts are central events, critical also to non-cardiac
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274 R.A. de Boer et al.
wound healing.1 – 5 Myofibroblasts produce and deposit ECM pro- ‘reactive’, some will have been ‘reparative’, some will be (or have
........................................................................................................................................................................
teins, such as collagens, glycoproteins and proteoglycans (e.g. become) static, and others dynamic. It is quite often not feasible
fibronectin, galectins, and periostin among many others), to offer to distinguish the various forms, as many features are shared and
local mechanic support to the failing heart. The formation of transition into one another is possible. Thus, identification of the
organized fibrotic structures and fibrils requires a multi-step pro- specific and probably dominant type of fibrosis will be important
cess that involves the degradation and processing of existing for individualized anti-fibrotic approaches.
ECM to remove damaged tissue, and the production, secretion,
cross-linking, and maturation of new ECM. In addition to cardiac
fibroblasts, which are the major source of ECM, monocytes and Understanding myocardial fibrosis
macrophages home to sites of injury and contribute to remod- in different phenotypes of heart
elling by secretion of pro-fibrotic growth factors. Finally, cardiomy-
ocytes also contribute to secretion of pro-fibrotic growth factors
failure
into the ECM via paracrine mechanisms. In addition to fibrillary Fibrosis is frequently described in experimental heart failure in pre-
ECM constituents, non-structural glycoproteins and proteoglycans clinical animal models. Given its complex pathophysiology, it is cru-
are important accessory mediators of fibrosis. Glycosylation is a cial in such studies to provide a minimum amount of information
highly prominent post-translational modification in ECM (reviewed to allow the reader understanding what fibrosis is referred to. Fur-
by Rienks et al.6 ) and glycoproteomics is a novel tool with promise ther, the triggers, dynamics, and characteristics of the fibrotic pro-
in the study of myocardial fibrosis.7,8 cess are very different among various aetiologies of heart failure.
Timely detection of fibrosis and determination of its state could Below, we discuss cardiac fibrosis in the setting of MI, pressure
potentially help to diagnose and stop heart failure progression early overload, and aging (Figure 2), as well as genetic cardiomyopathies
on. Capturing where fibrosis lies along the time continuum in a and heart failure with preserved ejection fraction (HFpEF).
specific patient may inform physicians if fibrosis is developing as an
early manifestation of the disease, and what type of targeted ther-
apy could be employed. Early post-MI therapy will most certainly
Myocardial fibrosis in post-myocardial
differ from the therapy of non-ischaemic diastolic dysfunction with infarction
a stiff left ventricle and even more from the treatment of end-stage Myocardial infarction is one of the most common causes of heart
heart failure with an often severely fibrotic myocardium. The exact failure. Several animal models have been developed to model
differences in disease states, including the identification of disease human MI. Permanent ligation of a coronary artery induces a
modulators, must be identified to improve and ideally establish an large transmural MI (rat, mouse, dog, sheep, pig), while tran-
individualized therapy of heart failure-related fibrosis. sient ligation causes ischaemia–reperfusion damage (mouse, rat,
dog, pig), with variable degrees of damage depending on dura-
tion of ischaemia, selection of coronary artery, location of the
Current classification of myocardial
ligature, and pre-treatment. MI causes a distinct tissue wound heal-
fibrosis ing response with an initial strong inflammatory response, start-
Traditionally, the form and stage of fibrosis have been denoted ing immediately after MI and peaking 3–7 days (depending on the
in line with the specific physiological phenomena that provoked species studied and model used) after MI. Neutrophils, mono-
the fibrotic response. Classically, the fibrotic process occurring cytes, macrophages, but also fibroblasts themselves release factors
after MI has been called ‘reparative’ or ‘replacement’ fibrosis. While that act on fibroblasts and trigger a pro-fibrotic response to form
scar formation is characterized by excessive accumulation of ECM, the infarct scar. The controlled invasion of inflammatory cells is a
fibrosis is generally regarded as inevitable, as its absence would prerequisite for proper infarct healing and prevention of myocar-
extend ventricular dilatation and could even result in ventricular dial rupture.9 – 13 After the initial phase, inflammation subsides and
rupture. Therefore, the infarct scar is a mandatory, albeit not per- the proliferative phase starts, where fibroblasts convert into myofi-
fect replacement, structural support. The post-MI scar is the result broblasts, migrate and proliferate, resulting in an increased capacity
of dramatic cardiomyocyte loss and the subsequent deposition for wound contraction and repair. Additionally, fibroblast progen-
of collagen fibrils that are cross-linked to provide a strong ECM net- itors as well as endothelial to mesenchymal transition are consid-
work. Reactive fibrosis, which is typically observed as perivascular ered important post-MI fibroblast sources. Collagen content begins
or interstitial fibrosis, is stimulated by ongoing long-run maladaptive to rise measurably 4–7 days after MI and peaks after 3–6 weeks,
signalling (e.g. by inflammatory cells, paracrine signals, and oxidative depending on the animal model used. Beside the amount of colla-
stress) that is part of progressive pathological cardiac remodelling. gen, the type of collagen fibres formed and the degree of collagen
Figure 1 summarizes the different types of fibrosis which may all cross-linking affect the mechanical properties of the tissue. Finally, a
be observed in parallel in the same heart, making it a challenging maturation phase is reached, where a stable scar is formed. During
exercise to target distinct fibrotic processes. It depicts an example this phase, it is unclear whether the reduction in ECM turnover
of histology from a virtual cardiac tissue biopsy — it becomes is due to reduced matrix synthesis, increased ECM breakdown,
instantly apparent that even within the tissue same sample, different or both.
forms of fibrosis may be present, and thus, the chances for sampling The precise role of fibroblasts and the fibroblast cell sources in
error in real life are very real. Some fibrotic manifestations will be the post-MI setting is incompletely understood, in part because
- 26 -
Figure 1 Different forms of fibrosis are not mutually exclusive. The left panels show replacement (upper panel), reactive interstitial (middle),
and perivascular (lower) fibrosis, with different cells playing the major role: fibroblasts (green), inflammatory cells (blue), and myocytes (red),
with fibrillar debris interpositioned. In reality, in a typical failing heart, all forms may occur (middle panel and right histology panels). (Illustration:
Maartje Kunen, Medical Visuals.)
of difficulties in labelling and identifying this cell type in vivo. of pressure overload-related fibrosis. It is activated by various
..............................................................
Recently, fibroblast activating protein (FAP) was identified as a circulating hormones such angiotensin II and endothelin-1, but
rather specific marker of activated, collagen-synthesizing fibrob- also by cellular stretch and strain. The TGF-𝛽𝛽 pathway leads to
lasts, whereas inactive fibroblasts, or fully differentiated myofibrob- activation of Smad2/3 and Rho/ROCK signalling, and activation
lasts and non-fibroblast cells in the infarct do not express FAP.11 of stress-related kinases and proteins such as p38, ERK1/2 and
Periostin is suggested as another marker of activated fibroblasts, elevated expression of connective tissue growth factor (CTGF).
suggestive for early fibroblast activation.14 Isolating post-MI car- Fibroblasts in models of pressure overload have been identified
diac fibroblasts from an in vivo-stimulated environment and evalu- as epicardial and endothelial cell-derived and Pax3-expressing cells
ating these cells ex vivo has provided insight into their functional (a major source under normal conditions and following pressure
responses.12,13 overload).15,16 Premature senescence of myofibroblasts was identi-
fied as an essential anti-fibrotic mechanism and potential therapeu-
Myocardial fibrosis in models of pressure tic target in myocardial fibrosis in response to pressure overload.17
overload (e.g. hypertension)
The importance of fibrogenesis in pressure overload has been
reviewed by Creemers and Pinto.3 Excessive myocardial ECM
Aging
formation and collagen production take place in both human and Aging is one of the key drivers of myocardial fibrosis (reviewed
experimental heart failure resulting from pressure overload, and in18 – 25 ). Animal models and human biopsy studies have
collagen formation becomes disproportionate to left ventricular demonstrated that collagen content of the heart progres-
mass when the stress becomes chronic and sustained.3 Transform- sively increase with advanced age, and collagen deposition is
ing growth factor (TGF)-𝛽𝛽 is a central protein in the formation associated with increased wall stress, and with diastolic and
- 27 -
Figure 2 Graphical depiction of time-dependent fibrosis formation in the heart after acute injury such as myocardial infarction, longstanding
injury such as hypertension, and intrinsic tissue changes during aging and senescence. The aetiological factors underpinning fibrosis, as
well as the (physiological) need for a fibrotic reparative response will dictate the extent and timing of the fibrotic process. (Illustration:
Maartje Kunen, Medical Visuals.) AngII, angiotensin II; CTGF, connective tissue growth factor; DAMPS, danger-associated molecular patterns;
ET-1, endothelin-1; IL, interleukin; L, lymphocyte; Ma, macrophage; MC, mast cell; MCP-1, monocyte chemoattractant protein-1; MF/MyoF,
myofibroblast; MMP, matrix metalloproteinase; MV, microvessel; N, neutrophil; PAI, plasminogen activator inhibitor; PDGF, platelet-derived
growth factor; TGF, transforming growth factor; TIMP, tissue inhibitor of metalloproteinase; TNF, tumour necrosis factor.
systolic ventricular dysfunction. With aging, not only the pro- when systolic function is still normal.26,27 Early fibrosis in cardiomy-
.................................................................
duction of collagen increases, but also the degradation becomes opathies is regarded as a malicious event as the need for cardiac
less effective.18,20,21 Also collagen processing and maturation is repair usually is minimal. Clearly, the events triggering fibrosis in
different, and cross-linking seems to increase.18,20,21 The triggers cardiomyopathies are very heterogeneous, and encompass events
for fibrosis in the aging heart are manifold, and, as a result, fibrosis such as cell death, metabolic derangements, neurohormonal acti-
may present in multiple forms. In response to cardiomyocyte vation, and direct toxic effects of mutated proteins.28
injury and cell loss, replacement fibrosis may be seen. At the same
time, with ongoing inflammation and age-dependent increases in
oxidative stress, interstitial fibrosis may occur. We must realize
that age-dependent fibrosis will usually develop alongside, so in Myocardial fibrosis in heart failure
concert with fibrosis that develops in response to cardiac injury,
with preserved ejection fraction
which complicates the understanding of what causes and then
supports sustained fibrotic processes. Heart failure with preserved ejection fraction accounts for almost
half of the cases of heart failure. Co-morbidities, including aging,
obesity, hypertension, and diabetes, are key factors for HFpEF pro-
Myocardial fibrosis in (genetic) gression into overt heart failure. Recent evidence suggests that
cardiomyopathies in HFpEF the extent of myocardial fibrosis (as measured by T1-MRI,
Fibrosis in (mono-) genetic cardiomyopathies can occur as fine see below) is related to the degree of diastolic dysfunction.29,30
interstitial fibrosis or replacement fibrosis, both due to structural Clearly, pro-fibrotic signals are diverse and differ from classical,
changes in response to the gene defect. Therefore, the observa- systolic, heart failure signals. Fibrosis in HFpEF usually presents
tion of fibrosis for instance on cardiac magnetic resonance imaging as perivascular and fine interstitial fibrosis and is associated with
(MRI) is generally regarded as an early sign of the disease, even systemic inflammation.31 As a consequence, fibrosis in HFpEF will
- 28 -
likely be multifaceted, with fibrosis due to aging, due to hyperten- macrophages.45 Most compelling evidence form the preclinical field
........................................................................................................................................................................
sion, and in response to inflammatory and metabolic (obesity) trig- was generated for tumour necrosis factor (TNF)-𝛼𝛼 inhibition43,46
gers, with occasional superimposed reparative fibrosis, in case of but surprisingly, clinical studies e.g. with steroids and TNF-𝛼𝛼 block-
(small) MI or myocarditis. Clearly, the current call to better pheno- ers showed no or even detrimental effects, so that initial translation
type HFpEF resonates particularly for the understanding of fibrosis of experimental observations to clinical medicine has failed,44 sug-
in this complex disease.31 gesting that broad targeting of the immune system will not be
a useful therapeutic strategy. Of interest, the recent CANTOS
trial showed that targeted inhibition of inteleukin-1𝛼𝛼 did reduce
The ‘chronic fibrotic response’ in heart cardiovascular (and cancer) outcomes, albeit to a small degree.47
failure
From the discussion above it becomes clear that in heart failure Proposal for a minimum assessment
(and in fact in more chronic diseases), a sustained fibrotic response
profile to screen cardiac fibrosis
is observed, that initially may be reparative, but at some point,
rather contributes to organ damage and failure. So, it seems that The term ‘myocardial fibrosis’ needs to be specified with more pre-
in certain forms and stages of heart failure the fibrotic response cision and potentially individualized to offer effective therapeutics
cannot be switched off, and that a certain degree of fibrogenesis to patients with heart failure and cardiac fibrosis. For experimental
remains persistent. This is different from physiological healing, studies, we propose a minimum set of parameters that should be
where the termination of the reparative phase is identified by the provided to allow readers to appreciate the nuances of the fibrosis
disappearance of activated myofibroblasts from the tissue.32,33 phenotype present. These items are listed in Table 1. In Table 2, we
It is currently unknown how to differentiate the endogenous, summarize the key functions, disease conditions, analytical meth-
necessary and beneficial fibrotic response or matrix turnover from ods and biomarkers in different forms of fibrosis. These insights are
the excessive, ongoing and harmful chronic fibrotic response that crucial to identify therapeutic opportunities for various subtypes of
leads to matrix deposition and tissue stiffening.34 We postulate fibrosis-induced heart failure.
that these triggers that cause this chronic fibrotic response are
multifold, including sustained fibroblast proliferation via feedback Improved methods are needed
loops, cardiomyocyte-mediated fibroblast activation, inhibition of
myofibroblast apoptosis, and the presence of sustained low-grade to detect fibrosis using
systemic and local inflammation. biomarkers and imaging
Although mechanistically this remains largely a black box,
several players have been recognized. As described above,
techniques
TGF-𝛽𝛽 plays a central role in fibroblast proliferation and Detection of myocardial fibrosis is not straightforward in animal mod-
fibroblast-to-myofibroblast conversion. TGF-𝛽𝛽 is produced in els and is even less so in the clinical setting where myocardial tissue
high numbers by myofibroblasts to create a vicious cycle of sampling is not readily available. The gold standard for human studies is
myofibroblast activation. TGF-𝛽𝛽 stimulates several growth factors to assess the quality (i.e. focal, interstitial or perivascular distribution)
(epidermal growth factor, insulin-like growth factor-1, growth dif- and to quantify fibrosis in myocardial tissue biopsies using histolog-
ical techniques (i.e. Masson’s Trichrome or Sirius Red histochemical
ferentiation factor-11), which mediate proliferation of fibroblasts,
staining). Although endomyocardial biopsies (EMBs) are limited by sam-
involving autocrine signalling via fibroblast growth factor-2 and/or
pling error and small tissue fragments, the study of explanted hearts
CTGF.35,36 TGF-𝛽𝛽 also prevents myofibroblast apoptosis, via for heart transplantation offers unique possibilities with regard to spa-
stimulation of PI3K/AKT pro-survival signalling pathway.37 ‘Myofi- tiotemporal histological analyses and modern -omics techniques, not
broblast persistence’ may lead to non-resolving and progressive hampered by lack of tissue. We aware of several (national) initiatives,
fibrosis, as exemplified by human idiopathic pulmonary fibrosis.38 where all explanted hearts will be archived centrally to ensure proper
Experimental drugs targeting the TGF-𝛽𝛽 and MAPK pathways sample size (so-called heart banks), and we foresee these will gener-
indicate that the myofibroblast phenotype can be reversed, but ate valuable information on fibrosis as well. But to date, tissue studies
whether this also can be achieved in vivo remains unclear.39,40 are mostly still carried out on EMBs, requiring an invasive proce-
The low-grade, persistent systemic inflammation that is dure with the associated risk for complications and sampling errors.48
observed in heart failure41 – 44 is a major driver of fibrosis. Thus, alternative, non-invasive and ideally equally or even more reliable
TGF-𝛽𝛽 has pleiotropic effects on the immune system and has both methods should be developed and broadly applied.
immunosuppressive and pro-inflammatory functions,44 and may
polarize macrophages and neutrophils towards a M2 phenotype, Circulating biomarkers of myocardial
which produces large quantities of inflammatory cytokines. fibrosis
Experimental studies suggest that regulating the inflammatory
Extracellular matrix proteins or cleaved processing products are
and immunomodulatory response may be effective in reducing often released into the systemic circulation and therefore measurable
MI-related remodelling, fibrosis and outcomes. For example, in in serum or plasma using reliable and approved methods (e.g. ELISAs).
a recent mouse study, neuregulin-1, an epidermal growth factor Commonly used fibrosis biomarkers give insight into collagen produc-
family member released by cardiac endothelial cells, attenuated tion [e.g. procollagen type I N-terminal propeptide, procollagen type
myocardial interstitial fibrosis by inhibiting activation of myocardial III N-terminal propeptide (PIIINP)] or the secretion of non-structural
- 29 -
Table 1 Proposed minimal dataset to describe fibrosis in animal studies
Parameter Example(s)
...........................................................................................................................................
Species Mouse, rat, sheep, pig
Precise reporting of strain, genetic background, age
Perturbation Pressure overload, MI by permanent LAD ligation or ischaemia/reperfusion injury, diet, salt
loading
Precise reporting of duration of intervention and period of ischaemia and pressure overload
Time course Reporting the time course of disease progression, with samples taken before and at several time
points [acute, subacute (days) and chronic (months)] post-disease induction
Assessments
Histology For instance: Masson, Picrosirius red
Percentage of LV tissue affected, sampled ROIs;
Use of validated antibodies for immune histology
• Reparative (scarring) fibrosis vs. reactive fibrosis (quantitative or semiquantitative)

• Amount of fibrosis (quantification), perivascular, interstitial, scarring
• Quality: thickness and % collagen cross-linking (Sirius red polarization, specific antibodies)
• Myofibroblast staining (smooth muscle cell actin staining)
• Electron microscopy for collagen fibre morphology
Inflammation glycoproteins-proteoglycans in - Acute vs. chronic process (duration of disease)?
the heart at RNA and protein level Glycoproteins/proteoglycans:
• Periostin
• Osteopontin
• Syndecans
• Thrombospondins
• Osteoglycin
• TGF-𝛽𝛽
• CTGF
• Galectin-3
• Interleukin 1, -10, -11
• Others pending on cardiac disease
- Quantification of inflammation (myeloperoxidase, CD45- and CD68-staining leucocytes).
- Collagen crosslinking enzymes (LOX’s)
- MMP/TIMPs at transcript level and zymography
Blood biomarkers Galectin-3
CITP
PIIINP
ST2
Imaging MRI (T1 mapping, late enhancement fibrosis)
Functional analyses Echocardiography and invasive haemodynamics for determining load-dependent diastolic and
systolic function
CITP, C-terminal propeptide of procollagen type I; CTGF, connective tissue growth factor; LAD, left anterior descending artery; LOX, lysyl oxidase; LV, left ventricular; MI,
myocardial infarction; MMP, matrix metalloproteinase; MRI, magnetic resonance imaging; PIIINP, procollagen type III N-terminal propeptide; ROI, region of interest; TGF,
transforming growth factor; TIMP, tissue inhibitor of metalloproteinases.
(glyco)proteins that modulate the collagen production itself or its mat- technical difficulties in measuring the proteins, often requiring labori-
....................................
uration (e.g. periostin, mimecan, monocyte chemoattractant protein-1, ous and expensive radioimmunoassays. Recently, several new emerg-
or galectin-3). In addition, several MMPs (e.g. MMP-3, MMP-9, MMP-11, ing fibrotic markers have been studied, including galectin-3, sST2, and
and MMP-12) and their tissue inhibitors (e.g. TIMP-1 and TIMP-3) periostin.51 These markers can generally be measured with Food and
involved in the balance of collagen degradation, are released into Drug Administration-cleared ELISA assays which allow fast turnaround
the blood stream and can be measured reliably. In fact, there is a times.
wide body of literature on the potential utility of these markers alone Circulating levels of fibrosis markers may not parallel findings in his-
or in concert.49 In general, many of these markers are valuable for tologically proven cardiac fibrosis and therefore caution is required in
clinical risk prediction. Interestingly, several factors have been shown the interpretation of systemic venous circulating biomarker levels in
to predict the response to treatment with anti-fibrotic properties, relation to myocardial disease. López et al.52 measured circulating levels
such as mineralocorticoid receptor antagonists.50 However, the use of many fibrotic markers and correlated these in the same patients
of these markers has not become a clinical standard because of limited to local cardiac tissue fibrosis volumes measured with histology. The
power in fully adjusted models with clinical variables, and because of results show that out of 28 potential biomarkers associated with
- 30 -
Table 2 Overview of key functions, conditions, analytical methods and biomarkers in different forms of fibrosis
Type of fibrosis Function Disease conditions Methods to detect in tissue Blood biomarkers
.........................................................................................................................................................................................
Reparative fibrosis Replacing necrotic cells Myocyte necrosis (ischaemia, Histochemistry (Sirius red and CITP, PICP
infection, autoimmunity, Azan blue) PINP, PIIINP
toxicity, gene mutations) Cardiac MRI, late enhancement
Reactive fibrosis New matrix production in Matrix production in response to Histochemistry CITP, PICP, Galectin-3, sST2,
between cells an acquired or genetic trigger, Cardiac MRI, T1 mapping of and periostin
such as stretch extracellular volume
Perivascular fibrosis New matrix produced around Perivascular fibrosis upon Histochemistry Unknown
vessels pressure overload or vascular
stress
Definition, quantification and treatment of fibrosis in heart failure
Cells involved
(Myo)fibroblasts Reparative and reactive Most diseased hearts Staining of periostin, FAP, SMA Periostin, mimecan, SPARC
Smooth muscle cells Perivascular and reactive Pressure overload, vasculitis Staining of SMA
- 31 -
Inflammatory cells Reparative and reactive Acute and chronic cardiac Staining of macrophages, sST2, CRP, galectin-3
disease monocytes, neutrophils
(CD45)
Content/mechanisms
Collagen production Structural proteins Healthy and diseased heart Immunostaining, rtPCR CITP, PICP, PINP, PIIINP
Glycoproteins/proteoglycans Inter-cellular communication Most diseased hearts Immunostaining, rtPCR Galectin-3, sST2, periostin,
mimecan, SPARC
MMP and their inhibitors Collagen degradation/production Healthy and diseased heart Immunostaining and activity MMP-1 and -9, TIMP-1 and -2
(TIMPs) balance assays, rtPCR
Growth factors: TGF, CTGF, Stimulate collagen production, Most diseased heart Immunoblots, signalling pathways ND
FGF, Wnt pathways affects inflammation
CITP, C-terminal propeptide of procollagen type I; CRP, C-reactive protein; MMP, matrix metalloproteinase; MRI, magnetic resonance imaging; PINP, amino-terminal propeptide of type I collagen; PIIINP, procollagen type III N-terminal
propeptide; PINP, procollagen type I N-terminal propeptide; rtPCR, reverse transcriptase-polymerase chain reaction; sST2, soluble ST2; TIMP, tissue inhibitor of metalloproteinases.
279
Figure 3 Systemic biomarkers, measured in the plasma of patients with heart failure, ideally reflect changes in the heart muscle. For
cardio-specific biomarkers, such as natriuretic peptides and troponins, this is very accurate. However, for many (more novel) markers that are
expressed by many organs outside the heart as well, the systemic levels only marginally reflects cardiac production. BNP, B-type natriuretic
peptide. (Illustration: Maartje Kunen, Medical Visuals.)
build-up or breakdown of myocardial fibrosis, only C-terminal propep- velocity imaging and global longitudinal systolic strain provide mechan-
.....................................................................................
tide of procollagen type I (CITP) and PIIINP correlated with histological tissue details that associate with myocardial fibrosis by biopsy
ical findings. This may be explained because in heart failure patients, examination.54 – 56 In addition to echocardiography, cardiac MRI is a
several other organs undergo fibrotic changes as well: liver, lungs, kid- technique that is replacing EMB as gold standard for human cardiac
neys, and vessels. A recent article by Du and colleagues showed that fibrosis identification and quantification. Clearly, the use of cardiac MRI
galectin-3, growth differentiation factor-15, and TIMP-1 plasma levels cannot fully replace echocardiography as first-choice imaging modal-
do not reflect myocardial fibrosis in mouse models of post-MI heart ity, given the high costs. But in order to perform in deep pheno-
failure, hypertensive heart failure, and HFpEF.53 Instead, production typing, with the aim to choose patients with specific pathophysio-
in extracardiac tissues such as fatty and lung tissue had much greater logical characteristics, or to monitor these during (drug) treatment,
impact on plasma levels of these markers. So ideally, we would need cardiac MRI has distinct benefits. Using delayed gadolinium enhance-
a marker that is specific for cardiac fibrosis, or at the very least, ade- ment, it is possible to visualize scar tissue, for instance after trans-
quately reflects changes in myocardial fibrosis. However, since most mural myocardial infarction. While delayed gadolinium enhancement
fibrotic pathways are shared amongst organs, such a marker may not mainly identifies focal reparative fibrosis, modern techniques in cardiac
exist and it is therefore simply impossible to use circulating fibrosis MRI are developing that may be able to provide more granularity in
markers as a perfect surrogate for myocardial fibrosis (Figure 3). Fur- imaging fibrosis. Most interestingly, T1 mapping is such an emerging
ther, the markers generally do no clearly distinguish between various cardiac MRI technique, measuring the longitudinal relaxation time of
forms of fibrosis, or between the trigger that causes fibrosis. There- individual protons, which is depicted as a pixelated map. T1 mapping
fore, the use of these factors for precision diagnostics is questionable, allows the quantification of extracellular volume (ECV) fraction of the
but excess local production however may be used to target specific myocardium. ECV is not a pure measure of fibrosis, although it has
treatment. Further, the potential of fibrotic markers as surrogate out- been evaluated to this aim,57,58 but ECV rather mirrors diffuse changes
comes in phase I/II trials is likely to be limited at this point, in view of including fibrosis, but also interstitial oedema, protein degradation and
the limited specificity of available fibrotic (bio-)markers. aggregation, lipid accumulation, and deposition of iron or amyloid. A
recent HFA position paper discusses in detail the (fast) developments
in imaging techniques.59 Furthermore, the presence and the extent
of MRI-proven fibrosis have been related to poor clinical outcomes.5
Imaging techniques to visualize
Collectively, different imaging (MRI) techniques may be applied as sur-
and quantify fibrosis rogate measures for the presence and extent of myocardial fibrosis.
The most widely applied imaging technique in contemporary heart The next challenge is to develop a therapeutic plan to reverse or pre-
failure management is echocardiography. Classical two-dimensional vent further development of fibrosis based on the cardiac magnetic
echocardiography, however, provides little information about the pres- resonance findings. A promising approach would be to label specific
ence or extent of fibrosis. More modern techniques such as tissue molecules with established relation to myocardial fibrosis, and image
- 32 -
those, e.g. by nuclear techniques, with the ultimate aim to target this its activity has proven beneficial in rodent models of MI (unpub-
........................................................................................................................................................................
specifically.60 lished), neonatal (rat) bronchopulmonary dysplasia,64 and thoracic
aorta constriction model.65 Clinical testing of FG-3019 indicates an
excellent safety profile and has been tested in approximately 400
New therapies are needed patients with diabetic kidney disease, pancreatic cancer, idiopathic
to directly target myocardial pulmonary fibrosis, or liver fibrosis.
Pirfenidone is a synthetic molecule that has been reported
fibrosis with specific drugs to decrease the expression of various pro-fibrotic factors,
It has been proposed for several years that direct targeting fibro- including TGF-𝛽𝛽1, TNF-𝛼𝛼, platelet derived growth factor and
sis might be useful in heart failure.1,61,62 Angiotensin-converting collagen.66 Results from experimental models provided evidence
enzyme inhibitors and mineralocorticoid receptor antagonists for a therapeutic utility of pirfenidone in pressure overload67 – 69
reduce fibrosis formation, but clearly a residual fibrotic burden and hypertension,68 leading to a reduction in arrhythmogenic
substrate.70
remains and with that, a potential need to target it in order to
improve outcomes. It is crucial to ascertain where the fibrotic pro-
cess is, at a given time point, what the triggers are, and which cells Matrix metalloproteinases
and proteoglycans play a role. The complexity of targeting fibrosis
The effects of regulating MMP activity on cardiac fibrosis
is illustrated by a recent article by Clarke and colleagues,62 pro-
and left ventricular remodelling outcomes have primarily been
viding an example for why MMP inhibition may not be as effective
assessed in MI models. Targeted deletion and transgenic mice or
as previously hypothesized. They postulate that early during the
MMP inhibitors (MMPi) reveal both beneficial and detrimental
remodelling phase, MMP inhibition might be less effective because
consequences.71 While early promises of MMPi in animal models
there is little collagen to degrade, while at later fibrotic phases
were encouraging, these findings have not translated to humans.
it is less effective because MMP levels have fallen to low levels.
This has been due to selectivity and specificity issues, as well as
Therefore, the setting, the aetiology and the timing, all appear very
our lack of understanding of the full range of MMP functions.71 For
important in MMP inhibition and this could in part explain the dis-
example, the MMP-9 substrate list includes hundreds of substrates
appointing results thus far. Next, we will discuss a few novel options
ranging from collagen and fibronectin, interleukin-1𝛽𝛽, pro-enzymes
that are on the horizon.
and citrate synthase.72,73 Further, not all MMPi have been beneficial,
as MMP-12i given at 3 h post-MI suppressed neutrophil apoptosis
Connective tissue growth factor to prolong inflammation, resulting in exacerbated left ventricular
dilatation.74 MMP-28 deletion inhibited M2 anti-inflammatory
and pirfenidone macrophage activation to stimulate left ventricular dysfunction
Inhibition of fibrosis formation in pressure overloaded heart is best and increase cardiac rupture rates.75 If anything, these results
achieved by alleviating the primary stressor,3 i.e. the elevated pres- indicate how complex the fibrotic process in heart failure is, and
sure. TGF-𝛽𝛽 (e.g. pirfenidone), angiotensin or endothelin receptor the specific role of MMPs herein. There is a need, therefore, to
blockers, ERK inhibitors or inhibition of CTGF are being tested delineate individual MMP roles under specific conditions and times.
as specifically fibrosis targeted treatments. Different from post-MI
fibrosis, it appears that inhibition of the excess fibrosis in pressure
overload is generally safe and well-tolerated. Galectin-3 inhibitors
Connective tissue growth factor (or CCN2) is a matricellular Galectin-3 is a lectin binding galactoside, and has been shown
protein and modulates the signalling of many cytokines and ECM to be upregulated in heart failure by myofibroblasts, mono-
signals including those of TGF-𝛽𝛽, bone morphogenetic protein, cytes and macrophages that are recruited towards sites of injury
Wnt, vascular endothelial growth factor, and integrins. Because and fibrosis.76,77 Studies in mice deficient for galectin-3 have sug-
it modulates multiple pathways simultaneously, and via several gested that galectin-3 is not a bystander but rather a culprit for
different mechanisms, the effects of CTGF are combinatorial myocardial fibrosis.78,79 Inhibition of galectin-3, either achieved with
and context-dependent (i.e. dependent on the environment and large carbohydrates,78,79 or antisense RNA,80 or small designer
mediators present), and therefore, the biology of CTGF is very molecules,81 effectively reduces organ fibrosis.82
complex.63 CTGF expression is induced by many different patho-
physiological insults, and when it becomes overexpressed, it helps
promote differentiation of cells to become activated myofibrob- Non-coding RNAs
lasts that deposit and remodel the ECM. CTGF is involved in Recently, non-coding RNA (both microRNA and long non-coding
multiple positive feedback loops that can propagate tissue remod- RNAs-based)-based treatment strategies for fibrosis have been
elling and fibrosis, and therefore it should be considered a central put forward.83,84 Specific non-coding RNAs seem to play crucial
mediator of fibrosis. Consequently, the goal of inhibiting CTGF is roles in the regulation of the cardiac fibroblast phenotype and
to disrupt these positive feedback loops and arrest the progres- their modulation seem to be effective both in animal as well
sive nature of fibrosis (and possibly reverse it). A human mono- as clinical studies; indeed there is currently a phase II trial in
clonal antibody, FG-3019, that binds to CTGF and interferes with patients with kidney fibrosis using an inhibitor of microRNA-21
- 33 -
(http://regulusrx.com/programs/pipeline/). Thus, non-coding
........................................................................................................................................................................
Table 3 Key recommendations
RNA-based treatment approaches might provide an opportunity
also for the treatment of cardiac fibrosis and remodelling, if
Challenges Requirements
those microRNA inhibitors could be selectively delivered in the ................................................................
heart — miRNA-21 is ubiquitously expressed. Other microRNAs, Improvement and 1 Describe species, genetic background,
such as miRNA-29b, appear to have a more cardio-specific effect.85 refinement in perturbation, background therapies
describing fibrosis 2 Describe disease and time point where
analyses were done
Future directions and conclusions 3 Describe quantity and quality of fibrosis
4 Describe culprit cells and associated
In this article we discuss several challenges and requirements in the
(glyco-) proteins
study of fibrosis (Table 3). For future applications, strategies that Improvement in 1 Need for better imaging tools
allow for differentiation of fibrosis subtype are needed. Preclinical detecting fibrosis 2 Need for cardio-specific biomarkers
studies in relevant animal models to better understand the dynam- with relation to myocardial fibrosis
ics of fibrosis formation, degradation, and their importance for 3 Improvement in -omics to better
the functional phenotype are therefore required. More advanced pinpoint key factors that drive fibrosis
in vitro models might allow a better functional control and mech- Targeting fibrosis 1 Gain precise awareness of what element
anistic understanding. Whereas further optimizations are needed at what time point may be targeted
to implement human cardiac disease parameters,86 these well con- 2 Novel (designer) drugs affecting
trolled environments allow longitudinal evaluations and screening deleterious fibrosis
of anti-fibrotic strategies. Accumulating data linking fibrosis to a
stronger inflammatory response are at the initial phases. At later templates for assessing fibrosis in both translational and clinical
time points, fibrosis-specific mediators and pathways (predomi- studies.
nantly fibroblast-specific factors such as TGF-𝛽𝛽, osteopontin, and
galectins) contribute to the progression of fibrosis, and are dis-
tinct from the mechanisms driving inflammation. The presence of
Funding
co-morbidities should be considered — e.g. it has recently been R.A.d.B. is supported by the Netherlands Heart Foundation
discussed that co-morbidities such as cancer may obscure the (CVON DOSIS, grant 2014-40, CVON SHE-PREDICTS-HF,
biomarkers’ signals.87 Thus, to design effective therapeutics for grant 2017-21, and CVON RED-CVD, grant 2017-11); and the
fibrotic disease, inflammation triggering fibrosis is to be consid- Innovational Research Incentives Scheme program of the Nether-
ered, and the challenge ahead is to target specific molecules and lands Organization for Scientific Research (NWO VIDI, grant
pathways that act on fibrosis (specific interleukins) while leav- 917.13.350). J.B. is supported is supported by the Deutsche
ing the (often beneficial) effects of the inflammatory response Forschungsgemeinschaft (DFG), Clinical Research Group 311
uninhibited. A vast diversity of inflammatory, immunological, and (KFO 311) ‘(Pre)terminal heart and lung failure: unloading
molecular mechanisms collectively contribute to cardiac fibrosis: and repair’ (DFG; TP1, BA 1742/9-1) and ‘MR-Focus’‘ (DFG BA
the complex interplay between adaptive immune system activation, 1742/8-1). J.S. has received funding from the European Research
fibroblasts-to-myofibroblast conversion and proliferation, mast cell Council (ERC) under the European Union’s Horizon 2020 research
activation, neutrophil influx, and production, modulation, matura- and innovation program (consolidator grant Evicare #725229)
tion and apposition of collagens, the embedding in the extracellular and by the Netherlands Heart Foundation (CVON-HUSTCARE).
milieu. These should all be considered and taken into account dur- M.M. is a BHF Chair Holder (CH/16/3/32406), with BHF program
ing the design and testing of new anti-fibrotic therapies. grant support (RG/16/14/32397), and was awarded a BHF Special
Clinically, disease-specific (bio-)markers and imaging modali- Project grant to participate in the ERA-CVD Translational Grant
ties — acting as surrogate parameters of specific temporal stages MacroERA. M.M. and T.T. are members of a network funded
of fibrosis — will help to identify patients who might benefit from by the Foundation Leducq. C.G.T. is supported by a Federico
a specific therapy. Until recently, attempts to inhibit fibrosis have II University/Ricerca di Ateneo grant. S.H. has received funding
been mostly focusing on single pro-fibrotic factors. Since fibrosis from the European Union Commission’s Seventh Framework
is driven and sustained by the activation of multiple interconnect- programme under grant agreement n. 305507 (HOMAGE), n.
ing and intercommunicating pro-fibrotic pathways, a multi-target 602904 (FIBROTARGETS) and FP7-Health-2013-Innovations-1
approach will likely help to slow down the progression of fibrosis. n. 602156 (HECATOS), CVON2016-Early HFPEF, 2015-10,
Using systems biology approaches and multi-omics technologies to and CVON SHE-PREDICTS-HF, grant 2017-21. C.M. is sup-
understand network signalling will aid in these efforts. Ultimately, ported by the DFG (Ma 2528/7-1, SFB 894, TRR-219) and the
a concerted anti-fibrotic strategy that collectively targets impor- Federal Ministry of Education and Science (BMBF; 01EO150,
tant inflammatory signalling molecules, pro-fibrotic cytokines, and CF.3, RC2).
cellular functions should be considered in developing therapies to Conflict of interest: The UMCG, which employs R.A.d.B., has
adequately treat fibrosis. received research grants and/or fees from AstraZeneca, Abbott,
In conclusion, in this position paper we have summarized the cur- Bristol-Myers Squibb, Novartis, Roche, Trevena, and ThermoFisher
rent knowledge gaps in the myocardial fibrosis field and provided GmbH. R.A.d.B. is a minority shareholder of scPharmaceuticals,
- 34 -
Inc.; received personal fees from MandalMed Inc, Novartis, and 15. Ali SR, Ranjbarvaziri S, Talkhabi M, Zhao P, Subat A, Hojjat A, Kamran P, Müller
........................................................................................................................................................................
AM, Volz KS, Tang Z, Red-Horse K, Ardehali R. Developmental heterogeneity of
Servier. J.B. received honoraria for lectures and/or consulting from
cardiac fibroblasts does not predict pathological proliferation and activation. Circ
Novartis, Pfizer, Vifor, Bayer, Servier, Orion, CVRx, Abiomed, Res 2014;115:625–635.
Abbott, Medtronic, and research support from Zoll, CVRx, Bayer, 16. Moore-Morris T, Tallquist MD, Evans SM. Sorting out where fibroblasts come
from. Circ Res 2014;115:602–604.
Vifor, Abiomed, Medtronic. T.T. has filed and licensed patents in the
17. Meyer K, Hodwin B, Ramanujam D, Engelhardt S, Sarikas A. Essential role for
field of noncoding RNAs; is founder of Cardior Pharmaceuticals premature senescence of myofibroblasts in myocardial fibrosis. J Am Coll Cardiol
GmbH. A.R.L. reports grants from Servier and Pfizer, and speaker 2016;67:2018–2028.
fees, advisory board fees and/or consultancy fees from Servier, 18. Burlew BS. Diastolic dysfunction in the elderly--the interstitial issue. Am J Geriatr
Cardiol 2004;13:29–38.
Pfizer, Novartis, Roche, Takeda, Boehringer Ingelheim, Amgen, 19. Singh M, Foster CR, Dalal S, Singh K. Role of osteopontin in heart failure
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Bayer, Bristol-Myers Squibb, Boehringer Ingelheim, Berlin Chemie, 22. Dai DF, Chen T, Johnson SC, Szeto H, Rabinovitch PS. Cardiac aging: from
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European Journal of Heart Failure (2019) 21, 402–424 CONSENSUS DOCUMENT
doi:10.1002/ejhf.1436
The role of ventricular–arterial coupling in

cardiac disease and heart failure: assessment,
clinical implications and therapeutic
interventions. A consensus document of the
European Society of Cardiology Working
Group on Aorta & Peripheral Vascular
Diseases, European Association of
Cardiovascular Imaging, and Heart
Failure Association
Ignatios Ikonomidis1*, Victor Aboyans2,3, Jacque Blacher4, Marianne Brodmann5,
Dirk L. Brutsaert6, Julio A. Chirinos7, Marco De Carlo8, Victoria Delgado9,
Patrizio Lancellotti10,11, John Lekakis1, Dania Mohty2,3,
Petros Nihoyannopoulos12,13, John Parissis14, Damiano Rizzoni15,
Frank Ruschitzka16, Petar Seferovic17, Eugenio Stabile18, Dimitrios Tousoulis13,
Dragos Vinereanu19, Charalambos Vlachopoulos13, Dimitrios Vlastos1,
Panagiotis Xaplanteris13, Reuven Zimlichman20, and Marco Metra21
1 Second Cardiology Department, Echocardiography Department and Laboratory of Preventive Cardiology, Athens University Hospital Attikon, National and Kapodistrian
University of Athens, School of Medicine, Athens, Greece; 2 Department of Cardiology, Dupuytren University Hospital, Limoges, France; 3 Inserm 1094, Limoges School of
Medicine, Limoges, France; 4 Diagnosis and Therapeutic Center, Hypertension and Cardiovascular Prevention Unit, Paris-Descartes University, Hôtel-Dieu Hospital, AP-HP, Paris,
France; 5 Division of Angiology, Department of Internal Medicine, Medical University Graz, Graz, Austria; 6 Department of Cardiology, University Hospital Antwerp, Edegem,
Belgium; 7 Perelman School of Medicine and Hospital of the University of Pennsylvania, University of Pennsylvania, Philadelphia, PA, USA; 8 Cardiac Catheterization Laboratory,
Cardiothoracic and Vascular Department, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy; 9 Department of Cardiology, Leiden University Medical Centre, Leiden, The
Netherlands; 10 Department of Cardiology, University of Liège Hospital, GIGA Cardiovascular Sciences, CHU SantTilman, Liège, Belgium; 11 Gruppo Villa Maria Care and
Research, Anthea Hospital, Bari, Italy; 12 NHLI - National Heart and Lung Institute, Imperial College London, London, UK; 13 1st Department of Cardiology, Hippokration
Hospital, National and Kapodistrian University of Athens, Medical School, Athens, Greece; 14 Heart Failure Unit, School of Medicine and Department of Cardiology, National and
Kapodistrian University of Athens, Athens University Hospital Attikon, Athens, Greece; 15 Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy;
16 Department of Cardiology, University Hospital, Zurich, University Heart Center, Zurich, Switzerland; 17 Cardiology Department, Clinical Centre Serbia, School of Medicine,
University of Belgrade, Belgrade, Serbia; 18 Department of Advanced Biomedical Sciences, ‘Federico II’ University, Naples, Italy; 19 University of Medicine and Pharmacy ‘Carol
Davila’, and Department of Cardiology, University and Emergency Hospital, Bucharest, Romania; 20 Department of Medicine and Hypertension Institute, Brunner Institute for
Cardiovascular Research, Sackler Faculty of Medicine, The E. Wolfson Medical Center, Institute for Quality in Medicine, Israeli Medical Association, Tel Aviv University, Tel Aviv,
Israel; and 21 Cardiology, Department of Medical and Surgical Specialties, Radiological Sciences, and Public Health, University of Brescia, Brescia, Italy
Received 10 July 2018; revised 9 January 2019; accepted 10 January 2019 ; online publish-ahead-of-print 12 March 2019
*Corresponding author. 2nd Cardiology Department, Attikon Hospital, National and Kapodistrian University of Athens (NKUA), Rimini 1, Haidari, 12462 Athens, Greece. Tel:
+30 210 5832187, Fax: +30 210 5832192, Email: ignoik@gmail.com
[Correction added on 21 March 2019, after first online publication: the spelling of Patrizio Lancellotti’s name was corrected.]
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Ventricular–arterial coupling in cardiac disease 403
Ventricular–arterial coupling (VAC) plays a major role in the physiology of cardiac and aortic mechanics, as well as in the pathophysiology
of cardiac disease. VAC assessment possesses independent diagnostic and prognostic value and may be used to refine riskstratification and
monitor therapeutic interventions. Traditionally, VAC is assessed by the non-invasive measurement of the ratio of arterial (Ea) to ventricular
end-systolic elastance (Ees). With disease progression, both Ea and Ees may become abnormal and the Ea/Ees ratio may approximate
its normal values. Therefore, the measurement of each component of this ratio or of novel more sensitive markers of myocardial (e.g.
global longitudinal strain) and arterial function (e.g. pulse wave velocity) may better characterize VAC. In valvular heart disease, systemic
arterial compliance and valvulo–arterial impedance have an established diagnostic and prognostic value and may monitor the effects of
valve replacement on vascular and cardiac function. Treatment guided to improve VAC through improvement of both or each one of its
components may delay incidence of heart failure and possibly improve prognosis in heart failure. In this consensus document, we describe
the pathophysiology, the methods of assessment as well as the clinical implications of VAC in cardiac diseases and heart failure. Finally, we
focus on interventions that may improve VAC and thus modify prognosis.
..........................................................................................................
Keywords Ventricular–arterial coupling • Arterial elastance • Ventricular elastance • Global longitudinal strain •
Pulse wave velocity • Valvular heart disease • Hypertension • Inflammatory disease •
Coronary artery disease • Heart failure • Prognosis • Treatment
Introduction
...............................................................................................................
A B
The important role of ventricular–arterial coupling (VAC) in the LV Pressure (mmHg)
ESPVR
physiology of cardiac and aortic mechanics, as well as in the patho-

Ea
physiology of cardiac disease has long been recognized. Despite
LV Pressure
Ees
its complexity, several invasive and non-invasive methods have

been developed to measure VAC. In this consensus document, we
describe the pathophysiology of VAC impairment and the mech-
anisms that can affect arterial and cardiac function and their rela-
tion. Traditional VAC assessment methods are presented, together Ees
0
with novel approaches. Furthermore, we analyse the clinical impli- LV Volume (mL) LV Volume
cations of VAC in arterial hypertension, systemic inflammatory
diseases, coronary artery disease (CAD), valvular heart disease, Figure 1 (A) Left ventricular (LV) end-systolic elastance (Ees)
estimated by pressure–volume loop family, end-systolic point
and heart failure (HF). Finally, we focus on invasive and non-invasive
line. By connecting all end-systolic points of pressure–volume
interventions that may improve VAC.
loops obtained during various loading conditions, the so-called
‘end-systolic pressure–volume relation’ (ESPVR) line is retrieved.
(B) LV Ees estimated as the end-systolic pressure/end-systolic
Pathophysiology stroke volume ratio and arterial elastance (Ea) estimated as the
end-systolic pressure/stroke volume ratio are used to calculate
of ventricular–arterial coupling Ea/Ees ratio as a marker of ventricular–arterial coupling using a
Heart–vessel coupling is constantly changing to match ventricular single pressure volume loop.
end-systolic and arterial elastances, a concept that finds its origins
in the pressure–volume (P-V) cardiac function analysis as assessed
by cardiac catheterization.1 By connecting all end-systolic points based on mechanoenergetic grounds, that stroke work generation
of a family of P-V loops obtained during various loading conditions, is maximal when the Ea/Ees ratio equals 1, while maximal cardiac
the so-called ‘end-systolic pressure–volume relation’ (ESPVR) line efficiency is achieved when the Ea/Ees ratio equals 0.5.2
is retrieved (Figure 1A).1 Suga and Sagawa1 found this relation to Ventricular–arterial stiffening amplifies the elevation of blood
be roughly linear within physiologic ranges, sensitive to inotropic pressure (BP) induced by exercise or mental stress and this may
changes, and insensitive to afterload, while the respective line slope further worsen left ventricular (LV) diastolic function and increase
has been termed as end-systolic elastance (Ees). Conceptualising cardiac energy costs to provide an adequate output.3 This may
the left ventricle as a closed volume, Ees represents the necessary exacerbate the effect of the systemic load on LV diastolic func-
intracavitary pressure to increase its volume by one unit.1 The tion and elevate cardiac metabolic demand, as well as LV diastolic
intersection between the ESPVR (upper left-hand corner of the filling pressures under stress causing HF symptoms, further com-
P-V loop) and a line drawn from the end-diastolic volume on the promising myocardial reserve in the long term.3,4
horizontal axis identifies a second line. The respective slope repre- Although the P-V analysis (Figure 1B) provides useful information
sents the end-systolic pressure to stroke volume (SV) ratio, termed regarding the operating mechanical efficiency and performance of
as effective arterial elastance (Ea) (Figure 1B). It has been shown, the ventricular–arterial system when LV ejection fraction is frankly
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404 I. Ikonomidis et al.
Pulse wave generation
Zc: proximal aortic impedance, determining

early and peak systolic myocardial stress
SV dec reas es syst emic perfusion,

resulting in neurohumoral and SNS
activation
Subendocardial ischemia, impaired SV inc rease s disp roportion ately Pulse
systolic myocardial deformation- Pressure in a stiff aorta resulting in further
LV diastolic dysfunction* vascular damage
PWV: index of arterial stiffness, determining

systolic myocardial stress; increased PWV
results in an early arrival of wave
reflections, accentuating late systolic stress;
positive correlation with Aix
Reflected wave Forward wave
Aix: index of contribution of wave

reflections to waveform, affecting late
systolic stress in the context of a stiffened
aorta
Pulse wave reflection sites
Figure 2 Vascular mechanisms that lead to impaired left ventricular (LV) function. Aix, augmentation index; PWV, pulse wave velocity; SNS,
sympathetic nervous system; SV, stroke volume.
abnormal, it is less informative in HF with preserved ejection stiffness [pulse wave velocity (PWV)] are closely related with LV
.........................................................................................
fraction (HFpEF), as discussed later. diastolic function, LV mass, and myocardial deformation [e.g. global
longitudinal strain (GLS)].5 – 8 In fact, LV diastolic dysfunction, LV
Effects of arterial function on left hypertrophy, abnormal myocardial deformation, and increased aor-
tic stiffness share many epidemiological and pathophysiological fea-
ventricular structure and performance
tures: they predominate in elderly subjects and hypertensives, have
The heart ejection generates forward pressure and flow waves, a predictive value for morbidity and mortality, and share under-
transmitted down the arterial tree, giving rise to reflections which, lying biochemical mechanisms of remodelling (collagen deposi-
in a stiffened aorta, arrive early in systole instead of diastole and, tion, increased cellular stiffness, production of advanced glycation
thus, increase central systolic BP and reduce diastolic BP, a key
end-products in diabetes mellitus). Furthermore, impairment of
determinant of the coronary perfusion gradient.4 The increase in
coronary flow reserve is associated with increased arterial stiffness
afterload increases myocardial oxygen demand, and the reduction
and myocardial dysfunction in hypertension, inflammatory diseases,
in coronary perfusion pressure decreases oxygen delivery creat-
and CAD.6
ing conditions of myocardial ischaemia, further deteriorating LV
Carotid to femoral PWV (cfPWV), aortic characteristic
systolic and diastolic performance (especially during exercise).4
impedance (Zc), and the magnitude and timing of wave reflec-
Furthermore, reflected waves increase late systolic load rela-
tions during systole summate the impact of arterial load on LV
tive to early systolic load, which has deleterious effects on the
function at systole and diastole7 that triggers the onset of clin-
myocardium.
In general, arterial load can be expressed as the combination of ical symptoms,8 and contributes to cardiovascular events.9 The
steady and various pulsatile components. The steady component vascular mechanisms that may lead to an impaired LV function
of afterload (i.e. total peripheral resistance) depends largely on are summarized in Figures 2 and 3. Increased arterial stiffness
microvascular properties. Pulsatile LV afterload is, in contrast, (as measured by PWV) results in faster pulse wave propagation,
predominantly influenced by the properties of conduit vessels. earlier reflection and arrival of backward pulse waves during late
Key parameters of pulsatile LV load include the characteristic systole, instead of diastole; thus, early arrival in systole augments
impedance of the proximal aorta (Zc), the magnitude and timing central aortic pressure and thus LV afterload and myocardial
of wave reflections, and the total compliance of the arterial tree oxygen demand, and lowers central diastolic arterial pressure
(‘total arterial compliance’) (for definitions see section ‘Markers of and thus coronary perfusion and myocardial oxygen delivery. The
arterial function’). imbalance between increased myocardial oxygen demands and
Arterial load (arterial compliance, total vascular resistance reduced coronary perfusion leads to myocardial ischaemia in the
index, and wave reflections measured in the ascending aorta) and absence of coronary stenosis (Figure 3).
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Degradation is the task of matrix metalloproteinases. In the pres-
........................................................................................................................................................................
ence of disease or with aging, extracellular matrix synthesis grad-
central PP, SBP, LV afterload
ually predominates, setting the stage for accelerated fibrosis.12,13
High galectin-3 levels, a marker of myocardial and vascular fibrosis,
predicted impaired VAC.13
Endothelial-derived nitric oxide, cytokines, oxidative stress
Pressure
DBP, coronary perfusion

proteins and growth factors determine myocardial microcircu-
latory function, as well as aortic and peripheral vasoreactivity.14
Moreover, neurohumoral factors including adipokines, leptin,
and sex hormones have also been implicated in the process
of ventricular–arterial decoupling by affecting LV hypertrophy,
Time vascular wall hypertrophy, and vasoconstriction.15,16 For example,
ventricular–arterial decoupling was associated with impaired LV
Figure 3 Effects of increased arterial stiffness and the concomi-
performance and was attributed to inflammation in septic shock.17
tant earlier arrival of wave reflections from the peripheral arteries
on central aortic pressure waveform. The pulse wave with blue
The above mechanisms act in parallel to modify arterial and cardiac
line indicates augmentation of aortic pressure in diastole by return function in adaptive or maladaptive ways.
wave reflections under conditions of normal arterial elastic prop-
erties while the aortic systolic component remains unaffected
(blue line). The pulse wave with red line indicates augmentation
Key points
of central aortic pressure in systole by the early arrival of wave • Reflected waves, which arrive in late systole, increase
reflection (orange line and orange arrow) because of increased end-systolic stress and impair diastolic function.
arterial stiffness and reduced central diastolic pressure compared
• Changes in LV SV affect vascular function.
to diastolic pressure during the normal (diastolic) arrival of wave
• Fibrosis, inflammation and oxidative stress are common
reflection (blue line) when arterial elasticity is not impaired. DBP,
diastolic blood pressure; LV, left ventricular; PP, pulse pressure;
biochemical pathways linking impaired ventricular–arterial
SBP, systolic blood pressure. function.
Methods to assess
Effects of cardiac function on arterial ventricular–arterial coupling
properties Although VAC is most frequently assessed in the P-V plane by cardiac
The left ventricle, aortic valve, aorta, and peripheral arteries catheterization, this approach has important limitations (Table 1).2
should be regarded as interdependent organs placed in a series Currently, the most widely used echocardiographic method for the
circuit. The principles of complementarity (all compartments determination of Ea/Ees (normal value 1.0 ± 0.36) is the single-beat
contribute additively to afterload) and competitiveness (one com- method developed by Chen et al.18 Although several methods are
partment cannot be lowered without raising the other one) reflect available, it remains unclear which provides the most reliable results.
According to this method, Ees can be calculated non-invasively by the
their interdependence and the common physiological mechanisms
formula:
that coordinate their function.10 During systole, a pulse wave is
propagated along the aorta to the periphery stretching the arterial Ees = (DBP– [End (est) × SBP × 0.9)] ∕End (est) × SV
wall. Moreover, capacitance vessels distend to accommodate the (normal value ∶ 2.3 ± 1.0 mmHg∕mL)
increased LV SV during exercise. Furthermore, LV SV reduction
does lead to neurohumoral and sympathetic activation, also where DBP and SBP are diastolic and systolic arm-cuff BPs, End(est) is
contributing to vascular dysfunction. the estimated normalized ventricular elastance at the onset of ejection,
and SV is Doppler-derived stroke volume. End(est) is described by the
following formula:
Common biochemical pathways End (est) = 0.0275 − 0.165 × EF + 0.3656
determining arterial and cardiac function × (DBP∕SBP × 0.9) + 0.515 × End (avg)
Extracellular matrix and cytoskeleton regulation processes are bio-
where EF is the basal ejection fraction and End(avg) is derived by a
chemical pathways that concomitantly affect cardiac and arterial
complicated formula:
structure and function through replacement or reactive fibrosis.
Transforming growth factor-𝛽𝛽 serves as a biochemical coordina- End (avg) = 0.35695 − 7.2266 × tNd + 74.249 × tNd2 − 307.39
tor, activating fibroblasts and myofibroblasts. The fibroblast plays × tNd3 + 684.54 × tNd4 –856.92 × tNd5
a key role in inflammation, proliferation/apoptosis, angiogenesis
+ 571.95 × tNd6 − 159.1 × tNd7
(induced by growth factors) and upon stimulation by angiotensin
II it produces collagen.11 Under normal conditions, a balance where tNd is the ratio of pre-ejection period to total systolic
between extracellular matrix synthesis and degradation exists. period.
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We note that this polynomial formula uses the ratio of pre-ejection effects and the local storage of blood in the proximal aorta and the
........................................................................................................................................................................
period to total systolic period raised to multiple powers (up to the sev- load initially experienced by the ventricle upon opening of the aor-
enth) such that small variations or errors in the measurements of time tic valve. It can be measured non-invasively. Two-dimensional guided
intervals will lead to relatively large changes in the estimated Ees value. mode echocardiography of the aortic root to assess aortic root diam-
Effective arterial elastance (Ea) can be computed using the following eter changes between systole (AoS) and diastole (AoD) combined
formula3 : with simultaneous sphygmomanometric measurements of the arterial
pressure (PP) at the brachial artery has been used to assess aortic
Ea = (SBP × 0.9) ∕SV (normal value ∶ 2.2 ± 0.8 mmHg∕mL) . distensibility (2 × (AoS − AoD)/(AoD × PP),21 though this index was
initially measured invasively. A stiff and narrow aorta leads to high Zc
However, a simplified formula frequently used to assess VAC is the
and low aortic distensibility, whereas a distensible, wide aorta to a
following:
low Zc and increased aortic distensibility. The local stiffness param-
Ea = ESP∕SV, Ees = ESP∕ESV
eter beta can also be calculated according to the formula Beta = ln
where ESP is end-systolic pressure, SV is stroke volume, and ESV is (Ps/Pd)/(Ds − Dd/Dd), where Ps and Pd are systolic and diastolic BP
end-systolic volume. Thus, Ea/Ees = (ESP/SV)/(ESP/ESV) and then by in the brachial artery measured by an automated sphygmomanometer,
eliminating ESP: and Ds and Dd are the maximal and minimal diameters of the right
common carotid artery measured by ultrasonic high resolution wall
Ea∕Ees = ESV∕SV, which equals to 1∕ (EF − 1) . tracking22 or of the aorta by echocardiography.21
It becomes readily apparent that the advantage of the Ea/Ees ratio as

a method to provide additional insights about the physiologic status of Large artery stiffness
the ventricular–arterial system is blunted, as it becomes a derivative of Carotid to femoral PWV, which is the velocity of the pulse as it travels
LV ejection fraction. Thus, the full formula by Chen et al.18 should be from the heart to the carotid and femoral artery, remains the most
used to calculate Ees and then to be divided to Ea in order to obtain commonly used non-invasive method and is considered as the ‘gold
an Ea/Ees ratio that accurately reflects invasive Ea/Ees measures. standard’. cfPWV is usually measured using surface tonometry probes
Three-dimensional echocardiography or magnetic resonance imag- at the right common carotid and right femoral artery. The transit time
ing measure LV volumes more accurately than two-dimensional is the time of travel of the wave over these sites. The distance (D)
echocardiography and should be preferred for the calculation of covered by the waves is usually assimilated to the skin distance between
LV (or right ventricular) volumes included in the aforementioned these two recording sites; PWV is calculated as PWV = D/Dt (m/s).20
VAC estimation formulas.19 Finally, in several cardiac diseases (e.g. Brachial–ankle PWV capitalizes on the concept that measurements
hypertension, inflammatory diseases, or diabetes), the components over a longer arterial length may provide additional information.20
Ea and Ees may be similarly impaired, providing an Ea/Ees ratio of
around 1; therefore, the extent of physiologic abnormalities should be
assessed by the absolute value of each component.2 The advantages Central haemodynamics/wave reflections
and disadvantages, as described in Table 1, pertain to both invasive Pressure and flow waves are generated with each heartbeat and are
and non-invasive determinations of the Ea/Ees ratio. However, we propagated towards the periphery where they are reflected back-
should acknowledge that cardiac catheterization provides more accu- wards, merge with the antegrade wave and amplify it. As a result,
rate measurement of Ea and Ees than non-invasive methods while peripheral BPs are higher compared to central (aortic) BPs. Central
non-invasive methods are applicable for repeated consecutive studies BPs are more relevant than peripheral ones, as the heart, brain
of VAC, e.g. before and after treatment in daily clinical practice. Thus, and kidneys are directly exposed to them. Central haemodynamic
we propose the simultaneous measurement of arterial and novel indices are either central BP parameters and derivatives (central
myocardial function markers, as described above, that may provide a systolic BP, pulse pressure, augmented pressure and amplification),
more accurate estimation of VAC and its changes in disease or after or indices that quantify timing and magnitude of wave reflections
treatment. (obtained by pulse wave analysis in the frequency domain and wave
separation analysis). A frequently used central augmentation index
is measured non-invasively by arterial tonometry and is calculated
Markers of arterial function as 100 × peak central systolic BP/central pressure at the inflection
Arterial load depends on the properties of small and large arteries. point and represents the pressure boost that is induced by the return
Indices of the properties of large vessels include aortic characteris- of the reflected waves at the aorta.20 Central pulse wave recordings
tic impedance (Zc), aortic distensibility, beta stiffness index, and large are obtained by cardiac catheterization or non-invasively by arterial
artery stiffness (estimated by aortic PWV) (Table 1). Finally, other tonometry or oscillometry devices (Figure 4A). Furthermore, the
indices ‘blend’ the effect of small and large arteries, such as central newly developed techniques of pressure–flow (Figure 4A–E) and
systolic BP and pulse pressure, indices of wave reflections (e.g. augmen- wave separation analysis (Figure 4F–G) may offer more insight into
tation index), brachial–ankle PWV, and total arterial compliance.20 the assessment of vascular haemodynamics in various disease states
by measurement of both forward and backward compression and
expansion pulse wave. Wave reflection assessment by wave separation
Regional arterial wall properties analysis is based on the principle that reflected waves add to forward
Characteristic impedance of the proximal aorta (Zc) can be intu- pressure and subtract from forward flow distorting the linear relation-
itively measured as the slope of the pulsatile pressure–flow relation ship between the increase in pressure and the increase in flow that
(where pressure and flow are measured in the same point within is seen in early systole when the pulsatile pressure–flow relation is
the artery) in the absence of reflected waves (Figure 4A–E). It is a governed by aortic root Zc (Figure 4E and G). Several lines of evidence
‘local’ arterial property and reflects the interplay between inertial support the importance of late systolic load from wave reflections
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Table 1 Advantages and disadvantages of ventricular–arterial coupling assessment modalities
VAC assessment Advantages Disadvantages

modality
...........................................................................................................................................
Ea/Ees • Widely used with extensive published data • Cardiac catheterization for pressure–volume loops
• Relatively simple and intuitive • Echocardiography provides an approximation of
• Characterizes mechanical indices that relate to Ea/Ees and its components
energetics (only when EF < ∼40%):
• External mechanical energy Disadvantages of Ea:
• Potential energy • It is not a pure index of arterial load because it is
• Energetic efficiency prominently influenced by heart rate
• Allows us to discern the determinants of stroke • It is mostly dependent on resistance and is insensitive
volume and EF to changes in pulsatile arterial load
• It is not a measure of arterial stiffness or total arterial
compliance
• Its derivation did not account for wave reflection or
transmission
• It does not discern the temporal pattern of load
(loading sequence) which is an important
determinant of diastolic dysfunction, maladaptive LV
remodelling and heart failure risk
Disadvantages of Ees:
• Non-linearity of the ESPVR
• It demonstrates afterload dependency
• It demonstrates some preload dependency
• It does not assess myocardial properties (only
‘chamber’ properties)
• Little validation of single-beat non-invasive methods
beyond the original derivation study
Disadvantages of Ea/Ees:
• It does not characterize (and neglects) LV loading
sequence
• In HFpEF, it may be normal because both Ea and Ees
are increased
• Ea/Ees derived by the simplified formula (ESV/SV
ratio) is related mathematically to EF (1/EF – 1) and
thus may not add substantial information to EF
measurement
Arterial stiffness markers
Total arterial compliance • Assessment of the compliance of the whole arterial • Depends non-linearly on arterial pressure
tree • It is size-dependent
• Measured non-invasively • There are systematic differences between different
methods, making it difficult to standardize
• Required expertise is high
• Limited prognostic and therapeutic data
Pulse wave velocity • Solid pathophysiological background • It depends on arterial pressure

• Can be measured non-invasively in a standardized • It represents a part of arterial system (segmental
manner at a low cost, requiring low expertise arterial stiffness)
• Significant prognostic and therapeutic data
• Reference values established
Central aortic • Solid pathophysiological background • Estimations are based on assumptions and
haemodynamics/wave • Can be measured non-invasively algorithms
reflections (central • Prognostic data are available • More prognostic and therapeutic data are needed
SBP, Aix) • Reference values established
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Table 1 Continued
VAC assessment Advantages Disadvantages

modality
...........................................................................................................................................
Characteristic • Solid pathophysiological background • It is dependent on blood pressure and aortic size
impedance of the • It can be measured non-invasively • Increased cost for the equipment
proximal aorta • Significant expertise needed for its estimation
(Zc)/aortic • Limited prognostic and therapeutic data
distensibility
Valvulo–arterial • Solid pathophysiological background • It is dependent on blood pressure and loading
impedance (Zva) • It can be measured non-invasively conditions
• Prognostic data are available • Technical limitations of Doppler echocardiographic
• Reference values are available measurements of LV stroke volume and pressure
gradient
Cardiac function markers
Internal linear dimensions
M-mode • Reproducible • Beam orientation frequently off axis
• High temporal resolution • Single dimension, i.e. representative only in
• Wealth of published data normally shaped ventricles
2D • Facilitates orientation perpendicular to the ventricular long • Lower frame rates than M-mode
axis • Single dimension, i.e. representative only in
normally shaped ventricles
Volume assessment
2D • Corrects for shape distortions • Apex frequently foreshortened
• Less geometrical assumptions compared with linear • Endocardial dropout
dimensions • Blind to shape distortions not visualized in the
apical two- and four-chamber planes
3D • No geometrical assumption • Lower temporal resolution
• Unaffected by foreshortening • Less published data on normal values
• More accurate and reproducible compared to other • Image quality dependent
imaging modalities
Myocardial function markers

Tissue Doppler • High temporal resolution • Angle-dependent, affected by noise
imaging • Established prognostic value of E’,S’ and E/E’ • Assessment of longitudinal and radial deformation
• Incorporated in all echo systems • Time consuming for strain analysis
• Reference values established • Moderate reproducibility/inter and intra-observer
variability for strain analysis
Speckle tracking • Angle-independent • Vendor dependent
modalities • Assessment of longitudinal, radial and circumferential • Dependent on good 2D image quality
deformation • Limited studies on clinical value of 3D strain and
• Assessment of LV twisting–untwisting properties myocardial work index by 2D strain
• Established prognostic value for GLS
• RV assessment
• Pressure–strain loops to assess myocardial work index
• Good reproducibility/inter and intra-observer variability
• 3D imaging is available
• Normal values available
Time-resolved wall • Calculation using a central pressure waveform derived • Limited studies on clinical value
stress curve non-invasively and time-resolved LV geometric information
derived from echocardiography or cine MRI
characterization of the myocardial loading sequence
PWV to GLS ratio • Established prognostic value for PWV and GLS • Limited studies on clinical value in hypertensives
• Sensitive markers of arterial and myocardial function
2D, two dimensional; 3D, three dimensional; Aix, augmentation index; Ea, arterial elastance; Ees, left ventricular elastance; EF, ejection fraction; ESPVR, end-systolic
pressure–volume relation; ESV, end-systolic volume; GLS, global longitudinal strain; LV, left ventricular; MRI, magnetic resonance imaging; PWV, pulse wave velocity; RV,
right ventricle; SBP, systolic blood pressure; SV, stroke volume; VAC, ventricular–arterial coupling.
© 2019 The Authors

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C D
E F
Figure 4 Legend on next page.
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Figure 4 Analyses of central pressure–flow relations and myocardial wall stress. (A) Arterial tonometry recording. (B) Pulsed wave Doppler
flow velocity recording of the left ventricular outflow tract; this velocity envelope can be multiplied by the left ventricular outflow tract
cross-sectional area to obtain volume outflow from the left ventricle, which equals aortic inflow. (C and D) Signal-averaged pressure and
flow waveforms. (E) Pressure–flow loop showing the linear early systolic pressure–flow relation (green segment); the slope of this line
approximates the aortic characteristic impedance (Zc), which equals the ratio of pulsatile pressure/pulsatile flow in the aortic root in the
absence of wave reflections; a deviation (upward shift) from this linear relation occurs upon the arrival of the reflected wave, which increases
pressure and reduces flow (red segment in the pressure–flow loop). (F) Wave separation analysis which decomposes the pressure waveform
into its forward (Pf) because of left ventricular contraction and backward (Pb) components because of wave reflection at peripheral arterial
sites (e.g. points of branching or change in arterial wall diameter). (G) Measured pressure in systole vs. product of flow time aortic root Zc
(blue area) that denotes the pressure in aortic root during left ventricular systolic contraction if wave reflections were absent; the red area
denotes the ‘excessive’ pulsatile pressure because of the arrival of wave reflections from the peripheral arteries, which is above that required
to ‘accommodate’ observed flow through the aortic root if reflections were absent. The early arrival of wave reflections in systole occurs
when pulse wave velocity is increased because of a stiff aorta; the pink area represents the diastolic component of the central aortic pulse wave
starting after the inflection point that indicates the aortic valve closure (AVC) (arrow). (H) Time-resolved myocardial wall stress in the same
subject, obtained via a combination of arterial tonometry and speckle tracking echocardiography; myocardial wall stress at each time point
during ejection is computed to generate a time-resolved stress curve; notice the early systolic myocardial wall stress peak, with lower values
of wall stress during late systole. (I) Ejection-phase pressure–stress plot showing that the lower wall stress values in late systole are related to
a mid-systolic shift of the pressure–stress relation (green arrow) which favours lower stress values in late systole despite rising pressure. This
mechanism may protect the myocardium against wave reflections, but is impaired in the presence of a low ejection fraction or left ventricular
concentric remodelling, and may be overcome when there is excessive wave reflection magnitude. AVO, aortic valve opening.
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Table 2 Studies presenting the independent value of markers of arterial stiffness as predictors of cardiovascular
events and incident heart failure
Source Year Population Design Follow-up Parameter Endpoint

duration
(median,
years)
...........................................................................................................................................
Chirinos et al.9 2012 Primary care population Prospective observational PPA, RM CV mortality and HF incidence 7.6
Aisu et al.24 2017 Risk factors for HF Retrospective observational PWV Hospitalization for new-onset HF 4.9
Chester et al.25 2017 Primary care population Prospective observational RM Incident HF 11.2
Chirinos et al.26 2014 Chronic kidney disease Prospective observational PWV, SBP, PP Hospitalization for new-onset HF 3.5
Ohyama et al.27 2017 Primary care population Prospective observational PWV Incident HF 10
Pandey et al.28 2017 Primary care population Prospective observational PWV Incident HF 11.4
Said et al.29 2018 Primary care population Prospective observational ASI, PP All-cause, CV and non-CV mortality 2.8
Tsao et al.30 2015 Primary care population Prospective observational PWV Incident HF 10.1
Feistritzer et al.87 2017 Acute STEMI Prospective observational PWV MACCE including incident HF 1.2
ASI, arterial stiffness index; CAD, coronary artery disease; CV, cardiovascular; HF, heart failure; MACCE, major adverse cardiac and cerebrovascular events including death,
non-fatal myocardial reinfarction, new-onset congestive HF, and stroke; PP, pulse pressure; PPA, pulse pressure amplification; PWV, pulse wave velocity; RM, reflection magnitude;
SBP, systolic blood pressure; STEMI, ST-elevation myocardial infarction.
as a determinant of maladaptive LV remodelling, diastolic and systolic in the myocardium (myocardial afterload) and is related to the amount
.........................................................................................................
dysfunction, and HF risk (Table 2).7 – 9,12,13 of force and work the muscle does during a contraction.
Normal values for PWV (< 10/ms) and central systolic BP In axisymmetric ventricles, average LV myocardial fibre stress can
(< 130 mmHg) have been described23 and their predictive value easily be approximated by the formula developed by Arts et al.38 :
for incident cardiovascular mortality and HF has been demonstrated
(Table 2).24 – 31 P
Fiber 𝜎𝜎 = ( )
1 Vw
Numerous methods have been suggested to estimate total arte-
3
ln 1 + Vlv
rial compliance based on the Windkessel (elastic reservoir) model;
most require both accurate pressure and flow wave recording at the When assuming rotational symmetry and homogeneity of mechan-
aorta and are hampered by practical and technical (mainly related to ical load in the wall, the dimensionless ratio of muscle fibre stress
complexity), as well as theoretical limitations (including not account- [sigma (𝜎𝜎) fiber] to LV pressure (P) appears to depend mainly on
ing for wave reflections).20 The SV over pulse pressure method has the dimensionless ratio of cavity volume (Vlv ) to wall volume (Vw ) (ln
been reintroduced recently and it requires accurate and reproducible denotes natural logarithm) and is quite independent of other geometric
echocardiographic measurement of cardiac output; however this ratio parameters.
is shown to overestimate compliance and further standardization of This method can be applied non-invasively to calculate time-resolved
the measurement is required20 (Table 1). ejection-phase fibre stress using a central pressure waveform and
time-resolved LV geometric information (derived from echocar-
diography or cine magnetic resonance imaging)2 (Figure 4A–D). A
Markers of myocardial performance. Novel echocardiography tech-
time-resolved wall stress curve allows for characterization of the
niques have permitted the evaluation of myocardial deformation in sys-
myocardial loading sequence, which can be expressed as a ratio of
tole and diastole by use of tissue Doppler imaging, two-dimensional,
the stress-time integral in late vs. early systole. A high late-to-early
and recently three-dimensional speckle tracking32 (Table 1). Studies
systolic stress time integral ratio has been shown to be associated
have shown impaired myocardial deformation (e.g. GLS < 20%) in the
with reduced indices of myocardial systolic contraction and diastolic
presence of normal ejection fraction in patients with hypertension,
relaxation7,8 and left atrial dysfunction,31 providing a link between
diabetes, CAD, valvular heart disease and HF.31,33 Myocardial defor-
wave reflections and the reported risk of incident HF in the general
mation markers have been related with myocardial fibrosis,34 arterial
population4,9,25 (Figure 4H–I).
stiffness,31,35 natriuretic peptides,8 exercise capacity,36 symptoms of
New echocardiography software construct arterial pressure–LV
HF,36 and have a prognostic value in valvular heart disease37 and in HF
longitudinal myocardial strain curves by speckle tracking echocardio-
with reduced and preserved ejection fraction.2 Thus, these myocardial
graphy and measure the area of the pressure–strain loop, termed
deformation markers may be surrogate markers of impaired myocardial
as myocardial work index (Figure 5). The software calculates the
function.
constructive and the wasted myocardial work.39 Further studies are
required to assess the performance of this method for physiologic
Novel markers to assess ventricular–arterial coupling. Arterial load and clinical evaluations as this method neglects the work performed
should always be interpreted by considering interactions between in the circumferential direction. Shear wave generation using an ultra-
arteries and the left ventricle as a pump3,4 and also between myocar- sonic burst focused on the myocardium is a novel promising assess-
dial elements and instantaneous LV geometry and the time-varying ment method of myocardial elasticity.40 Finally, the ratio of cfPWV
load imposed by the systemic circulation. Wall stress represents the to LV GLS appears to be a novel promising marker to assess VAC in
time-varying mechanical load experienced by the contractile elements hypertensives.41
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Figure 5 Myocardial work index comprises a novel method of ventricular–arterial coupling estimation derived by pressure–left ventricular
longitudinal myocardial strain loop during one cardiac cycle by speckle tracking echocardiography. (A) Before and (B) after cardiac
resynchronization therapy (CRT). Note the larger area of the pressure–strain loop after CRT compared to baseline, indicating an improved
myocardial work during systole after CRT. The bull’s eye shows the myocardial work index in each one of the 17 left ventricular wall segments.
(Echocardiography images provided as courtesy by Dr I. Ikonomidis, Echocardiography Department, Attikon Hospital, NKUA, Athens, Greece).
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In summary, the measurement of novel myocardial and arterial In a study including 320 hypertensive patients, increased PWV
........................................................................................................................................................................
function markers may be used to describe and quantify VAC in various was found to be related with abnormal LV longitudinal strain,
disease states. reduced LV untwisting and peak untwisting velocity as assessed
by speckle tracking echocardiography.48 In this study, impaired
LV myocardial deformation and untwisting were associated with
Key points reduced exercise capacity.48 Interestingly, increased PWV was
also associated with reduced coronary flow reserve,46 which
• The measurement of novel myocardial and arterial function mark- in turn was related to abnormal myocardial deformation in
ers may describe and quantify VAC, particularly if the traditional hypertensives.48 A similar association between arterial stiffness
Ea/Ees approximates 1, despite the suspicion or presence of overt and myocardial deformation was found in chronic kidney disease
cardiovascular disease (such as in HFpEF).
patients.49 Similarly, in the context of type 1 diabetes mellitus, a
• Comprehensive assessments of VAC in future studies should
negative correlation between PWV and left atrial strain has been
include proper measurements of pulsatile load and VAC (wave
underlined.50 Furthermore, in type 2 diabetics, increased PWV
reflections, Zc, wave intensity and wave power analyses), rather
than relying entirely on P-V analyses. and central aortic pressure were associated with impaired LV
• Other novel markers, such as myocardial work index, may be longitudinal deformation and untwisting before and after 6 months
informative and compensate for some of the classic method of antidiabetic treatment.51
limitations, but further clinical evidence of the utility of this Thus, in hypertension and diabetes there is a close link between
approach is required. arterial stiffness and myocardial deformation, which appears to be
a harbinger of HFpEF, if left untreated.
Clinical implications Interventions to improve ventricular–arterial coupling

of ventricular–arterial coupling in arterial hypertension
Ventricular–arterial coupling Antihypertensive treatment improved VAC, arterial stiffness,

and LV systolic and diastolic function in 527 patients with early
in hypertension, diabetes, and systemic stage hypertension.52 In the above study, changes in the Ea/Ees
diseases ratio were inversely correlated with those in ejection fraction,
The association between myocardial and arterial function markers stroke work index, LV efficiency and changes in mitral E/e’. It has
has been used to describe and quantify VAC in hypertension,41,42 also been shown that improved Ea/Ees after 6 months of antihy-
diabetes,43 and inflammatory diseases.44,45 More specifically, com- pertensive monotherapy is related with improved LV function and
bined ventricular and arterial stiffening has been demonstrated regression of LV hypertrophy, with angiotensin-converting enzyme
in HFpEF patients and hypertensives.3 The investigators found an (ACE) inhibitors, angiotensin II receptor blockers (ARBs), and
inverse correlation between total arterial compliance and Ees, dihydropyridine calcium antagonists having the most favourable
independently of body surface area and SV. Additionally, both hyper- effect on this index.53
tensive and HFpEF patients had reduced Ea/Ees (< 0.6) compared Indeed, the various antihypertensive drug classes have differential
to healthy controls.3,42 effects on pulsatile and central haemodynamics; ACE inhibitors,
Furthermore, in untreated patients with arterial hypertension, ARBs, calcium-channel blockers, and some vasodilating 𝛽𝛽-blockers
central augmentation index (measured by arterial tonometry) and are more effective in this regard, compared to diuretics and
aortic distensibility have been related with abnormal markers of some non-vasodilating 𝛽𝛽-blockers.54 – 56 ACE inhibitors represent
LV diastolic function as assessed by Doppler echocardiography,45 the first drug class for which a clear advantage over 𝛽𝛽-blockers
while PWV has been associated with E/E’ and E’/A’ as assessed by was demonstrated in terms of effects on central BP, arterial
tissue Doppler imaging.46 stiffness and wave reflections. Also ARBs and dihydropyridines
Moreover, an interrelation between conduit arterial stiffness and were demonstrated to be able to reduce PWV and improve central
subendocardial dysfunction as assessed by tissue Doppler imag- aortic haemodynamics.55,56 Conversely, the majority of studies have
ing in patients with diabetes, hypertension, or ischaemic dilated shown that diuretics have a neutral effect on arterial stiffness and
cardiomyopathy has been found.22 Additionally, in a study cohort central haemodynamics.
of hypertensives and diabetics, it has been shown that early dias- The differential effects of calcium-channel blockers on arte-
tolic velocity (E’) by tissue Doppler imaging varies inversely with rial stiffness may be related to better prognosis as shown by
Zc, Ea, and PWV.6 Late systolic load, as assessed by augmenta- the CAFÉ-ASCOT study (Table 3).54 – 56 Evidence showing that an
tion index and arterial compliance, had the strongest association improvement in wave reflection will lead to a reduction in cardio-
with E’. Similar associations were found between vascular markers vascular events was provided by the CAFÉ study,54 where, despite
and systolic mitral annulus velocity (S’).7 In morbidly obese sub- a similar reduction in peripheral systolic BP, a calcium-channel
jects, an inverse relationship between isovolumetric relaxation time blocker regimen (amlodipine with perindopril added as required)
and aortic distensibility (both assessed by echocardiography) was was more effective in lowering central systolic BP, and reduced
observed, while weight reduction after bariatric surgery improved future cardiovascular events compared to a 𝛽𝛽-blocker regimen
BP, aortic distensibility and LV diastolic dysfunction.47 (atenolol with bendroflumethiazide-K as required). It should be
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noted that the majority of patients received a combination of cause an increase in arterial stiffness, leading to increased Ea in
........................................................................................................................................................................
amlodipine with perindopril or atenolol with diuretic (only 26% parallel to myocardial stiffening causing an increased Ees.44
on monotherapy) and thus, the difference in cardiovascular events In a trial examining 80 patients with RA, the investigators demon-
and central haemodynamics should be related only to treatment strated that reduced systemic arterial compliance was related to
combinations and not to individual drugs. Additionally, antihyper- reduced LV longitudinal strain and strain rate and abnormal LV
tensive drug classes that have more pronounced effects on arterial twisting and untwisting velocity as assessed by speckle tracking
stiffness and wave reflection, are the same that cause significant echocardiography.59 Similarly, an increased PWV was associated
regression of LV hypertrophy.55 with reduced LV longitudinal strain in psoriatic patients.60 Further-
The effects of LCZ696 [angiotensin receptor-neprilysin inhibitor more, in a patients with Adamantiades–Behcet’s disease, reduced
(ARNI): sacubitril/valsartan] on aortic stiffness were evaluated aortic distensibility was associated with prolonged deceleration
in elderly patients with systolic hypertension and pulse pressure time, an established marker of LV diastolic dysfunction.21
> 60 mmHg. At week 12, sacubitril/valsartan reduced central
aortic systolic pressure to a greater extent than olmesartan by Interventions to improve
−3.7 mmHg. After 52 weeks, more patients required add-on anti-
hypertensive therapy with olmesartan (47%) vs. sacubitril/valsartan
ventricular–arterial coupling
(32%).57 in inflammatory disease
Pulse wave velocity and augmentation pressure were significantly Anti-inflammatory treatment has been shown to alleviate
and progressively reduced by renal denervation in patients with ventricular–arterial decoupling. In a double-blind, crossover
resistant hypertension, especially in hypertensive patients with study of RA patients, injection of anakinra [a recombinant inter-
more elevated PWV at baseline.58 After renal denervation, actual leukin (IL)-1 receptor antagonist] resulted in improved systemic
PWV measures were lower than the predicted age- and mean arterial compliance and systemic vascular resistance, improved
BP-corrected values, suggesting that this intervention might exert E/E’, in parallel with improved indices of LV myocardial deforma-
BP-independent effects on arterial stiffness. Additionally, renal tion and twisting as assessed by speckle tracking. Interestingly,
denervation diminished cardiac systolic work load as evident by the improvement in vascular and myocardial deformation mark-
shorter ejection duration and reduced systolic BP load after the ers was greater in the group of patients with coexisting CAD
procedure, suggesting a substantial effect on VAC. who showed a higher inflammatory burden.60 Administration of
Similarly, in type 2 diabetics, treatment with glucagon-like tocilizumab (an IL-6 antagonist) has been shown to reduce PWV,61
peptide-1 (GLP-1) caused a greater reduction of PWV, central improve cardiac function, and reduce LV mass in RA.62 Moreover,
aortic pressure and wave reflections, and greater improvement of anti-tumour necrosis factor-𝛼𝛼 therapy resulted in reduced PWV
LV longitudinal deformation and LV twisting-untwisting than met- after a 3-month follow-up period in patients with inflammatory
formin after 6 months of treatment, likely through reduction of arthropathy.63 Additionally, the Physical Activity in RA (PARA)
oxidative stress burden as assessed by the reduction of protein trial has shown that moderate intensity physical activity resulted
carbonyls and malondialdehyde.51 Indeed, in the above study, the in increased E/A and a trend towards decreased PWV and aug-
reduction of malondialdehyde after 6 months of GLP-1 treatment mentation index,64 suggesting the reversal of ventricular–arterial
was associated with the respective reduction of PWV which, in decoupling. Finally, in psoriatic patients, novel biological agents
turn, was related with improved LV GLS. reduced arterial stiffness, central aortic pressure and wave
reflections, and improved LV longitudinal deformation and LV
twisting-untwisting within 4 months, through inflammatory and
Key points oxidative stress burden reduction.65
• Myocardial dysfunction and vascular stiffness are present in Key points

newly diagnosed hypertensives and diabetics.
• Both may contribute to reduced exercise capacity and HF
• Systemic inflammation concomitantly impairs arterial and
symptoms.
myocardial function.
• There are treatment options that may improve both myocardial
• Anti-inflammatory treatment improves arterial stiffness in
dysfunction and vascular stiffness and thus improve VAC.
parallel with myocardial stiffness contributing to reversal of
ventricular–arterial decoupling.
Ventricular–arterial coupling
in systemic inflammatory disease Ventricular–arterial coupling
Atherosclerosis, subclinical LV dysfunction, and increased risk in valvular heart disease
of cardiovascular events characterise rheumatoid arthritis (RA),
systemic lupus erythematosus, ankylosing spondylitis, psoriasis, Aortic stenosis
gout, and medium- and large-vessel vasculitides.21,59,60 With regard In patients with aortic stenosis (AS), the left ventricle is often
to VAC, systemic inflammatory processes and oxidative stress may facing a double load: a valvular load imposed by AS and an
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Table 3 Effect of different antihypertensive drug classes on aortic stiffness, wave reflection and central blood pressure
Antihypertensive drugs Aortic Wave Central Augmentation Carotid

PWV/aortic reflection systolic index stiffness
stiffness pressure
...........................................................................................................................................
Diuretics ↓/↔ ↔ ↔ ↔↓ ↓/↔
𝛽𝛽-blockers ↓
Without vasodilating effects ↓ ↓/↔ ↓ ↓ ↔
With vasodilating effects ↓ ↓ ↑ ↑ ↓/↔
𝛼𝛼-blockers ↔ ↓ NA
Calcium-channel blockers ↓
Dihydropyridines ↓/↔ ↓ ↓ ↓ ↓/↔
Non-dihydropyridines ↓ ↓ ↓
ACE inhibitors ↓ ↓ ↓↓ ↓↓ ↓
Angiotensin II receptor blockers ↓ ↓ ↓ ↓ ↓/↔
Aldosterone antagonists ↓/↔ ↓ NA
Nitrates ↔ NA ↓↓ ↓↓ NA
ACE, angiotensin-converting enzyme; NA, not available; PWV, pulse wave velocity; ↑, increased; ↓, decreased; ↓↓, marked decrease; ↔, no change.
Adapted from Nilsson et al.55 and Boutouyrie et al.56
arterial load caused by a decrease in systemic arterial compliance low-gradient AS. These patients are typically elderly, hyperten-
.........................................................................................................
(or an increase in systemic vascular resistance) in the context sive, with stiff aorta, elevated arterial afterload despite similar
of existing co-morbidities (e.g. age, smoking, hypertension, dia- end-systolic wall stress70 and high Zva. Additionally, in patients with
betes) (Figure 6). low-flow, low-gradient AS, Zva was associated with lower aortic
Briand et al.66 proposed two practical indexes, systemic arte- mean gradient.70 Moreover, higher Zva is associated with impaired
rial compliance (SAC) and valvulo–arterial impedance (Zva) to longitudinal LV systolic function71 and lower survival.72,73 Zva, like
assess the effects of aortic wall properties on LV function in Ea, has limitations because the complex pulsatile afterload cannot
AS. SAC index is the ratio of SV indexed to body surface be lumped in a single parameter. Studies utilizing proper assess-
area/pulse pressure: SAC ≅ SVi/PP. In their study, 40% of patients ments of pulsatile LV afterload in AS are needed.
with severe AS had markedly reduced arterial compliance (SAC
index < 0.6 ml/m2 /mmHg) associated with LV dysfunction.66
Valvulo–arterial impedance represents the total haemodynamic Aortic regurgitation
load opposing LV blood ejection into aorta, combining both valvu-
Wilson et al.74 found in asymptomatic chronic aortic regurgita-
lar and vascular factors, and can be a used as a surrogate marker of
tion patients that reduced aortic distensibility was related with
VAC. Zva is obtained non-invasively by calculating the LV pressure
increased LV volumes, systolic wall stress and LV mass, and led
(sum of systolic pressure and the mean pressure gradient obtained
more rapidly to aortic valve replacement (AVR). In another study,75
by continuous wave Doppler) divided by SV/m2 : Zva ≅ LV pres-
20 patients with non-stenotic biscuspid aortic valve had reduced
sure/SVi (mL/m2 /mmHg); thus, it represents the cost in mmHg for
aortic elasticity and LV hypertrophy compared to controls.
each systemic mL of blood pumped by the left ventricle during
systole. A value > 4.5 mmHg/mL/m2 indicates a severely increased
total afterload. Interestingly, Zva was superior to valve area or gra-
dients to predict outcomes.62 Finally both Zva ≥ 4.9 mmHg/mL/m2
Interventions to improve
and LV GLS ≤ 15.9% independently predicted outcome in asymp-
ventricular–arterial coupling
tomatic moderate to severe AS (aortic valve area ≤ 0.6 cm2 /m2 ) Arterial hypertension and stiffness may alter VAC and, thus,
patients.67 accelerate symptoms in AS and deteriorate prognosis in patients
Arterial hypertension and stiffness may also alter VAC and, with paradoxical low-flow, low-gradient AS. Thus, in patients
thus, accelerate symptoms in AS. In a series of 193 AS patients,68 with coexisting hypertension, increased markers of arterial stiff-
symptoms occurred earlier in the subset of hypertensive patients, ness and/or impaired markers of VAC and AS, effective treat-
despite a larger valve area. Moreover, Weisz et al.69 demonstrated ment of hypertension with medication which has been also shown
that in patients with moderate to severe AS and preserved to improve arterial wall properties may delay the occurrence
LV ejection fraction, increased carotid and aortic stiffness was or reduce the intensity of symptoms. AVR may acutely impact
independently associated with elevated LV filling pressures, B-type VAC76 and promote the recovery of mid- and long-term LV
natriuretic peptide (BNP) levels, and symptoms. contractility77 and LV GLS.78 However, surgical manipulations of
Ventricular–arterial coupling and Zva have also important the aorta may impair perfusion and induce inflammation of the
prognostic implications in patients with paradoxical low-flow, aortic wall, resulting in reduced aortic elastance and consequently
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Figure 6 In aortic stenosis, increased systemic arterial and aortic valve load act complementarily and competitively, resulting in impaired
left ventricular (LV) elastance; the compensatory mechanisms activated due to tissue hypoperfusion complicate this interaction. Ea, arterial
elastance; Ees, end-systolic elastance; SNS, sympathetic nervous system; SVR, systemic vascular resistance; TAC, total arterial compliance;
VAC, ventricular–arterial coupling.
to ventricular–arterial decoupling.77 The early post-AVR deteri- regurgitation and dilated or ischaemic cardiomyopathy (LV ejec-
.....................................................................................
oration of aortic elastance is usually followed by a progressive tion fraction < 45%),83 there was a significant association between
improvement for up to 1 year.79 In the case of transcatheter aor- PWV and functional mitral regurgitation in the ischaemic group.
tic valve replacement (TAVR), the aortic root is only minimally Furthermore, the preservation of VAC after mitral clip implan-
manipulated. The acute decrease of LV pressure overload follow- tation has been associated with an increase in forward SV, despite
ing TAVR80 results in an early reduction of valvular load as well as a reduced ejection fraction.84
improved LV energetics, as demonstrated by VAC normalization.
However, VAC is not always improved post-TAVR. The
post-procedural decrease in afterload results in an abrupt decrease Mitral stenosis
of LV pressure and contractility (i.e. Ees), with a consequent VAC A study85 of patients with severe mitral stenosis undergoing percu-
disruption.80 Moreover, the relief of valvular obstruction acutely taneous balloon valvuloplasty and healthy subjects, demonstrated
increases SV and thus in the context of a stiff, non-compliant aorta, that mitral stenosis induced an increase in arterial stiffness that was
may cause a disproportionate increase of systolic aortic BP, posing improved after percutaneous balloon valvuloplasty.
an excessive afterload to the left ventricle. Therefore, arterial load
(i.e. Ea) is increased, negatively affecting LV efficiency81 and blunting
the haemodynamic benefits of TAVR. Thus, the pre-procedural Key points
state of aortic elasticity, myocardial function and VAC may affect
the response to TAVR. • VAC assessment possesses diagnostic and prognostic value in
valvular heart disease, over and above stenosis, regurgitation,
or ejection fraction quantification.
Mitral regurgitation • Systemic arterial compliance and Zva can specifically describe
In chronic severe organic mitral regurgitation, there is a progres- the haemodynamic consequences of AS.
sive deterioration of LV contractile state (i.e. Ees reduction), which • Zva and LV GLS offer prognostic information in AS even when
leads to VAC impairment that is prevented neither by stable Ea, nor asymptomatic.
by vasodilator therapy.82 Thus, in chronic mitral regurgitation, the • Impaired VAC may be the cause of symptoms in AS, despite a
progressive deterioration of VAC and pump efficiency suggests the large aortic orifice.
potential progression to clinically overt cardiac dysfunction requir- • The pre-procedural state of VAC in the context of increased
ing mitral valve surgery.82 In 175 patients with functional mitral aortic stiffness may compromise the beneficial effects of AVR.
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• Deteriorating VAC may suggest cardiac dysfunction in organic Ees) decreases, systemic tissue hypoperfusion occurs. The
........................................................................................................................................................................
mitral regurgitation. renin–angiotensin–aldosterone system and the sympathetic
• Mitral clip implantation in functional mitral regurgitation may nervous system are consequently over-activated, in an attempt
preserve VAC. to increase intravascular volume and arterial load, and counterbal-
ance the impaired systemic perfusion; thus, Ea is increased. The
increased Ea along with the direct cardiotoxicity of sympathetic
Ventricular–arterial coupling over-activation and the increased myocardial oxygen demands
in coronary artery disease of hyper-dynamic circulation create a vicious circle predisposing
to further worsening of cardiovascular function and syndrome
Coronary artery disease shares common pathophysiological pro-
progression (Figure 7).
cesses with aortic stiffening.59,86 The severity of CAD has been
Indeed, in a cohort of 466 patients with HFrEF, VAC (Ea/Ees)
associated with impaired markers of arterial stiffness.86 The pres-
was strongly associated with New York Heart Association (NYHA)
ence of significant CAD may negatively affect LV systolic func-
functional class, increase in natriuretic peptides, and adverse clinical
tion particularly in the longitudinal axis. Additionally, an increase
outcomes.90
of the arterial load due to increased aortic stiffness may also
A reduced GLS91 and/or a small GLS increase after stress
affect LV performance.29 Increased PWV was related with reduced
echocardiography (< 19%)92 have been demonstrated to be inde-
coronary flow reserve in CAD patients even after success-
pendent prognosticators of mortality in HFrEF. Furthermore,
ful revascularization5 and with elevated N-terminal pro BNP
markers of arterial stiffness (pulse pressure, PWV, central systolic
(NT-proBNP) post-myocardial infarction (Table 2).87 Myocardial
BP) have been found to be independent predictors of outcome in
strain imaging (LV GLS < 20%)7,27 has shown to detect subclinical
HFrEF.93
dysfunction in CAD patients and represents a more sensitive
method of identifying LV performance.21 Increased aortic stiffness
impairs LV function, mainly in the longitudinal axis, through inappro- Interventions to improve ventricular–arterial coupling
priate VAC with mechanisms discussed in detail above (Figure 2). in heart failure with reduced ejection fraction
Thus, non-invasive measurement of VAC can provide comprehen- Ventricular–arterial coupling may also be useful to assess response
sive assessment of LV performance and may also be incremental
to various therapeutic approaches in chronic HF. Table 4 summa-
to LV ejection fraction in the characterization and clinical manage-
rizes various therapeutic strategies having beneficial effects on VAC
ment of CAD patients. In 891 patients with suspected or known
in HFrEF.53,57,59,65,94 – 107
CAD who had negative stress echocardiography (mean LV ejec-
In a prospective clinical trial, 38 patients with HFrEF underwent
tion fraction 47%), it was shown that patients with impaired VAC
aggressive titration of vasoactive HF medications (ACE inhibitors,
reserve (measured as the change in Ea/Ees between peak stress
carvedilol, nitrates, MRAs) with assessment of central aortic
and rest) had increased rates of all-cause mortality, compared with
waveforms.94 Clinical response to treatment was assessed using the
patients with more preserved VAC reserve.88 Additionally, among
6-min walk test, which increased in 25 patients and decreased or
41 patients with ischaemic cardiomyopathy (LV ejection fraction
remained unchanged in 13. Patients with clinical improvement after
47 ± 13%), those with an Ea/Ees ratio < 1.47 had better survival
therapy displayed higher baseline aortic pressure wave pulsatility
than patients with higher (more impaired) Ea/Ees ratios (≥ 1.47).89
(central pulse pressure, reflected pressure wave, and reservoir
Furthermore, increased arterial wave reflections predict severe
pressure) than patients without improvement. After treatment,
cardiovascular events in patients undergoing percutaneous coro-
aortic pressure pulsatility decreased only in patients with functional
nary interventions, and various markers of arterial stiffness have
improvement. These differences in arterial load at baseline and on
been associated with adverse outcome in CAD.86
therapy were not apparent from conventional brachial artery cuff
pressure assessments. Thus, central aortic waveform analysis may
Key points allow an individualized treatment regimen for patients with HFrEF.
In a study including 877 elderly patients with HF (age ≥ 65
years, NYHA class ≥ II, LV ejection fraction ≤ 45 %), treated with
• There is evidence suggesting the use of LV GLS, VAC assess-
𝛽𝛽-blockers, underwent Doppler echocardiography before and after
ment, or aortic stiffness markers to refine risk stratification of
12 weeks of treatment.95 VAC, as assessed by Ea/Ees, improved
CAD patients.
after treatment. Ea decreased from 2.73 ± 1.16 to 2.40 ± 1.01,
resulting in a near-optimization of VAC ratio [from 1.70 ± 1.05
Ventricular–arterial coupling (1.46) to 1.50 ± 0.94 (1.29)]. A similar VAC response was evident
in patients with ischaemic and non-ischaemic HF and was related
in heart failure with lower degree of HF functional class (NYHA) after 𝛽𝛽-blocker
administration. The strongest predictor of VAC alteration was
Heart failure with reduced ejection
the LV ejection fraction increase. Thus, the beneficial effect of
fraction 𝛽𝛽-blockers in elderly HF patients may have been achieved, at least
In the context of HF with reduced ejection fraction (HFrEF), partly, by VAC optimization, associated with cardiac contractility
as cardiac function primarily declines and LV elastance (e.g. improvement.
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Figure 7 In the heart failure with reduced ejection fraction model of ventricular–arterial decoupling, a primary reduction of left ventricular
elastance results in a compensatory increase of systemic arterial elastance (Ea); their interaction creates a vicious circle. CO, cardiac output;
DCM, dilated cardiomyopathy; HR, heart rate; MI, myocardial infarction; RAAS, renin–angiotensin–aldosterone system; SNS, sympathetic
nervous system; SVR, systemic vascular resistance, SV, stroke volume; TAC, total arterial compliance; VAC, ventricular–arterial coupling.
Eplerenone improves endothelial function and vascular compli- in arterial compliance, peripheral resistance, wave reflections,
.....................................................................................
ance in HFrEF patients, while having beneficial effects on their skeletal muscle oxidative function, and arterial–venous oxygen
exercise capacity, quality of life, and prognosis. Moreover, this agent difference.101
exerts anti-fibrotic action, alleviating cardiac remodelling and LV
stiffness.96
Ivabradine (If inhibition) lowers heart rate and improves cardiac Heart failure with preserved ejection
function and prognosis in HFrEF.108 Ivabradine altered haemody- fraction
namics in the murine aorta by increasing the magnitude of shear Heart failure with preserved ejection fraction is a common
stress.97 This change was accompanied by endothelial nitric oxide condition in the elderly and is associated with a high bur-
synthase induction and vascular cell adhesion molecule-1 suppres- den of co-existing co-morbidities (especially arterial hypertension
sion. Thus, ivabradine creates local mechanical conditions that trig- and diabetes).44 Arterial stiffening contributes to the pathophysi-
ger protective anti-inflammatory responses in the arterial wall.97 ology of HFpEF via arterial–ventricular mismatching, particularly
Moreover, IL-1 inhibition by anakinra has been shown to improve with exertion, afterload-induced diastolic dysfunction, and suben-
exercise capacity in HFrEF patients after 12 weeks of treatment98 docardial ischaemia.9,20,22 Additionally, in acute hypertensive HF,
as well as to improve arterial load, coronary flow reserve and LV abnormal VAC can lead to acute pulmonary congestion. In HFpEF,
myocardial deformation in CAD patients with coexisting RA.61 impairment of VAC is related to inflammatory and mechanical over-
Steendijk et al.99 described the VAC and mechanical efficiency load caused by arterial hypertension and other co-morbidities;
improvement that is induced by cardiac resynchronization ther- thus abnormal VAC may be considered a primary mechanism for
apy in relation with the observed improvements in clinical and the clinical deterioration of HF (Figure 8). As LV and arterial elas-
functional status. Another study100 highlighted value of myocar- tances increase in parallel, the classic Ea/Ees ratio is insensitive to
dial strain–BP loops (reflecting the VAC status) to calculate abnormal VAC states in HFpEF. Thus, either each component of
myocardial work index non-invasively and thus to predict the the ratio should be examined separately or novel markers of VAC
long-term clinical response to cardiac resynchronization therapy assessment, as described above, should be utilized. Weber4 demon-
(Figure 5). strated that HFpEF is characterized by increased arterial stiffness
Lastly, cardiopulmonary rehabilitation on top of optimal treat- and wave reflections, which increase the late systolic pulsatile load
ment is associated with VAC and LV mechanical efficiency opti- of the left ventricle. Among the novel markers proposed to assess
mization in HFrEF patients with systolic HF. This beneficial effect the ventricular–arterial interaction, an increased PWV, a marker
is potentially multi-factorial, including significant improvements of arterial stiffness, is a major determinant of abnormal LV GLS, a
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Table 4 Main effects of medical therapy on ventricular–arterial coupling in chronic and acute heart failure patients
Therapeutic approach Main effect

...........................................................................................................................................
HFrEF
Vasodilators94 Reduction of central pressures and afterload
𝛽𝛽-blockers95 Improvement of ventricular–arterial interaction
MRAs96 Reduction of cardiac fibrosis and improvement of endothelial/vascular function
Ivabradine97 Vascular stiffness alleviation
Anakinra (IL-1 receptor antagonist)98 Reduction of inflammation and oxidative stress and improvement of exercise capacity,
arterial load and LV myocardial deformation
CRT99,100 Improvement of VAC and cardiac remodelling
Exercise training101 Improvement of arterial compliance and LV mechanical efficiency
HFpEF
Sodium restriction102 Improvement of arterial elastance and VAC
Anti-hypertensive therapy (RAAS inhibitors)53,103 Improvement of cardiac and vascular stiffness
Ivabradine97 Improvement of vascular stiffness, anti-fibrotic properties
Anakinra (IL-1 receptor antagonist)59 Reduction of inflammation and oxidative stress and improvement of vascular function,
Ustekinumab (IL-12 receptor antagonist)65 coronary flow reserve and LV myocardial deformation
ARNI (sacubitril/valsartan)57 Reduction of central pressures and afterload
Acute heart failure
IV vasodilators (IV nitrates)103 Reduction of preload and afterload/improvement of filling pressures
Serelaxin104 – 106 Reduction of afterload, organ protection, improvement of vascular function
Levosimendan107 Vasodilatation with positive lusitropic properties, improvement of right
ventricular–pulmonary arterial coupling
ARNI, angiotensin receptor-neprilysin inhibitor; CRT, cardiac resynchronization therapy; HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with
reduced ejection fraction; IL, interleukin; IV, intravenous; LV, left ventricular; MRA, mineralocorticoid receptor antagonist; RAAS, renin–angiotensin–aldosterone system;
VAC, ventricular–arterial coupling.
sensitive marker of LV dysfunction, and is associated with reduced nitrite, orally administered inorganic nitrate has a longer half-life
...................................................................................
aerobic exercise capacity in hypertensive heart disease48 while a (∼5–8 h) and does not seem to commonly induce hypotension
reduced LV GLS (< 16%), has been shown to predict mortality fol- with single or continued administration.113,114
lowing hospitalization for HFpEF.102 In a diabetic HFpEF mouse model, ivabradine administra-
tion improved vascular stiffness, LV contractility, and diastolic
Interventions to improve ventricular–arterial coupling function.115 Additionally, short-term treatment with ivabradine
in heart failure with preserved ejection fraction increased exercise capacity, due to improved LV filling pressure
response to exercise116 in humans, though others had failed to
Table 4 also describes therapeutic interventions that may restore
demonstrate meaningful improvement in VO2 .117
VAC in HFpEF. Furthermore, in hypertensives with HFpEF, a
sodium-restricted diet was associated with favourable changes in Recently, the novel combination ARNI (sacubitril/valsartan)
LV diastolic function, Ea, and VAC.109 led to a significant improvement of central aortic and brachial
Nitric oxide is an important regulator of muscular artery tone pressures in elderly patients with systolic hypertension,57 while
and the magnitude of wave reflection. Orally administered inor- effectively reduced NT-proBNP and circulating pro-fibrotic mark-
ganic nitrates (which are direct precursors of nitric oxide via the ers in HFpEF patients in the PARAMOUNT trial, suggesting bene-
nitrate–nitrite–nitric oxide pathway) have been shown to reduce ficial effects of the drug on VAC.118 PARAGON-HF is an ongoing
wave reflections and increase exercise capacity in HFpEF.110 How- trial that investigates the effect of ARNI on major cardiovascular
ever, the recent INDIE-HFpEF111 trial failed to demonstrate any outcomes in HFpEF.
improvement in peak oxygen uptake (VO2 ) with use of inhaled In acute hypertensive HF, intravenous nitrates103 or the new
sodium nitrite with short half-life (∼35–40 min) and pronounced agent serelaxin effectively reduced afterload, as well as pul-
drug fluctuations, which are an important barrier to its efficacy. The monary congestion by way of vascular stiffness alleviation and VAC
negative results of this and previous studies112 highlight the need optimization119 (Table 1). Although serelaxin improved 180-day
for more studies that use other outcome measures (besides VO2 ) mortality in phase II RELAX-AHF,104,105 this benefit on adverse out-
to evaluate the efficacy of nitric oxide donor agents in patients with come was not confirmed in the following phase III RELAX-AHF-2
HFpEF (e.g. cardiac function markers, biomarkers, and/or hospi- study in a larger patient cohort.106 Thus, the neutral results of
talizations for HF). However, these results may also indicate that trials such as NEAT-HFpEF (mean age 69 years, 57% women,
the use of inhaled sodium nitrite with its short half-life in not an objective evidence of HF, LV ejection fraction > 50% and reduced
effective treatment in this clinical setting. In contrast to inorganic self-reported activity levels), INDIE-HFpEF [mean age 68 years,
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Figure 8 In the heart failure with preserved ejection fraction model of ventricular–arterial decoupling, cardiovascular co-morbidities and risk
factors induce pro-inflammatory and pro-fibrotic cascades that concomitantly impair left ventricular and systemic arterial elastance; further
damage results from their interaction. CH, concentric hypertrophy; CRP, C-reactive protein; DM, diabetes mellitus; HTN, hypertension; IL-6,
interleukin-6; LV CR, left ventricular contractile reserve; NO, nitric oxide; PKG, protein kinase-G; SVR, systemic vascular resistance; TAC,
total arterial compliance; TGF-𝛽𝛽, transforming growth factor-𝛽𝛽; TNF-a, tumour necrosis factor alpha; VCAM, vascular cell adhesion molecule.
68% women, objective evidence of HF, LV ejection fraction Ventricular–arterial coupling

> 50% and reduced exercise capacity (peak VO2 ≤ 75%)], and
............................................................................................
RELAX-AHF-2 (mean age 73 years, 40% women, hospitalized for in pulmonary hypertension
acute decompensated HF, mean LV ejection fraction of 40%) The right ventricle undergoes adaptive changes in response
on cardiovascular risk reduction106,111,112 have raised questions to increased pulmonary artery pressures. Initially, the compen-
regarding the utility of targeting afterload reduction, the timing of satory increased contractility and hypertrophy suffice to match
intervention,104 and the drug of choice to improve vascular function the respective right ventricular afterload. Eventually, however,
and, thus, outcomes in HFpEF or acute decompensated HF. ventricular–arterial decoupling ensues with an increased Ea/Ees
In patients with right-sided HF due to LV dysfunction or primary ratio.122 Right ventricular–pulmonary arterial coupling may inde-
pulmonary hypertension, the inodilator levosimendan increases pendently predict transplantation-free survival of patients with
cardiac output by restoring right ventricular–pulmonary arterial pulmonary hypertension.123 Although data regarding humans are
coupling and decreasing pulmonary vascular resistance.107 Finally, limited, a number of pulmonary hypertension pharmacotherapies
treatment with IL-1 or IL-12 inhibitors has shown beneficial effects (e.g. drugs inducing pulmonary vasodilatation) have demonstrated
on arterial load, myocardial deformation and NT-proBNP, suggest- beneficial effects on right ventricular–arterial coupling in animal
ing an improvement of VAC in inflammatory disease.59,65 models.124
Although endurance exercise training improves exercise capac-
ity in older patients with HFpEF, it does not appear to have a
significant effect on markers of endothelial function and arterial Key points
stiffness.120,121
• Abnormal VAC is involved in the pathophysiology of right HF

Key points in pulmonary hypertension. Studies should further examine
whether improvement of VAC by treatment will also improve
symptoms and prognosis in pulmonary hypertension.
• Abnormal VAC is implicated in the pathophysiology of left and
right HF clinical deterioration.
• Different patterns of abnormal VAC are recognized in HFrEF
vs. HFpEF.
Conclusion
• Restoration of VAC may be a new therapeutic target in HF and Fibrosis, inflammation and oxidative stress are common bio-
pulmonary hypertension. chemical pathways linking impaired ventricular–arterial function.
• More mechanistic and VAC-guided therapy clinical trials are Increased arterial stiffness/wave reflections are associated with var-
needed in this field. ious maladaptive structural and functional LV changes, contributing
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doi:10.1002/ejhf.1461
Heart failure in cardiomyopathies: a position

paper from the Heart Failure Association
of the European Society of Cardiology
Petar M. Seferović1,2*, Marija Polovina1,3, Johann Bauersachs4, Michael Arad5,
Tuvia Ben Gal6, Lars H. Lund7, Stephan B. Felix8, Eloisa Arbustini9,
Alida L.P. Caforio10, Dimitrios Farmakis11, Gerasimos S. Filippatos11,
Elias Gialafos12, Vladimir Kanjuh2, Gordana Krljanac1,3, Giuseppe Limongelli13,
Aleš Linhart14, Alexander R. Lyon15, Ružica Maksimović1,16, Davor Miličić17,
Ivan Milinković3, Michel Noutsias18, Ali Oto19, Öztekin Oto20, Siniša U. Pavlović1,21,
Massimo F. Piepoli22, Arsen D. Ristić1,3, Giuseppe M.C. Rosano23,
Hubert Seggewiss24, Milika Ašanin1,3, Jelena P. Seferović25,26, Frank Ruschitzka27,
Jelena Čelutkiene28,29, Tiny Jaarsma30, Christian Mueller31, Brenda Moura32,
Loreena Hill33, Maurizio Volterrani34, Yuri Lopatin35, Marco Metra36,
Johannes Backs37,38, Wilfried Mullens39,40, Ovidiu Chioncel41,42, Rudolf A. de Boer43,
Stefan Anker44,45,46, Claudio Rapezzi47, Andrew J.S. Coats48,49,
and Carsten Tschöpe50
1 University of Belgrade Faculty of Medicine, Belgrade, Serbia; 2 Serbian Academy of Sciences and Arts, Belgrade, Serbia; 3 Department of Cardiology, Clinical Center of Serbia,
Belgrade, Serbia; 4 Department of Cardiology and Angiology, Medical School Hannover, Hannover, Germany; 5 Cardiomyopathy Clinic and Heart Failure Institute, Leviev Heart
Center, Sheba Medical Center and Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel; 6 Department of Cardiology, Rabin Medical Center, Sackler Faculty of Medicine,
Tel Aviv University, Tel Aviv, Israel; 7 Department of Medicine, Karolinska Institutet, and Heart and Vascular Theme, Karolinska University Hospital, Stockholm, Sweden;
8 Department of Internal Medicine B, University Medicine Greifswald, Greifswald, Germany; 9 Centre for Inherited Cardiovascular Diseases, IRCCS Foundation, University
Hospital Policlinico San Matteo, Pavia, Italy; 10 Division of Cardiology, Department of Cardiological, Thoracic and Vascular Sciences, University of Padua, Padua, Italy;
11 University of Cyprus Medical School, Nicosia, Cyprus; Heart Failure Unit, Department of Cardiology, Athens University Hospital Attikon, National and Kapodistrian University
of Athens, Athens, Greece; 12 Second Department of Cardiology, Heart Failure and Preventive Cardiology Section, Henry Dunant Hospital, Athens, Greece; 13 Department of
Cardiothoracic Sciences, Università della Campania ‘Luigi VanvitellI’, Monaldi Hospital, AORN Colli, Centro di Ricerca Cardiovascolare, Ospedale Monaldi, AORN Colli, Naples,
Italy, and UCL Institute of Cardiovascular Science, London, UK; 14 Second Department of Medicine, Department of Cardiovascular Medicine, General University Hospital, Charles
University in Prague, Prague, Czech Republic; 15 National Heart and Lung Institute, Imperial College London and Royal Brompton Hospital, London, UK; 16 Centre for Radiology
and Magnetic Resonance Imaging, Clinical Centre of Serbia, Belgrade, Serbia; 17 Department of Cardiovascular Diseases, University Hospital Center Zagreb, University of Zagreb,
Zagreb, Croatia; 18 Mid-German Heart Center, Department of Internal Medicine III, Division of Cardiology, Angiology and Intensive Medical Care, University Hospital Halle,
Martin-Luther-University Halle, Halle, Germany; 19 Department of Cardiology, Hacettepe University Faculty of Medicine, Ankara, Turkey; 20 Department of Cardiovascular
Surgery, Dokuz Eylül University Faculty of Medicine, İzmir, Turkey; 21 Pacemaker Center, Clinical Center of Serbia, Belgrade, Serbia; 22 Heart Failure Unit, Cardiology, G. da
Saliceto Hospital, Piacenza, Italy; 23 Department of Medical Sciences, IRCCS San Raffaele, Rome, Italy, and Cardiology Clinical Academic Group, St George’s Hospitals NHS Trust
University of London, London, UK; 24 Medizinische Klinik, Kardiologie & Internistische Intensivmedizin, Klinikum Würzburg-Mitte, Würzburg, Germany; 25 Cardiovascular Division,
Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA; 26 Clinic for Endocrinology, Diabetes and Metabolic Disorders, Clinical Center Serbia and Faculty of
Medicine, University of Belgrade, Belgrade, Serbia; 27 Department of Cardiology, University Heart Center, Zürich, Switzerland; 28 Clinic of Cardiac and Vascular Diseases, Institute
of Clinical Medicine, Faculty of Medicine, Vilnius University, Vilnius, Lithuania; 29 State Research Institute Centre for Innovative Medicine, Vilnius, Lithuania; 30 Department of Social
and Welfare Studies, Faculty of Health Science, Linköping University, Linköping, Sweden; 31 Cardiovascular Research Institute Basel (CRIB) and Department of Cardiology,
University Hospital Basel, University of Basel, Basel, Switzerland; 32 Cardiology Department, Centro Hospitalar São João, Porto, Portugal; 33 School of Nursing and Midwifery,
Queen’s University Belfast, Belfast, UK; 34 Department of Cardiology, IRCCS San Raffaele Pisana, Rome, Italy; 35 Volgograd State Medical University, Regional Cardiology Centre
Volgograd, Volgograd, Russia; 36 Cardiology, Department of Medical and Surgical Specialties, Radiological Sciences, and Public Health, University of Brescia, Brescia, Italy;
37 Department of Molecular Cardiology and Epigenetics, University of Heidelberg, Heidelberg, Germany; 38 DZHK (German Centre for Cardiovascular Research) partner site
Heidelberg/Mannheim, Heidelberg, Germany; 39 BIOMED - Biomedical Research Institute, Faculty of Medicine and Life Sciences, Hasselt University, Diepenbeek, Belgium;
40 Department of Cardiology, Ziekenhuis Oost-Limburg, Genk, Belgium; 41 University of Medicine Carol Davila, Bucharest, Romania; 42 Emergency Institute for Cardiovascular
Diseases, ‘Prof. C. C. Iliescu’, Bucharest, Romania; 43 Department of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands;
*Corresponding author. University of Belgrade, Faculty of Medicine and Heart Failure Center, Belgrade University Medical Center, Heart Failure Society of Serbia, 8 Koste
Todorovića, 11000 Belgrade, Serbia. Tel/Fax: +381 11 361 47 38, Email: seferovic.petar@gmail.com
© 2019 The Authors

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554 P.M. Seferović et al.
44 Divisionof Cardiology and Metabolism, Department of Cardiology (CVK), Charité, Berlin, Germany; 45 Berlin-Brandenburg Center for Regenerative Therapies (BCRT), Berlin,
Germany; 46 DZHK (German Centre for Cardiovascular Research) partner site Berlin, Charité, Berlin, Germany; 47 Cardiology, Department of Experimental, Diagnostic and
Specialty Medicine, Alma Mater Studiorum University of Bologna, Bologna, Italy; 48 Monash University, Australia, and University of Warwick, Coventry, UK; 49 Pharmacology,
Centre of Clinical and Experimental Medicine, IRCCS San Raffaele Pisana, Rome, Italy, and St George’s University of London, London, UK; and 50 Berlin-Brandenburg Center for
Regenerative Therapies, Deutsches Zentrum für Herz-Kreislauf-Forschung (DZHK) Berlin, Department of Cardiology, Campus Virchow Klinikum, Charite - Universitaetsmedizin
Berlin, Berlin, Germany
Received 15 January 2019; revised 20 February 2019; accepted 28 February 2019 ; online publish-ahead-of-print 16 April 2019
Cardiomyopathies are a heterogeneous group of heart muscle diseases and an important cause of heart failure (HF). Current knowledge
on incidence, pathophysiology and natural history of HF in cardiomyopathies is limited, and distinct features of their therapeutic responses
have not been systematically addressed. Therefore, this position paper focuses on epidemiology, pathophysiology, natural history and latest
developments in treatment of HF in patients with dilated (DCM), hypertrophic (HCM) and restrictive (RCM) cardiomyopathies. In DCM,
HF with reduced ejection fraction (HFrEF) has high incidence and prevalence and represents the most frequent cause of death, despite
improvements in treatment. In addition, advanced HF in DCM is one of the leading indications for heart transplantation. In HCM, HF with
preserved ejection (HFpEF) affects most patients with obstructive, and ∼10% of patients with non-obstructive HCM. A timely treatment is
important, since development of advanced HF, although rare in HCM, portends a poor prognosis. In RCM, HFpEF is common, while HFrEF
occurs later and more frequently in amyloidosis or iron overload/haemochromatosis. Irrespective of RCM aetiology, HF is a harbinger of
a poor outcome. Recent advances in our understanding of the mechanisms underlying the development of HF in cardiomyopathies have
significant implications for therapeutic decision-making. In addition, new aetiology-specific treatment options (e.g. enzyme replacement
therapy, transthyretin stabilizers, immunoadsorption, immunotherapy, etc.) have shown a potential to improve outcomes. Still, causative
therapies of many cardiomyopathies are lacking, highlighting the need for the development of effective strategies to prevent and treat HF in
cardiomyopathies.
..........................................................................................................
Keywords Heart failure • Dilated cardiomyopathy • Hypertrophic cardiomyopathy •
Restrictive cardiomyopathy • Peripartum cardiomyopathy • Epidemiology • Natural history •
Pathophysiology • Management
Introduction Since HF is often the presenting clinical syndrome in DCM, HCM

...............................................................................
and RCM, a practical stepwise approach has been suggested in

Cardiomyopathies are a heterogeneous group of heart mus- Figure 1. This approach should aid in clinical assessment of the
cle diseases, including dilated (DCM), hypertrophic (HCM), phenotype [including HFrEF; HF with mid-range ejection fraction
restrictive (RCM), arrhythmogenic right ventricular (ARVC), (40–49%); HF with preserved ejection fraction (≥ 50%, HFpEF)],
and non-classified cardiomyopathies that frequently present as the and aetiology of HF in cardiomyopathies.
syndrome of heart failure (HF).1 The variety of causes, multiple
underlying pathophysiological mechanisms and different pheno-
typic expressions influence their presentation and response to Heart failure in dilated
treatment.1 Although patients with cardiomyopathies have been cardiomyopathy
represented in clinical trials, distinct features of their therapeutic
responses, relative to other aetiologies of HF, remain unknown. Incidence and prevalence of heart failure
For HF with reduced ejection fraction (< 40%, HFrEF), standard in dilated cardiomyopathy
therapy is indicated regardless of the underlying cause. In contrast, Dilated cardiomyopathy is characterized by ventricular dilatation
for selected cardiomyopathies, specific treatment options have and systolic dysfunction in the absence of known abnormal loading
been introduced, targeting specific underlying pathophysiology conditions or significant coronary artery disease.1 It is considered
(e.g. enzyme replacement therapy, transthyretin stabilizers, gene one of the leading causes of HFrEF worldwide.2 The reported
silencing, monoclonal antibodies, immunotherapy, and others), thus prevalence of DCM in Europe and North America is ∼36 cases
increasing the perspectives for improved outcomes. Therefore, this per 100 000 population, and the annual incidence ranges between
position paper is focused on the incidence, pathophysiology, natural 5 and 7.9 cases per 100 000 population.3,4 The prevalence of DCM
history, outcomes and treatment of HF due to specific heart muscle is apparently lower in Eastern Asia (i.e. 14 cases per 100 000
diseases, including DCM, HCM and RCM. Clinical presentation in Japan),5 and it might be higher in Africa and Latin America
of ARVC is usually dominated by ventricular arrhythmia, while compared with Europe.6,7
HF (right heart or biventricular) may occur in the minority of Determining the incidence of HF in DCM is challenging, because
patients with advanced disease. Considering its specific clinical of variations in patient selection and underreporting of a specific
characteristic, ARVC has not been addressed in this document. HF aetiology in many clinical trials and observational studies.
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Heart failure in cardiomyopathies 555
Figure 1 Proposed clinical approach to the assessment of heart failure aetiology in cardiomyopathies. ACE, angiotensin-converting enzyme;
BNP, B-type natriuretic peptide; BP, blood pressure; CA, coronary angiography; CBC, complete blood count; CDI, colour Doppler imaging;
CK, creatine kinase, CMR, cardiac magnetic resonance; CRP, C-reactive protein; CT-CA, computed tomography coronary angiography; CWD,
continuous wave Doppler; DCM, dilated cardiomyopathy; ECG, electrocardiogram; ECV, extracellular volume; EMB, endomyocardial biopsy;
FDG, fluorodeoxyglucose; HCM, hypertrophic cardiomyopathy; HES, hypereosinophilic syndrome; HF, heart failure; HMDP, hydroxymethylene
diphosphonate; hsTnT, high sensitivity troponin T; IGF-1, insulin-like growth factor-1; LVEF, left ventricular ejection fraction; 99mTc-DPD,
technetium-99m 3,3-diphosphono-1,2-propanodicarboxylic acid; NT-proBNP, N-terminal pro B-type natriuretic peptide; PCR, polymerase
chain reaction; PET, positron emission tomography; PYP, pyrophosphate; PWD, pulsed wave Doppler; RCM, restrictive cardiomyopathy; SPECT,
single photon emission computed tomography; TDI, tissue Doppler imaging; TEE, transoesophageal echocardiography; TTE, transthoracic
echocardiography.
A recent study suggested that among patients with recent-onset 12–35% of individuals.12 – 14 In observational studies of HF patients,
.............................................................
(< 6 months) DCM, 32% presented with HF and 66% had at the prevalence of DCM ranged between 8% and 47%.11,15,16 In a
least one HF hospitalization before enrolment.8 Similarly, in a cohort of 156 013 patients hospitalized for HF in the USA, DCM
contemporary cohort of 881 patients with DCM, HF was the most was the stated underlying cause in 31%.17 These estimates are
common clinical presentation with a higher incidence in female often approximate because the precise diagnosis of DCM may be
compared to male patients (i.e. 64% vs. 54%).9 Compared with lacking in many patients who have not undergone a full diagnostic
men, women presented with more advanced HF as indicated by evaluation.
a higher proportion of the New York Heart Association (NYHA) Advanced HF in DCM accounts for > 40% of patients who
functional class III–IV symptoms (25% vs. 16%) and had a higher receive long-term mechanical circulatory support (MCS), either as
frequency of left bundle branch block (LBBB) at diagnosis (43% vs. a bridge to heart transplantation or for destination therapy.18,19
23%).9 In another study, self-declared black race was associated DCM is the most common indication for heart transplantation both
with a younger age and more severe HF symptoms at diagnosis in the adult and paediatric populations of advanced HF patients
compared with white race.10 Furthermore, in a cohort of 3078 and is the third most common indication for heart and lung
patients hospitalized for HF in Denmark and Sweden, individuals transplantation in adults.20 – 22 The proportion of patients being
with DCM were ∼10 years younger (median age, 64 years), and transplanted for DCM compared with other HF aetiologies has
had more severe symptoms and a lower left ventricular ejection increased in recent years. Currently, in younger (18–39 years) and
fraction (LVEF) (median LVEF, 24%) compared with other HF middle-aged adults (40–59 years), 64% and 51%, respectively, of
patients.11 all heart transplantations are attributable to DCM.22 After the
There is a broad variation in the reported prevalence of DCM age of 60 years, DCM is the second most common indication for
in patients with HF. In trials of HFrEF, DCM has been reported in heart transplantation preceded only by ischaemic heart disease,
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Figure 2 Aetiologies of dilated cardiomyopathy. HF, heart failure; HFrEF, heart failure with reduced ejection fraction; HIV, human
immunodeficiency virus.
and accounts for 39% of all heart transplantations. Following and phospholamban gene mutations,28,29 which confer high risk
..........................................................................................
transplantation, patients with DCM generally have a favourable of arrhythmia and sudden cardiac death (SCD) that may lower
short-term and long-term prognosis, with a median survival of the threshold for an implantable cardioverter-defibrillator (ICD)
12.2 years.22 implantation.30 Duchenne muscular dystrophy is an X-linked disor-
der caused by the absence of a sarcolemmal protein, dystrophin,
in the skeletal muscle and the heart, which compromises the link
Pathophysiology of heart failure between the cytoskeleton and the extracellular matrix leading to
in dilated cardiomyopathy progressive muscle wasting, degeneration of cardiomyocytes and
The pathophysiology of HF in DCM includes genetic causes, replacement fibrosis.31 Myocardial fibrosis is associated with dete-
as well as direct myocardial damage caused by infectious rioration in left ventricular (LV) systolic function and a propensity
or toxic agents, endocrine and metabolic abnormalities, for adverse outcomes.32 HF is one of the major causes of death
immune-mediated processes and peripartum cardiomyopathy in patients with Duchenne muscular dystrophy; treatment with
(PPCM)1 (Figure 2). The key morphological alterations under- perindopril and eplerenone has shown a capacity to slow cardiomy-
lying the pathophysiology of HF in DCM are summarized in opathy progression.33,34
Figure 3. Viral infection followed by an (auto)immune activation in the
A family history can be detected in 30–50% of cases23 and myocardium may play a major role in the development of HF in
a genetic determinant in up to 40% of DCM patients.1,24 How- DCM.35 Based on small animal studies, a three-phase model of
ever, this proportion is probably underestimated due to vari- inflammatory heart muscle disease has been proposed. Initially,
ability in disease penetrance and clinical presentation. To date, direct cytotoxic effects can occur within a few days after viral
more than 60 genes coding for sarcomere proteins, cytoskele- infection (e.g. enterovirus), leading to myocyte necrosis and acti-
ton, nuclear envelope, sarcolemma, ion channels and/or intercel- vation of host innate (i.e. natural killer cells and macrophages)
lular junction molecules have been implicated in the pathogene- and acquired (i.e. T lymphocytes) immunity. Later, (auto)immune
sis of DCM.24,25 Amongst the most common is truncating titin responses can occur in the subacute phase, lasting up to several
mutation, implicated in the pathogenesis of ∼13% and 25% of months. An increased activity of effector T lymphocytes has
non-familial and familial cases of DCM, respectively.26,27 Most muta- been described, targeting both the virus and cellular components
tions have an autosomal dominant inheritance pattern, but there (heat shock proteins, mitochondrial proteins, cardiac myosin,
are also X-linked, autosomal recessive and maternal transmission etc.) by the mechanism of molecular mimicry.36 In addition
(i.e. mitochondrial disorders) patterns. Routine genetic testing has to inflammatory myocardial damage, autoantibodies directed
a relatively low yield (30–35%) and, as yet, few implications for against the ADP/ATP carrier may contribute to LV dysfunction.37
the management of HF in DCM. The exceptions are lamin A/C Recently, myocardial inflammation characterized by the presence
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Figure 3 Characteristic alterations in cardiac morphology underlying heart failure in dilated cardiomyopathy.
of cytotoxic perforin-positive T lymphocytes has been shown The pathogenesis of PPCM is still not elucidated but several
..................................................................................................
to predict subsequent deterioration of LV function over the contributing factors have been implicated.46,47 Excessive oxidative
long-term follow-up period.38 These pathological processes may stress in the last trimester of pregnancy, possibly caused by insuf-
cause substantial myocardial cell loss and trigger adverse ven- ficient defence mechanisms, can promote activation of cathepsin
tricular remodelling and replacement fibrosis, eventually leading D and formation of a prolactin fragment with direct cardiotoxic
to the development of DCM and HF. At the same time, persis- properties.48 Myocardial inflammation, viral infection, angiogenic
tent viral genomes have been detected in cardiac tissue without imbalance during pregnancy and autoimmune responses character-
DCM,39 emphasizing the important role of the host response. ized by high titres of autoantibodies against the myocardial proteins
Increased susceptibility to the development of DCM has been have been also implicated.49 – 52 Susceptibility to PPCM is appar-
linked to upregulation of genes for matrix metalloproteinase-9 and ently higher in carriers of DCM-causing sarcomere gene muta-
type-1 procollagen in mast cells, which may result in pronounced tions, which supports a notion of a genetic predisposition in some
myocardial inflammation and necrosis, followed by replacement patients.53
fibrosis.40 Direct cardiotoxicity, along with a contribution from neurohor-
Other infectious causes of DCM may have specific geographic monal activation, altered calcium homeostasis, and oxidative stress
distributions. Most notable examples include human immunod- have been associated with the development of HF in the setting
eficiency virus (HIV) infection in sub-Saharan Africa, and Cha- of chemotherapy (e.g. anthracyclines, trastuzumab, etc.), chronic
gas disease (Trypanosoma cruzi infection) in South America.41 The alcohol abuse (alcoholic cardiomyopathy), and exposure to cer-
pathogenesis of HIV-mediated DCM and HF is not completely tain drugs and toxins54 – 59 (Figure 2). Cardiotoxicity is a relatively
understood, whereas, myocardial damage in Chagas disease results common complication of cancer therapy manifesting as LV dys-
from diffuse fibrosis due to parasitic infestation, microcirculatory function and HF (usually HFrEF).58 Risk factors for cardiotoxicity
damage and autoimmune mechanisms.42 include a history of HF or LV dysfunction (including pre-existing
Dilated cardiomyopathy may also occur in systemic DCM/HCM), coronary artery disease, hypertensive or valvular
immune-mediated diseases (SIDs) that include autoimmune heart disease, as well previous exposure to cardiotoxic drugs
and autoinflammatory disorders.43 In SIDs, autoantibodies may (e.g. anthracyclines) or radiotherapy. Depending on the cardiotoxic
promote inflammatory responses via immune complex formation agent and patients’ susceptibility, cardiotoxicity may present soon
or may directly participate in cardiac damage, also mediated by after exposure, or it may become clinically evident years after
aberrant cellular immunity, resulting in myocyte loss, fibrosis and treatment (late DCM), as a result of progressive myocardial injury
the development of DCM. Genetic susceptibility could be of (e.g. 23% of anthracycline-treated patients demonstrated late car-
crucial importance for the progression of HF after autoimmune diotoxicity after a median of 7-year follow-up).60 The prediction
myocarditis, since evidence suggests that organ-specific autoanti- of long-term outcomes in cancer patients is hampered by the fact
bodies predict the development of DCM in asymptomatic relatives that many patients receive multiple drugs and radiotherapy, which
of patients with established DCM.44,45 may have a potentiating cardiotoxic effect. Importantly, substantial
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reversal of LV dysfunction and recovery from HF may occur with end-diastolic diameter have been recognized as independent pre-
........................................................................................................................................................................
a timely withdrawal of the offending agent(s) and appropriate HF dictors of reverse LV remodelling.10 In addition, a lower extent
treatment. of late gadolinium enhancement (LGE) on cardiac magnetic reso-
nance (CMR), indicative of lower interstitial replacement fibrosis,
has been shown to provide incremental predictive value for reverse
The natural history and outcome of
LV remodelling in recent-onset DCM.8 Importantly, independent of
heart failure in dilated cardiomyopathy other factors, LV reverse remodelling was associated with ∼50%
The natural history of HF in DCM can be characterized by lower mortality rates at 10-year follow-up in DCM patients.68
three distinct pathways including: (i) a structural and functional On the other hand, male sex and advanced age (> 60 years) have
recovery following incident HF; (ii) a remission of HF symptoms been associated with a poorer prognosis in patients with DCM and
and improvement/stabilization of LV systolic function; and (iii) HF.9,10,69 Self-declared black race has also been related to more
progression to advanced HF and heart transplantation/death.61 severe HF at presentation, a lesser degree of LV reverse remod-
Complete functional and structural recovery is infrequent and can elling and approximately two-fold higher mortality at follow-up.10
occur if an acute insult did not cause significant myocardial loss, Other predictors of adverse outcomes include: lower baseline
which allows normalization of LV function once the insult has LVEF, higher NYHA class (III–IV), significant mitral regurgitation,68
resolved. The clinical course of HF in DCM may be variable, but a the presence of LBBB and higher natriuretic peptide levels.8,70
substantial functional recovery and reverse LV remodelling can on Severe functional mitral regurgitation (FMR) has been associated
occasion be achieved, especially with the use of guideline-directed with approximately two-fold increased risk of mortality or wors-
medical therapy (GDMT).62,63 ening HF in DCM.71 Persistence of severe FMR or worsening
Observational data prior to GDMT for the management of HF of non-severe FMR despite optimal GDMT has been shown to
indicate that significant clinical improvement occurred in less than predict adverse prognosis in patients with HFrEF, irrespective of
20% of HF patients with DCM, while 77% died within 2 years HF aetiology.72 In addition, a more pronounced mid-wall myocar-
of diagnosis, mostly due to progressive pump failure.64 SCD and dial LGE on CMR has been associated with higher all-cause and HF
systemic embolism, largely attributable to atrial fibrillation (AF), mortality and more frequent HF hospitalizations in DCM.70
accounted for the remainder of the cardiovascular mortality.64 Heart failure in DCM still carries a considerable mortality risk
Over the last three decades, outcomes have improved with that is similar to, or higher than mortality attributed to other
advances in HF treatment. In a cohort of Japanese DCM patients non-ischaemic HF aetiologies (e.g. valvular or hypertensive).11
enrolled between 1982 and 1989, the 5- and 10-year survival Advanced HF remains the most frequent cause of death in DCM,
rates were 61% and 35%, respectively.65 In patients assessed while SCD accounts for < 30% of mortality.9,70 Importantly, DCM
between 1990 and 2002, the 5- and 10-year survival rates had also confers a high risk of non-cardiovascular mortality, as approx-
increased to 81% and 65%, respectively.65 A favourable prognosis imately one third of patients die of cancer, infections, pulmonary
has been reported with GDMT, demonstrating transplant-free disease, or haemorrhage.9,73 The risk of non-cardiovascular death
survival at 1, 2, and 4 years of follow-up in 94%, 92%, and 88% increases with older age and more severe HF.9,73
of patients, respectively.10 Over the same period, survival free
of HF hospitalization was 88%, 82%, and 78%, respectively.10
ICD, cardiac resynchronization therapy (CRT), as well as MCS
Treatment of heart failure in dilated
and heart transplantation in advanced HF have all provided
further improvements in outcomes, and CRT and MCS in
cardiomyopathy
particular have been associated with reverse remodelling and Both HF-specific and aetiology-related therapies should be consid-
recovery. ered for the treatment of HF in DCM.
However, a recent randomized trial (TRED-HF) of 51 patients
with DCM and recovered LV function indicated that withdrawal of
GDMT for HF is associated with a 40% relapse of LV dysfunction Heart failure-related therapy
within 6 months.66 This strongly supports continuation of HF Guideline-directed medical therapy and implantable devices pro-
treatment even in patients with recovered DCM. vide proven outcome benefit for patients with chronic HF in DCM
Besides GDMT, several additional predictors of reverse LV (Table 1)12,73 – 85 . In acute/advanced HF, in-hospital treatment with
remodelling have been identified in DCM, which are related intravenous diuretics, vasodilators, or inotropes may be required,
to a more favourable long-term prognosis. In the IMPROVE-HF although there is no evidence that these interventions improve
study of 3994 HF patients (32% with a non-ischaemic aetiol- outcomes.74
ogy), almost 30% experienced a > 10% increase in LVEF over Concerns have been raised about the efficacy of certain ther-
the 2-year follow-up period. Female sex, a non-ischaemic HF apies in patients with DCM, compared with other aetiologies of
aetiology and the absence of digoxin use have been identified HF. Suggestions from observational studies of an increased mor-
as multivariable predictors of LV functional recovery.67 Several tality risk with digoxin and amiodarone in DCM patients with
cohort studies have specifically addressed LV functional recovery HF65,67 have not been confirmed in clinical trials.75,86 Prophylac-
in recent-onset DCM and observed a > 10% increase in LVEF tic ICD implantation for primary prevention of SCD is currently
in 30–70% of patients.8,10,68 Higher baseline LVEF and lower LV recommended in DCM patients with HF (NYHA class II–III) and
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Table 1 Outcomes in selected heart failure with reduced ejection fraction clinical trials in patients with idiopathic
dilated cardiomyopathy or non-ischaemic heart failure
Clinical trial, Intervention Number of Idiopathic Outcome

publication year patients and DCM or (treatment vs. comparator)
characteristics non-ischaemic
HF
...........................................................................................................................................
Medical therapy
SOLVD,12 1991 Enalapril vs. 2569; NYHA class I–IV; 17.9–18.6% All-cause death:
placebo LVEF ≤35% RR ↓27%
Death or hospitalization: RR ↓29%;
Interaction P = NS according to HF
aetiology (ischaemic vs.
non-ischaemic)
DIG,75 1997 Digoxin vs. 6800; NYHA class I–IV; 14.1–15.5% Death or HF hospitalization:
placebo LVEF ≤45% RR 0.67 (95% CI 0.58–0.77);
Interaction P = 0.06 according to HF
non-ischaemic)
MDC,76 1993 Metoprolol vs. 383; 94% NYHA class II–III, 100% All-cause death:
placebo LVEF <40% RR ↓34% (95% CI −6% to 62%,
P = 0.058).
Significant improvement in
symptoms, less clinical
deterioration with metoprolol
CIBIS,77 1994 Bisoprolol vs. 641; NYHA class III (95%) or IV 36% All-cause death:
placebo (5%); LVEF <40% Placebo vs. bisoprolol: 23/115 vs.
11/117; P = 0.01
RALES,78 1999 Spironolactone vs. 1663; NYHA class III–IV (NYHA 45–46%a All-cause death (overall study
placebo class IV within 6 months population):
before enrolment); HR 0.70 (95% CI 0.60–0.82);
LVEF ≤35% Interaction P = NS according to HF
aetiology (ischaemic. vs.
non-ischaemic)
CHARM-Alternative,79 Candesartan vs. 2028; NYHA class II–IV; 18.8–20.3% CV death or HF hospitalization
2003 placebo in LVEF ≤40% (overall study population):
patients HR 0.70 (95% CI 0.60–0.81)
intolerant to No reported interaction according
ACE inhibitors to HF aetiology
SHIFT,80 2010 Ivabradine vs. 6558; LVEF ≤35%; sinus rhythm 32–33%a CV death or HF hospitalization:
placebo >70 b.p.m.; NYHA class II–IV; HR 0.72 (95% CI 0.60–0.85);
HF hospitalization within the Interaction P =0.059 according to HF
previous 12 months aetiology (ischaemic. vs.
non-ischaemic)
EMPHASIS-HF,81 2011 Eplerenone vs. 2737; NYHA class II; LVEF <30% 30.1–31.8%a CV death or HF hospitalization
placebo (or LVEF 30–35% and QRS (overall study population):
>130 ms) HR 0.63 (95% CI 0.54–0.74);
Interaction P = 0.73 according to HF
non-ischaemic)
PARADIGM-HF,82 2014 Sacubitril/valsartan 10 521; NYHA class II–IV; 39.9–40.1%a CV death or HF hospitalization
vs. placebo LVEF ≤35–40%, BNP ≥150 (overall study population):
pg/mL or NT-proBNP ≥600 HR 0.80 (95% CI 0.73–0.87)
pg/mL, or HF hospitalization No reported interaction reported
within the previous 12 months + according to HF aetiology
BNP ≥100 pg/mL or
NT-proBNP ≥400 pg/mL
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Table 1 continued
Clinical trial, Intervention Number of Idiopathic Outcome

publication year patients and DCM or (treatment vs. comparator)
characteristicsnon-ischaemic
HF
...........................................................................................................................................
Devices
DEFINITE,83 2004 ICD vs. medical 458; LVEF ≤35%; VPC 100% All-cause death:
therapy and/or HR 0.65 (95% CI 0.40–1.06)
non-sustained VT Sudden cardiac death:
on GDMT HR 0.20 (95% CI 0.06–0.71)
SCD-HeFT,84 ICD vs. placebo 2521; NYHA class 48%a All-cause death:
2005 Amiodarone vs. II–III; LVEF ≤35% ICD vs. placebo,
placebo on GDMT HR 0.73 (95% CI 0.50–1.07)
Amiodarone vs. placebo,
HR 1.07 (95% CI 0.76–1.51)
aetiology (ischaemic vs. non-ischaemic)
COMPANION,85 CRT-P/CRT-D vs. 1520; NYHA class 44.9%a All-cause death:
2004 medical therapy III–IV; LVEF ≤35% CRT-P vs. placebo,
on GDMT; QRS HR 0.91 (95% CI 0.55–1.49)
≥120 ms CRT-D vs. placebo,
HR 0.50 (95% CI 0.29–0.88)
aetiology (ischaemic vs. non-ischaemic)
DANISH,73 2016 ICD vs. medical 1116; NYHA class 76% All-cause death:
therapy (58% in II–IV with HR 0.87 (95% CI 0.68–1.12)
both groups non-ischaemic HF; Sudden cardiac death:
received CRT) LVEF ≤35%; HR 0.50 (95% CI 0.31–0.82)
NT-proBNP >200 Interaction P = 0.80 according to HF
pg/mL aetiology (idiopathic vs. valvular vs.
hypertension vs. other)
ACE, angiotensin-converting enzyme; BNP, B-type natriuretic peptide; CI, confidence interval; CRT, cardiac resynchronization therapy; CRT-D, cardiac resynchronization
therapy with defibrillator; CRT-P, cardiac resynchronization therapy with pacemaker; CV, cardiovascular; DCM, dilated cardiomyopathy; GDMT, guideline-directed medical
therapy; HF, heart failure; HR, hazard ratio; ICD, implantable cardioverter-defibrillator; LVEF, left ventricular ejection fraction; NT-proBNP, N-terminal pro B-type natriuretic
peptide; NYHA, New York Heart Association; RR, relative risk; VPC, ventricular premature complexes; VT, ventricular tachycardia.
a Proportion of patients with non-ischaemic HF aetiology.
LVEF ≤ 35% on GDMT.74 This was based on earlier clinical tri- Substantial reverse remodelling is mostly observed with poten-
........................................................
als that have demonstrated a decrease in both arrhythmic and tially reversible causes of DCM, including alcohol-related, PPCM or
all-cause mortality in HF of both ischaemic and non-ischaemic tachycardia-induced cardiomyopathy, underlying the importance of
aetiology83,84 (Table 1). The results of the DANISH trial, in which aetiological assessment of HF in DCM. Those patients possibly may
> 50% of patients received a CRT on top of GDMT, have shown be protected against SCD during the recovery phase with wearable
that ICD implantation reduced the risk of SCD by 50% with no defibrillators, thus avoiding the requirement for permanent ICD
implantation.
significant effect on all-cause mortality.73 However, a recent sub-
analysis of the DANISH trial suggested that in patients ≤ 70 years
Correction of LV mechanical dyssynchrony (15–30% of DCM
patients with HF) has a significant positive impact on morbid-
old, ICD implantation reduced all-cause mortality.87 Also, in the
ity and mortality.85,89,90 Hence, CRT is currently recommend for
symptomatic HF patients with LVEF < 35% and QRS ≥ 130 ms, par-
COMPANION trial, the addition of a defibrillator function to CRT
(i.e. CRT-D) provided a greater reduction in all-cause mortality ticularly of LBBB morphology (a surrogate for LV dyssynchrony),
in patients with DCM on GDMT compared with patients with an treated for ≥ 3 months with GDMT, irrespective of HF aetiology.74
ischaemic HF aetiology.88 This underscores the need for improve- Based on the experience from surgical mitral valve repair (MVR)
ment in risk stratification for CRT eligible patients with DCM who of moderate-to-severe FMR, suggesting reverse LV remodelling
might derive most benefit from CRT-D for primary prevention. and functional improvement,91 a percutaneous interventional tech-
In addition, approximately one third of patients with DCM may nique has been developed for the correction of FMR. Percuta-
experience reverse LV remodelling and recovery from HF with neous transcatheter MVR with the MitraClip device demonstrated
GDMT, which, in turn, confers a significantly lower risk of SCD.68 similar efficacy but an improved safety compared with surgery.92
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Recently, two randomized clinical trials comparing the effectiveness Heart failure in hypertrophic
........................................................................................................................................................................
of percutaneous MVR with GDMT have demonstrated diverging
results. In the MITRA-FR trial the 1-year risk of death or HF hos- cardiomyopathy
pitalization did not differ significantly between patients who under-
Incidence and prevalence of heart failure
went percutaneous MVR and those who received GDMT alone.93
Conversely, in the COAPT trial, patients treated with percuta- in hypertrophic cardiomyopathy
neous edge-to-edge repair experienced markedly lower rates of Hypertrophic cardiomyopathy is defined by an increase in myocar-
all-cause mortality and HF hospitalization within 2 years compared dial wall thickness (≥ 15 mm in adults, or ≥ 13 mm in adults
with GDMT alone.94 with first degree relatives with HCM) in one or more of the
LV wall segments, that cannot be explained by abnormal load-
ing conditions.109,110 Most patients have an asymmetric septal
Aetiology-related therapy
hypertrophy and approximately 40–70% have an obstructive
Aetiology-related treatment of HF in DCM is an evolving field, HCM, diagnosed by a LV intracavitary gradient ≥ 30 mmHg at rest
which needs further evidence from clinical trials. In the case (∼25% of patients) or during exercise.109,111,112 Non-obstructive
of inflammatory DCM of autoimmune aetiology without HCM, demonstrating gradients < 30 mmHg at rest and/or with
viral persistence, this treatment includes immunosuppression exercise, is present in 30–60% patients.109,111,112 In several
and immunoadsorption, whereas, anti-viral agents may be con- reports from Europe, Asia and North America, the prevalence
sidered in the setting of biopsy-confirmed acute viral myocarditis of HCM is 2–5 per 1000 of the general population.113 – 116 In
or viral persistence. Several observational and randomized tri- 60% of patients, HCM results from autosomal dominant sar-
als have suggested that in virus-negative post-myocarditis DCM comere gene mutations, whereas other aetiologies including
with progressive HF, immunosuppression could be effective hereditary syndromes, neuromuscular disorders and storage
in achieving LV reverse remodelling and improvement in HF diseases characterized by intracellular accumulation of abnormal
symptoms.95 – 97 Accordingly, expert consensus documents substrates (e.g. Anderson–Fabry, Pompe, or Danon disease,
have recommended immunosuppression with azathioprine and etc.) account for 5–10% of patients110,117 (Figure 4). In about
prednisone for 6–12 months in patients with biopsy-proven, 30% of patients, the cause of HCM remains unknown.109 A
virus-negative DCM,35 but the exact role of immunosuppression suggested aetiological assessment of HF in HCM is presented in
is still unresolved. Immunosuppression is also recommended Figure 1.
in acute giant-cell and eosinophilic myocarditis and cardiac Heart failure has two distinct clinical features in HCM; in the
sarcoidosis.7,35,98 In biopsy-proven chronic enteroviral or adenovi- majority of patients, HF is manifested as a HFpEF phenotype, with
ral and/or Parvovirus B19 positive DCM, an immunomodulatory specific characteristics in patients with LV obstruction, while only
treatment with interferon beta has been recently shown to reduce a minority of patients develop HFrEF at a later stage. Due to a
viral load and improve functional capacity.99 Small open-label substantial aetiological and clinical heterogeneity, ascertaining the
controlled, or observational studies suggested that removal of incidence of HF in HCM is challenging. Data from a cohort of 1000
circulating antibodies in DCM by immunoadsorption, followed patients diagnosed with HCM at mid-adulthood (i.e. 30–59 years
by IgG substitution, resulted in improvement in cardiac func- of age) reveal HF incidence of ∼50%, with symptoms varying from
tion, symptom relief and increased exercise tolerance.100 – 102 mild to severe (NYHA class II–IV).118 In a contemporary registry of
At present, immunoadsorption is considered as an experimental 3208 individuals with cardiomyopathies in Europe, the prevalence
treatment option that requires further evaluation in outcome tri- of symptomatic HF in patients with HCM was 67% (NYHA class II
als. In anthracycline-induced cardiomyopathy, timely therapy with and III–IV symptoms, 49.9% and 17.4%, respectively).119 However,
angiotensin-converting enzyme (ACE) inhibitors and beta-blockers the mentioned prevalence of HF in HCM might be overestimated
confers a substantial improvement of LVEF.103 Treatment with due to possible under-representation of subjects with mild symp-
the prolactin inhibitor bromocriptine (accompanied by prophy- toms or asymptomatic HCM in registries. HF is prevalent in the
lactic anticoagulation) may provide a disease-specific therapy majority of patients with obstructive HCM and in 10% of patients
in patients with acute HF in PPCM.47,104,105 Further aetiologic with non-obstructive HCM.120 Acute HF is infrequent, however
therapies include cessation of the offending agent(s) (e.g. alco- it could be precipitated by conditions such as tachyarrhythmia
hol) and management of the underlying endocrine or metabolic (e.g. AF), ischaemia, acute or worsening mitral regurgitation (e.g.
disorders.106 chordal rupture), or co-morbidity (e.g. thyrotoxicosis).109,121,122
In light of the various monogenetic causes of DCM, gene Progression to advanced HF (e.g. NYHA class III–IV symptoms)
repair may be a promising target for the causative treatment occurs in 3.5–17% of individuals, usually as a consequence of severe
of HF. Following improvement in skeletal muscle function with LV obstruction and hypertrophy, or adverse LV remodelling lead-
CRISPR/Cas9 technology for gene repair in Duchenne mus- ing to systolic dysfunction.123 – 126 There are no gender or race
cular dystrophy,107 this technology is currently under assess- distinctions in the prevalence of HF in HCM, but patients with
ment for genome modification in cardiomyopathies.108 Thus, sarcomere protein disease tend to develop HF at a younger age
the emerging CRISPR/Cas9 technology may become an over- and have a higher propensity for progressive HF compared to
arching approach to the treatment of primary cause of some patients without mutations.127 Patients with rare inherited dis-
cardiomyopathies. orders (e.g. Anderson–Fabry, Danon, or mitochondrial disease)
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Figure 4 Aetiologies of hypertrophic cardiomyopathy.
Figure 5 Characteristic alterations in cardiac morphology underlying heart failure in hypertrophic cardiomyopathy.
demonstrate multi-system disease, but their clinical presentation is Pathophysiology of heart failure
..................................
often (∼60%) dominated by symptoms of HF as well as conduction

in hypertrophic cardiomyopathy
abnormalities.128
Hypertrophic cardiomyopathy due to sarcomere gene
Amongst HF patients, those with HCM account for 2–3%.16
mutations
Accordingly, the proportion of patients with HCM among all heart
transplant recipients for advanced HF is smaller relative to other In genetic HCM, myocyte hypertrophy and disarray occur
aetiologies, because HCM is a rare disease.22 However, compared in response to impaired energy balance due to the excessive
with other recipients, patients with HCM tend to be younger and energy utilization required to generate a hyperdynamic isokinetic
with fewer co-morbidities at the time of transplantation. This also tension within the sarcomere.129,130 Compromised energy bal-
accounts for similar or more favourable short-term and long-term ance, coupled with higher oxygen demand of the hypertrophied
prognosis after transplantation.22 myocardium result in recurrent episodes of demand ischaemia
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(e.g. during exercise or tachycardia) that can explain symptoms HF may have a progressive course culminating in end-stage disease
........................................................................................................................................................................
of chest pain, exercise intolerance and exertional dyspnoea.131 and severe HFrEF.
In some patients, the underlying pathophysiology may be further
aggravated by haemodynamic overload imposed by a dynamic LV
Hypertrophic cardiomyopathy due to storage disorders
outflow tract, mid-cavity or multi-level obstruction.132 Coronary
microvascular dysfunction, characterized by structural abnormal- In patients with HCM caused by rare storage disorders (e.g.
ities and decreased blood flow in intramural coronary arterioles, Anderson–Fabry, Danon and Pompe diseases), HF most commonly
also plays a role in recurrent episodes of myocardial ischaemia and takes the HFpEF phenotype due to an extensive, concentric
the development of HF.133 In addition, impaired termination of increase in LV wall thickness.145,146 The increased wall thickness
contraction at low intracellular Ca2+ levels produces incomplete is caused partly by myocyte hypertrophy (due to lysosomal accu-
myocyte relaxation and diastolic dysfunction, which may both mulation of glycosphingolipids), and partly by interstitial fibrosis
precede and follow the development of overt hypertrophy.134 stimulated by overproduction of profibrotic cytokines.146 Asym-
In some patients, a cumulative effect of these factors produces metric LV hypertrophy in storage disorders is rare (< 2.5%), while
myocyte energy depletion followed by progressive myocyte loss biventricular hypertrophy may occur in up to 25% of patients.145
and replacement fibrosis that eventually lead to adverse LV remod- In Anderson–Fabry disease, replacement fibrosis (detectable by
elling and progression to systolic dysfunction and HFrEF. Indeed, a LGE-CMR or by strain imaging) within the posterolateral wall
meta-analysis of 1063 HCM patients, followed for an average of may contribute to LV dysfunction and FMR.147 Most patients
3.1 years, demonstrated that replacement fibrosis on LGE-CMR have preserved LVEF with occasional evidence of subaortic LV
predicted a significantly increased risk of mortality due to HF.135 In obstruction.148 Overt HF is determined by the degree of LV dias-
a histologic study of 30 explanted hearts with end-stage evolution tolic dysfunction, which correlates with the extent LV hypertrophy
of HCM, more than one third of the LV myocardium was replaced and N-terminal pro B-type natriuretic peptide (NT-proBNP)
by fibrosis, particularly involving the LV apex and the mid-wall.136 levels.149 Rarely, diastolic dysfunction in storage disorders may
Patients with multiple genetic mutations in sarcomere proteins progress to a restrictive filling pattern, accompanied by a signifi-
(up to 5% of the HCM population) are particularly susceptible to cant biatrial enlargement.145 In those patients, cardiac involvement
accelerated progression to end-stage disease.137,138 Also, familial may take the characteristics of an RCM; thus, storage disorders
clustering of advanced HF has been recognized as a marker of risk need to be considered as underlying aetiology of both HCM and
for unfavourable outcomes in other family members.126 In addition, RCM. Development of LV systolic dysfunction and HFrEF invariably
co-morbidities (e.g. myocarditis or epicardial coronary artery dis- occurs in Danon disease and occasionally in patients with other
ease) may be rarely associated with adverse LV remodelling and metabolic cardiomyopathies.150
development of overt HF.111
In patients with obstructive HCM, the severity of HF is prin- The natural course and outcome of heart
cipally determined by pressure overload imposed by a dynamic
obstruction to LV outflow during systole.120 The characteristic
failure in hypertrophic cardiomyopathy
morphological changes responsible for HF development in HCM Hypertrophic cardiomyopathy due to sarcomere gene
are summarized in Figure 5. The intracavitary obstruction most mutations
commonly involves the outflow tract and is produced by a com- Typically, LV hypertrophy in HCM caused by sarcomere disorders
bination of physical obstruction by the septal hypertrophic tissue, develops in adolescence or early adulthood (although it may
by an abnormal systolic anterior motion (SAM) of the mitral valve, present from early childhood to the seventh decade), and remains
and by diastolic and contractile deficits. In 5–10% of patients, stable with preserved LV systolic function and variable degrees
the gradient is exclusively produced by mid-cavity obstruction of LV diastolic dysfunction.151 In patients with obstructive HCM,
due to an abnormal apposition of the hypertrophied septum and the severity and prognosis of HF are principally influenced by LV
anterolateral papillary muscle.120 Dynamic changes in gradients in outflow obstruction. This is highlighted by data demonstrating
response to changes in myocardial contractility and loading condi- that a gradient ≥ 30 mmHg at rest independently predicted HF
tions (e.g. exercise, hydration) explain temporal variability and low progression and increased mortality.152 Recent findings from a
reproducibility of HF symptoms in HCM.120 In patients without cohort of 324 patients with obstructive HCM and mild HF at
a significant gradient at rest, cardiopulmonary exercise testing is baseline, demonstrated progression to NYHA functional class
the preferred method for provoking obstruction.109 LV diastolic III–IV, at an annual rate of 3.2–7.4% depending on the degree of
dysfunction represents another important mechanism underlying outflow tract obstruction.153 As a result, severe HF was prevalent
the development of HF (i.e. HFpEF) in HCM. It is present in the in 20–38% of those patients following a period of 6.5 years.153
majority of patients, irrespective of intracavitary obstruction and Similarly, in a cohort of 293 HCM patients followed up for a median
is characterized by prolonged isometric relaxation and impaired of 6 years, advanced HF developed in 20% of those with severe
filling patterns.111 In addition, mitral valve abnormalities, coronary obstruction to LV outflow.123 The distinguishing features of these
myocardial bridging, apical aneurysms, atrial remodelling and patients were older age (50 ± 14 years) and a significantly increased
autonomic dysfunction may contribute to the development and LV wall thickness at baseline.123
severity of HF.124,139 – 144 In patients with non-obstructive HCM, Mid-cavity obstruction is often accompanied by severe HF symp-
HF is mostly caused by diastolic dysfunction, but in a small subset, toms and impaired survival. In a cohort of 423 patients, a mid-cavity
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obstruction was identified in 8% of patients that were more symp- symptoms of HF, while avoiding hypovolaemia. In patients with an
tomatic (> 90% with NYHA class ≥ II) and had higher mortality
........................................................................................................................................................................
intolerance or a contraindication to beta-blockers, verapamil or
compared with the rest of the cohort.154 diltiazem could be an alternative. However, there is a paucity of
Severe diastolic dysfunction (i.e. restrictive filling pattern) can evidence on how these medications influence the natural course
be demonstrated in up to 9.2% of patients with HCM, usually and outcomes in HCM.109
in the setting of severe myocardial hypertrophy, with or without In patients with obstructive HCM and preserved LVEF,
LV outflow tract obstruction. These patients generally present who remain symptomatic despite maximal tolerated doses of
with symptoms of low cardiac output (rather than with overt beta-blockers, disopyramide could be considered as a second-line,
congestion), and they have an independently increased risk of add-on therapy.109 Disopyramide exerts a negative inotropic effect
progression to advanced HF and end-stage disease.123,155 In one that can reduce LV outflow tract gradient in the majority of
study, those patients accounted for 48% of advanced HF cases, and patients and improve HF symptoms, without affecting mortality,
as a result of restrictive filling pattern they had significant left atrial or causing proarrhythmia.166 In patients with obstructive HCM,
enlargement et entry or during follow-up. who have a gradient ≥ 50 mmHg at rest, or during exercise,
In patients with non-obstructive HCM, the disease usually has and remain symptomatic (NYHA class III–IV) despite GDMT,
a benign and stable course and the majority remains free of HF invasive gradient reduction with surgical septal myectomy or
or has mild symptoms due to diastolic dysfunction. However, in septal alcohol ablation should be considered.109 Surgical septal
7–10% of patients with non-obstructive HCM (incidence, 1.6% per myectomy has been shown to abolish or significantly reduce
year),120,156 the disease can have a progressive course character- obstruction in > 90% of patients treated in experienced cen-
ized by LV dilatation, wall thinning, and development of LV systolic tres, followed by a long-term improvement in HF symptoms
dysfunction, including an LVEF in the low-normal range.151,157 and extended survival.167,168 Alternatively, alcohol septal ablation
Adverse LV remodelling is subtended by extensive myocardial has been shown to convey an improvement in outcomes com-
replacement fibrosis.151,158 The most advanced, ‘burned-out’, parable with surgery.169 Surgery seems less beneficial for older
phase occurs in 3% of patients and carries a considerable risk of patients and for those with residual AF.170 Alcohol septal ablation
mortality (11% per year).126 may be less effective in younger patients with higher baseline
In addition, left and right atrial enlargement have been rec- gradients.171 The periprocedural complications of both proce-
ognized as independent predictors of adverse outcomes in dures include atrioventricular block (7–20% of patients), bundle
HCM.123,153,159 Likewise, the occurrence of AF, usually at a branch block, or ventricular septal defect.109 These treatment
younger age than in the general population, significantly increases modalities are currently available in a small number of experienced
the risk of a detrimental clinical course.121,123 centres.
Dual-chamber pacing has failed to demonstrate convincing treat-
ment benefits.172 It is currently recommended in patients with
Hypertrophic cardiomyopathy due to storage disorders
obstructive HCM (and an indication for antibradycardia pacing),
In patients with HCM due to hereditary storage disorders, HF deemed unsuitable for, or unwilling to undergo surgery/alcohol
may become apparent at any time from childhood to the mature septal reduction.109
age depending on the extent of cardiac involvement, in rela- Patients with HCM are at an increased risk of SCD. For primary
tion to the severity of enzyme deficit.160 In Anderson–Fabry dis- prevention, European Society of Cardiology guidelines recommend
ease, the development of overt HF has been reported in 23% of the use of a validated prediction model (i.e. HCM Risk-SCD) to
patients usually between the third and the fifth decade of life.161 estimate an individual 5-year risk of SCD109 (Figure 6). Specifically,
The progression to advanced HF has been observed in 10% of in patients with HF due to HCM, additional features may be used
patients over a median period of 7.1 years.162 Increased levels of to refine risk assessment for SCD,126,140,173 but their incremental
cardiac biomarkers (troponin T, NT-proBNP) and higher extent prognostic value compared with HCM Risk-SCD remains unknown
of fibrosis have been associated with a reduction in LVEF dur- (Figure 6). Of note, HCM Risk-SCD has not been validated in
ing the follow-up.163 Cardiac disease may progress to LV systolic patients with storage/metabolic causes of HCM, or following myec-
dysfunction and HFrEF in 6–8% (in particular in the absence of tomy/septal ablation.
enzyme replacement therapy) and confers a great risk of HF-related Patients with non-obstructive HCM and reduced LVEF (< 50%)
mortality.164,165 should be treated with GDMT for HFrEF.109 In a setting of progres-
sive LV dysfunction, refractory HF symptoms and LBBB, limited
data supports CRT implantation in patients with LVEF < 50%,174
whereas patients with LVEF ≤ 35% and LBBB should be considered
Treatment of heart failure
in hypertrophic cardiomyopathy for CRT implantation as per current guidelines for the management
Treatment of HF in patients with HCM encompasses general HF of HF.74
and aetiology-related treatment. In patients with HCM and advanced HF, long-term MCS is
The first-line therapy of patients with HCM should include rarely considered suitable as a bridge to transplantation due to
non-vasodilating beta-blockers to reduce contractility and alleviate small LV cavity dimensions and severely impaired filling. How-
the consequences of LV diastolic dysfunction by lowering heart ever, a small study suggested an improvement in outcomes in
rate, in combination with low-dose loop diuretics to control HCM patients with an LV assist device comparable to patients
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Figure 6 Sudden cardiac death (SCD) risk assessment in patients with heart failure (HF) and hypertrophic cardiomyopathy (HCM). ICD,
implantable cardioverter-defibrillator; LA, left atrial; LGE, late gadolinium enhancement; LV, left ventricular; NSVT, non-sustained ventricular
tachycardia. *In selected low-to-moderate risk patients based on HCM Risk SCD assessment, an ICD may be recommended in the presence
of additional markers of increased SCD risk, following careful consideration of potential complications.
Table 2 Therapies of lysosomal storage disorders: relevance for the management of heart failure
Anderson–Fabry disease
Enzyme replacement therapy: agalsidase-𝛼𝛼 • Reduction in left ventricular mass index and a significant increase in mid-wall fractional shortening
or agalsidase-𝛽𝛽 • Improvement in a composite cardiac, renal and cerebrovascular outcome or mortality
• Partial loss of therapeutic effectiveness due to antibody formation may be alleviated by
immunomodulators or a combination with an oral chaperone
Oral chaperon: migalastat • Similar effect on a composite renal, cardiovascular and cerebrovascular outcome compared with
enzyme replacement therapy
• Possible positive impact on left ventricular fibrosis and hypertrophy
Pompe disease
Enzyme replacement therapy: 𝛼𝛼-glucosidase • Regression of left ventricular hypertrophy (if administered early in the course of the disease)
According to ref. 176, 177, 179–182
with DCM, but with a higher risk of complications.175 Heart with agalsidase-𝛼𝛼 and agalsidase-𝛽𝛽,176 – 178 or with an oral chap-
..................................
transplantation should be considered in patients who progress erone, migalastat,179,180 that should be instituted as early as
to advanced HF despite GDMT. At the time of transplantation possible (Table 2). For patients with Pompe disease (glycogen
most patients demonstrate significant LV systolic dysfunction
storage disease type II), enzyme replacement therapy with recom-
(i.e. ‘burned-out’ phase). A small proportion of HCM patients
may require heart transplantation for advanced HF despite binant human 𝛼𝛼-glucosidase is available (Table 2).181,182 Since no
preserved LVEF.157 specific therapy is available for patients with Danon disease, a
close follow-up is recommended due to the malignant nature
Treatment of patients with storage disorders of the disease, including low threshold for ICD implantation
For patients with HCM occurring in Anderson–Fabry dis- and early listing for heart transplantation in appropriate
ease, there is an effective enzyme replacement therapy candidates.183
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Heart failure in restrictive ventricular stiffness has been attributed to increased myofila-
........................................................................................................................................................................
ment sensitivity to calcium, increased deposition of collagen
cardiomyopathy type III, and intracellular aggregates of the mutant protein such
as desmin or filamin C.186 In infiltrative and storage diseases,
Incidence and prevalence of heart failure extracellular or intracellular accumulation of the pathological
in restrictive cardiomyopathy material in the myocardium accompanied by cardiomyocyte hyper-
Restrictive cardiomyopathy is defined by the presence of restrictive trophy and variable interstitial and/or replacement fibrosis are
physiology in patients with normal or reduced diastolic volumes responsible for increased myocardial stiffness. Endomyocardial
of one or both ventricles, and normal or reduced systolic fibrosis (EMF) caused by hypereosinophilic syndrome, carcinoid
volumes.110 Ventricular wall thickness is usually normal; however, in and exposure to chemo/radiotherapy may also result in restric-
infiltrative or storage disease aetiologies of RCM, there is a variable tive pathophysiology.195 Irrespective of the aetiology, RCM is
degree of ventricular wall thickening.184 The aetiology of RCM is characterized by severe diastolic dysfunction, presenting with a
heterogeneous, including idiopathic, hereditary and acquired cases restrictive filling abnormality.110 Markedly elevated filling pressure
of non-infiltrative and infiltrative myocardial disorders, storage dis- leads to prominent biatrial enlargement, and a predisposition
eases and endomyocardial disorders (Figure 7). Importantly, the to AF, which further diminishes ventricular filling.184 Although
clinical phenotype of cardiomyopathy due to specific aetiologies ventricular systolic function is preserved in RCM, stroke volume
may demonstrate and overlap between HCM and RCM (e.g. in may be decreased because impaired diastolic filling fails to provide
Anderson–Fabry, Pompe and Danon diseases), or a transformation sufficient preload. Consequently, patients with RCM typically have
from an RCM to DCM due to progressive nature of the underly- low-to-normal blood pressure, and may suffer from orthostatic
ing disorder (e.g. haemochromatosis/iron overload, amyloidosis). hypotension and hypoperfusion if volume is depleted (e.g. due to
The prevalence of RCM is currently unknown, but it is the least excessive diuresis).
frequent amongst the cardiomyopathies.110,185 Although cardiac amyloidosis is often considered as a cause of
The principal clinical manifestation of RCM is HFpEF, with HFpEF since LVEF often remains preserved until the late stage of
signs and symptoms of right, left or biventricular HF. HFrEF may the disease, in the majority of patients with HF, LV systolic function
present at the late stage of the disease, and is more prevalent is also compromised due to a reduction in LV longitudinal function
in cardiac amyloidosis and iron overload/haemochromatosis.186,187 and strain.196 Furthermore, myocardial contractility and inotropic
These aetiologies need to be considered in differential diagnosis reserve during exercise are also reduced in almost all patients with
between RCM and DCM (Figure 1). In addition, RCM is character- HF.197,198
ized by a greater risk of thromboembolism, conduction abnormal-
ities, arrhythmias and SCD.188
The prevalence of HF in patients with RCM is high, as evidenced
The natural course and outcome of heart
by a large European registry of cardiomyopathies, in which HF failure in restrictive cardiomyopathy
was prevalent in 83% of patients with RCM (NYHA class II, III, The prognosis of HF in RCM is poor, regardless of the underlying
and IV present in 41%, 40% and 1.6%, respectively).119 Similarly, cause of RCM.195 In a small cohort of paediatric patients with
in a cohort of 97 patients with primary RCM, 81% had overt HF, primary RCM, an extraordinary 53% experienced SCD shortly
with 53% of patients demonstrating symptoms in NYHA class after diagnosis; 75% of the remaining patients had HF, and all had
II, and 28% in NYHA class III–IV.189 In adults with echocardio- died or underwent heart transplantation within a few years of
graphically confirmed RCM (performed for screening because of a diagnosis.199 In adult patients with RCM and a confirmed genetic
family history of HCM), 63% of patients presented with HF, while background, the 5-year survival rate was 56%, and the main cause
incident HF occurred in 89% of those patients during the 5-year of death was HF (42%).190 Likewise, in a study of patients with
follow-up.190 Among individuals > 65 years of age, RCM due to idiopathic RCM (10–90 years of age), the 5-year mortality rate was
cardiac amyloidosis may be an underrecognized, albeit important
cause of unexplained HF.191 In a series of patients ≥ 90 years of
50%, and 68% of patients died of cardiovascular causes, including
HF.189 The risk of death doubled with each increment in NYHA
age who died of HF, autopsy revealed RCM in 10%.192 Studies class, independently of other characteristics.189
using a scintigraphy to diagnose transthyretin amyloidosis (ATTR) Caused by intramyocardial deposition of transthyretin-derived
demonstrated a 16% prevalence among patients undergoing percu- amyloid fibrils, transthyretin amyloid cardiomyopathy is the most
taneous aortic valve replacement for severe low-flow, low-gradient common cause of the infiltrative form of RCM.200
aortic stenosis193 and a 13% prevalence among patients Although there are > 30 amyloidogenic proteins, the two most
with HFpEF.194 common types of amyloidosis are the immunoglobulin light chain
amyloidosis (AL) and ATTR amyloidosis; the latter comprises a
mutant transthyretin form (ATTR-m) and a ‘wild-type’ transthyretin
Pathophysiology of heart failure
form (ATTR-wt). Cardiac involvement is the principal determinant
in restrictive cardiomyopathy of mortality in AL amyloidosis due to rapid loss of contractile
The hallmark of RCM is increased ventricular wall stiffness function and a transition from HFpEF to HFrEF.201 A direct toxicity
caused by abnormalities intrinsic to the myocardium, or to the of amyloidogenic light chains by increased oxidative stress has
endomyocardial layer (Figure 8). In primary RCM, abnormal been implicated in myocardial damage, which is often out of
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Figure 7 Aetiologies of restrictive cardiomyopathy.
Figure 8 Characteristic alterations in cardiac morphology underlying heart failure in restrictive cardiomyopathy.
proportion to amyloid deposition.201 This may explain severe and pericardial effusion, which all contribute to significant mor-
................................
and progressive HF in patients with seemingly mild-to-moderate bidity and mortality.186,188 Increased levels of NT-proBNP and
cardiac involvement.202 HF in AL amyloidosis is often manifested as troponin T, and extracellular volume expansion on CMR T1
right HF and frequently unresponsive to conventional treatment; a mapping have been shown to strongly predict poor survival
median survival of patients is approximately 6 months, whilst the in AL amyloidosis.205,206 Patients with ATTR amyloidosis (par-
5-year survival rate is < 10%.203,204 In addition to progressive HF, ticularly those with ATTR-wt or ‘senile amyloidosis’) have a
a significant proportion of patients die suddenly, mostly due to longer median survival of 24–66 months compared with AL
pulseless electrical activity for which ICD therapy is ineffective.202 amyloidosis; nevertheless, the prognosis is poor.207 ATTR-wt
Amyloid deposits may also cause conduction system abnor- has become increasingly recognized as a cause of unexplained
malities, ventricular and supraventricular arrhythmia, valvular HFpEF in elderly patients with biatrial enlargement, mild mitral
dysfunction, coronary ischaemia due to small vessel disease or tricuspid regurgitation, AF and/or conduction abnormalities.194
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It is frequently accompanied by carpal tunnel syndrome and a chronic phase, in which RCM prevails, with signs and symp-
........................................................................................................................................................................
autonomic neuropathy.208 A worse survival has been demon- toms of biventricular or right-sided HF.229 The clinical presenta-
strated with increasing levels of NT-proBNP and troponin T, and tion of HF is often dominated by massive ascites, which is out of
a risk stratification scheme based on cardiac biomarkers has been proportion to peripheral oedema. As a result of increased filling
proposed.194 pressures, significant mitral and tricuspid regurgitation and AF are
Clinically manifest cardiac involvement occurs in ∼5% of patients frequently encountered.230 Overt HF carries an ominous progno-
with sarcoidosis, with a male predominance.209 However, autopsy sis with a 75% mortality rate at 2 years.231 EMF accounts for 20%
findings reveal cardiac involvement in at least 25% of patients with of HF hospitalizations and 15% of cardiac deaths in the endemic
sarcoidosis.210,211 Isolated cardiac sarcoidosis may precede sys- regions.232,233
temic manifestations.212 Clinical presentation depends on the bur- In hypereosinophilic syndrome (formerly, Loeffler’s endocardi-
den and location of granulomatous infiltration, which most com- tis), which is characterized by persistently elevated eosinophil
monly affects the LV myocardium.209 The resulting cardiomyopa- blood count (> 1.5 × 109 /L), cardiac morbidity is caused by the
thy is either of a DCM type (more common) or an RCM type release of biologically active substances that damage the endothe-
(less common) and overt HF is present in 10–40% of patients lium and myocardium.186 Although occurring outside tropical
with cardiac sarcoidosis.186 Previously undiagnosed sarcoidosis has regions, hypereosinophilic syndrome bears a striking resemblance
been identified as an underlying cause of advanced HF in ∼3% to EMF with respect to the pathogenesis and clinical presenta-
of patients requiring MCS or heart transplantation.213,214 There is tion of RCM.186 In rare cases, carcinoid heart disease and car-
also a higher risk of high-degree atrioventricular block215,216 and diac fibroelastosis need to be considered as underlying causes
of RCM.
ventricular tachycardia,217 and there may be an increased risk of
SCD.209,214 The presence and severity of HF have been identified
as important predictors of mortality in patients with sarcoidosis, Treatment of heart failure in restrictive
with the expected 10-year transplantation-free survival of only 53% cardiomyopathy
in individuals with overt HF.212,218
Increased gastrointestinal iron absorption in haemochromato- Conventional treatment of HF in RCM includes recommenda-
sis, and chronic blood transfusions in hereditary anaemias (e.g. tions on fluid and sodium restriction (particularly in patients
with hyponatremia) and judicious use of loop diuretics and min-
thalassaemia, sickle cell anaemia), advanced renal insufficiency, and
eralocorticoid receptor antagonists since over-diuresis may lead
several haematological disorders (e.g. myelodysplastic syndrome),
to low output hypotension in the presence of restrictive filling
produce an iron overload state characterized by excessive cel-
abnormalities. Similarly, ACE inhibitors, or angiotensin receptor
lular uptake of non-transferrin bound iron.187 Iron excess in the
blockers may cause hypotension even at low-to-moderate doses,
myocardium produces an impairment in transmembrane Ca2+ flux
whereas beta-blockers may be poorly tolerated due to an increased
and diastolic dysfunction, followed by progressive myocyte loss,
risk of worsening HF (because a fixed stroke volume requires
replacement fibrosis, and chamber dilatation due to direct cyto-
a higher heart rate to maintain cardiac output).188 Therefore,
toxic effects of accumulated iron.219,220 If left untreated, cardiac
in patients with RCM, these medications need to be used with
involvement in iron overload/haemochromatosis advances from
caution. Tachyarrhythmias are often poorly tolerated and require
an early stage of an RCM with a HFpEF phenotype, to a late
prompt rate or rhythm control. There is an unresolved issue
stage of a DCM with a HFrEF phenotype.187 Less frequently, in
of an ICD implantation for primary prevention in patients with
elderly patients with severe iron overload, restrictive LV patho-
RCM and preserved LVEF. At present, pending clinical trial evi-
physiology promotes the development of pulmonary hypertension, dence, expert consensus suggests an individualized assessment of
right ventricular remodelling and failure, without LV dilatation.221 arrhythmic risk, aetiology, multi-organ involvement and survival
The occurrence of HF portends a poor prognosis, and < 50% of expectancy. There is limited experience with MCS in RCM patients
patients with thalassaemia survive up to 5 years following the onset with advanced HF. However, data from a small cohort of RCM
of HF.222,223 Early identification and follow-up of cardiac involve- patients treated with MCS demonstrate improved survival irre-
ment with NT-proBNP levels, echocardiography (in particular tis- spective of aetiology (i.e. amyloidosis vs. other aetiologies), espe-
sue Doppler and strain rate imaging) and CMR is highly relevant for cially among patients with larger LV dimensions.234 Heart trans-
the management of patients with iron overload syndromes224 – 227 plant or heart/liver transplant (in patients with ATTR-m) can be
(Figure 1). considered in patients with advanced HF unresponsive to medical
Endomyocardial fibrosis is the most frequently encountered treatment.235
endomyocardial disorder and is the leading cause of RCM in trop- Specific therapies should be considered after the aetiology of
ical regions of Africa, Asia and South America.228 Although the RCM has been established. The major goal of treatment for cardiac
aetiology of EMF is still elusive, genetic, dietary, and infectious amyloidosis is to inhibit the production, and to reduce the bur-
factors may promote inflammation responsible for endomyocardial den of amyloid protein infiltration. For AL amyloidosis, the estab-
damage and fibrosis.228 The disease affects young and middle-aged lished treatment strategy is chemotherapy, potentially combined
individuals, beginning with an active phase of eosinophilic inflam- with autologous stem cell transplantation. A recent retrospective
mation, followed by scar formation and a high risk for intracav- study has reported that a combination of bortezomib, dexametha-
itary thrombosis.228 Repeated episodes of active disease lead to sone, and an alkylating agent has been associated with improved
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survival in patients with HF due to AL amyloidosis.236 Recently, and ∼10% of patients with non-obstructive HCM. A timely recog-
........................................................................................................................................................................
a significant breakthrough in the treatment of cardiac amyloidosis nition and treatment of patients at risk of progressive HF is impor-
(ATTR-m and ATTR-wt) has been observed with an oral acting tant, since development of advanced HF, although rare in HCM,
transthyretin stabilizer, tafamidis. In the ATTR-ACT randomized confers a poor prognosis. Although RCM is the least common
trial, tafamidis has been associated with 30% reductions in all-cause amongst the cardiomyopathies, the majority of patients present
mortality and cardiovascular-related hospitalizations and a reduc- with HFpEF, while HFrEF usually occurs at a later stage and is
tion in the decline in functional capacity and quality of life compared more frequent in amyloidosis or iron overload/haemochromatosis.
with placebo.237 Currently, tafamidis is approved in Europe for the Regardless of the underlying aetiology, HF in RCM is a predictor
treatment of ATTR amyloidosis in adult patients with polyneu- of a poor outcome.
ropathy. Another strategy including pharmacological inhibition of Recently, new insights have occurred into the initiating causes
transthyretin gene expression with patisiran has shown promis- and prevailing mechanisms of HF development in several car-
ing results in decreasing adverse cardiac outcomes compared with diomyopathies. In addition, novel aetiology-specific therapies,
placebo in a subset of patients with cardiac ATTR-m amyloidosis.238 including transthyretin stabilizers in cardiac amyloidosis, enzyme
Observational data suggest that ventricular dysfunction and replacement therapies in Anderson–Fabry and Pompe diseases,
heart rhythm abnormalities can improve with immunosuppression immunoadsorption, immunotherapy, and selective administration
in cardiac sarcoidosis.239 In a Finnish registry (96% of patients of antiviral agents in DCM, as well as bromocriptine in PPCM,
on immunosuppression), transplantation-free survival at 1, 5 and have shown a potential to improve outcomes beyond GDMT of
10 years was 97%, 90%, and 83%, respectively.212 The choice of HF. Still, causative therapies of many cardiomyopathies are lacking,
the most effective immunosuppressive therapy and the duration which emphasizes the importance of developing evidence-based
of treatment remain yet to be determined. Importantly, a regular management that would improve outcomes in a majority of
follow-up to detect possible relapses is recommended. patients with HF in cardiomyopathies.
In iron overload/haemochromatosis, improvement in cardiac Conflict of interest: none declared.
function has been noted with timely and sustained iron removal.240
In patients with haemochromatosis, phlebotomy removes 200 to
250 mg of iron at each session, and should be performed once or References
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doi:10.1002/ejhf.1493
Pathophysiology, diagnosis and management of

peripartum cardiomyopathy: a position
statement from the Heart Failure Association
of the European Society of Cardiology Study
Group on peripartum cardiomyopathy
Johann Bauersachs1*, Tobias König1, Peter van der Meer2, Mark C. Petrie3,
Denise Hilfiker-Kleiner1, Amam Mbakwem4, Righab Hamdan5, Alice M. Jackson3,
Paul Forsyth3, Rudolf A. de Boer2, Christian Mueller6, Alexander R. Lyon7,
Lars H. Lund8, Massimo F. Piepoli9, Stephane Heymans10,11,12, Ovidiu Chioncel13,
Stefan D. Anker14, Piotr Ponikowski15, Petar M. Seferovic16, Mark R. Johnson17,
Alexandre Mebazaa18, and Karen Sliwa19
1 Department of Cardiology and Angiology, Hannover Medical School, Hannover, Germany; 2 Department of Cardiology, University Medical Center Groningen, Groningen, The
Netherlands; 3 Department of Cardiology, Institute of Cardiovascular and Medical Sciences, Glasgow University, Glasgow, UK; 4 Department of Medicine, College of Medicine,
University of Lagos, Nigeria; 5 Department of Cardiology, Beirut Cardiac Institute, Lebanon; 6 Department of Cardiology and Cardiovascular Research Institute Basel (CRIB),
University Hospital Basel, University of Basel, Switzerland; 7 Royal Brompton Hospital and Imperial College London, London, UK; 8 Department of Medicine, Karolinska Institutet
and Heart and Vascular Theme, Karolinska University Hospital, Stockholm, Sweden; 9 Heart Failure Unit, Cardiology, G. da Saliceto Hospital, Piacenza, Italy; 10 Department of
Cardiology, CARIM School for Cardiovascular Diseases, Faculty of Health, Medicine and Life Sciences, Maastricht University, Maastricht, The Netherlands; 11 Department of
Cardiovascular Sciences, Centre for Molecular and Vascular Biology, Leuven, Belgium; 12 The Netherlands Heart Institute, Nl-HI, Utrecht, The Netherlands; 13 Institute of
Emergency for Cardiovascular Disease, University of Medicine Carol Davila, Bucharest, Romania; 14 Division of Cardiology and Metabolism, Department of Cardiology (CVK),
Berlin-Brandenburg Center for Regenerative Therapies (BCRT), German Centre for Cardiovascular Research (DZHK) Partner Site Berlin, Charité Universitätsmedizin Berlin,
Berlin, Germany; 15 Department of Cardiology, Medical University, Clinical Military Hospital, Wroclaw, Poland; 16 University of Belgrade Faculty of Medicine and Heart Failure
Center, Belgrade University Medical Center, Belgrade, Serbia; 17 Department of Obstetrics, Imperial College School of Medicine, Chelsea and Westminster Hospital, London, UK;
18 Department of Anesthesiology and Critical Care Medicine, AP-HP, Saint Louis Lariboisière University Hospitals, University Paris Diderot, Paris, France; and 19 Hatter Institute
for Cardiovascular Research in Africa, Department of Cardiology and Medicine, University of Cape Town, Cape Town, South Africa
Received 7 January 2019; revised 21 March 2019; accepted 23 April 2019
Peripartum cardiomyopathy (PPCM) is a potentially life-threatening condition typically presenting as heart failure with reduced ejection
fraction (HFrEF) in the last month of pregnancy or in the months following delivery in women without another known cause of heart
failure. This updated position statement summarizes the knowledge about pathophysiological mechanisms, risk factors, clinical presentation,
diagnosis and management of PPCM. As shortness of breath, fatigue and leg oedema are common in the peripartum period, a high
index of suspicion is required to not miss the diagnosis. Measurement of natriuretic peptides, electrocardiography and echocardiography
are recommended to promptly diagnose or exclude heart failure/PPCM. Important differential diagnoses include pulmonary embolism,
myocardial infarction, hypertensive heart disease during pregnancy, and pre-existing heart disease. A genetic contribution is present in
up to 20% of PPCM, in particular titin truncating variant. PPCM is associated with high morbidity and mortality, but also with a high
probability of partial and often full recovery. Use of guideline-directed pharmacological therapy for HFrEF is recommended in all patients
*Corresponding author. Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany. Tel: +49 511 5323841, Fax: +49 511 5325412,
Email: bauersachs.johann@mh-hannover.de
© 2019 The Authors

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828 J. Bauersachs et al.
respecting contraindications during pregnancy/lactation. The oxidative stress-mediated cleavage of the hormone
prolactin into a cardiotoxic fragment has been identified as a driver of PPCM pathophysiology. Pharmacological
blockade of prolactin release using bromocriptine as a disease-specific therapy in addition to standard therapy
for heart failure treatment has shown promising results in two clinical trials. Thresholds for devices (implantable
cardioverter-defibrillators, cardiac resynchronization therapy and implanted long-term ventricular assist devices) are
higher in PPCM than in other conditions because of the high rate of recovery. The important role of education and
counselling around contraception and future pregnancies is emphasised.
..........................................................................................................
Keywords Peripartum cardiomyopathy • Heart failure • Pregnancy
Introduction differentiated from PPCM. Cases of acute Takotsubo syndrome
..................................................................................................................................
during the final trimester or following emergency delivery have
The aetiology of cardiomyopathies occurring de novo in association been reported, and these require careful assessment to differen-
with pregnancy is diverse. Cardiomyopathies are not very common tiate from PPCM.6,7
diseases, but may cause severe complications, making a substantial
contribution to maternal morbidity and mortality during pregnancy,
in the immediate peripartum period, and up to months later.1
Peripartum cardiomyopathy (PPCM) has to be differentiated from Definition of peripartum cardiomyopathy
other causes of heart failure. The ongoing international PPCM 1. Heart failure secondary to left ventricular systolic
registry in the EURObservational Research Programme (EORP) dysfuntion with a LVEF < 45%
has recruited over 750 patients and will be the largest dataset to 2. Occurrence towards the end of pregnancy or in the
provide important novel information on PPCM.2,3 It is unclear in months following delivery (mostly in the month following
what percentage PPCM persists to chronic, stable heart failure as delivery)
patients with non-specific symptoms around pregnancy may remain 3. No other identifiable cause of heart failure
undiagnosed and are only identified months or years later. How
often heart failure in younger women is caused by PPCM will not
be determined until there is a large pregnancy cohort study which The incidence of PPCM differs widely depending on the eth-
includes monitoring of cardiac function. nic/racial and regional background of women. Africans and African
Heart failure due to PPCM provides a challenge for treating Americans are at a higher risk for developing PPCM, with an esti-
physicians as PPCM presentation may vary from subtle signs and mated incidence of 1:100 pregnancies in Nigeria and 1:299 in Haiti
symptoms to severe acute heart failure, pulmonary oedema and/or whereas incidences in Caucasian populations range from 1:1500
cardiogenic shock.4,5 Moreover therapeutic interventions need pregnancies in Germany to 1:10 000 in Denmark.5,8 – 13 In a large
always to consider both the health of the mother and the foetus US cohort of well-phenotyped patients, African American women
or baby. While evidence-based data from randomized clinical trials were diagnosed with PPCM at a younger age and later in the
are scarce, in this position statement we summarize the current postpartum period, and were more likely to present with a LVEF
knowledge about pathophysiology and clinical best practice in the < 30% compared with non–African American women.10 In the
management of PPCM patients. USA, an increasing incidence was described over the past years.8 In
a Japanese cohort the incidence was as low as 1:20 000,14 however,
these data should be interpreted with caution due to methodologi-
Definition and epidemiology cal aspects and possible underreporting. In contrast, an analysis that
appears more representative of the Asian population was published
In 2010, the Study Group on peripartum cardiomyopathy of the
recently from a nationwide database and estimated the incidence
Heart Failure Association (HFA) of the European Society of Cardi-
of PPCM in South Korea at 1:1741.15,16
ology (ESC) defined PPCM as an idiopathic cardiomyopathy occur-
Predisposing factors for PPCM seem to be multiparity and
ring towards the end of pregnancy or in the months following
multiple pregnancies, family history, ethnicity, smoking, diabetes,
delivery, abortion or miscarriage, without other causes for heart
hypertension, pre-eclampsia, malnutrition, age of mother (with
failure, and with a left ventricular (LV) ejection fraction (EF) < 45%5
older mothers being at greater risk), and prolonged use of tocolytic
(see Box). Given the fact that there are some patients with typi-
beta-agonists.15,17 – 25
cal features of PPCM and a clear impairment of LVEF, also patients
with an EF value between 45% and 50% may occasionally be diag-
nosed with PPCM. Since no specific test to confirm PPCM exists,
it remains a diagnosis of exclusion, and differential diagnoses need
Pathophysiology
to be considered. In particular, aggravation of a pre-existing heart The aetiology of PPCM is uncertain. A combined ‘two-hit’ model
disease by pregnancy-mediated haemodynamic changes should be including systemic angiogenic imbalance and host susceptibility
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Pathophysiology, diagnosis and management of PPCM 829
(predisposition) is thought to be crucial in the pathophysiology An important differential diagnosis in patients presenting with
........................................................................................................................................................................
of PPCM.26,27 Possible factors leading to PPCM include genetic pre- acute heart failure at the end of pregnancy or directly post-delivery
disposition, low selenium levels, viral infections, stress-activated is severe (pre-)eclampsia leading to pulmonary oedema mainly due
cytokines, inflammation, autoimmune reaction, pathological to diastolic dysfunction. In a South African cohort comparing hyper-
response to haemodynamic stress, unbalanced oxidative stress and tensive heart failure of pregnancy (HHFP) and PPCM,39 PPCM was
induction of antiangiogenic factors.17 – 19,23,26,28 – 32 Particularly, the more often associated with twin pregnancy, smoking, cardiomegaly
oxidative stress-mediated cleavage of the hormone prolactin into with lower LVEF, left atrial hypertrophy, QRS abnormalities, T-wave
a smaller antiangiogenic subfragment, 16-kDa prolactin, may drive inversion and atrial fibrillation. By contrast, HHFP patients were
PPCM by inducing endothelial damage.29,33 Release of endothelial more likely to have a family history of hypertension, hypertension
microparticles loaded with active compounds such as microRNAs, and pre-eclampsia in a previous pregnancy, tachycardia at presen-
whose release into the circulation is also induced by 16-kDa tation, and LV hypertrophy. Mortality was 17% in PPCM compared
prolactin, may subsequently impair cardiomyocyte metabolism and to 0% among HHFP. Those data suggest significant differences in
further contribute to the manifestation of PPCM.13,27,29,33,34 The presentation and outcome of those two conditions that impact
link between vascular pregnancy complications (e.g. pre-eclampsia) the long-term management, prognosis and advice about subsequent
and PPCM was strengthened by the observation that women with pregnancy.
PPCM had high levels of soluble fms-like tyrosine kinase 1 (sFlt-1), In case of cardiogenic shock, pregnancy-associated myocar-
a potent vascular endothelial growth factor inhibitor, which has dial infarction, pulmonary embolism and amniotic fluid embolism
been implicated in the pathogenesis of pre-eclampsia, suggesting should be considered.4 In the post-delivery situation, PPCM often
an overlap between these conditions. Indeed, pro-angiogenic presents with slowly developing heart failure with non-specific
therapies could rescue the PPCM phenotype in experimental symptoms like shortness of breath, fatigue, chest pain, cough and
models. In conclusion, PPCM is a complex disease with a quite abdominal discomfort leading to late diagnosis.40 PPCM should be
heterogeneous and incompletely understood pathophysiology suspected in all women with a delayed return to the pre-pregnancy
involving angiogenic, metabolic, hormonal and oxidative stress state. Table 2 summarizes the diagnostic tests that are recom-
factors. mended for the diagnosis of PPCM at initial diagnosis and at
follow-up visits.
In general, PPCM has to be differentiated from other causes
Genetic aspects of heart failure such as (pre-existing) DCM, adult congenital
heart disease, toxic cardiomyopathy after e.g. chemotherapy, and
Genetically transmitted dilated cardiomyopathy (DCM) may Takotsubo syndrome.5,7,13,27 Particularly after a very stressful
manifest during early adulthood, and is sometimes difficult to dis- labour or emergency due to foetal complications, high mater-
tinguish from PPCM.17,19,35,36 Indeed, recent observations support nal catecholamine levels as well as uterotonic or tocolytic
the notion that around 15–20% of patients with peripartum heart drugs with catecholaminergic properties may trigger Takotsubo
failure carry mutations known to induce cardiomyopathies, i.e. in syndrome.7
genes like titin, beta-myosin heavy chain, myosin-binding protein In a recent analysis of the worldwide EORP PPCM registry,
C (MYBPC3), lamin A/C or sodium voltage-gated channel alpha characteristics and risk factors of PPCM patients with different
subunit 5 (SCN5A).17,19,35,36 One theory is that in gene-positive, ethnicities (including Asians) were reported.3 Despite the huge dif-
phenotype-negative women without clinical symptoms prior to ferences in ethnic and socio-economic backgrounds among regions
pregnancy, the physiological stress of pregnancy and delivery may of the world, the baseline characteristics and mode of presentation
unmask concealed DCM.37 Further investigation is needed regard- of PPCM patients were remarkably similar.
ing mutations or polymorphisms in genes regulating metabolism, Figure 1 summarizes the diagnostic pathway in patients with
oxidative stress response, angiogenesis and the immune system suspected PPCM including electrocardiogram (ECG), determina-
as well as the higher frequency of PPCM in women of African tion of natriuretic peptides, X-ray and echocardiography (accord-
ancestry.10,13,27,38 Genetic testing may be considered in PPCM, in ing to local availability not all four have to be performed in all
particular in those patients with a positive familial history. patients). Figure 2 provides an overview of different clinical sce-
narios in patients with PPCM according to clinical severity with
typical results from diagnostic tests and recommended monitoring
Clinical presentation and treatment.
and (differential) diagnosis
While the majority of patients with PPCM present in the early Electrocardiogram
postpartum period, there should also be a high index of suspicion An ECG should be performed in all patients with suspected PPCM
towards the end of pregnancy.3 The differential diagnoses differ because it is safe, inexpensive and may help distinguish PPCM
according to stage of presentation – pre- vs. postpartum. Table 1 from other causes of symptoms. Although there is no specific
summarizes differential diagnoses of PPCM and features of history, ECG pattern for PPCM, at initial evaluation, the ECG is rarely
onset, biomarkers and echocardiography that help in the differen- normal and repolarization abnormalities are common.41 – 43 Left
tiation from PPCM. bundle branch block may be an indirect sign for cardiomyopathy
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Table 1 Differential diagnoses of peripartum cardiomyopathy
830
History Onset Biomarkers

Echocardiography/ Differentiation
cardiac MRI from PPCM
.........................................................................................................................................................................................
PPCM No known cardiac disease, no Towards the end of pregnancy Elevated natriuretic peptides Reduced systolic LV function, –
HF signs and/or symptoms and the months following LVEF < 45%
prior pregnancy delivery
Myocarditis Prior viral infection (e.g. Acute or subacute onset after Elevated troponin, elevated Normal or reduced systolic LV Cardiac MRI (LE pattern),
respiratory) viral infection CRP function, typical myocardial myocardial biopsy
late gadolinium enhancement
pattern, pericardial effusion
Pre-existing idiopathic/ HF signs and/or symptoms During second trimester of Elevated natriuretic peptides Reduced systolic LV function, History, echocardiography,
familial dilated or and/or known heart disease pregnancy RV dysfunction possible, cardiac MRI (LE pattern)
acquired prior pregnancy typical myocardial LE pattern
cardiomyopathy (DCM)
Takotsubo syndrome Chest pain, very stressful Acute onset, during delivery or Elevated natriuretic peptides Regional wall motion History, echocardiography
delivery or emergency due to immediately after delivery abnormalities with typical
foetal complications anatomical patterns
Pregnancy-associated Chest pain, epigastric pain Acute onset, during pregnancy Elevated troponin Regional wall motion History, ECG, coronary
myocardial infarction or immediately after delivery abnormalities, ischaemic angiography, cardiac MRI
myocardial scar (LE pattern)
Pulmonary embolism Chest pain, unilateral leg Acute onset during pregnancy or Elevated natriuretic peptides RV dysfunction, RV dilatation, Computed tomography, VQ
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swelling, acute dyspnoea after delivery and/or troponin, elevated LV function usually normal scan
D-dimer
Amniotic fluid embolism Chest pain during/immediately Acute onset during delivery or Elevated natriuretic peptides Reduced RV systolic function, History, echocardiography
after delivery, acute dyspnoea immediately after delivery possible RV dilatation
Hypertensive heart Pre-existing or new-onset During second trimester of Elevated natriuretic peptides LV hypertrophy, diastolic History, echocardiography
disease/severe hypertension, proteinuria pregnancy dysfunction, transient LV
pre-eclampsia dysfunction
Hypertrophic Familial predisposition During second trimester of Elevated natriuretic peptides LV hypertrophy, typical History, echocardiography,
cardiomyopathy pregnancy myocardial late enhancement cardiac MRI (LE pattern)
pattern, LVOTO (HOCM)
HIV/AIDS HIV infection, AIDS During second trimester of Elevated natriuretic peptides Reduced systolic LV function, HIV serology/test
cardiomyopathy pregnancy LV/RV often not dilated
Pre-existing (unknown) HF signs and/or symptoms prior During second trimester of Elevated natriuretic peptides (Corrected) congenital heart History, echocardiography
congenital heart pregnancy, known heart pregnancy defects, cardiac shunts
disease disease, prior cardiac surgery
Pre-existing valvular HF signs and/or symptoms prior During second trimester of Elevated natriuretic peptides Valvular stenosis or History, echocardiography
heart disease pregnancy, known heart pregnancy regurgitation, prosthetic
disease heart valves
AIDS, acquired immunodeficiency syndrome; CRP, C-reactive protein; DCM, dilated cardiomyopathy; ECG, electrocardiogram; HOCM, hypertrophic obstructive cardiomyopathy; HF, heart failure; HIV, human immunodeficiency virus;
LE, late enhancement; LV, left ventricular; LVEF, left ventricular ejection fraction; LVOTO, left ventricular outflow tract obstruction; MRI, magnetic resonance imaging; PPCM, peripartum cardiomyopathy; RV, right ventricular; VQ,
ventilation–perfusion.
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J. Bauersachs et al.

Table 2 Diagnostic tests that are recommended for the diagnosis of peripartum cardiomyopathy at initial diagnosis
and at follow-up visits
Clinical ECG Natriuretic Echocardiography Chest Cardiac CT Coronary

examination peptides X-ray MRI scan angiography
...........................................................................................................................................
Diagnosis of PPCM X X X X X (X)b (X)b (X)b
4-6 weeks after diagnosis X X X X
3 months after diagnosis X X Xa X
6 months after diagnosis X X Xa X (X)b
Annually for at least 5 years X X Xa X
after diagnosis (especially if
not fully recovered)
Generally, an individual approach is recommended depending on the severity of the disease and/or potential differential diagnoses.
CT, computed tomography; ECG, electrocardiogram; MRI, magnetic resonance imaging; PPCM, peripartum cardiomyopathy.
a May be considered depending on costs and local availability.
b May be considered depending on the clinical presentation and/or differential diagnoses.
* Symptoms during end of pregnancy or months following delivery:
Suspected acute PPCM* dyspnoea, orthopnoea, peripheral oedema, chest pain, dizziness,
palpitations, fatigue, depression, cough
** Cut-off for acute HF: NT-proBNP >300 pg/ml, BNP >100 pg/ml
Natriuretic peptides, ECG,

chest X-ray, and echocardiography
Natriuretic peptides↑** Natriuretic peptides↑ Natriuretic peptides

and LVEF <45% and LVEF ≥45% normal and LVEF ≥45%
Acute PPCM likely
Exclude overt pre-existing Consider other cardiac and Consider extracardiac

heart disease extracardiac origin origin of symptoms
(e.g. chemotherapy-induced of symptoms (e.g. anaemia, pneumonia, renal
cardiomyopathy, congenital or (e.g. pulmonary embolism, amniotic disease, hypertensive disorders
fluid embolism, isolated RV dysfunction, of pregnancy, eclampsia, depression,
valvular heart disease,
hypertensive disorders of pregnancy, physiological changes)
hypertrophic cardiomyopathy)
eclampsia, sepsis)
Figure 1 Diagnostic pathway in patients with suspected peripartum cardiomyopathy (PPCM). BNP, B-type natriuretic peptide;
ECG, electrocardiogram; HF, heart failure; LVEF, left ventricular ejection fraction; NT-proBNP, N-terminal pro-B-type natriuretic peptide;
RV, right ventricular.
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Mild PPCM Moderate PPCM Severe PPCM
Clinical Subacute heart failure Acute heart failure Cardiogenic shock

presentation Haemodynamic stability Haemodynamic instability
Haemodynamic stability
Respiratory insufficiency Respiratory insufficiency
ECG No specific changes No specific changes, often tachycardia No specific changes, often tachycardia
Pulmonary congestion, Pulmonary congestion, Pulmonary congestion, enlarged cardiac

Chest X-ray
may also be normal enlarged cardiac silhouette silhouette, pleural effusion
Natriuretic
peptides ↑ ↑↑ ↑↑↑
LVEF <25%, RV dysfunction

Echocardiography LVEF 30-45% LVEF 20-35%
and dilatation possible
Normal ward, ambulatory treatment

Intermediate care (IMC), HF unit (HFU) Intensive care unit (ICU)
in selected patients possible
– Oral HF drugs – Diuretics i.v. – Diuretics i.v.

– Oral diuretics in case of fluid overload – Consider vasorelaxants if SBP >110 mmHg – Inotropes/catecholamines if needed
– Consider bromocriptine for 1 weeka – Supplemental O2, non-invasive ventilation – Invasive ventilation
Therapy if necessary – Mechanical circulatory support (Impella
and/or ECMO)
– Avoid inotropes/catecholamines
– Consider bromocriptine for 8 weeksa,
– Consider bromocriptine for 8 weeksa if uptitration depending on prolactin levels
LVEF <25% – Oral HF drugs after stabilization
– Oral HF drugs
Figure 2 Overview of different clinical scenarios in patients with peripartum cardiomyopathy (PPCM). Typical results from diagnostic tests
and recommended monitoring/treatment options are depicted according to disease severity. ECG, electrocardiogram; ECMO, extracorporeal
membrane oxygenation; HF, heart failure; HFU, heart failure unit; ICU, intensive care unit; IMC, intermediate care unit; LVEF, left ventricular
ejection fraction; RV, right ventricular; SBP, systolic blood pressure. a Bromocriptine may be considered in PPCM patients (class IIb
recommendation) and should be accompanied by at least prophylactic anticoagulation.
and structural heart disease should be ruled out in these women.44 can be ruled out with high probability), and they should not be
.............................................
A recent study identified a long QTc interval at baseline which was used solely to establish the diagnosis of PPCM. Although one study
found in almost 50% of the patients, and tachycardia as predictors demonstrated plasma BNP levels > 1860 pg/mL as an independent
of poor outcome in PPCM.45 factor for persistent LV dysfunction, prognostic properties of
natriuretic peptides remain uncertain.47,48 Serum troponin con-
centrations measured at baseline may predict persistent LV
Biomarkers dysfunction after 6 months.49 More specific biomarkers would be
Concerning diagnostic properties of natriuretic peptides, helpful to allow a faster and more reliable diagnosis of PPCM,
one should keep in mind that B-type natriuretic peptide but these are yet to be adequately defined. Candidates involve
(BNP)/N-terminal proBNP (NT-proBNP) levels are not or only 16 kDa-prolactin, interferon-gamma, asymmetric dimethylarginine
slightly elevated in normal pregnancy.46 By contrast, patients with (ADMA) and microRNA-146a.11,29,32 There is controversy on the
acute PPCM have consistently elevated plasma concentrations of impact of imbalanced angiogenesis. Recently, high placenta growth
natriuretic peptides, BNP or NT-proBNP.5,11 The most important factor (PlGF) and/or low sFlt-1/PlGF were suggested to be useful
role of natriuretic peptides is to rule out heart failure (with a to diagnose PPCM. More research in this field is needed before
threshold < 100 pg/mL for BNP and < 300 pg/mL for NT-proBNP any recommendations can be made.50
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Cardiac imaging did not show a beneficial effect on outcome.4,58 The terato-
........................................................................................................................................................................
genic effects of inotropic support and vasopressors in humans
Echocardiography is indicated as soon as possible in all cases of sus-
are unknown but their use may be necessary. In PPCM patients
pected PPCM to confirm the diagnosis, assess concomitant or
with severely reduced LV function and/or cardiogenic shock, VAD
pre-existing cardiac disease, exclude complications of PPCM (e.g.
implantation as bridge to recovery or transplantation can be nec-
LV thrombus) and obtain prognostic information (for example LVEF
essary (2–7% of PPCM patients).4,9,11 It is important to note,
and pulmonary hypertension). After stabilization, magnetic reso-
however, that a significant proportion of PPCM patients improve
nance imaging may provide a more accurate evaluation of cardiac
or normalize their LV function over the first 6 months after
structure and function, and can sometimes be helpful if there is
diagnosis, which must be considered when decisions are made.4
high suspicion for another diagnosis such as arrhythmogenic right
Short-term assist devices, e.g. microaxial pump, Centrimag or
ventricular cardiomyopathy and myocarditis. The incremental value
venoarterial extracorporeal membrane oxygenation (ECMO), may
of cardiac magnetic resonance imaging in addition to echocardio-
be required.59 Long-term assist devices with left VAD or biven-
graphy is uncertain. Administration of gadolinium to assess late
tricular VAD can be implanted and some have been explanted
enhancement should be avoided until after delivery due to the
after recovery.60,61 Due to the toxic effects of beta-adrenergic
increased risk of stillbirth, neonatal death, and rheumatological,
agonists specifically in PPCM, MCS may be considered with a
inflammatory, or infiltrative skin conditions.51
lower threshold than in other patients with inotrope-dependent
cardiogenic shock.25
Endomyocardial biopsy
Endomyocardial biopsy adds limited diagnostic or prognostic infor- Heart transplantation in peripartum
mation in PPCM. It may be used to exclude acute myocarditis
after delivery, reveal significant viral presence, and exclude rare
cardiomyopathy
autoimmune myocarditis, storage or metabolic disease.52 Whether Early cardiac transplantation should be reserved for patients
or not myocarditis can be a mechanism of PPCM or whether with refractory severe heart failure where MCS is not possible or
myocarditis is a distinct entity is unclear. Myocarditis has been not desirable for individual reasons, mainly for cases with biventric-
identified occasionally in patients thought to have PPCM.53 Rou- ular failure or severe initial right ventricular dysfunction.62 Patients
tine endomyocardial biopsy is not recommended in patients with with PPCM appear to have higher rates of graft failure and death
suspected PPCM. after heart transplantation, which may be partly explained by
higher allosensitization, higher pre-transplant acuity, and increased
rejection.63 As late recovery beyond 6–12 months is possible64 and
Management outcomes with heart transplantation in PPCM are worse than in
other causes of heart failure, delaying heart transplantation as long
Acute heart failure as possible is desirable.
In cases when PPCM presents with acute, decompensated heart
failure (see Figure 2, clinical scenario acute heart failure/cardiogenic
shock), the guidelines for the management of acute heart fail- Stabilized/chronic heart failure
ure apply.54,55 For rapid diagnosis and decision making in all preg- For treatment of stabilized/chronic heart failure, the pregnancy
nant women with acute heart failure, a pre-specified manage- status of the patient is important. Women who present with PPCM
ment algorithm and the establishment of a multidisciplinary team during pregnancy require joint cardiac and obstetric care.4,57 Pos-
is crucial.4,56,57 Multidisciplinary care includes cardiologists, inten- sible adverse effects on the foetus must be considered when
sivists, obstetricians, neonatologists, anaesthetists and cardiac sur- prescribing drugs. Drugs for heart failure that can and cannot be
geons (see Figure 1 in ref. 4). Timely diagnosis and treatment are used during pregnancy are described in Table 3. During pregnancy,
crucial. A recommended treatment algorithm for patients with angiotensin-converting enzyme (ACE) inhibitors, angiotensin
acute PPCM is given in Figure 2 in ref. 4. Clearly, the initial treat- receptor blockers (ARBs), angiotensin receptor–neprilysin
ment of patients with severe forms of acute PPCM is different to inhibitors (ARNI), ivabradine and mineralocorticoid receptor
those of stable patients (Figure 2). antagonists (MRAs) are contraindicated because of concerns of
If a patient is in cardiogenic shock/dependent on inotropes, teratogenicity and foetotoxicity.13,56 Hydralazine, e.g. 25 mg every
she should be transferred immediately to an advanced heart fail- 6 h, and nitrates, e.g. isosorbide dinitrate 20 mg once daily with
ure centre where mechanical circulatory support (MCS), ven- up-titration as tolerated, can be used during pregnancy instead
tricular assist devices (VAD), and transplant consult teams are of ACE inhibitors/ARBs for afterload reduction. Beta-blocker
available.4,55 Experimental data and a study in PPCM patients indi- treatment is indicated for all patients with PPCM whether or not
cated that patients with PPCM may be especially sensitive to the patient is pregnant or after delivery. These drugs should only
toxic effects of beta-adrenergic receptor stimulation which should be started in patients who are euvolaemic and clinically stable.
be avoided whenever possible.25 Norepinephrine is indicated to Diuretics should be used if patients have symptoms or signs of
restore blood pressure, and levosimendan may be considered, congestion whether or not they are pregnant, despite concerns
however the only (small) randomized clinical trial in PPCM patients about placental blood flow.
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834
Table 3 Medications safety during pregnancy and lactation J. Bauersachs et al.
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Table 3 Continued
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Table 3 Continued 836
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Green: may be used, use with caution; yellow: use with extreme caution; red: should be avoided/contraindicated.
ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; ARNI, angiotensin receptor–neprilysin inhibitor; ESC, European Society of Cardiology; LWMH, low molecular weight heparin; MRA, mineralocorticoid
receptor antagonist; NOAC, non-vitamin K antagonist oral anticoagulant; VKA, vitamin K antagonist.
© 2019 The Authors

J. Bauersachs et al.

Numbers in square brackets are references, which can be found online in the supplementary Appendix S1.
Post-delivery whether or not a woman is breastfeeding should be Delivery
........................................................................................................................................................................
established when considering the choice of drug therapy for heart
Vaginal delivery is always preferable if the patient is haemodynami-
failure. For those who are breastfeeding, the drugs that can and
cally stable and there are no absolute obstetric indications for cae-
cannot be used are also described in Table 3; it should be acknowl-
sarean delivery. Close haemodynamic monitoring is required.
edged that there are limited data to guide these recommendations.
Epidural analgesia is preferred. Urgent delivery irrespective of ges-
The risks of drugs during lactation cannot be described clearly
tation duration should be considered in women with advanced
but our expert-based recommendations attempt to balance the
heart failure and haemodynamic instability despite optimal heart
likely pros of therapy for heart failure against potential cons. Many
failure treatment.4 In these cases, caesarean section is recom-
drugs, including ACE inhibitors, beta-blockers and MRAs, pass into
mended with central neuraxial anaesthesia. To prevent abrupt pres-
human breast milk but this is often at clinically insignificant levels. A
sure or volume changes, epidural anaesthesia might be the method
summary of previously published guidance in national and interna-
of choice but should be carefully titrated, guided by an expert
tional guidelines (including from the World Health Organization) is
anaesthetic team.4,56,57 If MCS may become necessary, the patient
included in the online supplementary Table S1. These prior guide-
should be delivered by appropriate teams in hospitals capable of
lines illustrate a lack of definitive data as they are frequently discor-
providing such care.
dant both with each other and sometimes even within the same
document.
For those not breastfeeding, heart failure should be treated Breastfeeding
according to guidelines on acute and chronic heart failure including Breastfeeding in patients with heart failure is controversial. Accord-
ACE inhibition, beta-blockade and MRAs, and then replacing ACE ing to the 2018 ESC guidelines for the management of cardiovascu-
inhibitors and ARBs with ARNI13,54 (Table 4). As high resting heart lar diseases during pregnancy,56 in patients with severe heart failure
rate is a predictor of adverse outcome, treatment with ivabradine preventing lactation may be considered due to the high metabolic
might be useful in PPCM patients with high heart rate in sinus demands of lactation and breastfeeding (class IIb recommenda-
rhythm on top of beta-blockade.65,66 tion). These guidelines state that stopping lactation enables safe
All patients should remain on a combined drug regimen for treatment with all established heart failure drugs. Normal growth
heart failure until they experience complete myocardial recovery percentiles and no adverse outcome for infants were observed in
and for at least 12–24 months after full recovery of LV function.13 a collective of PPCM patients in South Africa where breastfeed-
Following complete recovery, how long medical therapy should ing was terminated.71 However, breastfeeding is tolerated by many
continue is unknown. Many clinicians recommend that all patients women with PPCM with respect to their heart failure status. Addi-
with PPCM remain on long-term therapy to avoid the potential tionally, many drugs for heart failure are also not contraindicated
decline in cardiac function which is a risk on stopping pharma- in breastfeeding mothers (see above and Table 3). Breastfeeding
cological therapy for heart failure.67 Others believe that drugs may also confer important benefits to infants and mothers, espe-
can be gradually withdrawn under careful surveillance with serial cially in developing countries. Numerous national and international
cardiac imaging and biomarker measurement. A full discussion guidelines, including from the World Health Organization, advise
between patient, family and clinicians is necessary where the pros that many heart failure drugs are compatible with breastfeeding if
and cons of stopping or continuing therapy are carefully consid- used with caution (see online supplementary Table S1). Data on
ered. Data to guide these decisions are limited. In a small cohort infant safety with breastfeeding is very limited however, and often
with recovered LV function post-PPCM who stopped their drug involves older therapeutic agents and tiny patient numbers. Many
therapy, none experienced worsening of LV function; but this is drugs, including ACE inhibitors, beta-blockers and MRAs, pass into
not definitive evidence for the safety of withdrawing drug therapy human breast milk but this is often at clinically insignificant levels
in patients who have PPCM.68 In those patients with an identi- (see online supplementary Table S1). Most studies often also involve
fied genetic contribution, indefinite continuation of heart failure single agents, rather than combinations of drugs. Breastfeeding may
therapy is recommended.69 When a patient wishes to consider a also confer important physical and psychological benefits to infants
subsequent pregnancy (following a fully informed decision-making and mothers, especially in developing countries.72
process) drug therapy can be withdrawn under close monitor- Decisions on whether to inhibit lactation, terminate breastfeed-
ing for around 6 months before embarking on conception and ing or continue breastfeeding with caution should be taken jointly
pregnancy. with the patient on a case-by-case basis, taking into consideration
Pro-coagulant activity is increased during and early after both the health of the mother and the risk:benefit ratio of breast-
pregnancy.70 In the context of reduced EF in PPCM, initial treat- feeding to the infant. Good counselling and shared decision-making
ment with low molecular weight heparin or oral anticoagulation are key. Online supplementary Table S1 summarizes the current lit-
at least in prophylactic dose is recommended because of the high erature around lactation safety and heart failure drugs and may help
rate of peripheral arterial and venous embolism (7% in the first guide clinicians, should mothers wish to continue breastfeeding.
30 days after delivery, data from the PPCM worldwide registry).3
Therapeutic anticoagulation is firmly recommended in patients
with intracardiac thrombus detected by imaging or evidence of Bromocriptine treatment
systemic embolism, as well as in patients with paroxysmal or Based on the above-mentioned pathophysiological pathway
persistent atrial fibrillation. of 16kD-prolactin-mediated PPCM, a small (n = 20) prospective
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Table 4 Chronic drug treatment in peripartum cardiomyopathy patients after delivery
Drug Persisting heart failure and absence Complete and sustained recovery (LVEF > 55%
of complete LV recovery and NYHA functional class I)
...........................................................................................................................................
Beta-blocker Essential for all patients in standard or maximally tolerated Continue all drugs (beta-blocker, ACEI/ARB/ARNI, MRA) for at
dosages least 12–24 months after full recovery, individual
approach/discuss with patient. Discontinue stepwise and
monitor symptoms and LV function:
1. MRA
2. ACEI/ARB/ARNI
3. Beta-blocker
ACEI Essential for all patients in standard or maximally tolerated
dosages
ARB Recommended in patients who do not tolerate ACEI
ARNI Recommended in patients with LVEF < 40% who are symptomatic
despite maximal dosages of beta-blocker, ACEI/ARB and MRA
MRA Recommended in patients with LVEF < 40%, preferably
eplerenone due to less hormonal side effects and less blood
pressure reduction compared to spironolactone
Ivabradine Recommended in patients in sinus rhythm with a persisting heart Discontinue if heart rate < 50 b.p.m. and/or in case of complete
rate > 70 b.p.m. at rest despite maximal tolerated beta-blocker recovery
up-titration
Diuretics Recommended in patients with fluid overload Taper dose/discontinue if no signs of fluid overload, maintain only
if part of antihypertensive therapy
Please note that initiation of all heart failure drugs is only possible in patients who do not breastfeed (see also Table 3 and online supplementary Table S1 for a more
comprehensive summary of compatibilities with breastfeeding).
ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; ARNI, angiotensin receptor–neprilysin inhibitor; LV, left ventricular; LVEF, left ventricular
ejection fraction; MRA, mineralocorticoid receptor antagonist; NYHA, New York Heart Association.
randomized pilot study supported the hypothesis that the addi- support.77 Individualized bromocriptine treatment with dose
.................................................................................
tion of the prolactin-blocker bromocriptine to standard heart up-titration until successful prolactin suppression is achieved is
failure therapy has beneficial effects on LVEF and mortality in a possible therapeutic option in these highly selected cases.59
women with severe acute PPCM.71 Furthermore, in the Ger- The safety profile seems reasonable when at least prophylactic
man PPCM registry, standard heart failure plus bromocriptine anticoagulation is administered.59
treatment was associated with low mortality.11 The randomized International variations in the use of bromocriptine are large:
prospective German bromocriptine study compared short- and in the USA bromocriptine is rarely used9 whereas in Germany
long-term bromocriptine treatment in patients with severe PPCM and non-EU countries in the worldwide PPCM registry, treatment
(EF < 35%).73 Both high and low doses were associated with with bromocriptine is common.3 There are no large, random-
low mortality (there was no placebo arm). A Canadian study ized, placebo-controlled trials of bromocriptine in PPCM. A small
reported a greater LV recovery in PPCM patients treated with (n = 60) bromocriptine vs. placebo trial is underway in Canada.
bromocriptine.74 Treatment with bromocriptine may especially Considerably larger, international placebo-controlled trials would
be considered in patients with right ventricular involvement.75 A be necessary to establish firm proof of clinical benefit, however, a
bromocriptine treatment scheme has been suggested: bromocrip- truly placebo-controlled trial will not be possible as the placebo
tine (2.5 mg once daily) for at least 1 week may be considered in arm would continue lactation and therefore blinding would not be
uncomplicated cases, whereas prolonged treatment (2.5 mg twice achievable.
daily for 2 weeks, then 2.5 mg once daily for another 6 weeks) may To date, bromocriptine may be considered in patients with
be applied in patients with EF < 25%, right ventricular involvement, PPCM (class IIb recommendation).56 As thromboembolic events
intensive care treatment, and/or cardiogenic shock (Figure 3).76 have been reported during the use of bromocriptine (albeit mostly
There is no consensus as to whether or not bromocriptine at higher dosages), bromocriptine treatment should always be
should be used in PPCM. Some believe that as acute heart failure accompanied by anticoagulation at least in prophylactic dosages.
due to PPCM can have a poor prognosis in some patients and Therapies for patients with acute PPCM have been proposed under
there are no evidence-based drug treatments, bromocriptine the BOARD label: Bromocriptine, Oral heart failure therapies,
should be used. Anticoagulants, vasoRelaxing agents, and Diuretics.78
Data on bromocriptine treatment in PPCM patients with If bromocriptine is not available, cabergoline may be used as an
cardiogenic shock are scarce. Elevated prolactin levels have alternative to bromocriptine, however apart from two reports12,79
been associated with poor outcome in patients receiving ECMO data are lacking regarding LV recovery with cabergoline in PPCM.
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BOARD scheme
Bromocriptine Oral HF drugs Anticoagulation Relaxants Diuretics

(dose according (beta-blocker, (at least in (intravenous (in case of fluid
to severity of ACE inhibitor/ prophylactic vasodilators if overload)
the disease) ARB, MRA) dose) SBP >110 mmHg)
LVEF ≥ 25%,
Bromocriptine 2.5 mg o.d. for 7 days,
no cardiogenic shock,
at least prophylactic anticoagulation
no ICU treatment
LVEF <25%, Bromocriptine 2.5 mg b.i.d. for 14 days

and/or RV dysfunction, followed by bromocriptine 2.5 mg o.d.
and/or cardiogenic shock, for another 42 days, at least
and/or ICU treatment prophylactic anticoagulation
Start with bromocriptine 2.5 mg b.i.d.,

ICU treatment, uptitrate to a maximum of 10-20 mg
cardiogenic shock daily depending on serum prolactin
with ventilation and/or MCS levels until successful suppression,
at least prophylactic anticoagulation
Figure 3 BOARD scheme for the therapy of patients with acute peripartum cardiomyopathy (PPCM). Of note, this scheme addresses
patients after delivery who do not breastfeed. If bromocriptine treatment is considered (class IIb recommendation), different regimens
are recommended according to disease severity. ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker; b.i.d., twice daily;
HF, heart failure; ICU, intensive care unit; LVEF, left ventricular ejection fraction; MCS, mechanical circulatory support; MRA, mineralocorticoid
receptor antagonist; o.d., once daily; RV, right ventricular; SBP, systolic blood pressure.
Prevention of sudden cardiac death (CRT) are recommended according to current ESC guidelines.54
..................................................
and device therapy Although in non-ischaemic cardiomyopathy the necessity of ICD

has been questioned in older patients,82 young patients with severe
Given the high rate of improvement of LV function dur- LV dysfunction despite optimal medical therapy may still derive
ing optimal heart failure drug therapy, early implantation benefit from ICD implantation.83 Subcutaneous ICDs represent an
of an implantable cardioverter-defibrillator (ICD) in patients alternative to transvenous systems, although they neither provide
with newly diagnosed PPCM is generally not advisable. Wearable anti-tachycardia pacing nor post-shock pacing, but can be more
cardioverter-defibrillators (WCDs) have been proposed as a
easily extracted if cardiac function recovers.
mechanism to prevent sudden cardiac death during the first
3–6 months after diagnosis until a definitive decision about ICD
implantation can be made.4,41,80,81 In a German registry of patients
Prognosis, counselling, subsequent
with severe PPCM, several appropriate shocks were delivered for
ventricular fibrillation within the first months.41,80 No randomized pregnancies
trials of WCDs in PPCM have yet been started. The HFA of the ESC Study Group on PPCM published in 2018 a
For women presenting with severe LV dysfunction > 6 months practical guidance paper on the long-term prognosis, subsequent
following first presentation despite optimal medical therapy, pregnancy, contraception and overall management of patients diag-
implantation of an ICD as well as cardiac resynchronization therapy nosed with PPCM.64
© 2019 The Authors

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Current evidence for long-term outcome is based mostly on from MyCartis, Critical diagnostics, outside the submitted work.
........................................................................................................................................................................
retrospective data or on single-centre prospective studies or R.A.d.B. reports grants from AstraZeneca, Bristol-Myers Squibb,
small registries covering only 6–12 months postpartum with a Abbott, Novo Nordisk, Roche, Trevena, Thermofisher GmbH,
wide variation in reported mortality rates, ranging from 2% in and personal fees from AstraZeneca, MandalMed, Inc., Novartis,
Germany11 to 12.6% from 206 patients with PPCM from South Servier, other from scPharmaceuticals, Inc., outside the submitted
Africa.66 African American women were more likely to worsen work. C.M. reports grants, personal fees and non-financial support
after initial diagnosis, had a lower chance to recover despite appar- from several diagnostic companies, outside the submitted work.
ent adequate treatment.10 Even after full recovery of LVEF, subtle A.R.L. reports personal fees from Servier, Novartis, Roche, Takeda,
diastolic dysfunction and reduced maximal exercise capacity (peak Boehringer Ingelheim, Amgen, Clinigen Group, Ferring Pharmaceu-
oxygen uptake) was reported recently in a Danish PPCM cohort ticals, Eli Lily, Bristol-Myers Squibb, Eisai Ltd; and grants and per-
compared to women with previous severe pre-eclampsia and previ- sonal fees from Pfizer, outside the submitted work. L.H.L. reports
ous uncomplicated pregnancies.84 Residual cardiac impairment was grants and other from Novartis, Vifor Pharma, Relypsa; other
also shown by assessing echocardiographic tissue Doppler imag- from Merck, Boehringer Ingelheim, Sanofi, AstraZeneca, Bayer; and
ing and speckle tracking for myocardial strain imaging.85 Imaging grants from Boston Scientific, outside the submitted work. O.C.
findings that are associated with an unfavourable outcome include reports grants from Novartis, Servier, and Vifor, outside the sub-
LV end-diastolic diameter > 60 mm, severely depressed LV function mitted work. S.D.A. reports grants and personal fees from Vifor Int,
(< 30%) and right ventricular dysfunction at initial diagnosis.9,86 Abbott Vascular/SJM; personal fees from Bayer, Boehringer Ingel-
All patients with a previously diagnosed PPCM and their partners heim, Novartis, Servier, outside the submitted work. P.M.S. reports
should receive careful counselling (class I recommendation) about grants/research supports from the Ministry of Education, Science
the longer-term prognosis and undergo a risk stratification if and Technological Development of Republic of Serbia; honoraria or
further pregnancies are considered (see Figure 1 in ref. 64). Based consultation fees from Servier, Boehringer Ingelheim, Hemofarm,
on a recent publication reporting on the outcome of women with Novartis, AstraZeneca, and participation in a company sponsored
PPCM and a subsequent pregnancy in cohorts from Germany, speaker’s bureau: Fondazione Internazionale Menarini. The other
Scotland and South Africa,76,87 women with an impaired systolic authors have nothing to disclose.
function are at substantial risk of relapse and death, and should
therefore be strongly advised against pregnancy. As any subsequent
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doi:10.1002/ejhf.1494
Heart Failure Association of the European

Society of Cardiology practical guidance on
the use of natriuretic peptide concentrations
Christian Mueller1*, Kenneth McDonald2, Rudolf A. de Boer3, Alan Maisel4,
John G.F. Cleland5, Nikola Kozhuharov1, Andrew J.S. Coats6,7,8, Marco Metra9,
Alexandre Mebazaa10, Frank Ruschitzka11, Mitja Lainscak12,13,
Gerasimos Filippatos14,15, Petar M. Seferovic16, Wouter C. Meijers3,
Antoni Bayes-Genis17,18, Thomas Mueller19, Mark Richards20,21,
and James L. Januzzi Jr22, on behalf of the Heart Failure Association of the
European Society of Cardiology
1 Department of Cardiology and Cardiovascular Research Institute Basel (CRIB), University Hospital Basel, University of Basel, Basel, Switzerland; 2 Department of Cardiology, St.
Vincent’s University Hospital, Dublin, Ireland; 3 University of Groningen, University Medical Center, Groningen, Department of Cardiology, The Netherlands; 4 University of
California, San Diego, CA, USA; 5 Robertson Institute of Biostatistics and Clinical Trials Unit, University of Glasgow, Glasgow, UK; 6 University of Warwick, Coventry, UK;
7 Monash University, Melbourne, Australia; 8 Pharmacology, Centre of Clinical and Experimental Medicine, San Raffaele Pisana Scientific Institute, Rome, Italy; 9 Institute of
Cardiology, Department of Medical and Surgical Specialties, Radiological Sciences, and Public Health, University of Brescia, Brescia, Italy; 10 Université de Paris, APHP
Département d’Anethésie-Réanimation Hôpitaux Universitaires Saint Louis Lariboisière, Paris, France; 11 Department of Cardiology, University Heart Centre, University Hospital
Zurich, Zurich, Switzerland; 12 Department of Internal Medicine, General Hospital Murska Sobota, Murska Sobota, Slovenia; 13 Faculty of Medicine, University of Ljubljana,
Slovenia; 14 Department of Cardiology, Athens University Hospital Attikon, University of Athens, Greece; 15 University of Cyprus, Medical School, Nicosia, Cyprus; 16 Faculty of
Medicine, University of Belgrade, Belgrade, Serbia; 17 Heart Institute, Hospital Universitari Germans Trias i Pujol, CIBERCV, Barcelona, Spain; 18 Department of Medicine,
Autonomous University of Barcelona, Barcelona, Spain; 19 Department of Clinical Pathology, Hospital of Bolzano, Bolzano, Italy; 20 Christchurch Heart Institute, Uinversity of
Otago, New Zealand; 21 Cardiovascular Research Institute, National University of Singapore, Singapore; and 22 Cardiology Division of the Department of Medicine, Massachusetts
General Hospital, Harvard Medical School, Boston, MA, USA
Received 18 December 2018; revised 4 April 2019; accepted 23 April 2019
Natriuretic peptide [NP; B-type NP (BNP), N-terminal proBNP (NT-proBNP), and midregional proANP (MR-proANP)] concentrations are
quantitative plasma biomarkers for the presence and severity of haemodynamic cardiac stress and heart failure (HF). End-diastolic wall stress,
intracardiac filling pressures, and intracardiac volumes seem to be the dominant triggers. This paper details the most important indications
for NPs and highlights 11 key principles underlying their clinical use shown below.
(i) NPs should always be used in conjunction with all other clinical information.
(ii) NPs are reasonable surrogates for intracardiac volumes and filling pressures.
(iii) NPs should be measured in all patients presenting with symptoms suggestive of HF such as dyspnoea and/or fatigue, as their use
facilitates the early diagnosis and risk stratification of HF.
(iv) NPs have very high diagnostic accuracy in discriminating HF from other causes of dyspnoea: the higher the NP, the higher the
likelihood that dyspnoea is caused by HF.
(v) Optimal NP cut-off concentrations for the diagnosis of acute HF (very high filling pressures) in patients presenting to the emergency
department with acute dyspnoea are higher compared with those used in the diagnosis of chronic HF in patients with dyspnoea on
exertion (mild increase in filling pressures at rest).
(vi) Obese patients have lower NP concentrations, mandating the use of lower cut-off concentrations (about 50% lower).
(vii) In stable HF patients, but also in patients with other cardiac disorders such as myocardial infarction, valvular heart disease, atrial
fibrillation or pulmonary embolism, NP concentrations have high prognostic accuracy for death and HF hospitalization.
*Corresponding author. Department of Cardiology and Cardiovascular Research Institute Basel (CRIB), University Hospital Basel, University of Basel, Basel, Switzerland. Tel: +41
61 328 65 49, Fax: +41 61 265 53 53, Email: christian.mueller@usb.ch
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716 C. Mueller et al.
(viii) Screening with NPs for the early detection of relevant cardiac disease including left ventricular systolic dysfunction in patients with
cardiovascular risk factors may help to identify patients at increased risk, therefore allowing targeted preventive measures to prevent
HF.
(ix) BNP, NT-proBNP and MR-proANP have comparable diagnostic and prognostic accuracy.
(x) In patients with shock, NPs cannot be used to identify cause (e.g. cardiogenic vs. septic shock), but remain prognostic.
(xi) NPs cannot identify the underlying cause of HF and, therefore, if elevated, must always be used in conjunction with cardiac imaging.
..........................................................................................................
Keywords Heart failure • Natriuretic peptides • Cut-off concentrations
Introduction Physiology
....................................................................................................................................
Natriuretic peptides [NP; B-type natriuretic peptide (BNP), Although NP levels can be modulated by lesser understood mech-
N-terminal proBNP (NT-proBNP)] are quantitative plasma anisms, the most important one is in the setting of volume
biomarkers of the presence and severity of haemodynamic car- expansion and/or pressure overload: the resulting end-diastolic
diac stress and heart failure (HF). This paper gives their most wall stress initiates synthesis of NP precursors in the ventricu-
important indications and highlights key principles underlying their lar and atrial myocardium.12,21 – 25 Furthermore, BNP/NT-proBNP
clinical use. are exclusively produced by the cardiac tissue and, as such, NP
Natriuretic peptides are of substantial medical value for the diag- production reflects wall stress, a product of intracardiac vol-
nostic evaluation of suspected HF.1,2 This indication is supported umes and filling pressures. Through binding to multiple NP recep-
by several diagnostic and randomised controlled studies and is con- tors, NPs lead to natriuresis, diuresis, vasodilatation, improved
sistently recommended in clinical practice guidelines.1,2 NPs also myocardial relaxation, and reduced myocardial fibrosis.26 There-
can help in a broad range of other indications, including prognos- fore, NPs serve an important regulatory role by opposing the
tication of patients with established cardiovascular disorders such vasoconstriction, sodium retention, and anti-diuretic effects of the
as myocardial infarction, valvular heart disease, HF and pulmonary activated renin–angiotensin–aldosterone and sympathetic nervous
embolism.3,4 Overall, BNP and NT-proBNP have comparable diag- systems.27 The biochemistry of NP release and breakdown is com-
nostic and prognostic accuracy5 – 8 ; other NPs such as atrial natri- plex and is discussed elsewhere.28 – 32
uretic peptide (ANP) [or midregional proANP (MR-proANP)] are A given NP concentration is a summation of many inputs and is a
also comparable, but less well documented. Therefore, all rec- measure of many aspects of cardiac function (Figure 1). It is critically
ommendations apply to the use of NPs in general. Although of important to remember that both BNP and NT-proBNP are not
substantial value for serially assessing prognosis in those with HF, solely biomarkers of left ventricular (LV) systolic function; indeed,
randomised controlled intervention trials have provided incon- a broad range of structural and functional cardiac abnormalities
sistent results on the medical value of using NP concentrations may lead to meaningful elevation of NPs, including LV diastolic dys-
to guide treatment in patients with HF, rendering this indication function, right ventricular (RV) dysfunction, valvular dysfunction,
controversial.9 – 11 The purpose of this review is to provide clini- increased pulmonary pressures, and atrial arrhythmias.12,23,33 – 35
cians with advice on the use of NP concentrations as a diagnostic
aid in their daily practice. Diagnosis of heart failure
The concentrations of the three appropriately validated NPs
(BNP, NT-proBNP, MR-proANP) correlate closely with each other. The unmet clinical need
However, their individual values are NOT interchangeable and their Heart failure, a progressive disease with a mortality exceeding most
normal ranges and optimal cut-off concentrations differ. cancers, presents a major burden to health care systems.36 Most
Two important principles should underlie the clinical use of patients with HF eventually present to the emergency department
NPs. First, a NP measurement should never be a stand-alone test. (ED) or hospital typically due to symptoms related to congestion.
It is always of greatest value when it complements the physi- Because HF occurs predominantly in older subjects, its presenta-
cian’s clinical skills along with other available diagnostic tools. tion is often complicated by multiple co-morbidities. This is unfor-
Results should always be interpreted in consideration of renal tunate, as the most common presentation of HF is dyspnoea, a
function, and body mass index (BMI), the two most powerful complaint that is neither specific nor sensitive for predicting the
confounders of NP concentrations.12 – 20 Second, NP concentra- presence of HF. Additionally, though physical findings in HF such
tions should be interpreted and used as continuous variables to as bilateral basal pulmonary end-inspiratory rales, elevated jugular
make full use of the biological information provided by the mea- venous pressure, and leg oedema are relatively specific for the diag-
surement (similar to calculated glomerular filtration rate). Cut-off nosis, their sensitivity is limited (only 50–60%). Similar limitations
concentrations may still be useful to make the application of NPs apply to the electrocardiogram (ECG) and chest X-ray. There-
easy for physicians without extensive experience with NP testing fore, diagnostic uncertainty frequently remains high after clinical
(Table 1). assessment.37 – 40 In the Breathing Not Properly study, at an 80%
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Cardiology practical guidance on the use of natriuretic peptide concentrations 717
Table 1 Key principles for the use of natriuretic peptides in clinical practice
• NPs should always be used in conjunction with all other clinical information
• NPs are reasonable surrogates for intracardiac volumes and filling pressures
• NPs should be measured in all patients presenting with symptoms suggestive of HF such as dyspnoea and/or fatigue, as their use facilitates the
early diagnosis and risk stratification of HF
• NPs have very high diagnostic accuracy in discriminating HF from other causes of dyspnoea: the higher the NP, the higher the likelihood that
dyspnoea is caused by HF
• Optimal NP cut-off concentrations for the diagnosis of acute HF (very high filling pressures) in patients presenting with acute dyspnoea to the
emergency department are higher as compared with those used in the diagnosis of chronic HF in patients with dyspnoea on exertion (mild
increase in filling pressures at rest)
• Obese patients have lower NP concentrations, mandating the use of lower cut-off concentrations (about 50% lower)
• In stable HF patients, but also in patients with other cardiac disorders such as myocardial infarction, valvular heart disease, atrial fibrillation, or
pulmonary embolism, NP concentrations have high prognostic accuracy for death and HF hospitalization
• Screening with NPs for the early detection of relevant cardiac disease including left ventricular systolic dysfunction in patients with cardiovascular
risk factors may help identify patients at increased risk, therefore allowing targeted preventive measures to prevent HF
• BNP, NT-proBNP and MR-proANP have comparable diagnostic and prognostic accuracy
• In patients with shock, NPs cannot be used to identify cause (e.g. cardiogenic vs. septic shock), but remain prognostic
• NPs cannot identify the underlying cause of HF and therefore, if elevated, must always be used in conjunction with cardiac imaging
BNP, B-type natriuretic peptide; HF, heart failure; MR-proANP, midregional pro-atrial natriuretic peptide; NP, natriuretic peptide; NT-proBNP, N-terminal proBNP.
Recommendation
.......................................................................................................
Natriuretic peptides should be measured in all patients presenting

with symptoms suggestive of new onset or worsening of HF such
as dyspnoea and/or fatigue, as their use facilitates both early
diagnosis or the early exclusion of HF.
Practical guidance
As a quantitative marker of HF, NP concentrations are best
interpreted as a continuous variable: very low NP concentrations
Figure 1 Haemodynamic determinants of natriuretic peptides have a very high negative predictive value (NPV) to exclude
(NPs). ANP, atrial natriuretic peptide; BNP, B-type natriuretic the presence of HF. Conversely, the higher the NP concentration,
peptide; HF, heart failure; LV, left ventricular; NT-proBNP, the higher the likelihood that dyspnoea is due to HF.38,39,45,46
N-terminal proBNP; RV, right ventricular. Also, optimum NP cut-off concentrations for the diagnosis of
acute HF (very high filling pressures) in patients presenting with
acute dyspnoea to the ED are higher as compared with those
used in the diagnosis of chronic HF in patients with dyspnoea
cut-off level of certainty of HF, clinical judgement had a sensitivity
on exertion (mild increase in filling pressures at rest; Table 2).
of only 49%.37
Combined with echocardiography in patients with elevated NPs,
NP testing enables the rapid and accurate diagnosis of HF, and its
phenotypes (Figure 2).47 Elevation of NP levels occurs in critically
The evidence ill patients, such as those with shock (including that caused by
Diagnostic studies comparing measurements of NPs against a sepsis), therefore elevated NP concentrations are not specific
reference standard diagnosis of HF (or alternative diagnosis) for cardiogenic causes of shock and other diagnostic approaches,
have consistently shown that NP levels have very high diagnos- including immediate echocardiography, need to be used. However,
tic accuracy for HF.16,41,42 Moreover, NPs improve the diagnos- elevated NP concentrations following shock of any cause are
tic accuracy of clinical judgement in the ED. This observation prognostic.48,49 In patients with an established diagnosis of HF, the
is also true for adults >75 years old, despite the slightly dimin- measurement of NPs is not necessary at all follow-up visits, but
ished diagnostic accuracy for NT-proBNP in this age group.16 should be carried out whenever it is unclear if and to what extent
In addition, three randomised controlled trials have shown that the reported symptoms are related to HF.
earlier and more accurate HF diagnosis translates into medical In patients with suspected acute HF, a BNP cut-off concen-
and economic value for patients, physicians and the health care tration of 100 pg/mL provides an excellent NPV to exclude the
system.38,43,44 presence of HF, while higher values (>400 pg/mL) deliver excellent
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Table 2 Recommended natriuretic peptide cut-offs for acute heart failure diagnosisa 1,12,16,39
Cut-off levels (pg/mL)

...........................................................................................................................
NT-proBNP BNP
....................................................... .......................................................
Age < 50 Age 50–75 Age > 75 Age < 50 Age 50–75 Age > 75
...........................................................................................................................................
Acute setting, patient with acute dyspnoea
HF unlikely <300 <100
‘Grey zone’ 300–450 300–900 300–1800 100–400
HF likely >450 >900 >1800 >400
Non-acute setting, patient with mild symptoms
HF unlikely <125 <35
‘Grey zone’ 125–600 35–150
HF likely >600 >150
BNP, B-type natriuretic peptide; HF, heart failure; NT-proBNP, N-terminal proBNP.
a Consider reducing the cut-off levels in obese patients by 50%.
acute coronary syndrome, primary pulmonary hypertension,

................................................................................................................
etc.) and renal failure, and therefore also represent HF

1) HF Diagnosis: Clinical + ECG + chest X-ray +NP
per se.52
2) HF Phenotype: Echo
Caveats in using natriuretic peptide
levels
LVEF ↓ Valves Isolated RV ↓ LA ⇧ ‘Grey zone’
HFrEF VHD RV-HF HFpEF The ‘grey zone’ is defined in Table 2.
HFmrEF Patients with levels in the grey zone needs extra physician atten-
(LVEF 40-50%) tion and ancillary testing. While the final diagnosis is often mild
to moderate HF,39,53 – 55 or HF with preserved ejection fraction
Figure 2 Diagnostic algorithm for heart failure (HF). ECG,
(HFpEF) rather than HF with reduced ejection fraction (HFrEF),
electrocardiogram; HFmrEF, heart failure with mid-range ejection
fraction; HFpEF, heart failure with preserved ejection fraction;
other causes of a modest rise in NP level should be considered.
HFrEF, heart failure with reduced ejection fraction; LA, left atrium; In acute dyspnoea, ‘grey zone’ NP values are present in 20%
LVEF, left ventricular ejection fraction; NP, natriuretic peptide; RV, of patients and about 50% of these will have acute HF. Other
right ventricular. causes include primary non-cardiac pathology that causes myocar-
dial stress, and includes pulmonary hypertension and RV dys-
function secondary to pulmonary embolism, pneumonia and cor
pulmonale.56 – 58
positive predictive value (PPV).39 As NT-proBNP concentra-
The grey zone levels are far more strongly associated with HF
tion correlates more strongly with age and renal dysfunction,
when concomitant clinical features are present, such as a history
age-dependent rule-in cut-offs are preferred for NT-proBNP
of HF, jugular venous pressure and prior diuretic use.55
(450/900/1800 pg/mL),41 however, independently of age, an
NT-proBNP concentration <300 pg/mL provides a very high NPV
for HF. These results were recently affirmed.16,17 Pulmonary disease
Considering ‘rule-in’ thresholds requires addressing the fact that In patients with chronic pulmonary disease, differentiating between
NPs may be persistently elevated in chronic HF and may not be rep- pulmonary causes of dyspnoea vs. confounding cardiac disease
resentative of an acute haemodynamic change. Knowledge of each can be clinically challenging. Importantly, previously unsuspected,
patient’s individual NP concentration when stable (the so-called ‘masked’ HF may be present in those individuals with chronic
dry NP concentration) helps to interpret concentrations of these obstructive pulmonary disease (COPD). In this context, elevation
markers when these patients present with acute symptoms; a of NPs may be useful to identify the presence of unrecognized HF,
change of 100% or more from the stable concentration suggests however it is necessary to remember that, in patients with pul-
a change in clinical state, such as decompensation.50,51 monary hypertension and RV dysfunction (e.g. in severe COPD),
When confronted with an elevated NP, other conditions NP levels are often in the grey zone and occasionally in the diag-
that result in an increased concentration of these peptides nostic zone for HF, reflecting the existence of major RV stress and,
should also be considered, including both those that result in in effect, right HF.56,57,59 – 63 The accuracy of NP to diagnose HF is
myocardial end-diastolic wall stress (acute pulmonary embolism, unchanged in the presence of pre-existing pulmonary disease.58,62,63
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Renal disease Patients treated with sacubitril/valsartan
........................................................................................................................................................................
There is an important interrelationship between cardiac and renal Sacubitril/valsartan seems to affect the concentration of NPs that
dysfunction. About one-third of outpatients with chronic HF have are cleared by neprilysin such as BNP and ANP also by its direct
renal dysfunction.64 Current data suggest that the cause of elevated pharmacologic effect on neprilysin (inhibition) and not only by its
NP concentrations in renal dysfunction is multifactorial, represent- effect on intracardiac filling pressures.73 – 75 While the mechanisms
ing in part a true counter-regulatory response from the heart to underlying the effect of sacubitril/valsartan on NP concentrations
the kidney, and not only diminished passive renal clearance.15,46 It is and NP activity are a matter of ongoing research,76,77 at this point
a major misconception that NPs are solely removed from circula- in time we consider NT-proBNP to be the preferred biomarker
tion by the kidneys. Indeed only 25% clearance of NPs is related to to quantify HF severity and monitor prognosis in patients on
renal filtration,20 with the balance of their clearance due to removal sacubitril/valsartan.33
by various organs with high blood flow.65 To maintain optimal diag-
nostic performance, the cut-off concentrations for detecting HF Patients with acute and chronic ischaemia
may need to be raised when estimated glomerular filtration rate
Natriuretic peptides independently and accurately predict mortal-
(eGFR) is <60 mL/min.46 Due to the strong correlation between
ity in patients with acute coronary syndrome, but do not seem
renal dysfunction and age, no additional adjustment seems nec-
to provide added diagnostic information.78 – 80 Similarly, NPs do
essary for NT-proBNP once using age-adjusted rule-in cut-offs.
not further increase diagnostic accuracy on top of clinical judge-
For BNP, the effect of renal dysfunction overall is smaller, and
ment and/or troponin measurements in the detection of inducible
increasing the rule-out cut-off to 200 pg/mL rather than 100 pg/mL
myocardial ischaemia.81,82 It is currently unclear how the patho-
seems sufficient.46 Overall, it is important to highlight that renal
physiological signals quantified by the elevation of NPs in acute
dysfunction and its associated cardiac co-morbidities, and not age
coronary syndrome patients could be best used clinically to mit-
per se, seem to be the major driver behind the higher NT-proBNP
igate the identified high mortality risk.78,83
and BNP concentrations in elderly patients.14 Due to incomplete
data, NP testing for HF should be discouraged in patients on dial-
ysis. Importantly, high NP concentrations should not be ignored Caveats: lower than expected
in the setting of renal dysfunction.66 Given the strong relationship concentration of natriuretic peptides
between cardiac and renal disease, clearly elevated NP concentra-
Obesity
tions suggest that cardiac disease is present and should influence
clinical decision-making. Concentrations of both BNP, NT-proBNP and MR-proANP
are lower in obese persons, both with and without HF.19,84 – 86
Although the reason for this interaction remains incompletely
Diastolic dysfunction understood (possibly including pericardial fat),85,87 given different
In accordance with the cardinal role of myocyte stretch in gener- mechanisms of clearance for BNP, NT-proBNP and MR-proANP,
ating NP synthesis and release, the severity of diastolic dysfunction this finding is most likely to be due to lower release of NPs in
is correlated with increased plasma concentrations of both BNP obesity, rather than increase in their clearance. Furthermore,
and NT-proBNP.67,68 with substantial weight loss, rises in NP concentrations are seen,
implying a ‘de-repression’ of their lower values.88 Mechanistically,
this may be due to suppression of the bnp gene by circulating fac-
Atrial arrhythmia tors such as androgens that may be produced by adipose tissue.89
It is well established that the presence of atrial arrhythmias such It is noteworthy that a unique relationship exists between BNP
as atrial fibrillation or flutter is associated with higher concentra- and adipose tissue: increased concentrations of NP receptors are
tions of NPs.69 On occasion, the values of these peptides may be found on adipocytes, and BNP induces lipolysis. This finding has led
in excess of the threshold for ‘HF’, even in the absence of further some people to postulate that increased clearance might add to
clinical support for the diagnosis.70 In those patients presenting lower BNP levels in obesity90,91 but, given the absence of clearance
with recent onset dyspnoea and concurrent atrial fibrillation, HF of NT-proBNP by NP receptors, this cannot entirely explain the
is present in at least 65% of cases. From a pathophysiological and inverse association between BMI and NP concentrations. Clinically,
clinical perspective, these patients should be considered to have caregivers should recognize risk for lower NP concentrations in
HF until proven otherwise. Sub-clinical myocardial stress must be those with BMI ≥30 kg/m2 ; such values are typically not ‘normal’,
assumed in such patients regardless of results from echocardiogra- and more often closer to diagnostic thresholds than not. To
phy. In addition, the onset of atrial arrhythmia is a common cause of optimize diagnostic accuracy, lowering the established cut-off
decompensated HF, and in the presence of such an arrhythmia, HF concentrations by up to 50% in obese patients is reasonable.18 As
is often more severe and associated with a worse prognosis.71 An there is a linear decrease in NP levels with increasing BMI, the
even more elevated plasma level of BNP or NT-proBNP in those higher the BMI the lower the cut-off concentration that provides
with atrial fibrillation or flutter is speculated to be due to release the highest accuracy.18,67 A very low BNP cut-off concentration
of peptide produced in the atria, however increased ventricular (<50 pg/mL) should be used to rule out HF in obese patients.
myocardium release, due to higher wall stress from tachycardia, is Neglecting this concept would invariably result in suboptimal
also possible.72 sensitivity.92 Recently, it was demonstrated that the differences
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ascribed to obesity are in part explained by sex differences: men Established role: diagnosing heart failure
........................................................................................................................................................................
have lower NP levels than women, but weigh much more.78 Given Diagnosing new-onset HF in the community can be challenging.
the large overlap between obesity and HFpEF, and the generally Suggestive symptoms are common, but often non-specific and phys-
lower levels of NP even in non-obese HFpEF, this aspect is par- ical signs often unremarkable. It is here that NPs can be very helpful
ticularly important for the diagnosis of HFpEF.92 – 94 Despite the to the physician. Much as in the ED setting, the evaluation of dys-
lower circulating levels, NP levels retain prognostic performance pnoea is often challenging, with numerous diagnostic possibilities.
in obese patients as well as in HFpEF patients.18,67,95,96 Therefore, use of NPs to clarify diagnostic evaluation in less acute
settings has the same rationale. Although the number of studies
Heart failure due to causes upstream from the left in primary care is smaller compared with studies performed in the
ventricle ED, most of the concepts and findings already discussed on the use
When HF is due to a cause upstream from the left ventricle, of NPs for diagnostic evaluation of HF in the ED also apply in out-
for example in mitral stenosis or acute mitral regurgitation, NP patient testing, including the importance of cardiac and non-cardiac
concentrations may be initially low despite severe symptoms. variables influencing the concentrations of these peptides.
The absence of a significant rise in LV wall stress in these acute Nonetheless, current evidence also strongly supports the use of NP
settings explains the lack of marked NP production and, while NP testing in primary care for the correct evaluation of HF.102 – 106
levels may still be higher than normal, they will not rise to the Natriuretic peptide testing in primary care is widely available
same degree as when HF occurs with a concomitant overload both at point-of-care, as well as using locally established sample
on the left ventricle. Similarly, pericardial abnormalities, such pathways to central laboratories. It empowers the position of the
as constriction and tamponade, can sometimes cause symptoms general practitioner and provides important guidance for linking
of HF. However, as the myocardial wall is not abnormally stressed, primary and secondary care.
NP levels are typically normal or only slightly elevated.97,98 Early In general, due to their lower concentrations in the primary care
echocardiography is mandatory whenever suspecting HF due to setting, the main application of NPs for outpatient use has focused
causes beyond the left ventricle, such as mitral stenosis as well as on their sensitivity and NPV; lower concentrations (e.g. BNP
in suspected pericardial tamponade. <35 pg/mL; NT-proBNP <125 pg/mL; MR-proANP <85 pmol/L)
exclude HF with high confidence, while higher concentrations
require further evaluation.107 A normal value has an excellent NPV
Flash pulmonary oedema
and, while an abnormal value does not confirm the diagnosis of
Natriuretic peptide levels may be relatively low in patients present- HF, it does underline the need for further diagnostic tests, in par-
ing with HF symptoms that develop abruptly, e.g. within 1 h. In this ticular Doppler echocardiography. Cut-off concentrations used to
setting, the time interval between the initial trigger and the mea- rule out HF vary somewhat, dependent on an agreed strategy
surement of NP levels is so short that it precedes the up-regulated of focusing on a strong rule-out test or a value that minimizes
peptide synthesis. As only very small quantities of BNP (com- false-positive results. At present, the European Society of Cardiol-
pared with ANP) are stored in secretory granules, the development ogy (ESC) guidelines recommend a cut-off concentration of 35 and
of elevated BNP concentrations in ‘flash’ pulmonary oedema is 125 pg/mL for BNP and NT-proBNP respectively, a strategy that
dependent upon de novo synthesis and secretion of the peptide.99 favours minimizing false-negative results. For NT-proBNP, a strat-
The incidence of this phenomenon seems to be very low, given the ified approach of 50/75/250 pg/mL for ages <50/50–75/>75 years
underlying sub-critical congestion in those individual who subse- may be considered as an alternative.1,108
quently develop ‘flash’ pulmonary oedema.38,39,100,101
Emerging role: natriuretic peptide screening to prevent

Fatigue
heart failure
In some patients with HF, fatigue is the dominant symptom, while
Rationale. HF prevention will play an increasingly important role in
dyspnoea is mild or even absent. The diagnostic performance
our strategies for the management of this syndrome. A significant
of NP and the optimal cut-off concentrations of NPs in this setting
challenge in this effort will be the requirement to individualise
are less well established, compared with patients with dyspnoea
risk beyond the presence of accepted risk factors. NPs have been
as the key symptom.1,2
shown to be a strong independent indicator of new-onset HF and
other cardiovascular disease.109 Therefore, in addition to their
Natriuretic peptide use in the diagnostic value, low NP concentrations provide useful reassurance
community: linking primary to the clinician on lower potential cardiovascular risk; this test, in
turn, may be useful for triage decision-making.
and secondary care The success of a population-based screening programme for a
Background disease condition is dependent on disease prevalence, the avail-
Although first coming to prominence in the acute setting, NP use ability of a screening test that is acceptable, safe and inexpensive,
may have its widest application in the community. Presently, there the presence of effective treatment for detected disease, as well as
are three clinical settings in which one should consider using NPs the existence of, and compliance with, a follow-up care system for
with varying levels of proof or guideline support. people at risk or who have positive tests.110 For several reasons
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NPs are attractive candidates for screening the general population concentrations to identify asymptomatic subjects with reduced LV
........................................................................................................................................................................
for sub-clinical disease. First, LV dysfunction and the other car- ejection fraction,114,120,121 or for a broader range of sub-clinical car-
diovascular diseases that are detectable by elevated NP levels are diovascular disorders.115 Therefore, some of these findings demon-
common and cause significant morbidity and mortality.111 Second, strate suboptimal accuracy of NPs as a screening test for LV sys-
NP levels may be elevated early in the disease process, allowing for tolic dysfunction in community cohorts.114 In the STOP-HF trial,
timely detection of disease before symptom onset.112 Third, early approximately three patients with cardiovascular risk factors had
treatment of latent disease with medications, such as angiotensin- to be screened to detect one patient with a BNP concentration
converting enzyme inhibitors, improves outcomes by preventing >50 pg/mL, which triggered cardiac work-up.112 Overall, applying
the development of symptomatic HFrEF.113 Notably, NPs have BNP screening using this specific cut-off in the STOP-HF popula-
limited accuracy in screening for mildly reduced LV ejection tion resulted in a very favourable cost-effectiveness with a €1104
fraction in asymptomatic patients.114 Finally, several studies have per quality-adjusted life year gain as cardiovascular hospitalization
shown that, in the right setting, screening with NPs may prove a savings offset increased outpatient and primary care costs.122
cost-effective approach.115 – 117 Recommendation: NP measurement by general practition-
ers and diabetologists in high-risk populations such as those
Evidence: randomized controlled intervention studies. Recently, the St. with hypertension or diabetes mellitus helps the targeted initi-
Vincent’s Screening To Prevent Heart Failure Study (STOP-HF) ation of preventive measures, including medicine up-titration of
project demonstrated that NP-defined risk and intervention renin–angiotensin system antagonists and, therefore, prevent or
reduced new-onset HF, asymptomatic LV dysfunction and, overall, slow the development of HF (Figure 3).
major adverse cardiovascular events among participants with
cardiovascular risk factors (mean age 65 years) recruited from 39 Additional role: assessing new symptoms in heart failure
primary care practices.112 Intervention-group participants with
Natriuretic peptide assessment can be a very useful investigation
BNP levels of 50 pg/mL or higher underwent echocardiography in the community when assessing clinical deterioration in patients
and collaborative care between their primary care physician and with established HF. These clinical settings can be challenging
specialist cardiovascular service. In total, 263 patients (41.6%) in especially as features can be non-specific and potentially explained
the intervention group had at least one BNP reading of 50 pg/mL by co-morbidities. In these circumstances, a significant increase
or higher. The intervention group underwent more cardiovascular in NP above a stable baseline value would support HF as the
investigations and received more renin–angiotensin–aldosterone cause of deterioration, alternatively a finding of no significant
system-based therapy at follow-up (control, 49.6%; intervention, change from the stable value would have the opposite, but equally
56.5%; P = 0.01). The primary endpoint of LV dysfunction with or important, implication. For this to be applied effectively, values
without HF was met in 59 (8.7%) of 677 in the control group and for NPs reflecting the clinically stable state need to be available
37 (5.3%) of 697 in the intervention group [odds ratio (OR), 0.55; in the patient’s record for comparison and would need to be
95% confidence interval (CI) 0.37–0.82; P = 0.003]. The incidence updated regularly.123,124
rates of emergency hospitalization for major cardiovascular events
were 40.4 per 1000 patient-years in the control group vs. 22.3 per
Challenges to use of natriuretic peptides in the
1000 patient-years in the intervention group (incidence rate ratio community
0.60; 95% CI 0.45–0.81; P = 0.002).112
The major challenge will be knowledge transfer to end-users,
These results were further strengthened by the NT-proBNP
to ensure that the nuances of NP interpretation and the influ-
Guided Primary Prevention of CV Events in Diabetic Patients
ence of multiple confounders are understood. While a very useful
(PONTIAC) trial in 300 patients with type 2 diabetes (mean age
biomarker, NP results may be open to misinterpretation, there-
68 years), elevated NT-proBNP (>125 pg/mL) but free of cardiac
fore potentially leading to incorrect decision-making. As in all other
disease.118 The control group was cared for at four diabetes care
settings, frequent modifiers of NPs include atrial fibrillation, renal
units; patients randomized to the ‘intensified’ group were addi-
failure, sepsis, and obesity. Above all else, there needs to under-
tionally treated at a cardiac outpatient clinic for the up-titration
stand that a biochemical change value of at least 50% is required
of renin–angiotensin system antagonists and 𝛽𝛽-blockers. The pri-
to accept that the change is likely to be of clinical relevance.
mary endpoint, hospitalization/death due to cardiac disease after
2 years, was significantly reduced in the intensified group.
Monitoring prognosis during heart
Evidence: diagnostic studies using echocardiography as the reference.
Many people with substantial LV dysfunction do not have typ- failure therapy
ical symptoms, but might be identified by a simple screen- Pre-discharge during hospitalization
ing test such as BNP/NT-proBNP.119 Although echocardiogra-
phy is the current gold standard for detection of LV systolic
for acute heart failure
dysfunction and many other structural cardiac abnormalities, its Rationale
cost, limited availability and complexity in assessing LV dias- With current management, patients hospitalised for acute
tolic dysfunction make it an impractical choice for population HF continue to have unacceptably high rates of mortality
screening. Several investigations have evaluated the use of NP and morbidity.1,2,12,125,126 Patients who are admitted to the
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GP/
Diabetologist
Clinical Presentation (= Anamnesis

+ Symptoms + Clinical Signs + ECG)
Patient Care, + NP Definitive Diagnosis?
Therapy, Working Diagnosis Heart Failure Cause of Heart
Monitoring Failure?
Cardiologist
Examination and Medical Clarification by a Cardiology Specialist,

mostly including an Echocardiogram
Heart Valves Isolated RV
Figure 3 Natriuretic peptide (NP) screening in patients at high cardiovascular risk by general practitioners (GP) and diabetologists is an
integral component of integrated patient care pathways aiming to prevent and/or early detect cardiovascular disease including heart failure
(HF). ECG, electrocardiogram; HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction;
LA, left atrium; LVEF, left ventricular ejection fraction; RV, right ventricle; RV-HF; right ventricular heart failure; VHD, valvular heart disease.
hospital with acute HF usually respond symptomatically to treat- is that a patient with concomitant right-sided HF and significant
.......................................................................................
ment, but clinical assessment is unable to assess whether the ascites and/or oedema might diurese many litres further before
optimal filling pressures have been achieved. Multiple studies have NP levels actually drop. This is likely to be due to mobilization of
shown that many patients are discharged while still congested and third-space fluid, rather than lowering of cardiac filling pressures.
the extent of remaining congestion is associated with mortality Continuing diuresis and/or vasodilatation should eventually lower
and the risk for another HF hospitalization.127,128 The fact that ‘wet’ NP levels. Finally, in some cases, treatment simply does not
NPs have a short half-life, are easily measured and provide a effectively correct central cardiac haemodynamic abnormalities
quantitative marker of HF severity and prognosis, suggests that and does not improve cardiomyocyte stress and one should not
they might be a useful guide to judging the success of therapy in expect, therefore, to see a decline in this setting; again; this is a
acute HF. The goals of using BNP or NT-proBNP is to determine high-risk patient.
whether a patient has received adequate decongestive therapy and It remains as yet unclear if changing therapy based on measured
if their risk for re-hospitalization has been reduced as much as is pre-discharge NP concentration can reduce re-hospitalization or
feasible during their acute treatment. avert death.9,132 A recent modest size randomised controlled pilot
Natriuretic peptide concentrations after treatment have prog- study was unable to document medical benefit; however, in both
nostic significance: those with lower values at the time of discharge study arms, those with a substantial reduction in NT-proBNP had
(or achieving greater relative reduction) have substantially better superior outcomes to ‘non-responders’. Common sense would
prognosis than those who are released from acute care with higher therefore dictate that for such higher risk patients, who do
concentrations.129,130 Discharge NP concentrations seem to be the not exhibit responsive NP concentrations after treatment, more
best predictor of 1-year death or re-hospitalization among patients aggressive monitoring and therapy may be wise. Pre-discharge
with acute HF, superior to admission values or the change in levels NP levels appear to be more cost-effective than comprehen-
from admission to discharge.130,131 sive Doppler echocardiographic examination for the prediction of
Although there are few data defining why NP levels do not future cardiac death or HF re-hospitalization.133 It is reasonable to
decline in some patients despite treatment, several clinical scenar- measure NP levels routinely before discharge when optivolaemic
ios should be considered. First and most importantly, a persistently status seems to have been achieved by clinical assessment. This
elevated NP concentration in a stably diuresed patient may actually approach also sets a baseline for continued monitoring in the out-
be the patient’s optivolaemic (dry) NP level at this time point due patient setting, in which NP measurement may be continued. It
to persistent increased ventricular wall stress, necessary to main- further allows for individualizing decision-making on timing, fre-
tain adequate cardiac output. This identifies a treatment-resistant, quency and intensity of follow-up; those patients with a signifi-
high-risk patient with a poor prognosis. Another possible scenario cant reduction in NP concentration after acute HF treatment are
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likely to have a benign early post-discharge course, whereas those receptor antagonists, 𝛽𝛽-blockers, diuretics, cardiac resynchro-
........................................................................................................................................................................
patients with higher or non-falling concentrations may merit close nization therapy, and exercise all tend to chronically reduce
follow-up, including potential monitoring at home.134 However, this concentration of NPs in parallel with their benefits; the sole
indication is still controversial, as a small prospective randomized exceptions to this rule include the effect of sacubitril/valsartan on
trial showed neutral results.10 BNP metabolism, in which therapy tends to modestly raise concen-
tration of the NP and the early NP raising effect of non-vasodilating
𝛽𝛽-blockers during their introduction and early titration.141
During outpatient visits for chronic heart The relationship between therapies for HF, drop in NP concen-
failure trations and the improvement in patient’s symptoms, improved LV
function and subsequent outcome has led to the hypothesis that
Rationale
NP-guided treatment might assist in adjusting chronic HF ther-
The concept of serial measurement of NPs as a quantitative mea- apy. Despite the neutral results of the Guiding Evidence-Based
sure of HF severity during outpatient visits for chronic HF mir- Therapy Using Biomarker Intensified Treatment in Heart Failure
rors the serial measurement of other key biomarkers in other (GUIDE-IT) trial, a recent meta-analysis of all published random-
settings such as, for example, eGFR in patients with kidney dis- ized controlled trials to date is suggestive of the benefit of a
orders, arterial blood pressure in arterial hypertension, and blood NP-guided treatment adjustment approach for all-cause mortality
glucose and glycated haemoglobin in diabetes mellitus. Therefore, in HFrEF patients (Figure 4).10,11,142
serial measurements of NP would allow physicians to empower, In general, it is necessary to recognize that the efficacy of any
educate and motivate HF patients, similar to the use of other dis- guide to therapy will be most realized in patients who are not
ease surrogates in chronic disease such as home blood pressure, receiving adequate, guideline-compliant medical therapy. In other
blood glucose and glycated haemoglobin. Serial measurement of words, patients managed with an aggressive application of therapies
NPs provides useful and incrementally powerful prognostic infor- for HF might not realise as much benefit from NP measurement
mation when measured in patients with chronic HF, not only in the to ‘guide’ their care, although NP concentrations maintain their
setting of HFrEF but also in HF with mid-range ejection fraction prognostic meaning in such patients.
and HFpEF.73,95,96,135,136 Changes in NPs over time in patients with The current understanding of NP-guided HF care suggests that
chronic HF not only prognosticate risk for adverse outcomes such the benefit of this approach is most obvious when: (i) a low target
as hospitalization or death, but also predict changes in LV size and NP concentration is attempted (BNP <100 pg/mL, NT-proBNP
function.136,137 <1000 pg/mL); (ii) therapies must be adjusted to achieve these
Although useful, several caveats exist on the interpretation of NP goals (i.e. if an elevated NP concentration is ignored, the concept of
concentrations in outpatient risk monitoring. When a change in a ‘guiding therapy’ is more likely to fail); and (iii) a change in therapy
NP concentration is not accompanied by a change in clinical status, would not have otherwise been made if NP measurement had not
this might reflect biological variability or a change in cardiac or renal been performed. Studies that have these characteristics suggest
function that has not yet resulted in symptoms or signs. As a result that the approach might improve outcome, when compared with
of both analytical and biological variabilities (haemodynamic, renal, usual care. Conversely, in studies with very aggressively applied
etc.), reference change values have been reported to be relatively usual care, the approach of NP guidance might not be as likely to
large for NPs, up to a doubling of results for each biomarker.138 – 140 further improve outcomes.10,143,144
Only one study investigated both chronic HF patients and normal Since the first randomized pilot study of 69 patients with HF and
subjects. The other studies only looked at normal subjects, in which LV systolic dysfunction showing that therapy guided by NP levels
very low NP concentrations were expected and small changes reduced total cardiovascular events and delayed the time to first
were very likely to be within the domain of biological and/or event, other trials have provided useful insights on the approach,
analytical variation. Any discussion of biological variation in HF and pooled analyses suggest the benefit towards reduction in
is immediately undermined by the fact that present pathological mortality, even considering recent neutral trials.10,11,143,145
changes determining NP concentration might be challenging to In the Trial of Intensified versus Standard Medical Therapy
non-invasively measure, such as filling pressures. Therefore, a more in Elderly Patients With Congestive Heart Failure (TIME-CHF)
accurate question to ask is: ‘How much change in NPs must occur trial of elderly patients,146 NP-guided HF therapy did not signif-
to identify presence of change in filling pressures?’ In this regard, icantly reduce the primary endpoint of 18-month survival free
among HF patients, a change of 50% seems to indicate a shift in of all-cause hospitalizations (hazard ratio 0.91; P = 0.39). How-
filling pressure.23 Furthermore, it has been demonstrated that even ever, survival free of HF hospitalization was reduced (hazard ratio
a considerably small change in weight can trigger a substantial NP 0.68; P = 0.01), particularly in patients aged <75 years (interaction
alteration.124 P < 0.02). This finding has led to the recognition of the importance
The combination of symptoms, weight gain and NP concentra- of co-morbidities for the ability to achieve optimal medication titra-
tion may be the best way to diagnose early decompensation. As for tion (and therefore reduction in NT-proBNP or BNP). As older
inpatients, proper adjustment of HF management requires NP to patients are more likely to have more complex medical conditions,
be measured together with renal function. limiting the application of guideline-directed medical therapies for
Therapies for HF, such as angiotensin-converting enzyme HF, it is hardly surprising that such patients are less likely to respond
inhibitors, angiotensin II receptor blockers, mineralocorticoid to NP-guided HF care.147,148 The ProBNP Outpatient Tailored
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A B
Figure 4 All-cause mortality comparison of N-terminal pro-B-type natriuretic peptide (NT-proBNP)-guided therapy vs. standard therapy in
chronic heart failure with reduced ejection fraction. (A) Forest analysis is shown for all-cause mortality in NT-proBNP-guided vs. standard
therapy. (B) Sensitivity analyses were used to assess the effect of sequential removal of studies on all-cause mortality. CI, confidence
interval; GUIDE-IT, Guiding Evidence-Based Therapy using Biomarker Intensified Treatment in Heart Failure; PRIMA, Can PRo-brain-natriuretic
peptide-guided therapy of chronic heart failure IMprove heart fAilure morbidity and mortality?; RR, risk ratio; SIGNAL-HF, Swedish Intervention
study-Guidelines and NT-proBNP AnaLysis in Heart Failure; TIME-CHF, Trial of Intensified versus Standard Medical Therapy in Elderly Patients
With Congestive Heart Failure.
Chronic HF Therapy (PROTECT) trial provided useful pilot data HF-related symptoms. If NP concentrations and, therefore, filling
.................................................................................................
on the value of NT-proBNP-guided HF care.149 In this study of 151 pressures are in the normal range or only mildly elevated (e.g. BNP
patients with HFrEF, NT-proBNP guided care with a goal value of < 100 pg/mL or NT-proBNP < 400 pg/mL), symptoms may have
<1000 pg/mL reduced total cardiovascular events compared with other causes and patients can be reassured that they are not
usual care (58 events vs. 100 events, P = 0.009; logistic odds for related to HF, and measures directed against the true cause can be
events 0.44, P = 0.02). taken.
Most recently, the GUIDE-IT study reported neutral results on
NT-proBNP-guided care.10 This trial was the largest randomized
study to date, examining 894 subjects with HFrEF and treated Risk stratification of pulmonary
with either a goal NT-proBNP <1000 pg/mL vs. usual care. After
a median of 15 months of follow-up, no benefit of NT-proBNP
embolism and pneumonia
guidance vs. usual care was seen (hazard ratio 0.98; P = 0.88). The haemodynamic cardiac stress of the left and right heart com-
Furthermore, this strategy of NT-proBNP-guided HF therapy had bined as quantified by NP concentrations has been shown to be
higher total costs and was not more effective than usual care in a powerful predictor of death both in patients with pulmonary
improving quality of life outcomes.150 Notably, those patients in embolism and in patients with pneumonia. As a single marker,
the usual care arm were seen for an average of 10 visits during NPs achieve similar prognostic accuracy as compared with com-
follow-up, had similar medication doses administered compared plex multivariable risk scores.153,154 Measuring NPs may there-
with the NT-proBNP arm, and achieved greater reduction in fore help in the appropriate triage, early admission to an inten-
NT-proBNP concentrations when compared with other trials in sive care unit, if at high risk of death, and possibly outpatient
this topic. This has led some people to speculate that more than management, if at very low risk or death. The ESC guidelines
standard intensity treatment was delivered to those in the usual state that NPs should be considered in patients with pulmonary
care arm and, conversely, that therapy in the marker-guided arm embolism.155 While the use in pneumonia has not been evaluated
of GUIDE-IT was not as aggressive as the trial protocol would in other guidelines, we think that the use of NPs in this indica-
appear to dictate.151,152 Therefore, in populations of patients with tion might allow the early detection of previously undiagnosed or
lesser aggressive application of standard HF medication, it would underestimated cardiac disease possibly amendable to therapeutic
still seem likely that NP measurements facilitate HF care. interventions in a relevant proportion of patients with pneumo-
In addition, it is important to highlight that nearly all HF nia and therefore hopefully ameliorate the substantial mortality
patients reported symptoms possibly related to HF during their observed in pneumonia and substantially elevated NPs.154,156 – 163
follow-up visits. NPs are of enormous help to evaluate whether By contrast, low NPs can rule out any relevant cardiac dysfunction.
these symptoms are related to HF and increased intracardiac The clinical relevance of NPs in patients with pneumonia and the
filling pressures. This assessment has direct therapeutic conse- proper timing of their measurement should be addressed in future
quences and will usually lead to adjustments of HF medication for research.
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Preoperative risk stratification Torrent Pharmaceuticals; personal fees from AstraZeneca, GSK,
........................................................................................................................................................................
Myokardia, Sanofi, Servier, Vifor; grants, personal fees and
in non-cardiac surgery non-financial support from Medtronic, Novartis; grants and
In patients undergoing non-cardiac surgery, judging the risk– non-financial support from Pharmacosmos, PharmaNord, out-
benefit ratio of the operation including postoperative compli- side the submitted work. J.L.J. reports grants and personal fees
cations is challenging for both the physician as well as the from Roche, Siemens, Singulex, Abbott, Prevencio, Philips; and
patient. In this regard, concentrations of BNP and NT-proBNP personal fees from Critical Diagnostics, during the conduct of
sampled before such surgeries have been shown to be power- the study; personal fees from Boehringer-Ingelheim, Siemens,
ful predictors of post-procedural complications, including death, Janssen, AbbVie, Pfizer, Merck, Bayer; grants and personal fees
myocardial infarction and acute HF to allow better informed from Novartis, outside the submitted work. K.McD. reports grants
decisions.164 – 166 and non-financial support from Alere, non-financial support from
Therefore, current Canadian clinical practice guidelines recom- Novartis, from null, outside the submitted work. A.M. reports
mend the measurement of NPs in patients who are 65 years of age personal fees from Novartis, Orion, Roche, Sanofi, Servier; grants
or older, or are 45–64 years of age with significant cardiovascular and personal fees from Adrenomed, Abbott, personal fees from,
disease for preoperative risk stratification.164 The ESC guidelines outside the submitted work. M.M. reports personal fees from
state that NPs may be considered in this indication.167 Consulting, honoraria from Bayer, Novartis, Fresenius, Servier for
participation to advisory board meetings and executive commit-
tees of clinical trials, outside the submitted work. G.F. reports
Other evolving indications Committee member from Novartis, Bayer, Medtronic, Servier,
Vifor, Boehringer Ingelheim, outside the submitted work. A.M.
Some promising alternative evolving indications include patients reports grants from Roche, personal fees from CriticalDiagnostics,
with primary pulmonary hypertension, patients with congenital outside the submitted work. M.R. reports grants, personal fees
heart disease, patients with valvular heart disease, and critically ill and non-financial support from Roche Diagnostics, during the
patients in the intensive care unit.168 – 176 conduct of the study; non-financial support from Roche Diagnos-
tics, outside the submitted work. F.R. reports grants and personal
fees from SJM/Abbott, Servier, Novartis, Bayer; personal fees from
Conclusion Zoll, Astra Zeneca, Sanofi, Amgen, BMS, Pfizer, Fresenius, Vifor,
Natriuretic peptides are the gold standard biomarkers for HF diag- Roche, Cardiorentis, Boehringer Ingelheim; other from Heart-
nosis and prognosis. The measurement of NPs can help clinicians ware, grants from Mars, during the conduct of the study; since
to manage patients in several clinical scenarios. They are helpful 1st January 2018, no personal payments, all payments directly to
in screening to identify or exclude cardiac disease, for the differen- the University of Zurich. All other authors have no conflicts of
tial diagnosis of symptoms that might be due to HF and are robust interest to declare. The sponsors had no role in the design and
powerful prognostic tools. Each NP has specific cut-off concentra- conduct of the study; collection, management, analysis, and inter-
tions. Plasma concentrations should be interpreted in the context pretation of the data; and preparation, review, or approval of the
of the clinical setting and as a quantitative marker of HF. The incre- manuscript.
mental value of NP-guided therapy remains controversial.
Conflict of interest: C.M. was supported by grants from the References
Swiss National Science Foundation (PP00B-102853), the Swiss 1. Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JG, Coats AJ, Falk V,
Heart Foundation, the University of Basel, Abbott, ALERE, González-Juanatey JR, Harjola VP, Jankowska EA, Jessup M, Linde C, Nihoy-
BRAHMS, and Pronota. In addition, he received lecture fees from
Abbott, ALERE, BRAHMS, Novartis and Roche. A.J.S.C. reports and treatment of acute and chronic heart failure: The Task Force for the diagno-
personal fees from Astra Zeneca, Faraday, WL Gore, Menarini, sis and treatment of acute and chronic heart failure of the European Society of
Respicardia, Servier, Stealth Peptides, Actimed, Vifor, and Verona, Association (HFA) of the ESC. Eur J Heart Fail 2016;18:891–975.
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doi:10.1002/ejhf.1499
Expert consensus document: Reporting

checklist for quantification of pulmonary
congestion by lung ultrasound in heart failure
Elke Platz1*, Pardeep S. Jhund2, Nicolas Girerd3, Emanuele Pivetta4,
John J.V. McMurray2, W. Frank Peacock5, Josep Masip6,7,
Francisco Javier Martin-Sanchez8, Òscar Miró9, Susanna Price10, Louise Cullen11,
Alan S. Maisel12, Christiaan Vrints13, Martin R. Cowie10, Salvatore DiSomma14,
Hector Bueno15, Alexandre Mebazaa16, Danielle M. Gualandro17,22,
Mucio Tavares17, Marco Metra18, Andrew J.S. Coats19, Frank Ruschitzka20,
Petar M. Seferovic21, and Christian Mueller22, on behalf of the Study Group on
Acute Heart Failure of the Acute Cardiovascular Care Association and the Heart
Failure Association of the European Society of Cardiology
1 Department of Emergency Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA; 2 BHF Cardiovascular Research Centre, Institute of
Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK; 3 INSERM, Centre d’Investigations Cliniques Plurithématique, INSERM U1116, CHRU de Nancy,
F-CRIN INI-CRCT, Université de Lorraine, Nancy, France; 4 Division of Emergency Medicine and High Dependency Unit, AOU Città della Salute e della Scienza di Torino, Cancer
Epidemiology Unit and CPO Piemonte, Department of Medical Sciences, University of Turin, Turin, Italy; 5 Henry JN Taub Department of Emergency Medicine, Baylor College of
Medicine, Houston, TX, USA; 6 ICU Department, Consorci Sanitari Integral, University of Barcelona, Barcelona, Spain; 7 Cardiology Department, Hospital Sanitas CIMA,
Barcelona, Spain; 8 Department of Emergency Medicine, Hospital Clínico San Carlos, Instituto de Investigación Sanitaria Hospital Clínico San Carlos (IdISSC), Universidad
Complutense de Madrid, Madrid, Spain; 9 Department of Emergency Medicine, Hospital Clínic, and Institut de Recerca Biomàdica August Pi i Sunyer (IDIBAPS), Barcelona, Spain;
10 Royal Brompton & Harefield NHS Foundation Trust, NHLI, Imperial College, London, UK; 11 Emergency and Trauma Centre, Royal Brisbane and Women’s Hospital, Brisbane,
Australia; 12 Coronary Care Unit and Heart Failure Program, Veteran Affairs (VA) San Diego, San Diego, CA, USA; 13 University of Antwerp, Antwerp University Hospital, Edegem,
Belgium; 14 Emergency Medicine, Department of Medical-Surgery Sciences and Translational Medicine, Sant’Andrea Hospital, University La Sapienza, Rome, Italy; 15 Centro
Nacional de Investigaciones Cardiovasculares (CNIC), Department of Cardiology and Cardiovascular Research Area, imas12 Research Institute; Hospital Universitario 12 de
Octubre, Universidad Complutense de Madrid, Madrid, Spain; 16 University Paris Diderot; APHP Hôpitaux Universitaires Saint Louis Lariboisière; Inserm 942, Paris, France;
17 Heart Institute (INCOR), University of Sao Paulo Medical School, Sao Paulo, Brazil; 18 Cardiology, Department of Medical and Surgical Specialties, Radiological Sciences, Public
Health, University of Brescia, Brescia, Italy; 19 San Raffaele Pisana Scientific Institute, Rome, Italy; 20 Department of Cardiology, University Heart Centre Zurich, Zurich,
Switzerland; 21 University of Belgrade School of Medicine, Belgrade, Serbia; and 22 Department of Cardiology and Cardiovascular Research Institute Basel (CRIB), University
Hospital Basel, University of Basel, Basel, Switzerland
Received 24 November 2018; revised 1 May 2019; accepted 2 May 2019
Lung ultrasound is a useful tool for the assessment of patients with both acute and chronic heart failure, but the use of different image
acquisition methods, inconsistent reporting of the technique employed and variable quantification of ‘B-lines,’ have all made it difficult to
compare published reports. We therefore need to ensure that future studies utilizing lung ultrasound in the assessment of heart failure
adopt a standardized approach to reporting the quantification of pulmonary congestion. Strategies to improve patient care by use of lung
ultrasound in the assessment of heart failure have been difficult to develop. In the present document, key aspects of standardization are
discussed, including equipment used, number of chest zones assessed, the method of quantifying B-lines, the presence and timing of additional
investigations (e.g. natriuretic peptides and echocardiography) and the impact of therapy. This consensus report includes a checklist to provide
standardization in the preparation, review and analysis of manuscripts. This will serve as a guide for investigators and clinicians and enhance
the quality and transparency of lung ultrasound research.
..........................................................................................................
Keywords Lung ultrasound • Heart failure • Methodology • Reporting checklist
*Corresponding author. Department of Emergency Medicine, Brigham and Women’s Hospital and Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA. Tel: +1 617
5257932, Fax: +1 617 2646848, Email: eplatz@partners.org
© 2019 The Authors
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Reporting checklist for quantification of pulmonary congestion 845
Introduction Participant characteristics,
........................................................................................................................................................................
Pulmonary congestion is one of the most important findings
co-morbidities and study setting
in heart failure (HF), yet traditional methods, such as clinical In studies of patients with known or suspected HF, the definition
examination and chest X-ray, are relatively insensitive for its of HF used should be described in detail and should be consis-
detection.1 – 3 Recently, there has been tremendous growth in tent with recognized definitions.16,17 Standard patient descriptors
the use of lung ultrasound (LUS) for the detection of pulmonary should be reported as should how and where the patients were
congestion in HF both in research and, more recently, in clinical recruited and whether any inclusion and exclusion criteria were
practice.2,4 – 10 LUS has been proposed as a useful tool in the assess- applied. Reported patient characteristics should include general
ment of patients with both acute and chronic HF.2,5,8,10 This tech- demographics, such as age, sex, and body mass index, vital signs
nique enables the detection of pulmonary congestion in patients including respiratory rate, blood pressure and heart rate, as well
presenting with acute dyspnoea with higher accuracy than chest as important co-morbidities, symptoms and signs of HF, measures
auscultation or chest X-ray.5 The LUS findings of pulmonary con- of cardiac function and natriuretic peptides.
gestion, commonly called B-lines, change dynamically with treat- Diffuse B-lines, which usually reflect pulmonary congestion, can
ment for acute HF and can provide prognostic information in both also be detected by LUS in other conditions such as pulmonary
acute and chronic HF.11,12 However, different methods and incon- contusions, adult respiratory distress syndrome, and interstitial
sistent reporting of the LUS technique used and the quantification lung disease.18 – 22 Pulmonary congestion can also result from con-
of B-lines make it difficult to compare existing studies. This lack of ditions other than HF, e.g. end-stage renal disease. Consequently,
standardization impedes the development of strategies to reduce it is essential that studies designed to detect potential pulmonary
pulmonary congestion and improve patient care.11 One previous congestion in patients with suspected or established HF also
international consensus statement described a wide variety of LUS make a statement about the presence or absence of these other
applications, but was not specifically focused on its use in HF and co-morbidities known to lead to B-lines on LUS (Table 1).11 With-
lacked a detailed description of the methodological aspects.4 With out a clear description of these variables, study results may be
the anticipated growth in the use of LUS in patients with HF, and confounded or misleading. If these conditions are exclusion cri-
in subsequent potential publications, there is a need to develop a teria, this should be clearly stated in the Methods section of the
standardized reporting guide for the quantification of pulmonary study. If patients having one of these conditions have been included,
congestion by LUS in HF. their potential significance must be evaluated, e.g. by undertaking
stratified, sensitivity and other analyses to determine whether they
have confounded the interpretation of potential pulmonary con-
Methods and aims gestion and change in congestion over time and/or in response to
treatment. Reporting of the setting of the study (e.g. pre-hospital,
Our aim was to create a checklist to enhance the quality and trans-
ambulatory care, emergency department, hospital ward, intensive
parency of LUS research and reporting. This consensus statement
is intended to serve as a guide for investigators, reviewers, edi-
care unit) is also important, as HF patients will demonstrate a
tors and readers in the preparation, evaluation and interpretation different spectrum of B-lines reflecting the likely degree of pul-
of manuscripts involving the use of LUS in HF.13 We convened a group monary congestion in each setting; interpretation and compar-
of cardiologists and emergency physicians with expertise in LUS, HF, ison of studies must therefore take study setting into account
epidemiological studies, and clinical trials to review the current litera- (Figures 1 and 2).5,11,23
ture in this area. Following discussion and agreement, they composed a
succinct evidence-based reporting checklist. In contrast to other exist-
ing guidelines, we focused on unique aspects of LUS research, including
study design and image analysis.
Ultrasound equipment, image
acquisition and image analysis
The manufacturer and model of the ultrasound equipment used
Reporting checklist should be described. The type of transducer, transducer orienta-
tion (transverse vs. sagittal) and clip duration (which may be lim-
Title, abstract and study design ited to shorter time-periods on pocket ultrasound devices) can
All reports should follow previously published guidelines regarding alter the number of detectable B-lines in patients with HF.24,25
the use of a structured abstract and appropriate title.14 The Specifically, phased array transducers (compared with curvilinear
relevant guidelines for the design of the study, e.g. observational transducers) and longer clip duration (6–7 s/video clip) allow for
vs. randomized clinical trial, should be used.14 For diagnostic observation of a greater number of B-lines in HF.24,25 Similarly,
studies, the reference standard should be clearly described and patient positioning during the LUS should be described and ide-
for prognostic studies, authors should report how the primary ally performed in a standardized position because of its effect on
outcome was adjudicated, as applicable.15 A description of the B-line count, as patients with acute HF may have a greater number
key aspects of both the general study design and LUS-specific of B-lines in the supine vs. the sitting postion.26
components is provided in the reporting checklist (Table 1 and The number and location of chest zones examined should be
Figure 1). clearly described. Previous studies in HF cohorts have reported
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846 E. Platz et al.
Table 1 Reporting checklist for lung ultrasound studies in heart failure cohorts
Lung ultrasound-specific aspects are highlighted in light blue.
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Type of HF cohort: Co-morbidities

Pre-hospital (e.g. pulmonary fibrosis, ESRD)
ED
In-hospital
Outpatient Additional investigations:
(e.g. natriuretic peptides,
other imaging studies)
• Timing in relation to
lung ultrasound & HF therapy
Imaging protocol:
Data analysis:
• Equipment used Image analysis:
• Distribution of B-lines Outcome
• Number & location of zones • B-line quantification method
• Missing zones measure*
• Duration of ultrasound clip (e.g. count, score)
(e.g. due to pleural effusions)
• Patient positioning
Blinding of Blinding of readers: Guideline-based assessment:

sonographers: • Clinical information • Pre-defined criteria
• Clinical information • Temporal blinding • Adjudication, if applicable
Figure 1 Overview of important methodological aspects in the quantification of pulmonary congestion by lung ultrasound in heart failure
(HF). ED, emergency department; ESRD, end-stage renal disease. *Outcome measures could represent B-line count/score, a diagnosis or
prognostically important event(s).
4–28 chest zones (Table 2), and in 2012 an international guide- Blinding and central image
..............................................................................................
line recommended either the use of 8 or 28 zones (Figure 3A).4

interpretation
Different approaches have since been described, e.g. using six
zones in the assessment of dyspnoeic patients in the emer- Blinding is an important methodological feature in diagnostic
gency department, without apparent loss of diagnostic accuracy.4,5 and prognostic studies to minimize bias and maximize the validity
Based on the currently available data, we suggest that at least of results. Sonographer knowledge of findings on clinical examina-
three zones on each hemithorax (six zones total; Figure 3B) tion or results of other diagnostic modalities, therapies and medi-
cal history, should be described when reporting image acquisition.
should be examined and the B-line number reported in patients
Blinding to these same aspects should be reported with respect
with HF.5
to the individuals undertaking B-line quantification. The temporal
For B-line quantification, two general approaches have been
aspects of blinding should be described for studies involving serial
reported in HF cohorts (Table 2):
LUS examinations. Although HF studies investigating the impact
of reader experience on both real-time and offline quantifica-
(i) A count-based method, in which the sum of B-lines in one
tion of B-lines have demonstrated similar results between novice
intercostal space per zone across all zones is reported.10,23
and expert readers, with high inter-reader agreement, the experi-
(ii) A scoring system, in which a minimum number of B-lines
ence of the personnel involved in analyses and the setting in which
in one intercostal space per zone is used to define a zone
the analyses are performed should be reported:25,33 specifically,
as ‘positive.’ Positive zones are then summed to delineate
a cut-off value. For example, ≥3 B-lines in two zones on
whether the LUS images were interpreted in real-time (at the bed-
side), off-line by investigators not involved in the image acquisition,
each hemithorax are consistent with a diagnosis of pulmonary or at a central core laboratory should be reported. In order to
oedema in dyspnoeic patients presenting to the emergency obtain unbiased results, blinded reading in a central core laboratory
department.5,27,31 clearly is preferable.
If software is used to quantify the number of B-lines, the man-

ufacturer and version of the software should be reported, as the
type of software could potentially contribute to variability in B-line
Additional investigations
number between vendors. In addition, definition of the cut-off pro- The results of additional investigations assessing haemodynamic
cess or decision limits for the detection of HF should be accurately or clinical congestion, such as chest radiography, echocardiogra-
described, if applicable. As large pleural effusions may interfere with phy, invasive haemodynamic measurements or natriuretic peptide
B-line quantification, the presence of pleural effusions (overall fre- levels, should be documented. Importantly, the temporal rela-
quency of unilateral or bilateral pleural effusions) and how pleural tionship between these investigations and the assessment of pul-
effusions were assessed should be reported, when possible. monary congestion by LUS should be reported. This information
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848 E. Platz et al.
large pleural effusions) is essential. More dependent zones are also
........................................................................................................................................................................
those most likely influenced by the presence of pleural effusions or,
HF Patients in the left hemithorax, by cardiomegaly. The method or methods
used to deal with missing B-line data or missing zones should be
- Co-morbidities clearly described.
- Setting (e.g. outpatient) Statistical methods appropriate for the quantification method
(e.g. score or count data) should be used and detailed in the
statistical analysis section. As B-lines are frequently not normally
distributed, the analysis should consider their distribution among
LUS Image Acquisition the patients studied.
- Type of ultrasound system & transducer
- Transducer orientation Presentation of results
- Patient positioning The presentation of results should include the number of patients
- Number & location of LUS zones enrolled and excluded from analysis or follow-up, the proportion
- LUS clip duration with adequate images and the number analysed. Authors should
provide reasons for non-participation at each stage, preferably
using a CONSORT flow diagram for illustration.35 The LUS data
description should include the number and variation of B-lines at
baseline and at follow-up, if applicable. In addition to the main study
LUS Image Analysis results, sources of potential bias and the generalizability of study
- Offline vs. real time analysis findings should be discussed, as well as any implications for clinical
- Blinding of readers (to which aspects?) practice with respect to the role of LUS.
- Method of B-line quantification
- Frequency of pleural effusions Gaps in current knowledge
While there is general agreement on how to diagnose pulmonary
oedema with LUS in patients with undifferentiated dyspnoea pre-
Data Analysis senting to the emergency department, the wide range of LUS meth-
ods used has made the establishment of a standardized approach
- Number of patients with missing LUS zones and cut-off values in other settings challenging. This hampers
- Number and variation of B-lines the performance of meta-analyses of available evidence and con-
sequently the creation of a widely accepted consensus. Studies
Figure 2 Practical aspects of lung ultrasound (LUS) in heart with larger sample sizes comparing different imaging protocols
failure (HF) cohorts. with respect to the number of zones and B-line quantification
method in both ambulatory and hospitalized HF patients (both
on admission and pre-discharge) would be useful to inform clin-
will also facilitate a better understanding of the sequence of the ical guidelines and future clinical trials. Whether LUS provides
dynamic changes of these congestion markers.34 For example, the incremental diagnostic or prognostic information beyond current
interpretation of the relationship between these investigations is methods in patients with suspected or known HF should be
affected by whether the chest radiograph was performed at the further addressed through well-designed, prospective investiga-
same time as the LUS study or whether it was performed 24 h tions, with appropriate statistical analyses that include, for example,
later. Similarly, the initiation of any therapy directed at congestion, comprehensive multivariable models incorporating other impor-
and any response that occurred between the LUS study and sup- tant diagnostic and prognostic variables. In addition, studies inves-
porting investigations should be clearly documented: for example, tigating treatment response and the adequacy of decongestive
if pulmonary artery pressures were measured, after which the therapy, for example at the time of hospital discharge in large,
patient received diuretics, followed by the LUS study should be well-defined HF cohorts will be important. In particular, outcome
documented. randomized controlled trials assigning patients to a treatment inter-
vention designed to maximize B-line resolution vs. standard of care
could inform clinical practice in the future. Similarly, the value
Data reporting and analysis and frequency of LUS use during outpatient clinic follow-up war-
Sonographic B-lines in patients with HF are known to be differ- rants further investigation. While B-lines can be detected irre-
entially distributed.12,30 As a higher prevalence of B-lines occurs spective of ejection fraction in both ambulatory and hospital-
in more dependent chest zones, the reporting of missing data in ized patients with HF, recent reports in patients with reduced
zones that could not be analysed (e.g. because of cardiomegaly or vs. preserved ejection fraction demonstrated differing results
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Table 2 Overview of common B-line quantification methods in patients with heart failure
Zones, n Location of zones Method B-line quantification Sample studies

...........................................................................................................................................
28 Anterior and lateral chest Count Sum of B-lines in all zones 8,9,28,29*
Score Mild: 6–15 B-lines in all zones 7,8
Moderate: 16–30 B-lines in all zones

Severe: >30 B-lines in all zones
11 Anterior and lateral chest Score 0 points: <3 B-lines per zone 30
1 point: ≥3 B-lines per zone

Score: Number of points
8 Anterior and lateral chest Count Sum of B-lines in all zones 8,10,23
Score 0 points: <3 B-lines per zone 8,9,27,31


5 Anterior and posterior chest Count Sum of B-lines in all zones 6
Score 0 points: ≤3 B-lines per zone 6
1 point: >3 B-lines per zone


* Some studies used semi-quantitative count based approaches.
A 8 zone method B 6 zone method
Figure 3 Example of eight (A) and six (B) chest zone protocol for lung ultrasound imaging. Adapted with permission from Platz et al.11 ,
Copyright (2017).
with respect to the number of B-lines in these HF cohorts.23,36 Consistent reporting of certain methodological aspects should be
...................................
These findings could result from different degrees of pulmonary considered in studies employing LUS in HF populations to ensure
congestion or other confounders. Further research is needed to the dissemination of high-quality research results and allow
better understand the impact of these factors on LUS findings in for future standardization.
patients with HF and how to best integrate LUS in the management
of these patients.
Funding
The writing of this manuscript was supported by a grant from
Conclusions the National Heart, Lung and Blood Institute (grant number
Lung ultrasound can provide useful information regarding the pres- K23HL123533) (Platz). The sponsors had no input or contribution
ence and degree of pulmonary congestion in patients with HF. in the development of the research and manuscript.
© 2019 The Authors

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850 E. Platz et al.
Conflict of interest: E.P. reports grants from NHLBI, during the in Piedmont. Lung ultrasound-implemented diagnosis of acute decompensated
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European Journal of Heart Failure (2019) 21, 1142–1148 RESEARCH ARTICLE
doi:10.1002/ejhf.1538
Regional differences in exercise training

implementation in heart failure: findings from
the Exercise Training in Heart Failure
(ExTraHF) survey
Massimo F. Piepoli1,2*, Simone Binno1, Andrew J.S. Coats3, Alain Cohen-Solal4,
Ugo Corrà5, Constantinos H. Davos6, Tiny Jaarsma7, Lars Lund8,
David Niederseer9, Francesco Orso10, Giovanni Q. Villani1,
Piergiuseppe Agostoni11,12, Maurizio Volterrani3, and Petar Seferovic13, on behalf of
the Committee on Exercise Physiology & Training of the Heart Failure Association
of the European Society of Cardiology
1 Heart Failure Unit, Cardiac Department, G. da Saliceto Polichirurgico Hospital, Piacenza, Italy; 2 Institute of Life Sciences, Sant’Anna School of Advanced Studies, Pisa, Italy;
3 Department of Cardiology, IRCCS San Raffaele Pisana, Rome, Italy; 4 Cardiologie, Hôpital Lariboisière, UMR-S 942, Paris, France; 5 Department of Cardiology, Istituti Clinici
Scientifici Salvatore Maugeri, IRCCS Veruno, Veruno, Italy; 6 Cardiovascular Research Laboratory, Biomedical Research Foundation, Academy of Athens, Greece; 7 Department of
Nursing, University of Linköping, Linköping, Sweden; 8 Department of Medicine, Karolinska Institutet; and Heart and Vascular Theme Karolinska University Hospital, Stockholm,
Sweden; 9 Department of Cardiology, University Heart Centre, Zürich, Switzerland; 10 Heart Failure Clinic, Geriatrics and Intensive Care Unit, University of Florence and AOU
Careggi, Florence, Italy; 11 Centro Cardiologico Monzino IRCCS, University of Milan, Milan, Italy; 12 Department of Clinical Sciences and Community Health, University of Milan,
Milan, Italy; and 13 Department of Cardiology, Clinical Centre of Serbia, University of Belgrade School of Medicine, Belgrade, Serbia
Received 6 January 2019; revised 8 April 2019; accepted 24 May 2019 ; online publish-ahead-of-print 25 July 2019
Background Exercise training programmes (ETPs) are a crucial component in cardiac rehabilitation in heart failure (HF) patients.
The Exercise Training in HF (ExTraHF) survey has reported poor implementation of ETPs in countries affiliated to the
European Society of Cardiology (ESC). The aim of the present sub-analysis was to investigate the regional variations
in the implementation of ETPs for HF patients.
.....................................................................................................................................................................
Methods The study was designed as a web-based survey of cardiac units, divided into five areas, according to the geographical
and results location of the countries surveyed. Overall, 172 centres replied to the survey, in charge of 78 514 patients,
differentiated in 52 Northern (n = 15 040), 48 Southern (n = 27 127), 34 Western (n = 11 769), 24 Eastern European
(n = 12 748), and 14 extra-European centres (n = 11 830). Greater ETP implementation was observed in Western
(76%) and Northern (63%) regions, whereas lower rates were seen in Southern (58%), Eastern European (50%)
and extra-European (36%) regions. The leading barrier was the lack of resources in all (83–65%) but Western region
(37%) where patients were enrolled in dedicated settings and specialized units (75%). In 40% of centres, non-inclusion
of ETP in the national or local guideline pathway accounted for the lack of ETP implementation.
.....................................................................................................................................................................
Conclusion Exercise training programmes are poorly implemented in the ESC affiliated countries, mainly because of the lack of
resources and/or national and local guidelines. The linkage with dedicated cardiac rehabilitation centres (as in the
Western region) or the model of local rehabilitation services adopted in Northern countries may be considered as
options to overcome these gaps.
..........................................................................................................
Keywords Heart failure • Cardiac rehabilitation • Exercise training • Implementation • Guidelines
*Corresponding author. Heart Failure Unit, Cardiac Department, G. da Saliceto Polichirurgico Hospital, Cantone del Cristo, 29122 Piacenza, Italy. Tel: +39 0523 303217, Fax:
+39 0523 303220, Email: m.piepoli@gmail.com
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Cardiac rehabilitation in Europe 1143
Introduction long-term maintenance programme. Exercise training modalities (i.e.
........................................................................................................................................................................
aerobic, resistance, balance, respiratory) and the tests performed to
Heart failure (HF) is a life-threatening disease.1 At the end of 2010, evaluate ETP efficacy were also investigated.
approximately 26 million people worldwide were living with HF, The survey was launched after the HFA Scientific Meeting held in
and the outlook was poor, with survival rates poorer than those Lisbon on May 2013, and data were collected until February 2014.
for colorectal, breast, or prostate cancer.1 A global approach to
the HF epidemic includes primary and secondary prevention of car-
Study sample and data collection
diovascular diseases, drug and device therapy, lifestyle changes and
physical exercise, and heart transplantation for some patients.1 – 3 According to the United Nations Organization division of the ESC
affiliated countries,11 five geographical areas were identified: four in
Cardiac rehabilitation (CR) comprises education, exercise train-
Europe (Northern, Southern, Western and Eastern) and one outside
ing and psychosocial support.4 The broadened eligibility of CR to
Europe (extra-EUR) (Figure 1). The study sample and data collection
HF has acted as a catalyst to improved care5,6 : CR in HF patients were achieved in the following steps: first, the identification of national
can reduce symptoms and the risk of acute decompensation of coordinators of HF scientific societies and/or working groups in the
HF with less need for emergency hospitalizations, improves prog- 46 ESC affiliated countries to which the questionnaire was sent; the
nosis and, ultimately, reduces mortality.6 – 8 Exercise training pro- coordinators were asked to forward the questionnaire to the leading
grammes (ETPs) are a key component highly recommended by HF centres and to the health care professionals involved. Thereafter,
both the prevention and the HF guidelines of the European Soci- responses of the participating centres were digitalized and the results
ety of Cardiology (ESC).1,9 However, ETPs are not yet offered to analysed as absolute numbers and percentages according to each
all, or even a majority of HF patients in countries affiliated to the geographical area.
ESC, as was recently shown by the Exercise Training in Heart Fail-
ure (ExTraHF) survey promoted by the Heart Failure Association
Analysis
(HFA).10 Several reasons were recognized, in particular the costs
of CR, the lack of personnel or equipment involved, and of local A descriptive statistics was performed. For purposes of readability,
the answering categories ‘always/mostly/usually’ were collapsed and
(or national) guidelines.10 It is known that large regional variations
reported as ‘yes’, and the categories ‘seldom/not usually/not’ were
in HF management and CR exist worldwide and more specifically
collapsed as ‘no’.
in Europe. In order to guide further implementation interventions,
data on regional variance are crucial, but no data on regional dif-
ferences in ETP implementation and in barriers among European Results
(EUR) regions are available.
Thus, based on the ExTraHF survey, and given the great het- Forty-one country coordinators out of the 46 contacted replied to
erogeneity between countries regarding HF care implementation our questionnaire (89%). This accounted for 172 cardiac centres
and prioritization, a secondary analysis was performed aimed at (Figure 1): 30% in Northern, 28% in Southern, 20% in Western and
investigating regional variations in the use of ETP for HF across 14% in Eastern Europe. Fourteen (8%) centres were located in the
Europe and other extra-EUR ESC affiliated countries, and at iden- extra-EUR area. These 172 HF centres reported to be in charge of
tifying specific/local barriers to ETP implementation. a total of 78 514 HF patients allocated as follows: 15 040 (20%) in
Northern, 27 127 (35%) in Southern, 11 769 (15%) in Western, and
12 748 (15%) in Eastern Europe. Of note, 11 830 (15%) patients
Methods were in the extra-EUR area (Figure 1). In general, most centres
were general cardiac units (83%), either in EUR or extra-EUR areas,
ExTraHF was designed as a web survey questionnaire addressed to all
whereas 17% were specifically CR dedicated.
cardiac centres of ESC affiliated countries, as previously described.10 In
The status of the centres was public in 84% (of note, 86% in
brief, the questionnaire (online supplementary Methods S1), developed
by the Committee on Exercise Physiology & Training of the HFA, and extra-EUR), and public centres were equally distributed across EUR
translated into a web form by the European Heart House, included geographical areas (85%, 90%, 74% and 92% in Northern, Southern,
the following information: (i) contact details of the person who filled Western and Eastern Europe, respectively).
in the questionnaire; (ii) characteristics of the reference hospital/health Overall, 68 (39.5%) centres reported lack of an ETP (Table 1):
care centre; (iii) the dimension of the treated HF population per centre ETP was not available in 36% of centres in Northern, 41% in
(without individual patient data). The questionnaire was not translated Southern, 23% in Western, 50% in Eastern, and 64% in extra-EUR
into different languages, but the opportunity was given to contact our areas. In 10% and 16% of centres of Southern and Northern areas,
centre by email and via a dedicated telephone line if needed. respectively, an ETP was active but was subsequently stopped for
If an ETP was available, the following information was collected: insti- unspecified reasons.
tutions covering the costs, professional staff involved and the personnel
responsible for conducting the ETP, and presence of inclusion/exclusion
criteria in the national and local guidelines.10 If no ETP was available for Reasons for lack of implementation
the HF population, the determining factors were requested.
In case of ETP availability, information on the structure, organization
of exercise training programmes
and mode of long-term follow-up was collected, considering the follow- Figure 2 depicts the main reasons for the lack of implementa-
ing three phases of ETP: (i) in-hospital; (ii) early post-discharge; and (iii) tion of ETPs in the study population. The reason for no ETP
© 2019 The Authors

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1144 M.F. Piepoli et al.
Extra-
Northern Southern Western Eastern
Europe
Centres 52 48 34 24 14
Patients 15 040 27 127 11 769 12 748 11 830
Figure 1 Geographical distribution of European Society of Cardiology (ESC) affiliated countries.
implementation varied across the different geographical areas. confident or not having sufficient skill or knowledge to manage ETP,
.........................................................................
Overall, the major cause was lack of resources, except for the with a variation of percentage from 0% in Northern and Eastern
Western area where this factor was reported only by 38% of EUR to 13% in Western EUR areas.
centres.
The lack of inclusion of ETP in the contract with the referring
institutes was declared by 32% centres in Northern, 20% in Exercise training modalities
Southern, 13% in Western, 42% in Eastern, and 44% in extra-EUR Overall, aerobic continuous exercise was the most common
areas, whereas ETP was not included in local or national guidelines modality of training programme in all regions with the exception
in 32% centres in Northern, 40% in Southern, 25% in Western, of the Northern region where this modality was implemented in
25% in Eastern, and 67% in extra-EUR areas. only 27% of cases and, in contrast, low-intensity interval training
An ETP was not locally implemented because patients was mostly used (54% of cases) (Table 2).
were finally referred to other units or to specialized services, High-intensity exercise training was implemented in around
with percentages of 42%, 30%, 75%, 25%, and 11% in the 15% of cases, but in Eastern and extra-EUR countries this
Northern, Southern, Western, Eastern, and extra-EUR areas, modality was employed in less than 5% of cases. Resis-
respectively. tance training was highly implemented only in the Western
A perceived lack of importance of ETP, safety concerns, and areas (53%) followed by Southern (40%) and Northern (37%)
uncertainties about the usefulness of ETP, all played a marginal role. regions.
Specifically, a lack of interest in ETP ranged from 0% in Northern Bicycle training was used in most cases (>70%) except in
to 25% in Eastern areas; safety concerns were seen in 0%, 5%, extra-EUR countries where treadmill modality was mostly
25%, 25% and 33% in Western, Northern, Southern, Eastern, and employed (60%). Other mode of aerobic endurance training with
extra-EUR areas, respectively; doubts about the clinical benefits other cardio fitness facilities (e.g. elliptical trainer) was imple-
provided by ETP were reported in 11%, 20%, 13%, 25%, and 22% mented in a minority of the centres (around 10%), except for the
in Northern, Southern, Western, Eastern, and extra-EUR areas, Northern region where this modality was implemented in 30% of
respectively. Finally, physicians (staff involved) reported not being the centres.
© 2019 The Authors

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6%
Lack of
evidence of 13%
efficacy of Referred to other
6% ETP in HF
centres
Lack of evidence of safety of
ETP in HF
6%
13%
6%
11% 16%
HF services (GPs, time
OPD) already meet 27%

11% staff
the needs for ETP
15%
25%
4%
Lack of interest from local HF 4%
25% accommodation Not enough
173 5 %: transport
service
2%
11% resources
2% equipment
You are not confident in 24%
treating HF 13% finances
9%
13% 10%
ETP in HF is
9%
not included 10% ETP in HF is not
in the local ETP in HF is included in the
guidelines / not included in contract with the
pathways the contract referring
with the NHS institution
Figure 2 Causes for the lack of implementation of exercise training programmes (ETP). GP, general practitioner; HF, heart failure; OPD,
outpatient department; NHS, National Health System.
Table 1 The numbers of centres with no implemented exercise training programme, the numbers of heart failure
patients followed, and the two major causes, in different European and extra-European regions
Northern Southern Western Eastern Extra-European

...........................................................................................................................................
Centres 19 (36%) 20 (41%) 8 (23%) 12 (50%) 9 (64%)
Patients 6677 (44%) 13 743 (50%) 4350 (37%) 5370 (42%) 6870 (58%)
Primary cause Lack of resources Lack of resources Admission to another Lack of resources Lack of resources
(68%) (65%) ETP (75%) (83%) (78%)
Secondary Admission to another ETP not included in Lack of resources (37%) ETP not included in ETP not included in
cause ETP (42%) national/local national/local national/local
guidelines (40%) guidelines (41%) guidelines (66%)
ETP, exercise training programme.

The total percentages in primary and secondary causes are > 100% because multiple answers were allowed.
In centres and patients, figures are showing absolute numbers and percentage with respect to the total number for centres and patients.
Cardiopulmonary exercise testing was extensively implemented follow-up programme was absent in most EUR regions, but in the
......................................
in Western and Southern areas (88% and 46%, respectively), but Northern region these programmes were described in more than
poorly used in the Northern one (6%). 64% of the centres and were mainly lead by nurses.
Structure and long-term organization Discussion

Cardiologists, nurses, psychologists, exercise physiologists/ The main findings of this survey are (i) ETPs, a recommended
therapists, dieticians, physiotherapists, are all figures involved, treatment in patients with HF, are still poorly implemented in ESC
in all settings, in more than 50%, with the exception of the car- affiliated countries, mainly because of the lack of resources and the
diologists that are involved in only 10% in the Northern regions. exclusion in national and local guidelines; (ii) a wider recognition
Consequently, cardiologists are the leading figures responsible for and implementation of ESC guideline recommendations are impor-
ETPs in all (80–90% of the centres) but the Northern region, tant points where the Scientific Associations of the ESC (namely
where nurses are playing this role (73%). A structured long-term HFA, the European Association of Preventive Cardiology, and the
© 2019 The Authors

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Table 2 Implementation of exercise training modalities, including strength training and aerobic endurance, and of
cardiopulmonary exercise testing in European and extra-European regions
Northern Southern Western Eastern Extra-European

(n = 52) (n = 48) (n = 34) (n = 24) (n = 14)
...........................................................................................................................................
Aerobic exercise training (mostly/usually >20%)
Continuous/constant load 14 (27%) 18 (37%) 18 (53%) 7 (29%) 3 (21%)
Interval/high intensity 7 (13%) 8 (17%) 7 (20%) 1 (4%) 0 (0%)
Interval low-intensity 28 (54%) 10 (21%) 14 (41%) 6 (25%) 1 (7%)
Resistance exercise training (mostly/usually >20%)
Dynamic (including balance/coordinative skills) 19 (37%) 19 (40%) 18 (53%) 3 (12%) 2 (17%)
Respiratory muscle training 9 (17%) 16 (33%) 11 (32%) 5 (21%) 2 (14%)
Cardiopulmonary exercise testing (mostly/usually >20%) 3 (6%) 22 (46%) 30 (88%) 9 (37%) 3 (21%)
Association of Cardiovascular Nursing & Allied Professions) can economic support (i.e. lack of resources) rather than scientific
...........................................................................................................................
play a crucial role; (iii) the development of linkage with special- motivations.
ized centres dedicated to CR (mainly present only in the Western Exercise intolerance, frequently manifested by fatigue or short-
region) or the model of local rehabilitation services adopted in ness of breath on minimal exertion, is a hallmark of HF1 : one of
Northern countries can overcome some of these gaps. the principal goals of treatment is to improve exercise capacity,
In particular, a network of specialized centres can be mostly and interventions designed to change this leading symptom in HF
dedicated to in-hospital care of the more severe and fragile HF have been shown to improve outcomes.6 – 8 ETP is an important
cases (high-intensity settings), while local rehabilitation centres adjunct to non-pharmacological treatment that has a proven pos-
with low-intensity level should be considered for more stable HF itive effects on mortality, morbidity, exercise capacity and quality
cases and for the maintenance of regular physical activity on the of life.8,14 – 27 Based on the analysis of 801 patients enrolled in nine
long term. randomized controlled clinical trials, the ExTraMATCH collabora-
The therapeutic approach to HF (either pharmacological or tive group calculated a 35% (P < 0.05) lower risk for mortality and
non-pharmacological, including ETP) is complex and plays an impor- a 28% (P < 0.05) lower risk for the composite endpoint of mor-
tant role in patients’ quality of life and prognosis.1,3,4 Although ETP tality or hospitalization in favour of ETP.8 Smart and Marwick15
alone or as a core component of CR programmes is highly recom- conducted a meta-analysis on 11 randomized clinical trials (includ-
mended in HF by current guidelines,1 it is poorly implemented in ing 729 patients) and found a 39% lower relative risk for mortality
clinical practice, but the causes have been rarely investigated. In the in the ETP group. The Heart Failure-A Controlled Trial Investi-
Get With the Guidelines-Heart Failure Registry, the referral rate to gating Outcomes of exercise TraiNing (HF-ACTION), until now
CR programmes in hospitalized HF patients was only 10.4%, with the largest multicentre, randomized controlled trial involving 2331
the main clinical factors associated with lack of referral being older patients with severe left ventricular systolic dysfunction on optimal
age, female gender, and co-morbidities.12 Besides our experience, medical therapy, showed reduced all-cause mortality or all-cause
only one report from a single country of Central America has anal- hospital stay by ETP after adjustment for pre-defined prognostic
ysed non-clinical reasons for CR and ETP referral.13 Only 4.4% of predictors (11%, P = 0.03).7,8
eligible patients were referred to CR in Mexico, and financial crisis Post-hoc sub-analyses demonstrated that ETP was effective also
(83%), lack of skilled personnel (67%), deficient equipment (46%), in special HF populations.16 – 19 Selection of HF patients for ETP is
inadequate areas (42%), and a reduced number of operating centres founded on clinical stability and optimal medical therapy,8,20 and its
(38%) were reported.13,14 continuation is related to maintaining clinical and therapy stability,
In individual patients, variations in treatment strategy may treatment adherence, exercise capacity responsiveness and control
be justified given the complexity of the underlying disease and of psychological factors.21 – 23 Thus, if appropriately prescribed,20
patient personal preferences, but one would expect to find ETP acts as a filter or ‘safety net’ beyond its intrinsic effects, as it
certain treatment patterns uniformly distributed among most of enables better HF management through monitoring of symptoms
the ESC affiliated countries. Although this survey is based on and signs,.
voluntary participation and did not approach all hospitals in EUR The present results demonstrate that ETPs are more frequently
and extra-EUR areas, some initial conclusions can be drawn as prescribed in Northern and Western EUR areas, while lack of ETP
it was a comprehensive collection, from 89% of EUR countries, implementation is observed in Southern, Eastern and extra-EUR
representing 72% of the country members of the ESC. areas. As such, ETPs are not systematically applied across EUR
The main findings are: (i) ETPs are recommended in the majority and extra-EUR regions, and variability in ETP implementation is a
of HF centres, but with heterogeneity across EUR and extra-EUR potentially important clinical observation, particularly if suboptimal
areas; (ii) unavailability of ETPs is still present in many cen- HF management strategies result in poor health outcomes. The
tres, mostly related to lack of equipment, health professional most frequent reason for not implementing ETPs is shortage of
participation, mentioning in national and local guidelines, and resources across EUR areas. Although specific reasons cannot be
© 2019 The Authors

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defined (e.g. time, staff, equipment, accommodation and transport, In our opinion, this limitation cannot be overcome by the devel-
........................................................................................................................................................................
finances), most reasons are related to administrative and economic opment of different guidelines for the different geographical areas
issues. (Southern/Northern/Western/Eastern/extra-EUR), but by a better
Regarding ETP modalities, differences were observed across implementation of the existing ones in all ESC countries. However,
regions in relation to specific experiences (e.g. high-intensity we must recognize that the different implementation of guidelines
exercise training in Northern regions). However, multiple answers is due to different economic conditions, and therefore availability
were allowed, making a correct comparison between the dif- of resources, including therapeutic tools and organization models.
ferent areas, and therefore the interpretation of our findings,
difficult.
A variety of health care professionals have a role in HF man-
Conclusion
agement programmes,23,24 and because multidisciplinary teams can Exercise training programmes are legitimately prescribed in more
be costly, economic reasons might have limited the number of pro- than 50% of committed HF centres, but a considerable imple-
gramme members.25 – 28 Finally, patient and health care professional mentation gap still exists between recommendations of practical
education can differ markedly between countries/regions: in most guidelines.2,3 Based on our findings, shortage of resources is the
EUR countries, no formal education exists for ETPs, with most main reason for the lack of ETP implementation in these cen-
of the applicable knowledge and skills being gained from ‘clinical tres: therefore, structural and financial issues must be considered
experience’ and ‘training on the job’. to achieve better ETP dissemination across regions. Whatever
the reasons, lack of ETP implementation might favour heath care
inequalities, and the pervasiveness of inefficiency in the health care
Study limitations sector.29 – 31 The excess variability in HF management raises ques-
These findings should be interpreted with caution because of tions about the quality, equity, and efficiency of care. Education pro-
differences in health care organizations across EUR and extra-EUR grammes for patients, health care professionals, family members
areas, the complexity of HF management, and the potential bias and caregivers, as well as avoiding fragmentation of health care plans
of the operator who filled in the questionnaire.10 In addition, our along socio-economic lines, strengthening doctor–patient relation-
study is based on the responses collected: data concerning the ships and refining multidisciplinary team responsibility could have
number of HF centres contacted by the national coordinators and a dramatic impact on outcome improvement. In addition, the col-
therefore the effective response rate are unavailable. laboration with health care authorities is crucial along with ESC
As in all voluntarily completed surveys, there is the issue of qual- efforts to persuade health care authorities of affiliated countries
ity control of the provided information. Discrepancies in HF man- to reimburse ETPs and/or increase financial resources.
agement in general and in ETP implementation have been described
between general practitioners and hospital-based specialists, and Supplementary Information
between internists and cardiologists within the same hospital.1,10
Moreover, tradition, equipment availability, additional cost and dif- Additional supporting information may be found online in the
ferences in national guidelines may have played a role. Although Supporting Information section at the end of the article.
inaccuracies and biases are intrinsic to all surveys, this limitation Methods S1. ExTraHF web survey questionnaire.
may have been controlled in this study by the sizable number of Conflict of interest: none declared.
centres in EUR and extra-EUR areas, specialized in HF manage-
ment, which were contacted. EUR minimal standards for ETP in HF
are missing. This is important for the minimum alignments of ETP References
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European Heart Journal (2019) 40, 3297–3317 CLINICAL RESEARCH
doi:10.1093/eurheartj/ehz641 Heart failure/cardiomyopathy
How to diagnose heart failure with preserved

ejection fraction: the HFA–PEFF diagnostic
algorithm: a consensus recommendation from
Downloaded from https://academic.oup.com/eurheartj/article-abstract/40/40/3297/5557740 by guest on 19 May 2020

the Heart Failure Association (HFA) of the
European Society of Cardiology (ESC)
Burkert Pieske1,2,3,4*, Carsten Tschöpe1,2,5, Rudolf A. de Boer 6, Alan G. Fraser7,
Stefan D. Anker1,2,5,8, Erwan Donal9, Frank Edelmann1,2, Michael Fu10,
Marco Guazzi11,12, Carolyn S.P. Lam13,14, Patrizio Lancellotti15,
Vojtech Melenovsky16, Daniel A. Morris1, Eike Nagel 17,18,
Elisabeth Pieske-Kraigher1, Piotr Ponikowski19, Scott D. Solomon20,
Ramachandran S. Vasan21, Frans H. Rutten 22, Adriaan A. Voors6,
Frank Ruschitzka23, Walter J. Paulus24, Petar Seferovic25, and
Gerasimos Filippatos26,27
1
Department of Internal Medicine and Cardiology, Charité - Universitätsmedizin Berlin, Campus Virchow Klinikum; 2German Center for Cardiovascular Research (DZHK),
Berlin, Partner Site, Germany; 3Department of Internal Medicine and Cardiology, German Heart Institute, Berlin, Germany; 4Berlin Institute of Health (BIH), Germany; 5Berlin
Institute of Health (BIH) Center for Regenerative Therapies (BCRT), Charite, Berlin, Germany; 6University Medical Centre Groningen, University of Groningen, Department of
Cardiology, Groningen, the Netherlands; 7School of Medicine, Cardiff University, Cardiff, UK; 8Department of Cardiology and Pneumology, University Medicine Göttingen
(UMG), Germany; 9Cardiology and CIC, IT1414, CHU de Rennes LTSI, Université Rennes-1, INSERM 1099, Rennes, France; 10Section of Cardiology, Department of Medicine,
Sahlgrenska University Hosptal/Ostra, Göteborg, Sweden; 11Department of Biomedical Sciences for Health, University of Milan, IRCCS, Milan, Italy; 12Department of Cardiology,
IRCCS Policlinico, San Donato Milanese, Milan, Italy, 13National Heart Centre, Singapore & Duke-National University of Singapore; 14University Medical Centre Groningen, The
Netherlands; 15Department of Cardiology, Heart Valve Clinic, University of Liège Hospital, GIGA Cardiovascular Sciences, CHU Sart Tilman, Liège, Belgium; 16Institute for
Clinical and Experimental Medicine - IKEM, Prague, Czech Republic; 17Institute for Experimental and Translational Cardiovascular Imaging, University Hospital Frankfurt;
18
German Centre for Cardiovascular Research (DZHK), Partner Site Frankfurt, Germany; 19Medical University, Clinical Military Hospital, Wroclaw, Poland; 20Cardiovascular
Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA; 21Section of Preventive Medicine and Epidemiology and Cardiovascular Medicine,
Department of Medicine, Boston University School of Medicine, Boston, MA, USA; 22Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht,
Utrecht University, Utrecht, The Netherlands; 23University Heart Centre, University Hospital Zurich, Switzerland; 24Department of Physiology and Amsterdam Cardiovascular
Sciences, Amsterdam University Medical Center, The Netherlands; 25University of Belgrade School of Medicine, Belgrade University Medical Center, Serbia; 26Department of
Cardiology, National and Kapodistrian University of Athens Medical School; University Hospital “Attikon”, Athens, Greece; and 27University of Cyprus, School of Medicine,
Nicosia, Cyprus
Received 16 May 2018; revised 30 October 2018; editorial decision 16 August 2019; accepted 26 August 2019; online publish-ahead-of-print 31 August 2019
Making a firm diagnosis of chronic heart failure with preserved ejection fraction (HFpEF) remains a challenge. We recommend a new step-
wise diagnostic process, the ‘HFA–PEFF diagnostic algorithm’. Step 1 (P=Pre-test assessment) is typically performed in the ambulatory set-
ting and includes assessment for HF symptoms and signs, typical clinical demographics (obesity, hypertension, diabetes mellitus, elderly,
atrial fibrillation), and diagnostic laboratory tests, electrocardiogram, and echocardiography. In the absence of overt non-cardiac causes of
breathlessness, HFpEF can be suspected if there is a normal left ventricular ejection fraction, no significant heart valve disease or cardiac
ischaemia, and at least one typical risk factor. Elevated natriuretic peptides support, but normal levels do not exclude a diagnosis of
HFpEF. The second step (E: Echocardiography and Natriuretic Peptide Score) requires comprehensive echocardiography and is typically
performed by a cardiologist. Measures include mitral annular early diastolic velocity (e0 ), left ventricular (LV) filling pressure estimated
using E/e0 , left atrial volume index, LV mass index, LV relative wall thickness, tricuspid regurgitation velocity, LV global longitudinal systolic
* Corresponding author. Tel: þ49 30 450 553702, Fax: þ49 30 450 7 553702, Email: burkert.pieske@charite.de
Published on behalf of the European Society of Cardiology. All rights reserved. V
C The Author(s) 2019. For permissions, please email: journals.permissions@oup.com.
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3298 B. Pieske et al.
strain, and serum natriuretic peptide levels. Major (2 points) and Minor (1 point) criteria were defined from these measures. A score >_5
points implies definite HFpEF; <_1 point makes HFpEF unlikely. An intermediate score (2–4 points) implies diagnostic uncertainty, in which
case Step 3 (F1: Functional testing) is recommended with echocardiographic or invasive haemodynamic exercise stress tests. Step 4 (F2:
Final aetiology) is recommended to establish a possible specific cause of HFpEF or alternative explanations. Further research is needed for
a better classification of HFpEF.
...................................................................................................................................................................................................
Keywords Heart failure • HFpEF • diagnosis • echocardiography • biomarkers • natriuretic peptides • exercise
echocardiography

..
Introduction .. Why new diagnostic
..
In the general population aged >_60 years, 4.9% were identified to
.. recommendations for heart
..
have heart failure with preserved ejection fraction (HFpEF),1 imply- .. failure with preserved ejection
..
ing several millions of affected individuals in Europe. This number .. fraction?
is expected to increase further as people live longer and obesity ..
..
and diabetes become more common.1–3 Heart failure with pre- .. The key criteria in the previous HFA recommendations were: (i)
served ejection fraction already accounts for more than half of all .. symptoms and/or signs of HF, (ii) normal or only mildly abnormal LV
..
heart failure (HF) hospital admissions.1 Providing effective manage- .. systolic function, and (iii) LV diastolic dysfunction.4 Diagnostic param-
ment is a major unmet clinical need that will depend on a clear .. eters were invasive measurements, echocardiographic indices of LV
..
diagnosis. .. diastolic function and filling pressures, LV hypertrophy (LVH), left
The Heart Failure Association (HFA) of the European Society ..
.. atrial (LA) enlargement, serum natriuretic peptides (NP), and atrial
of Cardiology (ESC) published a consensus statement in 2007 .. fibrillation (AF).4 Over time, both advantages and disadvantages of
on ‘How to diagnose diastolic heart failure’.4 Since then, termin- ..
.. this approach have been reported.
ology has evolved through HF with normal ejection fraction .. Cut-offs for key non-invasive parameters are often based on lim-
(HFnEF) to the current definition as ‘HF with preserved ejec- ..
.. ited data, and may fall in a non-diagnostic intermediate range. The
tion fraction’.4 .. non-invasive diagnosis or exclusion of HFpEF will not depend on a
Additional diagnostic criteria for HFpEF have been published, ..
.. single parameter above or below a certain cut-off, but on a combin-
including one scoring system,5 but they differ in echocardiographic .. ation of parameters derived from clinical, laboratory, and imaging
cut-off values, the role of comorbidities, the inclusion of biomarkers,
..
.. tests that together will give a probability for the diagnosis. A recent
the role of invasive haemodynamic assessment, and the role of exer- .. example of such an approach was a composite HFpEF diagnostic
cise stress testing.3,4,6–8 Understanding of the pathophysiology of
..
.. score, derived retrospectively from clinical characteristics (age
HFpEF has advanced,9–13 diagnostic options have evolved,14–17 and .. >60 years, obesity, atrial fibrillation, treatment with >_2 antihyperten-
this novel information needs to be integrated into a new comprehen-
..
.. sive drugs) and echocardiographic measurements [E/e0 >9, pulmon-
sive diagnostic algorithm for suspected HFpEF. .. ary artery systolic pressure (PASP) >35 mmHg].5
A writing committee initiated by the HFA of the ESC has
..
..
therefore produced an updated consensus recommendation— ..
.. Echocardiographic criteria for diagnosing
the HFA–PEFF diagnostic algorithm (Figure 1). Its key elements ..
are (i) the concept that identification of HFpEF involves all lev- .. heart failure with preserved ejection
.. fraction
els of care, including general practitioners, internists, general ..
cardiologists, HF specialists, and invasive cardiologists; (ii) a .. Left ventricular ejection fraction (LVEF) estimates global function but
..
stepwise diagnostic approach from initial clinical assessment to .. does not indicate LV volume or stroke volume. Despite a preserved
more specialized tests will therefore be useful; (iii) the diagnosis .. LVEF, patients with HFpEF have impaired LV long-axis systolic func-
..
is not always straightforward, so the integration of distinct .. tion, which can be measured using mitral annular systolic excursion
parameters from complementary diagnostic domains into a new .. or systolic velocities or LV global longitudinal strain (GLS).19 As well
..
diagnostic score is recommended; (iv) for the subset of patients .. as global diastolic dysfunction, they have long-axis diastolic dysfunc-
with an inconclusive score, definitive diagnosis (or exclusion) .. tion which can be measured from the velocity of long-axis lengthen-
..
will require invasive haemodynamics and/or non-invasive or in- .. ing of the LV in early diastole (from mitral annular velocity, e0 ). These
vasive exercise stress tests; and (v) underlying pathophysiologic- .. were not considered in the previous HFA recommendations.4
..
al alterations (such as chronotropic incompetence, reduced LV .. A mean E/e0 index >_15 at rest has good diagnostic value for identi-
compliance) and specific aetiologies (such as amyloidosis18) .. fying a high mean pulmonary capillary wedge pressure (mPCWP),
..
have to be considered. A precise diagnosis is increasingly im- .. supporting the likelihood of HFpEF,20,21 but an E/e0 ratio within the
portant since new targeted therapies are becoming available for
.. intermediate range (9–14) is less sensitive.22 The E/e0 ratio has limita-
..
defined subsets of HFpEF patients. . tions that are relevant in routine clinical practice23–29 and its use as a
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How to diagnose HFpEF 3299

Figure 1 HFA-PEFF diagnostic algorithm. Overview of the diagnostic heart failure with preserved ejection fraction steps 1–4 (P–F). CT, computed
tomography; PET, positron emission tomography.
..
single diagnostic index above all other non-invasive measures of filling ..
..
Defining aetiology and
pressures (such as retrograde pulmonary venous flow) cannot be
.. pathophysiology
recommended. In consequence, HFpEF cannot be diagnosed from a ..
single echocardiographic measure, and inclusion of recently validated ..
.. Heart failure with preserved ejection fraction typically evolves from a
functional and structural parameters into a diagnostic score may bet- .. combination of risk factors and comorbidities, including advanced
ter define this heterogeneous disorder. ..
.. age, female sex, obesity, systemic arterial hypertension, diabetes mel-
.. litus, renal dysfunction, anaemia, iron deficiency, sleep disorders, and
Usefulness of natriuretic peptides ..
.. chronic obstructive pulmonary disease.1,2,11,42–44 Heart failure with
In general, NP levels are higher in patients presenting with acute .. preserved ejection fraction ‘masqueraders’ such as heart valve dis-
shortness of breath for cardiac reason or in acute HF, than in
..
.. ease, arrhythmias, and pericardial constriction need to be excluded.
patients who have chronic HF.30,31 Of note, our recommendations .. Similarly, a patient with a normal LVEF and HF-like symptoms caused
target stable symptomatic HFpEF, and natriuretic peptide levels
..
.. by significant coronary artery disease (CAD) is also not considered
can be normal in these patients even with invasively confirmed .. to have HFpEF.
HFpEF. In consequence, normal NP levels do not exclude HFpEF,
..
.. Similar to current practice for heart failure with reduced ejection
especially in the presence of obesity.32,33 Interpretation depends .. fraction (HFrEF), we recommend applying the descriptive term
..
also on whether the patient is in sinus rhythm (SR) or has AF, .. HFpEF for both the classical form with typical risk factors and comor-
which itself is associated with increased NP levels even in the ab- .. bidities, and for rarer cases with a specific aetiology, provided that the
..
sence of HF.34,35 .. key diagnostic criteria are met. Specific aetiologies that may be treat-
Besides obesity, sex, age, and renal function affect NP levels,36,37 .. able include inherited or acquired infiltrative, restrictive, inflamma-
..
but using stratified cut-points only marginally improves diagnostic ac- .. tory, or genetic cardiomyopathies45–48 (Table 2). They should always
curacy (net reclassification index 3%),38 at the expense of less every- .. be considered once a diagnosis of HFpEF has been made (Table 2,
..
day utility. The variability of repeated measurements in individual .. Supplementary material online, S2–S4). It has been suggested that
patients is up to 100%, so a rise or fall of <_100% may not necessarily ..
.. patients with HFrEF share a common mechanism that responds to
indicate recovery or progression of disease.39,40 .. common treatment (inhibition of the renin-angiotensin system)3 but
..
.. there are other treatments for subsets of patients with HFrEF that
Diagnostic algorithms for heart failure .. are specific (such as treating ischaemia when there is hibernating myo-
..
with preserved ejection fraction .. cardium, using targeted antiviral therapy or immune modulation in in-
The concept of a diagnostic algorithm that incorporates imaging and .. flammatory HFrEF, and corticosteroid therapy in sarcoidosis-related
..
biomarkers (NPs) was recommended by the HFA in 2007,4 and .. HFrEF); in that respect, our proposed use of the generic term HFpEF
adapted by others.41 It allowed parallel diagnostic pathways starting .. is similar and should include specific myocardial aetiologies.
..
from haemodynamic measurements, echocardiography, or NPs,4 .. Basic mechanisms affecting the myocardium in HFpEF include
that could yield different results for the same patients. In addition, the .. myocyte hypertrophy, systolic and diastolic dysfunction, energetic
..
proportion of non-classifiable patients was substantial. Thus, our .. abnormalities, interstitial fibrosis, inflammation, increased oxidative
revised algorithm (see below) proposes a novel stepwise diagnostic
.. stress, endothelial dysfunction, and impaired density and autoregula-
..
approach that has only one entry point, and all patients will be .. tion of the microcirculation.9,10,12,45–48,154,155 Cardiovascular patho-
classifiable.
.. physiological processes include increased systemic vascular
- 136 -
resistance, increased conduit arterial stiffness, abnormal ventricular-

arterial coupling, reduced LV long-axis systolic function, slowed early
diastolic relaxation, reduced LV compliance with increased end-
diastolic stiffness, reduced LA reservoir and contractile function,
impaired right ventricular (RV) function, and chronotropic incompe-
tence.52,156–164 Patients often have reduced reserve of stroke vol-
ume, heart rate, and cardiac output (CO), and the increase in CO
relative to oxygen consumption is blunted.165 Heart failure with pre-
served ejection fraction patients typically have high LV filling pres-
sures, whether at rest and/or on exercise, and they may develop fluid
retention and an expanded plasma volume.28,159,164,166,167 All these
mechanisms might be targets for treatment.

In a meta-analysis, exercise capacity in HFpEF was related to chro-
notropic incompetence, high mPCWP, blunted augmentation of ar-
teriovenous oxygen-content difference (implying inadequate
perfusion of exercising skeletal muscles), reduced stroke volume re-
serve, and pulmonary hypertension.168 Changes in pulmonary artery
pressure (PAP) on exercise are determined by the interplay between
CO, PA compliance, pulmonary vascular resistance, and mPCWP.
The increase in PAP is flow-dependent so it is best reported in rela-
tion to the increase in CO; the upper limit of normal is þ3 mmHg/L/
min.169 There are haemodynamic differences between patients with
pre- and post-capillary pulmonary hypertension.164
We recommend that the pathophysiological phenotype(s) prevail-
ing in an individual HFpEF patient are determined, as that may allow
the selection of specific therapies (see diagnostic Step 4 below).
Figure 2 Flowchart of the HFA-PEFF diagnostic algorithm. Step P

The new Heart Failure is meant to identify patients with the potential diagnosis of heart fail-
ure with preserved ejection fraction, and exclude or identify other
Association diagnostic specific causes for their heart failure-like symptoms. Patients likely
to have heart failure with preserved ejection fraction are those with
recommendations typical demographics (e.g. elderly, female, and comorbidities), a pre-
The flowchart (Figure 2) provides an overview of the new diagnostic served left ventricular ejection fraction on a standard echocardiog-
raphy, and other easily detectable findings such as elevated
algorithm.
natriuretic peptides or atrial fibrillation. Alternative causes such as
coronary artery disease, significant valvular disease, pulmonary dis-
Step 1(P): Pre-test assessment ease, and anaemia should be excluded during this initial workup. If
Step 1(P) should be performed in any patient who presents with Step P is positive, the second Step E should be done, which includes
symptoms and/or signs compatible with a diagnosis of HF. It requires a comprehensive echocardiography and brain natriuretic peptide/
a detailed clinical and demographic history; an electrocardiogram N-terminal natriuretic peptide levels, if not already done on Step P.
(ECG); blood tests; standard echocardiography to exclude other Step F1 should be done, if Step E is inconclusive. Depended on clin-
causes such as HFrEF or heart valve disease; and investigations for is- ical facilities and patient conditions an invasive or non-invasive stress
chaemia, arrhythmias, anaemia, or pulmonary disease (Figure 2). NP test is recommended. However, the invasive stress test has a higher
validity and is an option, if the result of the non-invasive stress test is
levels can be obtained if the assay is available; elevated levels suggest
not conclusive. The fourth Step, Step F2 is designed to identify a spe-
heart disease but normal levels do not exclude HFpEF. Step 1(P) mir-
cific aetiology, if appropriate, when heart failure with preserved
rors the 2016 ESC HF guidelines concerning initial HF diagnostic ejection fraction has been diagnosed. For details of steps 2–4, see
workup.3 Figures 3–5.
Symptoms and signs

Breathlessness on exertion (New York Heart Association Class II or ..
III) is highly sensitive for a diagnosis of HF but only moderately specific .. Electrocardiographic abnormalities
(about 50%) for a cardiac cause.170 Orthopnoea is quite specific but .. Patients may have electrocardiographic features of LVH (such as a
..
relatively insensitive. Patients with HFpEF often report reduced exer- .. Sokolov-Lyon Index >_3.5 mV; abnormal repolarisation) and/or LA
cise capacity and fatigue, out of proportion to cardiac abnormalities .. enlargement, but there are no pathognomonic signs and the diagnos-
..
at rest. In elderly, overweight and deconditioned persons, poor exer- .. tic value of an ECG to identify HFpEF is poor.5 The most important
cise capacity, dyspnoea on exertion, and peripheral oedema may also
.. indication is to detect atrial fibrillation (AF), which is highly predictive
..
have a non-cardiac origin. . of underlying HFpEF.5,148
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Laboratory tests
Table 1 Risk factors and findings consistent with
Several tests are recommended, including: sodium, potassium, urea, heart failure with preserved ejection fraction in a
and creatinine (with an estimated glomerular filtration rate); liver symptomatic patient
function tests; HbA1c (metabolic syndrome and type 2 diabetes are
common comorbidities); thyroid stimulating hormone; and full Early (age >_ 70 in men or >_ in women)
blood count, ferritin, transferrin saturation, and for anaemia. Anaemia Overweight/obesity
associated with HFpEF aggravates symptoms and exercise Metabolic syndrome/diabetes mellitus
intolerance.171,172 Physical inactivity/deconditioning
Arterial hypertension
Natriuretic peptides Atrial fibrillation
Multiple studies in primary care have shown that serum levels ECG abnormalities (beyond atrial fibrillation)
Elevated natriuretic peptide levels (if available, BNP >_ 35 pg/mL or

<125 pg/mL (or ng/L) for N-terminal pro-brain natriuretic peptide
(NT-proBNP) or <35 pg/mL for BNP, have high negative predictive NT-proBNP >_ 125 pg/mL)
values (NPV; 95–99%) for excluding any heart failure.39,40,121,173–177
The main trigger for release of NPs is high LV end-diastolic wall
stress, which is inversely proportional to wall thickness. It is therefore
..
understandable that the excellent NPV of NPs is true particularly for .. (CMR) imaging, or myocardial scintigraphy, or an anatomical ap-
HFrEF with a dilated LV, but not necessarily for HFpEF where LVH .. proach using coronary computed tomography (CT) angiography or
..
tends to normalize wall stress. In consequence, it has become clear .. invasive angiography, should be considered if CAD is suspected.187
that up to 20% of patients with invasively proven HFpEF have NPs .. A stress test provides information about exercise capacity, the
..
below these diagnostic thresholds,28,178–180 which represents a limi- .. blood pressure response to exercise (which may be hypertensive),
tation to the use of NPs. Therefore, it is important to understand .. and the heart rate response. Chronotropic incompetence is present
..
that with our SCORE approach HFpEF can still be diagnosed even, if .. in 33–77% of HFpEF patients,188,189 and defined as the failure to reach
NP cut-offs (stratified by SR vs. AF) are below the given thresh- .. 70–80%188–190 of the predicted maximal heart rate. Reduced heart
..
olds’.28,178–180 .. rate recovery after exercise has prognostic value.191–193 Reduced ex-
.. ercise capacity can be defined as a peak workload <_75% of the value
..
Echocardiography .. predicted for age. In elderly patients with suspected HFpEF a 6-
.. minute walk test (6MWT) distance <_300 m can be considered abnor-
Standard echocardiography should be performed in every breathless ..
patient in whom there is clinical suspicion of HF, unless all the factors .. mal193 but 6MWT performance is affected by non-cardiac as well as
.. cardiopulmonary conditions.193,194
listed in Table 1 are absent or negative. Echocardiography may ex- ..
clude alternative causes of dyspnoea such as HFrEF, valve disease, pri- .. In selected cases, advanced cardiopulmonary exercise testing
..
mary pulmonary hypertension, or pericardial effusion.181,182 .. (CPET) with spiro-ergometry may be performed. Reduced exercise
Left ventricular ejection fraction should be measured, not esti- .. capacity is defined as a peak oxygen consumption (VO2 max)
..
mated, ideally from biplane or three-dimensional images. Only small .. <_20 mL/kg/min, and ventilatory inefficiency as a VE/VCO2 slope
variations in normal ranges for EF by age, gender, and ethnic group .. >_30.166,195 Cardiopulmonary exercise testing provides objective evi-
..
have been reported, so it is recommended that a single cut-point of .. dence of exercise capacity and may differentiate between cardiac and
>_50% is applied to define a ‘preserved’ EF. Left ventricular diameters .. non-cardiac causes (pulmonary, peripheral) for dyspnoea,157,166,196–200
..
and volumes should also be recorded. A diagnosis of HFpEF is sug- .. but its value to distinguish between HFpEF and non-cardiac causes
gested if there is a non-dilated LV with a normal EF, concentric .. may be limited.166 Cardiopulmonary exercise testing is not a typical
..
remodelling or LVH, and left atrial enlargement. Echocardiographic .. element in the initial HFpEF workup (see below).
findings at rest compatible with this HFpEF phenotype are often .. If HFpEF is suspected after Step 1(P), a more specific assessment
..
found in asymptomatic patients, who are at risk of progressing to .. may confirm or exclude the diagnosis (Step 2(E)).
overt HFpEF.183,184 Of note, the presence of structural alterations on
..
..
echocardiography supports, but its absence does not exclude HFpEF. ..
A more detailed or advanced echocardiographic study (see Step
.. Step 2(E): Echocardiographic and
..
2(E); Supplementary material online, S1) is not necessary at this step, .. natriuretic peptide heart failure with
but if it can be performed then only one examination will be needed.
.. preserved ejection fraction diagnostic
..
.. score
..
Exercise tests .. There is no single non-invasive diagnostic criterion for HFpEF so we
Coexisting epicardial stenotic coronary artery disease in patients .. recommend a combination of echocardiographic measurements of
..
with HFpEF impacts on mortality and should be detected and .. cardiac structure and function, and NP levels. Some may already be
treated.133 Coronary microvascular dysfunction is part of the HFpEF .. available from Step 1(P).
..
pathophysiology134 so non-invasive stress testing can give false- .. Many of these measurements are continuously distributed within a
positive results.134,186 Nonetheless, a bicycle or treadmill exercise
.. population, from normal to possibly abnormal and to overtly abnor-
..
test, or tests with higher sensitivity to detect ischaemia such as .. mal values. Diagnostic cut-points may vary according to age, gender,
dobutamine stress echocardiography, cardiac magnetic resonance
.. body weight, renal function, and the presence of atrial fibrillation.
- 138 -
Table 2 Potential specific aetiologies underlying heart failure with preserved ejection fraction-like syndromes in
Step 4 (F2)
Abnormalities of the myocardium

....................................................................................................................................................................................................................
lschaemic Myocardial post-infarction/scar49
Myocardial stunning50
Epicardial coronary artery disease51
Microvascular and endothelial dysfunction52,53–55
Toxic Recreational substance abuse Such as alcohol,56 cocaine,57 and anabolic steroids58
Heavy metals Such as iron,59 lead,60 cadmium,60 cobalt,61 copper (M. Wilson)62
Medications Such as chloroquine,63 ergotamine,64 cytostatic drugs (e.g. anthracy-

clines),64 immunomodulating drugs (e.g. interferons monoclonal
antibodies such as trastuzumab, cetuximab)64
Radiation Mean cardiac radiation doses > 3 Gy65,66
Immune and inflammatory Related to infection Such as cardiotropic viruses,67,68 HIV,69–71 hepatitis,72 helminths,73
parasites (e.g. Chagas’ disease74)
Not related to infection Lymphocytic myocarditis,75–79 autoimmune diseases (e.g. rheumatoid
arthritis,80 connective tissue disorders like scleroderma,81
M. Raynaud,55 systemic lupus erythematosus,82 dermato/polymyosi-
tis,83 and hypersensitivity and eosinophilic myocarditis73,84–87
Infiltrative Related to malignancy Direct infiltrations and metastases88–90
Not related to malignancy Amyloidosis,19,91 sarcoidosis,92,93 primarily and secondary haemo-
chromatosis,94–96 storage diseases97 (e.g. Fabry disease,98,99 Danon
disease,100–102 Pompe disease,99,102 PRKAG2 deficiency,99
Gaucher’s disease99)103,104,105,106
Metabolic Hormonal Such as thyroid diseases,107,108 parathyroid diseases,109 acromegaly,110
GH deficiency,111 Cushing disease,112 Conn’s disease,113 Addison
disease,114 phaeochromocytoma,115 pathologies related to preg-
nancy and peripartum116,117
Nutritional Such as deficiencies in thiamine,118 L-carnitine,119 selenium,120 (func-
tional) iron,121,122 complex malnutrition (e.g. AIDS, infections,73
anorexia nervosa73,123,124)
Genetic Diverse forms Such as HCM,97,125,126 restrictive cardiomyopathies,103,104,106 hyper-
trophic form of non-compaction cardiomyopathy,127,128
early forms of muscu-
lar dystrophies (Duchenne/Becker disease129).
Endomyocardial HES,84 EMF,71,127 endocardial fibroelastosis,128 carcinoid,130,131 endo-
cardial calcification (Paget’s disease132)
....................................................................................................................................................................................................................
Abnormalities of loading conditions
....................................................................................................................................................................................................................
Hypertension Primary and secondary forms of hypertension112,113,115,130,131
Valvular and structural defects Acquired Heart valve diseases133,134
Valvular and structural defects Congenital Septal defects132,135,136
Pericardial and endomyocardial pathologies Pericardial Constrictive pericarditis and pericardial effusion137,138
Endomyocardial HES,86 EMF,73,139 endocardial fibroelastosis,140 carcinoid,141,142 endo-
cardial calcification (Paget’s disease143)
High output states Severe anaemia,144 sepsis,145 thyrotoxicosis,105 arteriovenous fis-
tula,146 and pregnancy147
Volume overload Renal failure and fluid overload148,149,150
Abnormalities of the cardiac rhythm
Rhythm disorders Atrial/ventricular arrhythmias, pacing, conduction disorders38,151–153
EMF, endomyocardial fibrosis; GH, growth hormone; HCM, hypertrophic cardiomyopathy; HES, hypereosinophilic syndrome (formerly known as Löffler’s endocarditis); HIV/
AIDS, human immunodeficiency virus/acquired immune deficiency; LV, left ventricular; PRKAG2, protein kinase AMP-activated non-catalytic subunit gamma 2.
- 139 -
..
To take account of these factors, we recommend the use of major .. Average septal-lateral E/e0 ratio
and minor diagnostic criteria according to the severity of an abnor- ..
mality and the presence of modifiers. Major criteria (and cut-points)
.. Major criterion: average septal–lateral E=e0 ratio >_15
..
have been selected for their high specificity, while minor criteria ..
.. Minor criterion: average septal–lateral E=e0 ratio 9 -14
should be more sensitive. Cut-points were derived particularly from ..
studies that compared echocardiographic parameters against invasive .. The ratio of the peak velocity of mitral inflow during early diastole
..
haemodynamic data.5,28,166 .. (E), recorded by pulsed Doppler between the tips of the mitral leaf-
In one cohort with 64% prevalence of HFpEF determined by inva- .. lets, over the average of septal and lateral mitral annular early diastol-
..
sive measurements, the univariable sensitivity of septal e0 velocity .. ic peak velocities (e0 ) recorded by pulsed tissue Doppler, reflects the
<7 cm/s to diagnose HFpEF, without adjusting for age or other varia- .. mPCWP.41 The mitral E/e0 index correlates with LV stiffness and fi-
..
bles, was 46%, while its specificity was 76%.5 The sensitivity and speci- .. brosis20,21 and is less age-dependent than e0 .206 It also has diagnostic
ficity of an E/e0 ratio >9 were 78% and 59%, compared with 46% and .. value during exercise.28,158 The E/e0 index is little influenced by

..
86% for E/e0 >13. The sensitivity and specificity of LA volume index .. changes in volume but it is influenced by the severity of LVH.23,24
>30 mL/m2 were about 70%. Measurements of LV mass had low sen- ..
..
sitivity (26%) for HFpEF but high specificity (86%) if LVH was present. .. Tricuspid regurgitation peak velocity or
PAP >35 mmHg [derived from tricuspid regurgitation (TR) velocity] .. pulmonary arterial systolic pressure
..
was 46% sensitive and 86% specific for HFpEF,5 which makes it an im- ..
portant diagnostic criterion. The utility of GLS <16% was moderate
.. Major criterion: TR peak velocity >2:8 m=s
..
(sensitivity 62% and specificity 56%5).201 .. Major criterion: Pulmonary artery systolic pressure >35 mmHg
The utility of NP levels varies according to several factors including
..
..
cardiac rhythm. For NT-proBNP >275 pg/mL, a sensitivity of 59% .. Pulmonary arterial systolic pressure is calculated from the modified
and a specificity of 77% were reported (accuracy 68%).5 Sensitivity
.. Bernoulli equation as 4 � peak TR velocity plus estimated right atrial
..
decreased to 46% while specificity increased to 85% if the cut-off was .. pressure. Elevated PASP and reduced RV function are important pre-
increased to >450 pg/mL (accuracy 66%). At our lowest recom-
.. dictors of mortality in HFpEF.207–211 Even a moderate increase in
..
mended cut-off of 125 pg/mL (minor criterion, if the patient is in sinus .. PASP can lead to increased ventricular interaction since a leftward
.. shift of the ventricular septum impedes LV filling.212 A PASP
rhythm), the sensitivity reported in that study was 77% and the speci- ..
ficity 53% (accuracy 65%). Of note, 39% of patients in that study .. >35 mmHg discriminates HFpEF from hypertensives and controls.207
.. A TR peak velocity >2.8 m/s indicates increased PASP41,213 and is an
were in AF or had a history of paroxysmal AF.5 Combining the results ..
of E/e0 and NT-proBNP can increase their predictive value, notably .. indirect marker of LV diastolic dysfunction.41
..
their sensitivity to diagnose HFpEF.202 ..
.. Left ventricular global longitudinal
.. systolic strain
Echocardiographic measurements of function and ..
morphology ..
.. Minor criterion: GLS < 16%
In Step 1(P) we recommend standard echocardiography, at least to ..
assess LVEF and LV diameter. In Step 2(E) we recommend more
.. Left ventricular peak systolic GLS is not angle-dependent, unlike
..
detailed echocardiographic measurements (Supplementary material .. myocardial velocities recorded by tissue Doppler.186 It is measured
online, S1). These could all be obtained during a single study. The
..
.. using speckle-tracking echocardiography as the average of systolic
echocardiographic criteria in the HFA–PEFF score, listed below, mir- .. strain obtained from all LV segments in the apical 4-chamber, apical
..
ror consensus recommendations for the diagnosis of LV diastolic .. 2-chamber, and apical long-axis views.214
function.41 .. Reduced LV longitudinal systolic strain and LV early diastolic strain
..
.. rate have both been identified in HFpEF.19,215,216 Impaired GLS pre-
Septal and lateral mitral annular peak early diastolic velocity (e0 ) .. dicts HF hospitalization, cardiovascular death, or cardiac arrest.216,217
..
.. It correlates with invasive measurements of LV stiffness and with NP
Major criterion: septal e0 <7 cm=s; or lateral e0 <10 cm=s .. levels.19,204,218 All strain values are dimensionless and are expressed
..
½subjects aged <75 years� .. as percentages. For ease of use in these recommendations, we sug-
.. gest a cut-point of 16% in absolute values;219–222 and a value below
Major criterion: septal e0 <5 cm=s; or lateral e0 <7 cm=s ..
.. 16% (e.g. 14%) is recommended as a minor criterion.
½subjects aged >_75 years� ..
..
.. Left atrial volume index
The main determinant of e0 , the early diastolic velocity of mitral annu- ..
lar motion, is LV relaxation. It reflects LV lengthening and is influ- .. Major criterion: >34 mL=m2 ½in sinus rhythm�
..
enced by preload.203,204 Left ventricular longitudinal e0 velocity ..
.. Major criterion: >40 mL=m2 ½in atrial fibrillation�
declines with age;205 normative ranges reported from elderly partici- ..
pants were found to be lower than those given in the 2007 HFA con- .. Minor criterion: 29-34 mL=m2 ½in sinus rhythm�
sensus.206 We include age-specific e0 criteria in the HFA–PEFF score,
..
.. Minor criterion: 34–40 mL=m2 ½in atrial fibrillation�
measured as recommended.41 .
- 140 -
The maximal volume of the LA, measured at end-systole from bi- .. Minor criterion: NT-proBNP 125–220 pg=mL; or
plane or three-dimensional images and indexed to body surface area .. BNP 35–80 pg=mL ½in sinus rhythm�
[left atrial volume index (LAVI)] is an indirect correlate of LV filling
..
..
pressures.41 It is more accurate as a marker of chronic LA remodel- .. Minor criterion: NT-proBNP 375–660 pg=mL; or
..
ling than either LA area or diameter223–225 and it correlates with ..
other echocardiographic indices of LV diastolic function.226 A LAVI .. BNP 105–240 pg=mL ½in atrial fibrillation�
..
of 29–34 mL/m2 is considered as a minor criterion since it represents .. In Step 1(P), a single low cut-point was recommended in order to
the upper limit in healthy subjects.227,228 ..
.. have a sensitive marker for cardiac abnormalities. In this step, in order
In patients without AF or heart valve disease, LAVI >34 mL/m2 in- .. to increase specificity, a higher cut-off value is recommended as a
dependently predicts death, heart failure, AF, and ischaemic ..
.. major criterion, in agreement with ESC guidelines.3 Cut-offs are also
stroke.229–231 In patients with HFpEF and permanent AF, LAVI was .. stratified for the presence of SR or AF.
35% more enlarged than it was in HFpEF patients in SR.34 Patients ..

.. Natriuretic peptide levels should always be interpreted in con-
with permanent AF may have a large LAVI even if they have no LV .. text.180 Definitive cut-offs to diagnose HFpEF in patients with SR or
diastolic dysfunction.34,41 We therefore recommend separate cut- ..
.. in AF are not well established, and trials have used different val-
offs for LAVI in SR vs. AF. .. ues.237,238 In the setting of screening, average NPs have been
..
.. reported to be 3–3.5 fold higher in patients with AF than in patients
Left ventricular mass index and relative .. in SR.239 Average NPs were found to be threefold higher in patients
wall thickness ... with AF than in patients in SR.34,35,240 In prevalent symptomatic
..
.. HFpEF with AF, levels tend to be even higher.241 For diagnosing
Major criterion: LVMI >_149 g=m2 in men or >_122 g=m2 ..
.. HFpEF, we hence recommend values in patients with AF that are
in women and RWT >0:42 .. three times higher than used for patients in SR.
..
Minor criterion: LVMI >_115 g=m2 in men or >_95 g=m2 in women ..
..
or RWT >0:42 or LV end-diastolic wall thickness >_12 mm ..
.. Calculating and interpreting the
..
Increased LV diastolic wall thickness in a non-dilated heart implies .. HFA–PEFF score
that the patient has LVH. It develops first in the basal segments of the ..
.. The score has functional, morphological, and biomarker domains.
ventricular septum,232 and a wall thickness >_12 mm at that site is ..
common in elderly people. Localized septal hypertrophy may be a .. Within each domain, a major criterion scores 2 points or a minor cri-
.. terion 1 point (Figure 3; Supplementary material online, Table S1).
consequence of abnormal ventricular–arterial coupling but it is not ..
sufficient to indicate that there is significant global LV remodelling or .. Each domain can contribute maximally 2 points, if any major criterion
.. from this domain is positive, or 1 point if no major but any minor cri-
hypertrophy. ..
Left ventricular geometry is often classified using relative wall .. terion is positive. If several major criteria within a single domain are
.. positive, this domain still contributes 2 points; and if no major but sev-
thickness (RWT), calculated as twice the LV posterior wall thickness ..
divided by the LV internal diameter at end-diastole (LVPW � 2/ .. eral minor criteria are positive the contribution still is 1 point. Major
.. and minor criteria are not additive in a single domain. Points are
LVIDD), and using left ventricular mass index (LVMI) normalized to ..
body surface area or height. Four patterns are described: normal
.. added only when they come from different domains.
.. For example, 2 major (E/e0 >15, and TR >2.8 m/s) and 1 minor
(normal LVMI, RWT <_0.42), concentric remodelling (normal LVMI, ..
RWT >0.42), concentric hypertrophy (increased LVMI, RWT
.. (GLS <16) criteria, all in the functional domain, will lead to a total
..
>0.42), and eccentric hypertrophy (increased LVMI, RWT .. score from that domain of 2 points. The total score would be 5, if at
<_0.42).41,233,234 In patients with HFpEF, both concentric LVH and
.. least one minor criterion (LAVI <34 mL/m2; LV wall thickness
..
concentric remodelling can be observed.235 .. >12 mm) and one major criterion (BNP in SR >80 pg/mL) would be
The absence of LVH on echocardiography does not exclude
.. present coming from the morphological and biomarker domains, re-
..
HFpEF.5 We therefore recommend the finding of concentric hyper- .. spectively. It is important to understand that not all parameters from
.. each domain need to be recordable (which is typically the case). The
trophy (increased LVMI and increased RWT) as a major criterion, or ..
any one of a lesser degree of LVH, RWT, and LV end-diastolic wall .. HFA-PEFF score can be calculated even if not all parameters are
.. obtained, which adds to the practical utility of the score.
thickness as a minor criterion.227,234,236 ..
.. A total score >_5 points is considered to be diagnostic of HFpEF,
.. while a score of <_1 point is considered to make a diagnosis of HFpEF
Natriuretic peptides ..
.. very unlikely and to mandate investigations for alternative causes.
Major criterion: NT-proBNP >220 pg=mL; .. Patients with an intermediate score (2–4 points, Figures 2 and 3) need
..
or BNP >80 pg=mL ½in sinus rhythm� .. further evaluation (Step 3(F1); Figures 4A,B).
.. If LAVI, LVMI, or wall thickness cannot be assessed by echocardi-
..
Major criterion: NT-proBNP >660 pg=mL or .. ography, we recommend using measurements obtained from CMR
.. imaging instead. Of note, there are some systematic differences in
BNP >240 pg=mL ½in atrial fibrillation� ..
. measurements of LV volumes and LVEF between imaging
- 141 -

Figure 3 Step 2 (E): Echocardiographic and natriuretic peptide heart failure with preserved ejection fraction workup and scoring system (diagnos-
tic workup).
..
modalities.242 In one comparative study, LV volumes were larger and .. Many patients with HFpEF have symptoms mainly on exertion that
LVEF was lower but not statistically different with CMR compared .. are usually attributed to the increase in LV filling pressures which is
..
with other imaging modalities.243 .. needed to maintain adequate filling and stroke volume.159,249
.. Acquiring echocardiographic data during exercise can unmask LV dia-
..
Step 3 (F1): Functional testing .. stolic and systolic dysfunction. The parameters that have been
.. studied most often, during or immediately after exercise, are the mi-
Symptoms compatible with HF can be confirmed to originate from ..
.. tral E/e0 ratio and the TR peak velocity, which indicate increases in
the heart if haemodynamic abnormalities such as reduced stroke vol- ..
.. mPCWP and PASP, respectively.28,41,244–248,250
ume, reduced CO, and elevated LV filling pressures are detected ei-
.. Ideally a semi-supine bicycle test with imaging during exercise, or
ther at rest or during exercise. In a typical elderly patient with ..
.. else a treadmill or upright bicycle exercise protocol with imaging
multiple comorbidities, the presence or absence of isolated cardiac
.. at or immediately after peak stress, is recommended41,244 but
structural and/or functional abnormalities at rest does not always es- .. there are no universally adopted protocols. The European
tablish or exclude the diagnosis of HFpEF. If invasive testing demon- ..
.. Association of Cardiovascular Imaging and the American Society of
strates a high LV filling pressure [left ventricular end-diastolic ..
.. Echocardiography recommend a stepped protocol, starting at
pressure (LVEDP) >_16 mmHg, PCWP >_15 mmHg] at rest, then the .. 25 W at 60 r.p.m. with the load increasing by 25 W every 3 min
diagnosis may be confirmed; otherwise, assessment during exercise is ..
.. until the patient has reached his maximal predicted workload and/
recommended, either by non-invasive exercise stress echocardiog-
raphy or by invasive haemodynamics (Figures 2 and 4A,B). ... or maximal predicted heart rate (220—age in years) and/or devel-
.. oped limiting symptoms.244 Some patients cannot perform that
..
.. protocol, and a ramped exercise test on a semi-supine bicycle at
Exercise stress echocardiography: the diastolic stress test .. 60 r.p.m. starting at 15 W and with increments of 5 W every mi-
..
During exercise in healthy people, enhanced LV untwisting and early .. nute has also been proposed, to a submaximal target heart rate of
diastolic suction maintain or increase stroke volume despite shorten- .. 100–110/min or until the patient develops limiting symptoms.245
..
ing of the filling time and without increasing LV filling pressures. In .. None of these protocols have been shown to be superior to
patients with HFpEF, impaired early diastolic relaxation, reduced .. others.
..
increments in suction, and poor LV compliance lead to inadequate .. The mitral E/e0 ratio and peak TR velocity should be acquired at
increases in stroke volume and CO on exercise, increased LV filling .. baseline, during each stage including peak exercise, and during a
..
pressures, and increased PASP.28,41,244–248 High LV filling pressures .. submaximal stage before fusion of the mitral E and A velocities213
and inadequate CO responses during exercise can also impair RV
.. or during the first 2 min of the recovery phase when mitral E and A
..
reserve.52 . velocities are no longer fused and LV filling pressures remain
- 142 -

Figure 4 Step 3 (F): Functional tests in cases of diagnostic uncertainty. (A, upper panel) It shows the diastolic stress test workup with exercise
echocardiography is shown. If key haemodynamic abnormalities are identified, a definite heart failure with preserved ejection fraction diagnosis can
be made. (B, lower panel) It shows the invasive haemodynamic measurements at rest (left) or during exercise (right) that may complement stress
echocardiography and are recommended in cases with remaining diagnostic uncertainty.
elevated.41,244 Changes in CO can be assessed by measuring

.. during submaximal exercise (20 W) and in about 20% of HFpEF
..
the velocity integral of flow in the LV outflow tract, multiplied .. patients during peak exercise, and that TR velocity was measurable in
by the HR.
.. only 50%; about 20% of controls were considered to have false-posi-
..
Exercise echocardiography should be considered abnormal if .. tive tests.28 Data from stress echocardiography are not sufficient to
..
average E/e0 ratio at peak stress increases to >_15, with or without .. substitute for invasive haemodynamic data under all circumstances. If
a peak TR velocity >3.4 m/s.28,41,244 An increase only in TR velocity .. the score remains <5 points or if exercise echocardiography cannot
..
should not be used to diagnose HFpEF because it might be caused .. be performed, we recommend an invasive haemodynamic stress test
simply by a normal hyperdynamic response to exercise (with .. in any case of doubt, especially if a therapeutic decision depends on
..
increased pulmonary blood flow) in the absence of LV diastolic .. the results.
dysfunction.251 ..
..
An average E/e0 ratio during exercise >_15 adds 2 points to the ..
HFA–PEFF score. An average E/e0 ratio >_15 with a peak TR velocity .. Invasive haemodynamic tests at rest and with exercise
..
>3.4 m/s adds 3 points to the previous score from Step 2(E). If the .. Left ventricular end-diastolic pressure LVEDP in the resting supine
combined score from Step 2(E) and Step 3(F1) is >_5 points, then the .. position is typically obtained in the context of left heart catheteriza-
..
diagnosis of HFpEF can be confirmed. .. tion and bears important diagnostic information in the workup of un-
However, echocardiographic stress tests also have limitations. It .. explained dyspnoea. In selected patients, LV compliance and stiffness
..
was reported that E/e0 was not measurable in about 10% of subjects . can be determined directly by using a multiple-loop conductance
- 143 -
..
catheter to record the end-diastolic pressure–volume relationship .. Step 4(F2): Final aetiology
(EDPVR) during preload reduction, giving a volume-independent par- .. Most cases of HFpEF are related to common risk factors and comor-
..
ameter for LV stiffness (constant of chamber stiffness, b, normal .. bidities, but the possibility of a specific underlying aetiology should al-
<0.27252).21,159,253–255 Invasive demonstration of impaired LV relax- ..
.. ways be considered (Table 2, Supplementary material online, Tables
ation at rest, measured by high-fidelity pressure catheters as the time .. S2–S4; Figure 5A,B). We postulate that identification of specific HFpEF
constant of LV relaxation (tau, s > 48 ms4) or of elevated LV filling ..
.. aetiologies will advance the field of targeted therapies.
pressures at rest (LVEDP >_16 mmHg) confirms definite evidence of .. Specific heart muscle diseases that may present with
HFpEF. ..
.. the HFpEF phenotype include hypertrophic cardiomyopa-
Right heart catheterization should be considered for the struc- .. thies,125,264–266 myocarditis and chronic inflammatory cardiomyop-
tured workup of suspected HFpEF, especially when left heart pres- ..
.. athy,67,75–77,97,137,267,268 autoimmune diseases,78,79 non-infiltrative
sures are not available. When resting mPCWP, measured using a .. and infiltrative cardiomyopathies,83,125 idiopathic or acquired endo-
Swan-Ganz catheter, is elevated in the presence of a normal LV end- ..

.. myocardial fibrosis,269 storage diseases,125,269 and other genetic dis-
diastolic volume index, then usually LV end-diastolic distensibility is .. orders including early stages of cardiomyopathies associated with
reduced. A resting mPCWP >_15 mmHg3 confirms definite evidence
..
.. muscular dystrophy.103 Rare causes such as toxicity from drugs or
of HFpEF. .. heavy metals, radiation, and metabolic causes related to hormonal or
However, normal LVEDP or mPCWP levels at rest do not exclude
..
.. nutritional disease, should also be considered (Table 2). The trigger
HFpEF. In compensated HFpEF, haemodynamic alterations may be .. may occur long before the onset of symptoms. For instance
detected only during exercise or when the patient deterio-
..
.. radiation-induced HFpEF develops after 10–15 years, even when low
rates.28,179,230,256,257 Also, volume depletion or intensified diuretic .. mean cardiac radiation doses of 3.3 Gy are used.104,129
treatment may shift the diastolic pressure–volume relationship to the
..
.. Aetiological workup may include a standard exercise stress test
left, without changing LV compliance (dV/dP; the inverse of LV stiff- .. that may identify myocardial ischaemia, an abnormal blood pressure
..
ness252) If resting filling pressures are normal, exercise right heart .. response to exercise, chronotropic incompetence, or supraventricu-
catheterization is recommended for the definite workup of unex- .. lar and ventricular arrhythmias (Figure 5A; Supplementary material
..
plained exertional dyspnoea,179 especially if the patient has an inter- .. online, S2). These findings can immediately translate into manage-
mediate Score in Step 2(E) or if exercise echocardiography is .. ment strategies, such as anti-ischaemic therapy, improved blood
..
inconclusive or not feasible (Figures 2 and 4B). Specialized centres .. pressure control, removal of bradycardic agents (such as beta-
may perform exercise right heart catheterization upfront in the ab- ..
.. blockers often prescribed for hypertension), and control of exercise-
sence of exercise echocardiography, depending on the individual ex- .. induced cardiac arrhythmias.
perience of the site. ..
.. More sophisticated tools for aetiological workup include CMR
During supine exercise in healthy control subjects, cut-offs for .. which is most accurate for determining LA and LV volumes and
peak PCWP and LVEDP are <20–23 mmHg258,259 and <25 ..
.. mass,270 detects scar and myocardial ischaemia due to epicardial cor-
mmHg,260,261 respectively. Patients with values <25 mmHg during .. onary disease or microvascular dysfunction,65 and stress perfusion
peak exercise are classified as having non-cardiac dyspnoea. A ..
.. imaging to reveal diffuse subendocardial defects. Regional and diffuse
steep increase in PCWP during exercise is a typical haemodynamic .. myocardial oedema (T2-imaging) and infiltration or fibrosis are quan-
response in HFpEF,256,262 indicating that the dyspnoea on exertion ..
.. tified using late gadolinium enhancement [LGE; for extracellular vol-
is mainly of cardiac origin. Patients with peak exercise PCWP .. ume fraction (ECV)] or T1-mapping137,267,271–274 (Supplementary
>_25 mmHg are classified as having HFpEF (Supplementary material
..
.. material online, Table S3). Right or left ventricular myocardial biopsy,
online, S2). An increase in LV filling pressure during exercise that is .. (99m)Tc-DPD scintigraphy to identify cardiac amyloidosis, positron
not accompanied by increases in end-diastolic volume, indicates
..
.. emission tomography (PET)-CT, as well as specific genetic and la-
limitation to LV filling or the development of pericardial .. boratory tests (Figure 5B) should be considered in selected cases
constraint.256
..
.. where a specific aetiology is suspected.
A high resting mPCWP and a pathological increase in mPCWP .. Of note, we do not intend to lump together all causes of the clinic-
during exercise predict poor outcomes from HFpEF.168,249,263
..
.. al syndrome of heart failure with a normal ejection fraction under the
Patients with a normal mPCWP at rest (<12 mmHg) but a steep in- .. term ‘HFpEF’, but instead to stress the importance to always consider
..
crease during exercise (to >_25 mmHg) have a two-fold increase in .. specific aetiologies if the clinical diagnosis of HFpEF is made. It is also
mortality.263 Ten-year mortality was 6.6% if resting mPCWP was .. important to understand that non-myocardial aetiologies (Table 2)
..
<_12 mmHg and peak exercise mPCWP was <25 mmHg; 28.2% in .. that may mimic HFpEF, such as constrictive pericarditis, primary
patients with low mPCWP at rest and high exercise mPCWP; and ..
.. valvular heart disease, or high output failure should not be considered
35.2% in those with high resting mPCWP and high peak exercise .. part of the HFpEF syndrome.
mPCWP (>_25 mmHg).263 ..
..
Exercise mPCWP reclassifies patients with a normal resting ..
mPCWP and stratifies risk. If other investigations have been inconclu- .. Limitations, gaps in evidence, and
..
sive, invasive measurement of mPCWP or LVEDP is considered as .. unanswered questions
the clinical reference investigation for diagnosing HFpEF28 (see .. Heart failure with preserved ejection fraction is a clinical syndrome
..
Supplementary material online, S7 about how to perform an invasive .. with multiple contributing factors, aetiologies, and pathophysiological
stress test). Other causes such as significant CAD, mitral stenosis, or .. expressions.168,275 It is a limitation that we suggest an algorithm that
..
pericardial constriction must be excluded. . reduces it to a single clinical diagnosis. Future studies should evaluate
- 144 -

Figure 5 Step 4 (F2): Final aetiological workup. (A) It shows the role of ergometry to detect underlying causes such as inadequate blood pressure
response, chronotropic incompetence, or myocardial ischaemia during exercise. (B) It shows the aetiological workup using cardiac magnetic reson-
ance (CMR). CT, computed tomography; PET, positron emission tomography.
and refine the recommended diagnostic algorithm and classify HFpEF

.. real-time non-invasive assessments of chamber volumes, stroke vol-
..
patients into specific subgroups. Ideally, a large and unselected sample .. umes, and CO, as well as filling pressures, in combination with in-
of breathless patients, and age-matched controls, would undergo all
.. novative markers of systolic and diastolic function, will markedly
..
tests including echocardiography and the ‘gold standard’ invasive .. reduce the significance of LVEF in characterizing HF.
haemodynamic assessment.
.. We have recommended exercise testing as a component of the
..
The stage and severity of HFpEF may impact on the accuracy of a .. diagnostic workflow in cases of uncertainty, but there is no consensus
..
specific diagnostic parameter. In a recent trial 45% of patients had .. yet about which stress protocol should be used or which measure-
‘early’ HFpEF with normal filling pressures at rest, and elevated filling .. ments are most important. It is uncertain if a simple parameter such
..
pressures only during invasive haemodynamic exercise testing.5 .. as the 6MWT distance could be as useful as detailed cardiopulmon-
Because of the intermittent diastolic pressure overload in early .. ary stress testing, which can be difficult to perform in breathless eld-
..
HFpEF, LAVI may be smaller (and less diagnostic), and functional indi- .. erly subjects.193
ces such as global LA strain or LA conduit strain might be more ap- .. Besides increases in filling pressures, HFpEF patients may be
..
propriate diagnostic parameters.276 In consequence, the patient mix .. haemodynamically limited by their inability to adequately enhance
under investigation may affect the test results. Prospective testing .. stroke volume during exercise,165,278,279,283 but no cut-points
..
and retesting in distinct HFpEF patients populations is needed to sort .. have been published to diagnose the resulting impaired reserve of
this out. .. CO. Unfortunately, reliable data on LV diastolic properties,
..
The diagnosis of HF is still based on LVEF, partly for historical rea- .. stroke volume, and CO can currently only be obtained invasively,
sons and despite its limitations277 for predicting cardiac functional re- .. ideally by conductance catheterization. 3D echocardiography
..
serve and symptoms. Exercise capacity correlates better with long- .. and CMR is now reaching a state where pressure–volume loops
axis functional reserve of the LV52,278–281 and with peripheral blood .. and stroke volumes can be obtained non-invasively,20,284 but
..
flow282 than with LVEF. In fact, a preserved LVEF has no diagnostic .. these measurements still await validation in broader HFpEF
role for HFpEF except to exclude HF with reduced LVEF. In future,
.. cohorts.
- 145 -
..
It will be important not just to confirm the diagnosis using the scor- .. reviewing panels provided declaration of interest forms for all rela-
ing system that we propose, but to document which specific abnor- .. tionships that might be perceived as real or potential sources of con-
..
malities correlate with individual responses to treatment, in order to .. flicts of interest. Figures were drawn by Medical Visuals, Maartje
dissect out specific pathophysiological mechanisms that need differ- .. Kunen.
..
ent treatments.285,286 We recommend that future HFpEF studies and .. Conflict of interest: Dr B.P. has received research funds from
registries should collect, record, and analyse the detailed compo- ..
.. Bayer Healthcare, Servier, and Astra-Zeneca, as well as speakers hon-
nents that are included in the HF–PEFF Score. .. oraria/committee membership fees from Novartis, Bayer Healthcare,
There is a close relationship between HFpEF and AF. There is ..
.. Daiichi-Sankyo, MSD, Stealth Peptides, Astra-Zeneca, Sanofi, Vifor,
overlap in symptoms, signs, echocardiographic findings, and NP levels .. and Servier. Dr R.A.d.B. is supported by the Netherlands Heart
between the two conditions, and a substantial proportion of patients ..
.. Foundation (CVON DOSIS, grant 2014-40, CVON SHE-PREDICTS-
in HFpEF registries and trials have AF. We have provided distinct ..
diagnostic thresholds for NP and LAVI in SR vs. AF, based on existing .. HF, grant 2017-21, and CVON RED-CVD, grant 2017-11); and the

.. Innovational Research Incentives Scheme program of the
literature and consensus. These thresholds need more prospective ..
research for their validation. In addition, other functional measures
.. Netherlands Organization for Scientific Research (NWO VIDI, grant
.. 917.13.350). The UMCG, which employs Dr De Boer has received
are also likely to be affected by concomitant AF. Of note, we did not ..
adopt the alternative view that AF per se could be used as a stand-
.. research grants and/or fees from AstraZeneca, Abbott, Bristol-Myers
.. Squibb, Novartis, Roche, Trevena, and ThermoFisher GmbH. Dr
alone indicator of HFpEF, but we again emphasize the close associ- ..
ation between AF and HFpEF.
.. R.A.d.B. received personal fees from MandalMed Inc., Novartis, and
.. Servier. Dr A.A.V. has received consultancy fees and/or research
There is controversy about the best non-invasive indicators of ele- ..
vated LV filling pressures and mPCWP.287 The E/e0 index has gained a
.. grants from Amgen, Bayer, Boehringer Ingelheim, Merck/Merck Sharp
.. & Dohme, Novartis, Roche Diagnostics, Sanofi Aventis, Servier,
supremacy in clinical practice that is not fully supported by all clinical ..
.. Stealth Peptides, Singulex, Sphingotec, Trevena, and Vifor. Dr C.T.
investigations.288,289 The diagnostic utility of alternative indices such .. received research grants from Novartis and speaker fees from Astra
as retrograde pulmonary venous flow,290,291 estimated LV stiffness ..
.. Zeneca, Berlin Chemie, Akcea, Impulse Dynamics, Servier, Bayer,
(diastolic pressure–volume quotient),284 and left atrial strain rate dur- .. Pfizer, Abbott, Boston Scientific. Dr S.D.A. has received consultancy
ing atrial contraction74,161,276,292 in patients in sinus rhythm, and the L ..
.. fees and/or research grants from Abbott Vascular, Bayer, Boehringer
wave of mitral inflow293 and left atrial strain during reservoir func- .. Ingelheim, Brahms, Novartis, Servier, Stealth Peptides, and Vifor. Dr
tion160,294 in patients in AF, merit further investigation. ..
.. C.S.L. is supported by a Clinician Scientist Award from the National
Modern imaging methods generate a huge quantity of digital data .. Medical Research Council of Singapore; has received research sup-
about global and regional left ventricular morphology and function ..
.. port from Boston Scientific, Bayer, Roche Diagnostics, AstraZeneca,
throughout the cardiac cycle, and about arterial and endothelial func- .. Medtronic, and Vifor Pharma; has served as consultant or on the
tion and myocardial perfusion, which can be coupled with compre- ..
.. Advisory Board/ Steering Committee/ Executive Committee for
hensive demographic data including traditional risk factors and new .. Boston Scientific, Bayer, Roche Diagnostics, AstraZeneca, Medtronic,
biomarkers and with proteomic, metabolomic, and genomic data. ..
.. Vifor Pharma, Novartis, Amgen, Merck, Janssen Research &
Making sense of all this information is a challenge that can likely be ..
met by machine learning. Recent studies suggest that it may be useful .. Development LLC, Menarini, Boehringer Ingelheim, Novo Nordisk,
.. Abbott Diagnostics, Corvia, Stealth BioTherapeutics, JanaCare,
for diagnosis and for defining pathophysiology,15,295,296 but long-term ..
studies in large populations are needed to unravel which features
.. Biofourmis, Darma, Applied Therapeutics, MyoKardia, WebMD
.. Global LLC, Radcliffe Group Ltd and Corpus. Patent pending: PCT/
best predict clinical outcomes and responses to treatment. ..
Molecular phenotyping for a better identification of distinct HFpEF
.. SG2016/050217. Co-founder & non-executive director: eKo.a; Dr
.. W.J.P. is supported by grants from CardioVasculair Onderzoek
phenotypes is emerging and may also help to develop targeted ..
therapies.
.. Nederland (CVON), Dutch Heart Foundation, The Hague, The
.. Netherlands (RECONNECT, EARLY-HFPEF). Dr E.N. has received
..
.. research grants from Bayer AG and fees/speaker honoraria from
.. Bayer AG and Siemens Healthiness. Dr F.E. reports personal fees
Supplementary material ..
.. from Novartis, grants and personal fees from Boehringer Ingelheim,
.. personal fees from CVRx, Pfizer, Medtronic, Resmed, grants and per-
Supplementary material is available at European Heart Journal online. ..
.. sonal fees from Servier, from MSD, Bayer, Vifor, Berlin Chemie. Dr
.. E.P.-K. reports research grants and consulting fees from Bayer
Acknowledgements ..
.. Healthcare and MSD. Dr G.F. received research grants from the
We acknowledge the continuous support of the Heart Failure .. European Union and is Committee member of trials and registries
Association (HFA) for this manuscript. Members of this Task Force ..
.. sponsored by Novartis, Medtronic, BI, Vifor, Servier, Bayer. The
were selected by the HFA Board and HFA HFpEF Committee to .. remaining authors have no conflicts of interest to declare.
represent professionals involved with the medical care of patients ..
..
with HFpEF. Selected experts in the field undertook a comprehensive ..
review of the published evidence for diagnosis of HFpEF according to .. References
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278. Tan YT, Wenzelburger F, Lee E, Heatlie G, Frenneaux M, Sanderson JE. .. RO, Huang CC, Deo RC. Phenomapping for novel classification of heart failure
Abnormal left ventricular function occurs on exercise in well-treated hyperten- .. with preserved ejection fraction. Circulation 2015;131:269–279.
sive subjects with normal resting echocardiography. Heart 2010;96:948–955. .. 296. Sanchez-Martinez S, Duchateau N, Erdei T, Kunszt G, Aakhus S, Degiovanni A,
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doi:10.1002/ejhf.1531
Clinical practice update on heart failure 2019:

pharmacotherapy, procedures, devices and
patient management. An expert consensus
meeting report of the Heart Failure
Association of the European Society
of Cardiology
Petar M. Seferovic1, Piotr Ponikowski2, Stefan D. Anker3*, Johann Bauersachs4,
Ovidiu Chioncel5, John G.F. Cleland6, Rudolf A. de Boer7, Heinz Drexel8,
Tuvia Ben Gal9, Loreena Hill10, Tiny Jaarsma11, Ewa A. Jankowska2,
Markus S. Anker12, Mitja Lainscak13, Basil S. Lewis14, Theresa McDonagh15,
Marco Metra16, Davor Milicic17, Wilfried Mullens18, Massimo F. Piepoli19,
Giuseppe Rosano20, Frank Ruschitzka21, Maurizio Volterrani22, Adriaan A. Voors7,
Gerasimos Filippatos23, and Andrew J.S. Coats24*
1 Serbian Academy of Sciences and Arts, Heart Failure Center, Faculty of Medicine, Belgrade University Medical Center, Belgrade, Serbia; 2 Centre for Heart Diseases, University
Hospital, Wroclaw, Department of Heart Diseases, Wroclaw Medical University, Wroclaw, Poland; 3 Department of Cardiology (CVK), Berlin Institute of Health Center for
Regenerative Therapies (BCRT), German Centre for Cardiovascular Research (DZHK) partner site Berlin, Charité Universitätsmedizin Berlin, Germany; 4 Department of
Cardiology and Angiology, Hannover Medical School, Hannover, Germany; 5 Emergency Institute for Cardiovascular Diseases ‘Prof. C.C. Iliescu’, Bucharest, and University of
Medicine Carol Davila, Bucharest, Romania; 6 National Heart and Lung Institute, Royal Brompton and Harefield Hospitals, Imperial College, London, UK, Robertson Centre for
Biostatistics and Clinical Trials, Glasgow, UK; 7 Department of Cardiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands;
8 Vorarlberg Institute for Vascular Investigation and Treatment (VIVIT), Feldkirch, Austria, Private University of the Principality of Liechtenstein, Triesen, Liechtenstein, Division of
Angiology, Swiss Cardiovascular Center, University Hospital Berne, Berne, Switzerland, Drexel University College of Medicine, Philadelphia, PA, USA; 9 Department of Cardiology,
Rabin Medical Center (Beilinson Campus), Petah Tikva, Israel, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; 10 School of Nursing and Midwifery, Queen’s
University, Belfast, UK; 11 Department of Nursing, Faculty of Medicine and Health Sciences, University of Linköping, Linköping, Sweden; 12 Division of Cardiology and Metabolism,
Department of Cardiology & Berlin Institute of Health Center for Regenerative Therapies (BCRT), DZHK (German Centre for Cardiovascular Research), Partner Site Berlin,
Charité-Universitätsmedizin Berlin (CVK), Berlin, Germany, Department of Cardiology, Charité Campus Benjamin Franklin, Berlin, Germany; 13 Division of Cardiology, General
Hospital Murska Sobota, Murska Sobota, Slovenia, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia; 14 Lady Davis Carmel Medical Center and Ruth and Bruce
Rappaport School of Medicine, Technion-Israel Institute of Technology, Haifa, Israel; 15 Cardiology Department, King’s College Hospital, London, UK; 16 Cardiology, Department of
Medical and Surgical Specialties, Radiological Sciences, and Public Health, University of Brescia, Italy; 17 Department for Cardiovascular Diseases, University Hospital Center
Zagreb, University of Zagreb, Croatia; 18 Ziekenhuis Oost Limburg, Genk, University Hasselt, Belgium; 19 Heart Failure Unit, Cardiology, G. da Saliceto Hospital, Piacenza, Italy;
20 Cardiovascular Clinical Academic Group, St George’s Hospitals NHS Trust University of London, London, UK, IRCCS San Raffaele Pisana, Rome, Italy; 21 Department of
Cardiology, University Hospital, University Heart Center, Zurich, Switzerland; 22 Department of Cardiology, IRCCS San Raffaele Pisana, Rome, Italy; 23 Heart Failure Unit, Attikon
University Hospital, National and Kapodistrian University of Athens, Greece, School of Medicine, University of Cyprus, Nicosia, Cyprus; and 24 Department of Cardiology, IRCCS
San Raffaele Pisana, Rome, Italy
Received 30 April 2019; revised 17 May 2019; accepted 17 May 2019 ; online publish-ahead-of-print 30 August 2019
The European Society of Cardiology (ESC) has published a series of guidelines on heart failure (HF) over the last 25 years, most recently in
2016. Given the amount of new information that has become available since then, the Heart Failure Association (HFA) of the ESC recognized
the need to review and summarise recent developments in a consensus document. Here we report from the HFA workshop that was held
*Corresponding authors. Andrew J.S. Coats, Department of Cardiology, IRCCS San Raffaele Pisana, Rome, Italy. Email: ajscoats@aol.com Stefan D. Anker, Department of Cardiology,
Charité Campus CVK, Berlin, Germany. Email: s.anker@cachexia.de
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1170 P.M. Seferovic et al.
in January 2019 in Frankfurt, Germany. This expert consensus report is neither a guideline update nor a position statement, but rather
a summary and consensus view in the form of consensus recommendations. The report describes how these guidance statements are
supported by evidence, it makes some practical comments, and it highlights new research areas and how progress might change the clinical
management of HF. We have avoided re-interpretation of information already considered in the 2016 ESC/HFA guidelines.
Specific new recommendations have been made based on the evidence from major trials published since 2016, including sodium–glucose
co-transporter 2 inhibitors in type 2 diabetes mellitus, MitraClip for functional mitral regurgitation, atrial fibrillation ablation in HF, tafamidis
in cardiac transthyretin amyloidosis, rivaroxaban in HF, implantable cardioverter-defibrillators in non-ischaemic HF, and telemedicine for HF.
In addition, new trial evidence from smaller trials and updated meta-analyses have given us the chance to provide refined recommendations
in selected other areas.
Further, new trial evidence is due in many of these areas and others over the next 2 years, in time for the planned 2021 ESC guidelines on
the diagnosis and treatment of acute and chronic heart failure.
..........................................................................................................
Keywords Heart failure • Therapy • Drugs • Devices • Consensus
Introduction/preamble .....................................................................................................................
clinical management of HF. We have avoided re-interpretation
of information already considered in the 2016 ESC/HFA
The European Society of Cardiology (ESC) has published a series guidelines.
of guidelines on heart failure (HF) over the last 25 years, most
recently in 2016.1–6 The next ESC guideline is not due until 2021.
Given the amount of new information that has become avail-
able since 2016, the Heart Failure Association (HFA) of the ESC
Pharmacotherapy
recognized the need to review and summarise recent develop- Sodium–glucose co-transporter 2
ments in a consensus document. The growing appreciation that inhibitors
HF is caused by a great diversity of aetiologies, with various
Consensus recommendation
phenotypes and co-morbidities that affect the response to and,
therefore, the choice of therapy creates exciting new opportu- The 2016 guidelines indicated that empagliflozin should be consid-
nities to improve overall and personalised care, to the individual ered in patients with type 2 diabetes mellitus (T2DM) in order to
patient.7 prevent or delay the onset of HF or prolong life.8
This document is a report from the HFA workshop that was The 2019 expert consensus was that canagliflozin and
held in January 2019 in Frankfurt, Germany. The meeting brought dapagliflozin should also be considered for patients with T2DM
together an international group of experts on HF to discuss and and either established cardiovascular (CV) disease or at high CV
evaluate new evidence published after finalisation of the 2016 risk in order to prevent or delay the onset of and hospitalizations
ESC guidelines for the diagnosis and treatment of acute and for HF.
chronic HF that occurred in March 2016 prior to its publication At this stage, no specific recommendations for the use of
in May 2016.8 There was no industry support for the meeting or sodium–glucose co-transporter 2 (SGLT2) inhibitors in patients
any aspect of the consensus report, and there was no industry with established HF can be made.
representation at the meeting. This expert consensus report is
neither a guideline update nor a position statement, but rather Supporting evidence. Empagliflozin was compared to placebo in
a summary and consensus view in the form of consensus rec- the EMPA-REG OUTCOME (Empagliflozin Cardiovascular Out-
ommendations (see also online supplementary Tables S1 and S2). come Event Trial in Type 2 Diabetes Mellitus Patients) trial in
The consensus report uses standard recommendation language to patients with T2DM and established CV disease. Patients assigned
make our opinions understood in context and using comparable to empagliflozin had a 30% reduction in all-cause mortality, a
language, but it refrains from providing formal (numbered) rec- 38% reduction in CV mortality, and a 35% reduction in HF
ommendation classes or evidence levels. In general, the process hospitalizations.9 Thereafter, similar findings were reported with
followed was that the leadership group reviewed the covered regard to reductions in HF hospitalizations for dapagliflozin10 in
field and assessed any new evidence that had been peer-review the DECLARE-TIMI 58 (Multicenter Trial to Evaluate the Effect
published since 2016. We opened this to all participants at the of Dapagliflozin on the Incidence of Cardiovascular Events) study
meeting and by email, and we agreed by consensus which fields and for canagliflozin11 in the CANVAS (CANagliflozin cardioVas-
were eligible for new statements via an iterative process to reach cular Assessment Study) programme, that included T2DM with
eventual consensus on all issues. No voting was required. The established CV disease or increased CV risk, respectively, but not
report describes how these guidance statements are supported for all-cause mortality [hazard ratio (HR) 0.90 and 0.93, respec-
by evidence, it makes some practical comments, and it high- tively] or CV mortality (HR 0.96 and 0.93, respectively). Of note,
lights new research areas and how progress might change the in none of these trials was the presence of HF at baseline well
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Clinical practice update on heart failure 2019 1171
characterised or phenotyped, so that any recommendation with SGLT2 inhibitors may interact with the effects of loop diuretic
........................................................................................................................................................................
regard to treating established HF and T2DM will be necessarily agents. Adjustment of the doses of diuretic agents and/or SGLT2
cautious. inhibitors may be required. Temporary withdrawal of SGLT2
Most recently in the CREDENCE (Evaluation of the Effects of inhibitors and diuretics and administration of fluids and sodium may
Canagliflozin on Renal and Cardiovascular Outcomes in Partici- be necessary for patients with clinical hypovolaemia or ketoaci-
pants With Diabetic Nephropathy) trial,12 which enrolled patients dosis. Genital infection in the context of treatment with SGLT2
at high risk of CV disease and mild to moderate chronic kid- inhibitors can be prevented by better hygiene, and patients should
ney disease (CKD), canagliflozin reduced HF hospitalisation by be made aware of the risk of this complication.
39% (P < 0.001) and CV death by 22% (P = 0.05). All of these
trials required patients to have T2DM, but fewer than 15% had Directions for future development. In T2DM, new onset HF is com-
HF at baseline. Inclusion criteria and endpoints varied. Positive mon and is associated with a high mortality. Further subgroup anal-
results for SGLT2 inhibitors regarding renal protection effects yses of existing trials should be conducted to confirm that SGLT2
were also reported from the EMPA-REG OUTCOME trial with inhibitors do indeed prevent new-onset HF for patients who did
empagliflozin,13 the DECLARE-TIMI 58 study with dapagliflozin10 not have HF at baseline. The results of clinical trials of patients with
and the CANVAS programme with canagliflozin.11 prevalent and well defined HFrEF and HFpEF (with and without
The consensus view was that there is sufficient evidence to con- T2DM being present at baseline) are awaited before recommend-
sider that the ability of SGLT2 inhibitors to prevent hospitalizations ing these agents for the management of HF itself, rather than only
for HF in patients with T2DM is a class effect. There is insufficient for the treatment of T2DM (Table 1).
evidence to extend this observation to reductions in either CV or
all-cause mortality or to patients without T2DM. Further clarifica-
tion on whether the reduction in HF hospitalization occurs both in Canakinumab
patients with and without pre-existing HF is required. One report Consensus recommendation
from the CANVAS programme suggests that the reduction in hos-
Evidence is not sufficient to provide a recommendation for its use
pitalizations for HF was observed only for patients with pre-existing
in patients with HF.
HF.14
Subgroup analyses on the primary endpoints of the above
mentioned trials have generally found similar relative benefit for Supporting evidence. The CANTOS [Cardiovascular Risk Reduction
patients with and without pre-existing HF, suggesting that the Study (Reduction in Recurrent Major CV Disease Events)] trial17
randomized 10 061 patients with prior myocardial infarction and
absolute benefit in patients with HF may be greater due to their
elevated C-reactive protein to canakinumab or placebo. During a
high baseline risk. However, the diagnosis and phenotype of HF
median follow-up of 3.7 years, 385 patients were hospitalized due
have generally not been well characterized. Of 10 142 participants
to HF. Canakinumab use was associated with a dose-dependent
in the CANVAS programme, 14.4% had a history of HF and
reduction of hospitalization for HF and of the composite of
these patients experienced a greater reduction of CV death or HF
hospitalization for HF or HF-related mortality. A similar effect was
hospitalization [HR 0.61, 95% confidence interval (CI) 0.46–0.80]
observed in a subgroup of 2173 patients (21.6%) with HF.17,18
compared to those without a history of HF at baseline (HR
The consensus group considers the results on HF as hypothesis
0.87; 95% CI 0.72–1.06).14 Similar data were reported from the
generating.
EMPA-REG OUTCOME trial where 706 patients (10.1%) were
reported to have HF at baseline. But as in CANVAS, left ventricular
ejection fraction (LVEF), New York Heart Association (NYHA) Practical comments. In CANTOS, canakinumab was given as a subcu-
class or levels of natriuretic peptides are not known.15 In a post-hoc taneous injection ensuring high adherence. The substantial annual
analysis of DECLARE-TIMI 58, benefits were greater in patients cost and lack of major benefit limit its use.
who were classified as HF with reduced ejection fraction (HFrEF)
compared to patients classified as HF with preserved ejection Directions for future development. The Food and Drug Administra-
fraction (HFpEF), but measurement of LVEF was missing in 25% tion (FDA) denied regulatory approval for canakinumab for patients
of patients.16 with coronary artery disease.19 A new potential therapeutic area
Clinical trials in HF patients with and without T2DM and with is lung and potentially other forms of cancer.20 Relevant trials are
HFrEF or HFpEF are ongoing (Table 1). These trials have recruited ongoing.
thousands of patients and have not yet been stopped for benefit or
harm by their data monitoring committees.
Sacubitril/valsartan
Practical comments. SGLT2 inhibitors are already used for the man- Consensus recommendation
agement of T2DM. After initiating an SGLT2 inhibitor, on aver- Sacubitril/valsartan is recommended as a replacement for
age, estimated glomerular filtration rate (eGFR) will deteriorate by angiotensin-converting enzyme inhibitors (ACE-I)/angiotensin
3–5 mL/min, but the long-term rate of decline in eGFR is slowed.13 receptor blockers (ARB) to reduce the risk of HF hospitaliza-
These observations await confirmation in the setting of HF. tion and death in ambulatory patients with HFrEF who remain
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Table 1 Eighteen ongoing randomized trials of sodium–glucose co-transporter 2 inhibitors in patients with heart
failure
SGLT2 inhibitor Trial Primary outcome Disease No. patients

...........................................................................................................................................
Empagliflozin EMPEROR-Preserved Time to first CV death or hospitalization for HF HFpEF ∼5500
(NCT03057951)
EMPEROR-Reduced Time to first CV death or hospitalization for HF HFrEF ∼3350
(NCT03057977)
EMPERIAL-Reduced Change in 6-min walk distance HFrEF 300
(NCT03448419)
EMPERIAL-Preserved Change in 6-min walk distance HFpEF 300
(NCT03448406)
Empire HF Change in NT-proBNP HFrEF 189
(NCT03198585)
SUGAR Left ventricular end-systolic volume index and HFrEF 130
(NCT03485092) left ventricular global longitudinal strain
Effects of Empagliflozin on Exercise Capacity Change in 6-min walk distance HFpEF 100
and Left Ventricular Diastolic Function in
Patients With Heart Failure With
Preserved Ejection Fraction and Type 2
Diabetes Mellitus
(NCT03753087)
A Study That Looks at the Function of the Change in PCr/ATP ratio in the resting state HF 86
Heart in Patients With Heart Failure
Who Take Empagliflozin
(NCT03332212)
ELSI Skin sodium content HFrEF 84
(NCT03128528)
EMBRACE-HF Change in pulmonary artery diastolic pressure HF 60
(NCT03030222)
Dapagliflozin DAPA-HF Time to first CV death, hospitalization for HF, HFrEF 4744
(NCT03036124) or urgent HF visit
DELIVER Time to first occurrence of CV death, HFpEF ∼4700
(NCT03619213) hospitalization for HF, urgent HF visit
PRESERVED-HF Change in NT-proBNP HFpEF 320
(NCT03030235)
DETERMINE-Reduced Change in 6-min walk distance HFrEF 300
(NCT03877237)
DETERMINE-Preserved Change in 6-min walk distance HFpEF 400
(NCT03877224)
DEFINE-HF Change in NT-proBNP HFrEF 263
(NCT02653482)
Sotagliflozin SOLOIST-WHF Time to first CV death or hospitalization for HF HFrEF 4000
(NCT03521934)
Ertugliflozin ERTU-GLS Global longitudinal strain HF 120
(NCT03717194)
ATP, adenosine triphosphate; CV, cardiovascular; HF, heart failure; HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction;
NT-proBNP, N-terminal pro-B-type natriuretic peptide; PCr, phosphocreatine; SGLT2, sodium–glucose co-transporter 2.
symptomatic despite optimal medical treatment with an ACE-I, a no need to check plasma concentrations of natriuretic peptides
........................
beta-blocker and a mineralocorticoid receptor antagonist (MRA). prior to initiating sacubitril/valsartan. As indicated in the 2016
Initiation of sacubitril/valsartan rather than an ACE-I or an ARB HF guidelines,8 ambulatory patients with HFrEF should have an
may be considered for patients hospitalized with new-onset HF elevated plasma concentration of natriuretic peptides indicating
or decompensated chronic HF to reduce the short-term risk increased risk and the need for more effective therapy.
of adverse events and to simplify management (by avoiding the
need to titrate ACE-I first and then switch to sacubitril/valsartan). Supporting evidence. In secondary analyses of PARADIGM-HF
Because these patients are already at high risk of events, there is (Prospective Comparison of ARNI with ACEI to Determine
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Impact on Global Mortality and Morbidity in Heart Failure), patients with ambulatory chronic HF and mild symptoms, in
........................................................................................................................................................................
sacubitril/valsartan has been shown to improve survival in a broad whom the benefit of sacubitril/valsartan is uncertain, if plasma
range of patients who fulfilled the trial’s inclusion/exclusion cri- concentrations of natriuretic peptides are not elevated.31
teria, including those aged ≥75 years, and/or with co-morbidities
such as T2DM.21–23 Compared with enalapril, administration of Directions for future development. The PIONEER-HF trial provides
sacubitril/valsartan reduced the incidence of diabetes requiring limited evidence that it is safe to initiate sacubitril/valsartan in
insulin treatment,24 and the incidence of hyperkalaemia in those on ACE-I naïve patients; more evidence would be very welcome.
an MRA.25 The rate of decline in eGFR was also found lower with Further results from an extensive trial programme including
sacubitril/valsartan,26 but this is not yet supported by ‘slope of HFpEF (PARAGON-HF, NCT01920711) and patients with left
decline’ analyses. Hypotension occurs more commonly with sacu- ventricular dysfunction after myocardial infarction (PARADISE-MI,
bitril/valsartan than with enalapril. However, patients who develop NCT02924727) may further extend the indications for sacubi-
hypotension still appear to benefit from sacubitril/valsartan.27 tril/valsartan. It would also be of interest to understand whether
In the PIONEER-HF (Comparison of Sacubitril/valsartan Versus the use of potassium binders can reduce hyperkalaemia and
Enalapril on Effect on NT-proBNP in Patients Stabilized from an enable more patients to tolerate sacubitril/valsartan at all, or at
Acute Heart Failure Episode) trial, patients with HFrEF hospital- a higher dose.
ized for new-onset (about one third) or worsening chronic HF
(about two thirds) were stabilized and then randomly assigned
to receive either sacubitril/valsartan or enalapril; the reduction Potassium binders
in N-terminal pro-B-type natriuretic peptide (NT-proBNP) was
greater in those assigned to sacubitril/valsartan at weeks 4 and
8 (the primary endpoint of this biomarker study).28 The rates of Patiromer and ZS-9 may be considered in patients with HF
worsening renal function, hyperkalaemia, symptomatic hypoten- with or without CKD to manage hyperkalaemia. In selected
sion and angioedema were similar in the two groups28 but there patients these therapies may enable use of MRAs and other
were fewer HF-related adverse events in patients assigned to sacu- renin–angiotensin–aldosterone system inhibitors (RAASi) in
bitril/valsartan. more patients and at higher doses, but it is not known whether
In the open-label TRANSITION (Comparison of Pre- and this will improve patient outcomes.
Post-discharge Initiation of LCZ696 Therapy in HFrEF Patients Patiromer and ZS-9 may be considered in selected patients with HF
After an Acute Decompensation Event) trial,29 more than 1000 with or without CKD in order to enable up-titration of MRA while
patients with HFrEF hospitalized for worsening HF were random- avoiding hyperkalaemia.
ized to start sacubitril/valsartan either before (initiated ≥24 h after
haemodynamic stabilization) or after discharge (initiated within Supporting evidence. Hyperkalaemia is an important reason for
14 days after discharge). Safety outcomes were similar for each under-use of life-saving therapy with RAASi in HF, and it is
strategy, indicating no disadvantage to early initiation, which may particularly frequent in patients with more advanced kidney dis-
simplify management from both a clinician and patient perspec- ease and T2DM.32 Besides PEARL-HF (Evaluation of Patiromer
tive. A meaningful proportion of patients, 53% in PIONEER-HF and in Heart Failure Patients),33 a phase-2 trial published in 2011,
24% in TRANSITION, respectively, were ACE-I/ARB naïve prior new evidence is available from trials of patients with CKD and
to sacubitril/valsartan initiation suggesting that the drug has similar hypertension that also included subgroups of HF patients. The
efficacy and safety in these patients. subgroup analysis of the AMETHYST-DN (Patiromer in the
Treatment of Hyperkalaemia in Patients With Hypertension
Practical comments. Sacubitril/valsartan is safe and effective in a and Diabetic Nephropathy) trial34 included 105 HF patients on
broad spectrum of patients with HFrEF.21–25,27,30 Its safety is sim- RAASi. Per protocol, RAASi dose could not be down-titrated
ilar in ACE-I/ARB naïve patients and thus its initiation may be but patiromer could be up-titrated using a study-defined dosing
considered also in these patients. In PIONEER-HF,28 the incidence algorithm. Patiromer was effective in maintaining normokalaemia
of hyperkalaemia (≥5.5 mmol/L) was similar for those assigned to and was well tolerated over 52 weeks of intervention. Findings
enalapril (9.3%) or sacubitril/valsartan (11.6%). Amongst patients were similar in groups with mild (K 5.0–5.5 mmol/L; all received
receiving MRA in the PARADIGM-HF trial, sacubitril/valsartan spironolactone up to 50 mg on top of RAASi) and moderate
reduced the risk of severe hyperkalaemia (>6.0 mmol/L) as com- (K 5.5–6.0 mmol/L) hyperkalaemia at baseline. The ability of
pared with enalapril (3.1 vs. 2.2 per 100 patient-years; HR 1.37; patiromer to enable spironolactone initiation and up-titration in
P = 0.02).25 Sacubitril/valsartan may slow the rate of decline in patients with HF and CKD was studied in 63 normokalaemic
eGFR and, in patients with T2DM, improve glycaemic control.24 (K 4.3–5.1 mmol/L) patients in an open label design.35 Patients
PIONEER-HF required patients to have and NT-proBNP were up-titrated to spironolactone 50 mg once daily and the
>1600 pg/mL (BNP >400 pg/mL). However, if the diagnosis of HF patiromer dose was adjusted to maintain potassium within the
is certain and the patient has severe enough decompensation to range of 3.5–5.5 mmmol/L which at week 8 was achieved in 90%
require hospital admission, plasma concentrations of natriuretic of patients. Both studies followed potassium and renal function
peptides will usually be elevated and therefore their measurement regularly and demonstrated that patiromer had a good safety
might not be necessary. This is a very different situation from profile. No new evidence is available for ZS-9 in the field of HF.
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Practical comments. Patiromer and ZS-9 are approved for clinical Supporting evidence. Under the auspices of the Beta-blockers
........................................................................................................................................................................
use in many European countries and the USA, but in others in Heart Failure Collaborative Group (BBmeta-HF), individual
regulatory approval for local use is incomplete, and hence these patient data (IPD) from 11 major HF clinical trials, comparing
drugs are not available everywhere. beta-blockers and placebo, were pooled and meta-analysed.40 In
a subgroup of 575 patients with LVEF 40–49% in sinus rhythm
Directions for future development. Subgroup results for HF patients (ischaemic aetiology 91%, NYHA class III–IV 24%, ACE-I/ARB 91%,
enrolled in the AMBER (Spironolactone With Patiromer in the MRA 6%, diuretics 65%), beta-blockers reduced the risk of all-cause
Treatment of Resistant Hypertension in Chronic Kidney Disease) and CV death (primary outcomes for this analysis). The absolute
trial are not yet available. A smaller trial of ZS-9 in HF patients to reduction in CV mortality in this subgroup was 4.7% [number
enable RAASi therapy (n = 280) has been initiated (PRIORITIZE HF, needed to treat (NNT) to prevent one CV death = 21 during a
NCT03532009). A substantial clinical trial of patiromer (n > 2000) median follow-up of 1.3 years].40 Beta-blockers did not modify the
is underway investigating its effects on morbidity and mortality risk of either the first CV hospitalization or the composite of CV
(DIAMOND, NCT03888066). death and CV hospitalization (time to first event) in patients with
HFmrEF in sinus rhythm. Beta-blockers had no effect on either pri-
Treatment of congestion using diuretics mary or secondary clinical outcomes in patients with HFmrEF and
atrial fibrillation (AF).40
Evidence is not sufficient to provide new practical recommenda-
tions for the use of diuretics. Directions for future development. These findings should be inter-
preted with caution as this was a post-hoc analysis. Specific trials
in HFmrEF (possibly studied together with HFpEF patients) would
Supporting evidence. No new evidence was published since 2016 for
be of interest.
diuretic therapy. The ADVOR (Acetazolamide in Decompensated
Heart Failure With Volume Overload) trial with acetazolamide is
ongoing.36 Candesartan for heart failure with
Practical comments. With no strong evidence at hand, most of the
mid-range ejection fraction
volume management recommendations are consensus based and Consensus recommendation
must focus on individual patients in whom tailored therapy is Candesartan may be considered for ambulatory patients with symp-
necessary. An HFA position statement with emphasis on clinical tomatic HFmrEF in order to reduce the risk of HF hospitalization
management was recently published.37 and CV death.
Directions for future development. There are several tri- Supporting evidence. The post-hoc analysis of the pooled data from
als ongoing, including ADVOR (testing acetazolamide – the CHARM programme compared the impact of candesartan on
NCT03505788), TRANSFORM-HF (testing torsemide vs. clinical outcomes in patients with HF across the whole spectrum
furosemide – NCT03296813), EMPA-RESPONSE-AHF (test- of LVEF.41 In a subgroup of 1322 patients with an LVEF 40–49%
ing empagliflozin in acute HF – NCT03200860), and a trial of (ischaemic aetiology 67%, NYHA class III–IV 42%, ACE-I 27%,
metolazone vs. chlorothiazide (NCT03574857). The development beta-blocker 58%, MRA 11%, diuretics 74%), candesartan reduced
of user-friendly systems to deliver subcutaneous furosemide will the risk of CV death and HF hospitalization (primary outcome for
require evaluation in clinical trials.38,39 this analysis), the risk of first HF hospitalization and the risk of
recurrent HF hospitalizations.42 Candesartan did not modify the
Pharmacotherapy in heart failure risk of either all-cause or CV death.
with mid-range ejection fraction
Directions for future development. These findings should be inter-
No prospective trial has been conducted in patients with HF with
preted with caution as this was a post-hoc analysis. However, there
mid-range ejection fraction (HFmrEF) to date. All analyses and
was no statistical interaction between LVEF phenotype and can-
related recommendations are based on post-hoc analyses from
desartan treatment.42 Specific trials in HFmrEF (possibly studied
HFrEF and/or HFpEF trials, with inclusion criteria that included
together with HFpEF patients) would be of interest.
patients now classified as HFmrEF.
Beta-blockers for heart failure with Spironolactone for heart failure with
mid-range ejection fraction mid-range ejection fraction
Consensus recommendation Consensus recommendation
A beta-blocker may be considered for ambulatory patients with Spironolactone may be considered for ambulatory patients with
symptomatic HFmrEF in sinus rhythm in order to reduce the risk symptomatic HFmrEF without contraindications in order to reduce
of all-cause and CV death. the risk of CV death and HF hospitalization.
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Supporting evidence. A post-hoc analysis of the TOPCAT (Aldos- (IRONMAN – NCT02642562, AFFIRM-AHF – NCT02937454,
........................................................................................................................................................................
terone Antagonist Therapy for Adults With Heart Failure and Pre- FAIR-HF2 – NCT03036462, HEART-FID – NCT03037931) and
served Systolic Function) trial (spironolactone in HF with LVEF HFpEF (FAIR-HFpEF – NCT03074591). Uncertainties also exist
≥ 45%) suggested that in a subgroup of patients with LVEF 44–49% about the safety and efficacy of long-term IV supplementation,
(n = 520), spironolactone reduced the risk of the primary endpoint although a recent trial in patients with CKD [PIVOTAL (UK Multi-
(defined as CV death, HF hospitalization, or resuscitated sudden centre Open-label Randomised Controlled Trial of IV Iron Therapy
death), which was mostly due to a reduction in CV mortality with in Incident Haemodialysis Patients), EudraCT: 2013-002267-25]
spironolactone and most clearly observed in patients enrolled in does not suggest any serious issues.48 The key trials, so far, have
North and South America.42 been conducted with ferric carboxymaltose. Whether other iron
preparations are similarly effective and safe should be established.
Directions for future development. The evidence is based on a Controversy also exists about which test is best for the diagnosis
post-hoc analysis, in a small subgroup of patients classified as of ID, and whether more than one biomarker measure is required.
HFmrEF based on measurements of LVEF made by investigators, In addition, more mechanistic studies like Ferric-HF II (EudraCT:
which will suffer from substantial measurement variability and 2012-005592-13)49 are needed.
error, in a clinical trial which overall was neutral. These results
do, however, provide the rationale and basis for the design
of future trials in patients with HFmrEF,43 including SPIRIT-HF Tafamidis in cardiac transthyretin
(EudraCT 2017-000697-11) and SPIRRIT (NCT02901184).
amyloidosis
Given its well-proven anti-hypertensive effect, spironolactone
may be especially useful in patients with poorly controlled Consensus recommendation
hypertension. Older patients with symptomatic HF, particularly those with
HFpEF (who are not hypertensive) or those who have features of
hypertrophic or restrictive cardiomyopathy, or degenerative aor-
Intravenous iron for heart failure with tic stenosis and end-diastolic interventricular septal wall thickness
mid-range ejection fraction exceeding 12 mm, should be considered for screening for cardiac
transthyretin amyloidosis (ATTR).
Tafamidis should be considered in patients with symptomatic
Evidence is insufficient to provide new practical recommendations. HF due to confirmed transthyretin amyloidosis [both autosomal
dominant inherited disease (ATTRm) and wild-type transthyretin
Supporting evidence. Iron deficiency (ID) is common in patients with (ATTRwt)] in order to improve exercise capacity and quality
and without anaemia with HFrEF, HFmrEF and HFpEF, and is asso- of life, and to reduce CV hospitalizations and mortality. This
ciated with worse symptoms, quality of life and clinical outcomes recommendation is limited to patients who fulfil the inclusion
of patients with HF across the whole spectrum of LVEF.43,44 Epi- and exclusion criteria of the ATTR-ACT (Safety and Efficacy of
demiological evidence emphasises the need for screening for ID Tafamidis in Patients with Transthyretin Cardiomyopathy) trial
in patients with HF, regardless of LVEF, if blood haemoglobin is (Table 2).50 These include confirmation of the presence of amyloid
<14 g/dL. deposits on analysis of biopsy specimens obtained from the heart
Clinical trials investigating the effects of intravenous (IV) ferric or other tissues (e.g. fat aspirate, gastrointestinal mucosa sites,
carboxymaltose in ambulatory patients with symptomatic HF, LVEF
≤45% and ID [FAIR-HF (A Study to Compare the Use of Ferric Car-
salivary glands, or bone marrow).
Special note: the cost of tafamidis is currently extremely high, therefore
boxymaltose With Placebo in Patients With Chronic Heart Failure many patients and health services may currently not be able to pay for it.
and Iron Deficiency), CONFIRM-HF (A Study to Compare the Use
of Ferric Carboxymaltose With Placebo in Patients With Chronic
Supporting evidence. Amyloidosis includes a variety of pathologies
Heart Failure and Iron Deficiency) and EFFECT-HF (Effect of Ferric
caused by the extracellular accumulation of amyloid fibrils, lead-
Carboxymaltose on Exercise Capacity in Patients With Iron Defi-
ing to a progressive damage of the involved organ. When it affects
ciency and Chronic Heart Failure)] included approximately 150
the heart, it may cause HF which is often resistant to treatment
patients with LVEF 40–45% (HFmrEF).45–47 Subgroup analysis by
and associated with a high mortality.51,52 Systemic immunoglobu-
LVEF categories has not been published.
lin light-chain amyloidosis (AL) is caused by plasma cell dyscrasias
that may (myeloma) or may not (monoclonal gammopathy of uncer-
Practical comments. All symptomatic patients with HF should have tain significance) be malignant. This accounts for about 80% of
tests done for ID, if haemoglobin is <14 g/dL. contemporary cases of cardiac amyloid and is rapidly lethal if the
underlying cause cannot be reversed. Transthyretin amyloidosis
Directions for future development. Given the high prevalence accounts for 15–25% of all cardiac amyloidosis and has a bet-
of ID and its association with an unfavourable outcome in ter prognosis, on average, than AL amyloid. Transthyretin amy-
patients with HF regardless of LVEF, more clinical trial evi- loidosis has two forms: ATTRm and ATTRwt, which occurs spo-
dence for IV iron supplementation is awaited for HFrEF radically. ATTR affects 20–30% of people aged >80 years and is
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stages of development.58 We fully support efforts to reduce the
........................................................................................................................................................................
Table 2 Exclusion criteria of the ATTR-ACT trial58
high cost of this therapy.
1 They had, in the opinion of the investigator, heart failure that

was not due to transthyretin amyloid cardiomyopathy Rivaroxaban in heart failure
2 New York Heart Association class IV heart failure
3 The presence of light-chain amyloidosis
4 A history of liver or heart transplantation For ambulatory patients with coronary artery disease (CAD) and
5 An implanted cardiac device chronic HF in NYHA class I/II with an LVEF >30%, addition of
6 Previous treatment with tafamidis rivaroxaban 2.5 mg bid to background treatment with aspirin may
7 An estimated glomerular filtration rate <25 mL/min/1.73 m2 be considered in order to reduce the risk of stroke and CV death.
of body surface area For chronic HF patients with a recent HF hospitalization or per-
8 Liver transaminase levels exceeding two times the upper limit
sistent NYHA class III/IV, initiation of treatment with rivaroxaban
of the normal range
cannot be recommended, as there is no demonstrable benefit.
9 Severe malnutrition as defined by a modified body mass
index of <600 calculated as the serum albumin level in g/L
multiplied by the conventional body mass index (the weight Supporting evidence. The COMMANDER-HF (A Study to Assess
in kg/m2 ) the Effectiveness and Safety of Rivaroxaban in Reducing the Risk
10 Concurrent treatment with non-steroidal anti-inflammatory of Death, Myocardial Infarction or Stroke in Participants With
drugs, tauroursodeoxycholate, doxycycline, calcium channel Heart Failure and Coronary Artery Disease Following an Episode
blockers, or digitalis of Decompensated Heart Failure) trial enrolled 5022 patients with
chronic HFrEF, CAD, a recent HF hospitalization and no AF59
and randomised them to rivaroxaban 2.5 mg bid, added to back-
more common in patients with HFpEF and/or degenerative aor-
ground antiplatelet therapy, mostly aspirin, but including a substan-
tic stenosis.51–55 Novel single photon emission computed tomog-
tial proportion on dual antiplatelet therapy. The mean follow-up
raphy cardiac imaging with bone-avid tracers (99mTc pyrophos-
was 21 months. The study was neutral on its primary endpoint of
phate, 3,3-diphosphono1,2-propanedicarboxylic acid, and hydrox-
all-cause death, stroke, or acute myocardial infarction. Rivaroxaban
ymethylene diphosphonate (HMDP) help identify cases with high
did not reduce HF hospitalization but did reduce the rate of stroke
specificity, non-invasively,56 obviating the need for endomyocardial
from 3.0% to 2.0% (HR 0.66, 95% CI 0.47–0.95). A post-hoc anal-
biopsy. Similarly, the myocardial radiotracer uptake during bone
ysis investigating the effect on a broad definition of vascular events
scintigraphy could be used in clinical practice, as this was >99%
(predominantly myocardial infarction, stroke, and sudden death)60
specific and 86% sensitive to detect cardiac ATTR amyloid.57
demonstrated a significant reduction, although rivaroxaban had no
Tafamidis prevents transthyretin tetramer dissociation and
effect on HF-related hospitalizations or HF deaths. There was an
amyloidogenesis. In the ATTR-ACT trial, 441 patients with
increase in major bleeding (from 2.0% to 3.3%; HR 1.68, 95% CI
transthyretin amyloid cardiomyopathy and symptoms of HF
1.18–2.39). The difference was driven mainly by the number of
received, in a 2:1:2 ratio, 80 mg of tafamidis, 20 mg of tafamidis,
participants with a fall in haemoglobin of >2.0 g/dL, with a neutral
or placebo for 30 months. Transthyretin amyloid cardiomyopa-
effect on bleeding requiring hospitalization or resulting in death.
thy (ATTRwt or ATTRm) was confirmed by the presence of
The COMPASS (Rivaroxaban for the Prevention of Major Car-
amyloid deposits on tissue biopsies and, in patients without
diovascular Events in Coronary or Peripheral Artery Disease)
ATTRm, by the presence of transthyretin precursor protein
trial enrolled 27 395 patients, of whom 5902 had HF (predomi-
nantly with LVEF ≥40%; n = 4250) and randomly assigned them
confirmed on immunohistochemical analysis, scintigraphy, or
mass spectrometry.50 Tafamidis reduced the risk of the combined
(double-blind) to aspirin 100 mg/day, rivaroxaban 2.5 mg bid plus
primary endpoint (all-cause death and CV-related hospitaliza-
aspirin 100 mg/day or rivaroxaban 5 mg bid.61 Patients with NYHA
tion), independently reducing all-cause mortality and the rate
class III/IV HF or a LVEF <30% were excluded. Mean follow-up was
of CV-related hospitalizations. Tafamidis also slowed the rate of
23 months. Overall, compared to aspirin alone, the combination
decline in both the 6-min walk distance and quality of life.51
reduced stroke (from 1.6% to 0.9%; HR 0.58, IC 95% 0.44–0.76)
and all-cause mortality (from 4.1% to 3.4%; HR 0.82, IC 95%
Practical comments. The high prevalence of undiagnosed 0.71–0.96), but not myocardial infarction (from 2.2% to 1.9%)
transthyretin amyloidosis in older patients with HF, particu- or HF hospitalization (from 2.1% to 2.2%). Major bleeding events
larly those with HFpEF with or without aortic stenosis, should be were higher on the combination (1.9% vs. 3.1%; HR 1.70, 95% CI
recognized. Non-invasive, nuclear imaging simplifies diagnosis, and 1.40–2.05), although rarely fatal (10 vs. 15 events). Rivaroxaban
may in the future serve as preferred screening and diagnostic tool. was neither superior to aspirin alone nor inferior to the combina-
The major obstacle for widespread implementation of this therapy tion. The combination exerted similar relative effects for patients
is the very high cost of therapy. with and without HF but the absolute gain was greater for patients
with HF. For patients with HF, the combination reduced all-cause
Directions for future development. Novel selective transthyretin mortality from 6.5% to 4.4% (HR 0.66, 95% CI 0.50–0.86). Ben-
stabilizers (e.g. AG10) and TTR gene silencers are at different efit was clearest amongst patients with HFpEF/HFmrEF, although
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statistical tests could not confirm heterogeneity according to left fail to reach target doses. Simplifying medication regimens and
........................................................................................................................................................................
ventricular phenotype. The effect of rivaroxaban 5 mg bid com- reducing total pill intake may be welcomed by patients and
pared to aspirin 100 mg/day on all-cause mortality approached sig- health professionals and improve adherence. Prospective tri-
nificance (HR 0.80, 95% CI 0.61–1.03). Amongst patients with HF, als investigating the effects of fixed-dose combinations should
major bleeding events were higher on the combination (2.5%) com- be encouraged.
pared to aspirin alone (1.8%; HR 1.36, 95% CI 0.88–2.09); although
the risk appeared somewhat less than for patients without HF (3.3
vs. 1.9%, HR 1.79, 95% CI 1.45–2.21), tests for statistical hetero- Approaches to improving guideline
geneity were not significant.
adherence for drug therapy in heart
For chronic HF patients with a recent HF hospitalization or
persistent NYHA class III/IV, based on COMMANDER-HF, initiation failure
of treatment with rivaroxaban cannot be recommended. However, Consensus recommendation
stopping of pre-existing therapy with rivaroxaban in such patients Evidence is insufficient to provide new practical recommendations.
cannot be recommended, as there is no related evidence.
Supporting evidence. The 2016 ESC guidelines8 state that implemen-
Practical comments. A large proportion of patients with advanced tation of multidisciplinary strategies in order to improve adher-
HF have non-valvular AF. Relevant ESC guidelines indicate that ence to guideline-recommended medicines is recommended for
these patients should receive a direct oral anticoagulant. Rivarox- patients with HFrEF in order to reduce the risk of HF hospital-
aban 2.5 mg bid is not considered to be an effective dose for the ization and CV and all-cause mortality. The ESC guidelines pro-
prevention of thromboembolic events in patients with AF. vide a framework to deliver evidence-based multidisciplinary care
In summary, it appears that for patients with CAD rivaroxaban that translates into better quality of life and improved clinical out-
2.5 mg bid in addition to low-dose aspirin reduces the risk of vas- comes in patients with HFrEF. However, adherence to guideline
cular events in patients without HF and with mild HF. However, for recommendations remains suboptimal for many reasons, includ-
patients with advanced HF, myocardial dysfunction and congestion ing provider and patient education, lack of sufficient resources to
rather than vascular events determine outcome. advise patients, some patients’ reluctance to take more medica-
tion, side effects and cost. A substantial group of patients with
Directions for future development. These trials provide insights into HF do not receive appropriate pharmacotherapy with adequate
the contribution of vascular events to the outcome of patients doses, and receives intracardiac devices without prior optimization
at various points across a broad spectrum of HF. The benefit of pharmacotherapy.
and safety of aspirin in patients with HF remain in doubt, which In QUALIFY (QUality of Adherence to guideline recommenda-
should be addressed by further clinical trials. The strong trend for a tions for LIFe-saving treatment in heart failure surveY), an inter-
reduction in mortality with rivaroxaban alone compared to aspirin national, prospective, observational, longitudinal survey, amongst
alone (and its non-inferiority to combination therapy) should be 6669 outpatients with HFrEF after recent HF hospitalization, good
investigated further. adherence for treatment with ACE-I, ARB, beta-blocker, MRA
and ivabradine, with a prescription of at least 50% of recom-
Fixed dose drug combinations in heart mended doses (which, however, is still less than what is achieved
in many trials), was associated with a better clinical outcomes dur-
failure
ing 6-month follow-up (e.g. reduced mortality).64 Similarly, in the
Consensus recommendation BIOSTAT-CHF (a systems BIOlogy Study to TAilored Treatment
Evidence is insufficient to provide new practical recommendations. in Chronic Heart Failure) study, which was specifically designed to
study up-titration of ACE-I/ARB and/or beta-blocker and enrolled
Supporting evidence. The incremental use of combinations of 2516 patients with worsening HF, those treated with less than
disease-modifying therapies has resulted in the progressive 50% of recommended doses had a greater risk of death and/or HF
improvement in clinical outcomes for patients with HFrEF.8,62 hospitalization.65
In a network analysis, the most effective combinations for
HFrEF were (i) sacubitril/valsartan + beta-blocker + MRA, and (ii) Directions for future development. There is a need to develop more
ACE-I + beta-blocker + MRA + ivabradine, leading to reductions in practical strategies to improve adherence to guidelines. They
all-cause mortality (vs. placebo) of 62% and 59%, respectively, and should be based on multidisciplinary models, involving HF teams,
in all-cause hospitalizations of 42% for each combination.63 The structured referral schemes, telemedicine (using home-based
administration of fixed-dose combinations improves compliance, methodology or also implantable pulmonary artery pressure and
blood pressure control and clinical outcomes in patients with left atrial pressure monitoring systems), synchronized education
hypertension but this has not yet been demonstrated for HF.63 of patients and health care providers, care standardization, quality
control and audit. The development of centres of excellence, such
Directions for future development. Many guideline-recommended as those recently described for the treatment of advanced HF,66
medications remain underutilized in community practice and many may contribute to this goal.
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Device-based therapies SAD, this intervention may only be useful for some highly selected
........................................................................................................................................................................
patient groups.
Implantable cardioverter-defibrillators
Consensus recommendation Atrial fibrillation ablation
The consensus group did not identify any new evidence to Consensus recommendation
alter the 2016 guideline recommendations8 on implantable
Pulmonary vein (PV) ablation of patients with HF and symptomatic
cardioverter-defibrillator (ICD) implantation in patients with
paroxysmal AF may be considered, if paroxysms cause troublesome
HFrEF and CAD.
symptoms despite implementation of guideline-recommended
The consensus view was that one may consider not to implant
pharmacological and device therapy.
an ICD in patients with non-ischaemic HFrEF who (i) are aged
Atrio-ventricular (AV) node ablation, usually with bi-ventricular
>70 years, or (ii) have advanced symptoms (NYHA class III/IV), or
rather than right ventricular pacing, may be considered if paroxysms
(iii) have life-shortening co-morbidity (e.g. severe lung disease or
provoke severe symptoms and PV ablation has failed or is not
Stage IV CKD) and hence are likely to die for reasons other than
possible.
sudden arrhythmic death (SAD).
Pulmonary vein ablation for persistent AF may be considered for
patients with HFrEF who have an implanted device (to prevent
Supporting evidence. A randomised trial of patients with
non-ischaemic symptomatic HF and an LVEF ≤35% [DANISH
bradycardia; ICD, CRT or permanent pacemaker) if achieving and
maintaining sinus rhythm is considered likely, especially if the onset
(Danish ICD Study in Patients With Dilated Cardiomyopathy)] did of atrial AF was associated with a deterioration in symptoms of HF
not show that implanting an ICD for primary prevention reduced or the patient has (or is a candidate for) CRT. PV ablation is less
overall mortality despite a reduction in sudden deaths.67 Many likely to be successful in patients with long-standing AF and severe
patients had a broad QRS and were randomised to receive cardiac right and or left atrial dilatation.
resynchronization therapy (CRT) with a pacemaker (CRT-P) or a Atrio-ventricular node ablation is not recommended in patients
defibrillator (CRT-D) (58% of participants) but, similar to the main with CRT and AF with controlled heart rate due to a lack of evi-
trial, no difference in mortality was observed in this subgroup. dence of clinical benefit that ablation is superior to pharmacological
For patients aged <59 years, implantation of an ICD almost halved rate control.
mortality but for those aged 59–67 years mortality was reduced
by only 25% and for those aged 68 years or older, there was a
Supporting evidence. The debate on whether rate or rhythm con-
19% excess mortality. ICDs probably reduce sudden cardiac death
trol is the better strategy for managing AF complicating HF con-
throughout the age spectrum but fail to reduce all-cause mortality
tinues. Anticoagulants should be continued even if sinus rhythm
in older patients due to high rates of death due to worsening
is restored because the risk of recurrent AF is high. An optimal
HF and non-cardiac co-morbidities. Patients with an NT-proBNP
rate control strategy must avoid excessive heart rate reduction
>1000 pg/mL did not benefit from an ICD. Pharmacological ther-
as well as toxic antiarrhythmic agents, potentially including higher
apy should be optimized before a decision is made to implant an
doses of amiodarone or plasma concentrations of digoxin. A mod-
ICD. The risk of deferring ICD implantation by a few months in
est dose of beta-blocker may be the safest option for rate con-
order to optimise therapy is low.
trol in patients with AF, even if beta-blockers do not appear to
The benefit of the ICD is determined by the risk of sudden car-
improve outcome when titrated to conventional target doses.70
diac death over the risk of non-sudden cardiac death incorporating
A rate control strategy for persistent AF avoids the need for
the high co-morbidity burden in HF patients. The rate of SAD
procedures and potentially toxic drugs and the problems that
appears to be declining, possibly due to improvements in pharma-
relapse into AF can cause. For those with symptomatic paroxys-
cological care,68 which might reduce the absolute effect of ICDs on
mortality. For patients with a LVEF ≤35% who do not have CAD,
mal AF and HF there is a stronger rationale for a rhythm control
strategy.
the most recent trial reported an annual risk of SAD of about 1%
There is no substantial trial investigating PV or AV node ablation
in patients who were assigned not to receive an ICD.
for paroxysmal AF in patients with HF. However, where there is a
clear association between paroxysmal AF and marked worsening of
Practical comments. For younger patients (e.g. <70 years), implanta- symptoms which persist despite guideline-recommended therapy,
tion of an ICD is recommended provided the patient is considered then PV ablation or, if that fails, AV node ablation should be
unlikely to die of a cause other than SAD in the following 5 years considered.
(predicted reduction in mortality over 5 years of up to 5%). Patients (n = 3103) with HF and persistent AF were evalu-
ated for inclusion in the CASTLE-AF (Catheter Ablation vs. Stan-
Directions for future development. More trials comparing CRT-P and dard Conventional Treatment in Patients With Left Ventricular
CRT-D are required, such as RESET-CRT (NCT03494933). The Dysfunction and Atrial Fibrillation) trial comparing pharmacolog-
VEST trial (Vest Prevention of Early Sudden Death)69 showed a ical rate or rhythm control with PV ablation in patients with
reduction in mortality although not SAD in patients with an acute HFrEF (LVEF <35%) and an ICD or CRT-D device (to prevent
myocardial infarction and an LVEF <35%. Trials for patients with HF post-ablation bradycardia).71 Finally, only 363 patients were ran-
may be warranted although, given the generally low annual risk of domized (about 50 patients per year) of whom only 317 received
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their assigned strategy. PV ablation often failed, with a residual bur- CRT. Neither the safety nor efficacy of PV ablation for persistent AF
........................................................................................................................................................................
den of AF of about 25%. Neither patients nor investigators were and HF in the absence of back-up pacing has been demonstrated.
blind to assigned management strategy and 33 patients were lost to
follow-up. A reduction in the primary composite endpoint of death Directions for future development. The group believes that a series of
from any cause or hospitalization for worsening HF was reported randomized controlled trials is required comparing ‘non-aggressive’
for the intervention arm patients (28% vs. 45%; HR 0.62, 95% CI pharmacological rate control, avoiding amiodarone or Class I
0.43–0.87). The effect was consistent over primary endpoint com-
posites (HR 0.53 and 0.56, respectively, P ≤ 0.01 for both). After
antiarrhythmic agents and higher doses or plasma concentrations
of digoxin with the following procedures:
3 years of follow-up, at which time there were fewer than 100
patients in each group, a difference in mortality appeared (24 deaths 1 PV (and/or AV node) ablation for paroxysmal AF and HF vs
with ablation vs. 46 deaths in control). Patients with less advanced ‘non-aggressive’ pharmacological rate control (and avoiding all
HF (LVEF >25%, NYHA class II, <65 years old) potentially derived of: amiodarone, Class I antiarrhythmic agents, higher doses or
greater benefit. higher plasma concentrations of digoxin).
The CABANA (Catheter Ablation vs. Antiarrhythmic Drug 2 PV (and/or AV node) ablation for persistent AF and HF with or
Therapy for Atrial Fibrillation) trial also compared PV ablation to without a back-up pacing device vs ‘non-aggressive’ pharma-
medical therapy.72,73 Only 337 of 2204 patients randomized had cological rate control (and avoiding all of: amiodarone, Class I
HF at baseline. Overall, the trial was neutral for its primary com- antiarrhythmic agents, higher doses or higher plasma concen-
posite endpoint (HR 0.86, 95% CI 0.65–1.15). The point-estimate trations of digoxin).
was somewhat better for patients with HF (HR 0.61, 95%CI 3 PV (and/or AV node) ablation in HF patients with CRT vs. usual
0.35–1.08), and was associated with an improvement in quality of care.
life at 12 months. 4 There is also a need for randomized controlled trials comparing
A meta-analysis of older trials reported 18 deaths amongst different rate control strategies, including:
patients assigned to control compared to 9 assigned to ablation.74
In summary, the data suggesting that a rhythm rather than a (i) high- vs. low-dose beta-blocker;
rate control strategy is superior is not robust for patients with (ii) addition of digoxin to beta-blockers. The ongoing
persistent AF. The trials were not blinded and the patients highly DIGIT-HF (DIGitoxin to Improve ouTcomes in patients
selected. Further trials are required. with advanced chronic Heart Failure) trial includes
Several trials show that bi-ventricular pacing is superior to patients with AF, but excludes patients in need of rate
right ventricular pacing after AV node ablation.75 This may reflect control with digitalis glycosides.78
the deleterious effects of right ventricular pacing rather than any
benefit of bi-ventricular pacing. The landmark trials all required 5 There is also a need for randomized controlled trials investi-
patients to be in sinus rhythm. CRT may require AV as well as gating:
bi-ventricular resynchronization to be effective. A small, (n = 102)
unblinded trial comparing AV node ablation with pharmacological (i) new agents for pharmacological rhythm control
treatment suggested benefit to the ablation strategy but there (double-blind vs. placebo);
were too few events to be convincing.76 Accordingly, the consensus (ii) prevention of AF (double-blind vs. placebo);
opinion was to avoid this strategy until more evidence of benefit is (iii) better treatments to prevent AF recurrence
obtained. (double-blind vs. placebo).
Although AV node ablation will increase bi-ventricular capture,
there is no evidence from adequately designed randomized con-
trolled trials that this improves patient well-being or outcome.77 MitraClip
Practical comments. Ensure that the patient is receiving an effec- Referral of patients with HF and secondary (i.e. functional) mitral
tive anticoagulant regimen. The optimal resting ventricular rate regurgitation to a multidisciplinary HF team that will decide on
for patients with HF and AF may be 70–90 bpm. Antiarrhyth- management is recommended.
mic agents should generally be avoided other than to control Reduction in mitral regurgitation using a MitraClip device may
symptomatic paroxysmal AF; PV ablation may be a better strat- be considered for patients with HFrEF who fulfil the COAPT (Car-
egy than amiodarone/dronedarone, the latter is contraindicated diovascular Outcomes Assessment of the MitraClip Percutaneous
in HF. Ablation is best reserved for patients with paroxysmal AF Therapy for Heart Failure Patients With Functional Mitral Regur-
where episodes cause marked worsening of symptoms despite gitation) selection criteria (Table 3).79
guideline-recommended therapy at optimal doses. There is little
evidence of benefit from CRT in the absence of sinus rhythm or that Supporting evidence. The MITRA-FR (Multicentre Study of Percuta-
AV node ablation to increase bi-ventricular capture improves out- neous Mitral Valve Repair MitraClip Device in Patients With Severe
comes. AV node ablation should be an intervention of last resort. Secondary Mitral Regurgitation)80 and COAPT79 trials (recruiting
PV ablation to restore sinus rhythm is preferred in patients with 303 and 614 patients, respectively) included different populations
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Table 3 Inclusion/exclusion criteria from the COAPT trial87
Inclusion criteria (all must be present)

1 Symptomatic secondary mitral regurgitation (3+ or 4+ by independent echocardiographic core laboratory assessment) due to cardiomyopathy of either ischaemic
or non-ischaemic aetiology
2 Subject has been adequately treated per applicable standards, including for coronary artery disease, left ventricular dysfunction, mitral regurgitation and heart
failure
3 New York Heart Association functional class II, III or ambulatory IV
4 Subject has had at least one hospitalization for heart failure in the 12 months prior to enrolment and/or a correcteda BNP ≥300 pg/mL or a correcteda
NT-proBNP ≥1500 pg/mL
5 Local heart team has determined that mitral valve surgery will not be offered as a treatment option, even if the subject is randomized to the control group
6 Left ventricular ejection fraction ≥20% and ≤50%
7 Left ventricular end-systolic dimension ≤70 mm
8 The primary regurgitant jet is non-commissural, and in the opinion of the MitraClip implanting investigator can successfully be treated by the MitraClip (if a
secondary jet exists, it must be considered clinically insignificant)
9 Creatine kinase-MB obtained within prior 14 days is less than the local laboratory upper limit of normal
10 Transseptal catheterization and femoral vein access is feasible per the MitraClip implanting investigator
11 Age ≥18 years
12 Subject or guardian agrees to all provisions of the protocol, including the possibility of randomization to the control group and returning for all required
post-procedure follow-up visits, and has provided written informed consent
Exclusion criteria (all must be absent)
1 Untreated clinically significant coronary artery disease requiring revascularization
2 CABG, PCI, or TAVR within the prior 30 days
3 Aortic or tricuspid valve disease requiring surgery or transcatheter intervention
4 COPD requiring continuous home oxygen therapy or chronic outpatient oral steroid use
5 Cerebrovascular accident within prior 30 days
6 Severe symptomatic carotid stenosis (>70% by ultrasound)
7 Carotid surgery or stenting within prior 30 days
8 ACC/AHA Stage D heart failure
9 Presence of any of the following: estimated PASP >70 mmHg assessed by site based on echocardiography or right heart catheterization, unless active vasodilator
therapy in the cath lab is able to reduce PVR to <3 Wood Units or between 3 and 4.5 Wood Units with v wave less than twice the mean of PCWP
10 Hypertrophic cardiomyopathy, restrictive cardiomyopathy, constrictive pericarditis, or any other structural heart disease causing heart failure other than dilated
cardiomyopathy of either ischaemic or non-ischaemic aetiology
11 Infiltrative cardiomyopathies (e.g. amyloidosis, haemochromatosis, sarcoidosis)
12 Haemodynamic instability requiring inotropic support or mechanical heart assistance
13 Physical evidence of right-sided congestive heart failure with echocardiographic evidence of moderate or severe right ventricular dysfunction
14 Implant of CRT or CRT-D within the last 30 days
15 Mitral valve orifice area <4.0 cm2 by site-assessed transthoracic echocardiography
16 Leaflet anatomy which may preclude MitraClip implantation, proper MitraClip positioning on the leaflets, or sufficient reduction in mitral regurgitation by the
MitraClip
17 Haemodynamic instability defined as systolic pressure <90 mmHg with or without afterload reduction, cardiogenic shock, or the need for inotropic support or
intra-aortic balloon pump or other haemodynamic support device
18 Need for emergent or urgent surgery for any reason or any planned cardiac surgery within the next 12 months
19 Life expectancy <12 months due to non-cardiac conditions
20 Modified Rankin Scale ≥4 disability
21 Status 1 heart transplant or prior orthotopic heart transplantation
22 Prior mitral valve leaflet surgery or any currently implanted prosthetic mitral valve, or any prior transcatheter mitral valve procedure
23 Echocardiographic evidence of intracardiac mass, thrombus, or vegetation
24 Active endocarditis or active rheumatic heart disease or leaflets degenerated from rheumatic disease (i.e. non-compliant, perforated)
25 Active infections requiring current antibiotic therapy
26 Transoesophageal echocardiography is contraindicated or high risk
27 Known hypersensitivity or contraindication to procedural medications which cannot be adequately managed medically
28 Pregnant or planning pregnancy within the next 12 months
29 Currently participating in an investigational drug or another device study that has not reached its primary endpoint
30 Subject belongs to a vulnerable population or has any disorder that compromises his/her ability to give written informed consent and/or to comply with study
procedures
ACC, American College of Cardiology; AHA, American Heart Association; BNP, B-type natriuretic peptide; CABG, coronary artery bypass graft; COPD, chronic obstructive pulmonary disease; CRT,
cardiac resynchronization therapy; CRT-D, cardiac resynchronization therapy with defibrillator; NT-proBNP, N-terminal pro-B-type natriuretic peptide; PASP, pulmonary artery systolic pressure; PCI,
percutaneous coronary intervention; PCWP, pulmonary capillary wedge pressure; PVR, pulmonary vascular resistance; TAVR, transcatheter aortic valve replacement.
a ‘Corrected’ refers to a 4% reduction in the BNP or NT-proBNP cutoff for every increase of 1 kg/m2 in body mass index above a reference of 20 kg/m2 .
and reported very different results on the clinical efficacy of Mitr- beta-blockers (93% vs. 87%, P = 0.02). In COAPT, the baseline LVEF
..................
aClip. In COAPT, patients assigned to MitraClip were more likely was 31% (vs. 33% in MITRA-FR), the left ventricular end-diastolic
to be prescribed ACE-I, ARB or angiotensin receptor–neprilysin diameter was 62 ± 7 mm (vs. 68 ± 8 mm in MITRA-FR), and the
inhibitor (ARNI) at baseline (72% compared to 63%, P = 0.02). By effective regurgitant orifice area was on average 40 ± 15 mm2 (vs.
12 months this difference had increased (77% compared to 63%, 31 ± 10 mm2 in MITRA-FR). Over 24 months, COAPT reduced HF
P = 0.002) and more patients assigned to MitraClip were receiving hospitalizations by 47% (P < 0.001) and all-cause mortality by 38%
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(P < 0.001) and improved average 6 min-walking test distance by for PNS for the treatment of severe CSA. However, the ran-
........................................................................................................................................................................
>50 m (P < 0.001). Over a follow-up of 12 months, no such bene- domized trial included only 151 patients (73 assigned to PNS)
fits were observed in MITRA-FR. However, the outcomes of these of whom only 96 had HF (48 assigned to PNS – and per-
two trials at 1 year were not statistically different.7 Longer-term haps only half of these had HFrEF) and follow-up was for only
follow-up for the MITRA-FR trial might reveal a deferred benefit. 6 months. PNS improved apnoea-hypopnoea index and symptoms,
although blinding may have been imperfect; two deaths occurred in
Practical comments. If interventional therapy is considered, a multi- each group.
disciplinary team involving HF specialists, interventionalists, imag-
ing experts and cardiac surgeons should be involved in patient Practical comments. Phrenic nerve stimulation received FDA
evaluation and decision making. Medical therapy should be opti- approval in 2018 and is also reimbursed in a number of Euro-
mized before deciding on intervention. Treatment with sacubi- pean countries. Further clinical trials are required before making
tril/valsartan for HFrEF may also be of some importance as demon- positive recommendations. The learning curve for this new thera-
strated recently in the PRIME (Pharmacological Reduction of Func- peutic approach is considered to be 3–10 cases for experienced
tional, Ischaemic Mitral Regurgitation) trial.81 Of note, the PRIME interventionalists. Patients can on occasion feel the stimulation,
study was a small (n = 118) double-blind randomized controlled an effect which reduces over a few weeks. The device is designed
trial comparing sacubitril/valsartan to valsartan alone in HF patients to stimulate only during sleep, thereby reducing the chance of
with chronic functional mitral regurgitation. The primary endpoint, ongoing stimulation awareness.
the reduction in echo-derived effective regurgitant orifice area, was
reached at a borderline level of significance (−0.058 ± 0.095 vs. Directions for future development. The prevalence of CSA to some
−0.018 ± 0.105 cm2 ; P = 0.032). The trial was too small to show degree depends on the disease definition and HF severity. A study
any clinical benefits and echo-derived parameters of mitral regurgi- to investigate the impact on morbidity and mortality of PNS is
tation severity are not considered to constitute evidence of clinical required before making recommendations for broader use in the
benefit. The ratio of the severity of mitral regurgitation to the HF population.
severity of left ventricular dilatation may be a key determinant of
the response to mitral valve repair; patients with disproportion-
Cardiac contractility modulation
ately severe mitral regurgitation may benefit more.
Directions for future development. The Reshape-HF2 trial Cardiac contractility modulation (CCM) may be considered in
(NCT02444338) is ongoing and will have more patient-year patients with HFrEF (LVEF 25–45%) and a narrow QRS complex
follow-up than either published trial. (<130 ms) in order to improve exercise capacity, quality of life and
alleviate HF symptoms.
Treatment of central sleep apnoea Supporting evidence. In the FiX-HF 5C (Evaluate Safety and Efficacy
Consensus recommendation of the OPTIMIZER® System in Subjects With Moderate-to-Severe
Heart Failure) trial,84 CCM increased peak oxygen uptake by 0.84
Patients with HF and suspected sleep apnoea who are being con-
[95% Bayesian credible interval: 0.123–1.552 mL O2 /kg/min (the
sidered for positive pressure airway mask therapy are recommended
primary endpoint), and the Minnesota Living With Heart Failure
to undergo a specialized sleep study in order to diagnose the char-
questionnaire] (P < 0.001), NYHA functional class (P < 0.001), and
acteristics of the sleep apnoea present, in particular whether the
6-min hall walk (P = 0.02). This trial used an FDA-approved design
sleep apnoea is predominantly obstructive or central in nature.
and analysis to confirm the results on an earlier subgroup analysis.
In patients with predominantly central sleep apnoea (CSA)
Although its limitations, i.e. the unblinded nature, and a small sam-
and concomitant HFrEF, evidence is insufficient to recommend
ple size (160 patients), with short follow-up duration (24 weeks),
CSA therapy for any putative benefit in HF itself, and treatments
not powered to look at outcomes, the point-estimate showed
directed at CSA should be reviewed and avoided, unless compelling
the composite of CV death and HF hospitalizations reduced from
symptomatic indications for treatment of CSA exist, in which
10.8% to 2.9% (P = 0.048).
case positive pressure airway mask therapy should be avoided and
phrenic nerve stimulation (PNS) may be considered as an alternative.
Practical comments. Cardiac contractility modulation is now
Supporting evidence. HFrEF patients with predominantly CSA suf- approved in the USA and Europe. CCM may be used to improve
fered an increase in mortality in SERVE-HF (Treatment of Pre- symptoms and exercise capacity in selected HFrEF patients with
dominant Central Sleep Apnoea by Adaptive Servo Ventilation troublesome symptoms despite pharmacological therapy who
in Patients With Heart Failure),82 so that it is essential to have a QRS duration of <130 ms and are therefore not indicated
know if such patients have CSA prior to starting positive air- for CRT.
way pressure therapy. One small trial [Pivotal (A Randomized
Trial Evaluating the Safety and Effectiveness of the remedē® Sys- Directions for future development. A study to investigate the impact
tem in Patients With Central Sleep Apnea)]83 showed promise of CCM on morbidity and mortality is being planned.
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Mechanical ventricular assist devices Salt/sodium intake
........................................................................................................................................................................
Consensus recommendation Consensus recommendation
There is limited evidence to make new recommendations. For There is no robust new evidence on the benefits of manipulating
patients with advanced HF that are considered for implantation salt intake on clinical status amongst either outpatients or inpa-
of a HeartMate left ventricular assist device, a HeartMate 3 rather tients.
than HeartMate II device should be considered.
Supporting evidence. A recent systematic review90 identified nine
Supporting evidence. ROADMAP (Risk Assessment and Compara- trials involving 479 unique participants, none including more than
tive Effectiveness of Left Ventricular Assist Device and Medical 100 patients; results were inconclusive. Although there was a
Management)85 tested the HeartMate II vs. optimized medical ther- trend toward improvement in the clinical signs and symptoms
apy as destination therapy. No difference for survival was found, but of HF with reduced intake of dietary salt, no clinically relevant
use of HeartMate II was associated with better functional capacity data on whether reduced dietary salt intake affected outcomes
and quality of life. ENDURANCE (The HeartWare™ Ventricular such as CV-associated or all-cause mortality, CV-associated events,
Assist System as Destination Therapy of Advanced Heart Failure)86 hospitalization, or length of hospital stay were found.
tested the HeartMate HVAD system vs. HeartMate II in patients
with advanced HF eligible for heart transplantation, and showed Directions for future development. Several trials investigating salt
non-inferiority for the HVAD system; however, stroke and device restriction in HF are in progress. Sodium, chloride and water bal-
malfunction rates were increased with this system. MOMENTUM 3 ance are all important. Oedema and congestion are volumetrically
(Multi-center Study of MagLev Technology in Patients Undergoing mainly due to water. Many patients with severe HF have hypona-
MCS Therapy With HeartMate 3™ IDE Clinical Study)87 is a piv- traemia. Ensuring that net loss of water exceeds that of salt may
otal trial for HeartMate 3 vs. HeartMate II. Use of HeartMate 3 was be important for the management of oedema. Well-designed, ade-
associated with better 2-year survival and fewer adverse events. quately powered studies are needed to reduce uncertainty about
sodium restriction in HF patients.
Disease management and lifestyle

Exercise-based cardiac rehabilitation
Multidisciplinary heart failure Consensus recommendation
management programmes It is recommended that patients with HFrEF are enrolled in an
Consensus recommendation exercise-based cardiac rehabilitation programme to reduce the risk
As already stated in the 2016 ESC HF guidelines, it is recom- of HF hospitalization.
mended that HF patients are enrolled in a multidisciplinary HF
management programme. Both home-based and clinic-based pro- Supporting evidence. A new meta-analysis91 and an updated
grammes can improve outcomes. Self-management strategies are Cochrane meta-analysis92 identified 44 trials that included 5783
encouraged. people with HFrEF and both showed that exercise rehabilitation
reduced hospital admissions overall, as well as for HF. The effect
Supporting evidence. Although evidence on the effectiveness of on health-related quality of life is uncertain due to lower-quality
multidisciplinary HF management programmes was established evidence. However, neither the participants nor the investigators
in the 2016 guidelines,8 new studies have been published since were blind to intervention and many older patients with HF will
then, often investigating the optimal components and intensity have been excluded due to their inability to comply with trial
of these programmes. In 2017, van Spall et al.88 published a net- requirements.
work meta-analysis of 53 randomized controlled trials, conclud-
ing that both nurse home visits and disease management clin- Directions for future development. Further evidence is needed to
ics reduced all-cause mortality compared to usual care; nurse show whether exercise rehabilitation benefits older, frailer patients
home visits being most effective. Jonkman et al.89 published an IPD and those with HFpEF (currently under investigation) as well as
meta-analysis of 20 studies, including 5624 patients, and concluded the impact of and alternative delivery settings including home- and
that self-management interventions in HF patients improve out- using technology-based programmes.93
comes despite heterogeneity, diversity in intensity, content and
personnel who deliver the intervention.
Telemedicine
Directions for future development. Studies addressing the benefits Consensus recommendation
of multidisciplinary HF disease management programmes, bar- Home telemonitoring using an approach that is similar to the one
riers and opportunities for their implementation and interac- used in TIM-HF2 (Telemedical Interventional Management in Heart
tions and synergies with a variety of health care systems would Failure II) may be considered for patients with HF in order to reduce
be valuable. the risk recurrent CV and HF hospitalizations and CV death.
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Supporting evidence. The TIM-HF2 trial94 included 1571 patients Servier, Berlin-Chemie, Boehringer Ingelheim, Pfizer, AstraZeneca.
........................................................................................................................................................................
and demonstrated that remote telemonitoring including home M.S.A. reports personal fees from Servier. M.L. reports personal
assessment of weight, blood pressure, electrocardiogram and gen- fees from Novartis, Pfizer, Boehringer Ingelheim, AstraZeneca
eral health status in the context of a 24/7 support system, reduced and Vifor, grant support from Roche Diagnostics. B.S.L. reports
the proportion of days lost due to unplanned CV (mainly HF) research grants and contracts from MSD, Vifor, AstraZeneca,
hospitalizations or death (P = 0.046). This study also documented Pfizer, Kowa. T.McD. reports honoraria from Bayer, Novartis,
a reduction in all-cause mortality for patients managed using Pfizer and Vifor. M.M. reports honoraria from Bayer, Novartis and
telemedicine (HR 0.70; P = 0.028). Servier for participation in trials’ committees and advisory boards.
Of note, through an oversight, the 2016 ESC guidelines8 failed W.M. reports research grants from Novartis, Vifor, Medtronic,
to refer to a systematic Cochrane review of home telemonitoring Biotronik, Abbott and Boston Scientific. A.V. reports consultancy
published in late 2015 (after the guideline had done its major fees and/or research grants from Amgen, Applied Therapeutics.
literature search). This Cochrane review95 identified 25 relevant AstraZeneca, Bayer, Boehringer Ingelheim, Cytokinetics, GSK,
trials and found that telemonitoring reduced all-cause mortality by Myokardia, Novartis, Roche Diagnostics, Servier. G.F. participated
about 20% and HF hospitalization by about 30%. in committees of trials and registries sponsored by Medtronic, BI,
Novartis, Vifor, Servier. A.J.S.C. reports for the last 3 years hon-
Practical comments. Home telemonitoring may be used to enhance oraria and/or lecture fees from AstraZeneca, Menarini, Novartis,
patient education and motivation and delivery of care but must Nutricia, Respicardia, Servier, Stealth Peptides, Vifor, Actimed,
be adapted to work in synergy with existing health care provision. Faraday, and WL Gore. The other authors have nothing to disclose.
Remote monitoring should not be impersonal. As with many inter-
ventions, the cost/benefit ratio needs to be adequately assessed.
Supplementary Information
Directions for future development. Further research is required and Additional supporting information may be found online in the
will be facilitated by advances in sensor and communication tech- Supporting Information section at the end of the article.
nology, smart algorithms and machine-learning and the growing Table S1. List of consensus recommendations regarding the
number of effective interventions that require monitoring. The management of patients with heart failure: pharmacotherapy.
TIM-HF2 intervention protocol should be tested in other countries Table S2. List of consensus recommendations regarding the
and different health care systems. management of patients with heart failure: interventions, devices,
and management strategies.
Conflict of interest: P.P. reports personal fees for consul-
tancy and honoraria for lectures from Vifor Pharma, Novartis,
Boehringer Ingelheim, Respicardia, and AstraZeneca. S.D.A.
reports grant support and personal fees from Vifor, grant sup-
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doi:10.1002/ejhf.1611
Heart Failure Association/European Society

of Cardiology position paper on frailty in
patients with heart failure
Cristiana Vitale1*, Ewa Jankowska2, Loreena Hill3, Massimo Piepoli4,5,
Wolfram Doehner6, Stefan D. Anker7, Mitja Lainscak8, Tiny Jaarsma9,
Piotr Ponikowski2, Giuseppe M.C. Rosano1, Petar Seferovic10, and Andrew J. Coats1
1 Centre for Clinical and Basic Research, Department of Medical Sciences, IRCCS San Raffaele Pisana, Rome, Italy; 2 Department of Heart Diseases, Wroclaw Medical University,
Centre for Heart Diseases, Military Hospital, Wroclaw, Poland; 3 School of Nursing and Midwifery, Queen’s University, Belfast, UK; 4 Heart Failure Unit, Cardiology, Guglielmo da
Saliceto Hospital, Piacenza, Italy; 5 Institute of Life Sciences, Scuola Superiore Sant’Anna, Sant’Anna School of Advanced Studies, Pisa, Italy; 6 Department of Cardiology (Virchow
Klinikum), German Centre for Cardiovascular Research (DZHK), partner site Berlin, and BCRT - Berlin Institute of Health Center for Regenerative Therapies, and Center for
Stroke Research Berlin, Charité Universitätsmedizin Berlin, Berlin, Germany; 7 Department of Cardiology (CVK); and Berlin Institute of Health Center for Regenerative Therapies
(BCRT); German Centre for Cardiovascular Research (DZHK) partner site Berlin, Charité Universitätsmedizin Berlin, Berlin, Germany; 8 Faculty of Medicine, University of
Ljubljana and Department of Internal Medicine, General Hospital Murska Sobota, Ljubljana, Slovenia; 9 Facutly of Medical and Health sciences, Linköping University, Linköping,
Sweden; and 10 Faculty of Medicine, University Medical Center Belgrade, Belgrade, Serbia
Received 30 March 2019; revised 17 June 2019; accepted 11 August 2019 ; online publish-ahead-of-print 23 October 2019
Heart failure (HF) and frailty are two distinct yet commonly associated conditions. The interplay between the two conditions is complex, due
to overlaps in underlying mechanisms, symptoms and prognosis. The assessment of frailty in patients with HF is crucial, as it is associated with
both unfavourable outcomes and reduced access and tolerance to treatments. However, to date a consensus definition of frailty in patients
with HF remains lacking and the need for a validated assessment score, for identifying those HF patients with frailty, is high and timely. This
position paper proposes a new definition of frailty for use by healthcare professionals in the setting of HF and creates a foundation for the
design of a tailored and validated score for this common condition.
..........................................................................................................
Keywords Heart failure • Frailty • Aging • Instruments • Score
Introduction (ii) to build a common understanding concerning the importance

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of the assessment of frailty in HF patients; (iii) to identify the main

The European Society of Cardiology (ESC) guidelines on heart domains of a new score, the HFA Frailty Score, specifically tailored
failure (HF) suggest that healthcare professionals should ‘monitor for HF patients.
frailty and seek and address reversible causes (cardiovascular and Although the concept of frailty is extensively used, in clinical
non-cardiovascular) of deterioration in frailty score in elderly and research settings, an internationally accepted definition is
patients’.1 The increasing evidence concerning the importance of still lacking and there is no agreement on which is the best
frailty in HF patients and the lack of a validated instrument to method or instrument to assess frailty. Several definitions of
correctly identify it have both highlighted the need for a position frailty and a plethora of different instruments have been used
paper to improve clarity on the role of frailty in HF. for the identification of frailty within a variety of disease states
This executive document reflects the key points of a meeting and settings.2–8 This has limited the possibility not only to ‘speak
organised by the Heart Failure Association (HFA) of the ESC on a common language’ and to compare the results from different
the topic ‘Frailty in heart failure’. Aims of this meeting were: (i) studies, but has challenged the possibility for correct diagnosis
to identify a consensus definition of frailty in patients with HF; and interventions. In addition, the lack of a gold standard method
*Corresponding author. Centre for Clinical & Basic Research, IRCCS San Raffaele Pisana, Via della Pisana 235, 00163 Rome, Italy. Tel: +39 06 52252409, Fax: +39 06 52255567,
Email: cristiana.vitale@gmail.com
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1300 C. Vitale et al.
Figure 1 The four main domains – clinical, physical-functional, cognitive-psychological, and social – defining the Heart Failure Association
(HFA) Frailty Score. Reversible and/or treatable variables are identified by asterisks. ADL, activities of daily living; HF, heart failure; IADL,
instrumental activities of daily living. Adapted from Gorodeski et al.9
and the inconvenience of using a number of available assessment be incorporated as determinants of the proposed new HF frailty
............................................................................
instruments (due to time, availability of special equipment, patient score as they well reflect the holistic approach of the HFA score.
limitations, etc.) have limited the routine assessment of frailty in
daily practice. This has facilitated the use of the clinical subjective
judgments (eyeball test or foot-of-the-bed assessment) to define Overview of frailty definition
frailty in busy HF clinical settings.2 and assessment tools
The presence of a complex overlap between frailty and HF, the
Frailty is commonly considered a biologic or geriatric syndrome
emerging and increasing data on the prognostic role of frailty as
characterised by a state of increased vulnerability to endogenous
well as the interference of frailty with the possible treatments for
and exogenous stressors, due to age-related declines in physio-
HF patients form the basis for the need of a validated diagnostic
logic reserve and function across multiple physiologic systems.4
and predictive assessment score tailored for patients with HF.
This increased vulnerability contributes to higher risk of falls, insti-
As the HFA strongly believes that a holistic approach is more tutionalisation, disability, and death.
reliable than the physical approach in recognising those patients Although several conceptual definitions of frailty have been used
with HF that are also frail, it convened a workshop to both devise in medicine, the available instruments to evaluate frailty derive from
a new definition of frailty in HF and to design a new HF frailty two basic concepts of frailty: the physical frailty phenotype4 and the
assessment score, the HFA Frailty Score. cumulative deficit model.5,6
This new score has been built considering four The physical frailty phenotype, proposed and validated by Fried
domains – clinical, physical-functional, cognitive-psychological and colleagues in community dwelling older adults in the Cardiovas-
and social – as the main determinants of frailty in HF patients cular Health Study,4 described frailty as a biological syndrome that
(Figure 1). causes age-related physical decline, in which three or more of the
These four domains have been suggested by Gorodeski and following physical components are present: unintentional weight
colleagues9 as the main contributors of health outcomes to con- loss [>10 lbs (4.5 kgs) in the last year]; self-reported exhaustion;
sider in older adults with HF. However, although Gorodeski and weakness (reduced handgrip strength); slow walking speed (time
colleagues consider frailty as only one of the determinant of the in seconds – usual pace – over 15 ft); low self-reported physical
physical domain, HFA believe that all these four domains have to activity. A pre-frail status is accordingly when one or two criteria
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Frailty in heart failure 1301
are present, identifying an individual at high risk of progressing to Conversely to what it may be thought, frailty seems more
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frailty. common in patients with HF with preserved ejection fraction
The cumulative deficit model, proposed and validated by Rock- (HFpEF) than in those with reduced ejection fraction (HFrEF), this
wood and colleagues in community dwelling older adults in the possibly related to the greater burden of cardiac and non-cardiac
Canadian Study of Health and Aging,5,6 described frailty as a state co-morbidities typically experienced by patients with HFpEF.22
of vulnerability, resulting from an accumulation of a range of indi- The relation between the New York Heart Association func-
vidual impairments and conditions, thus creating a frailty index. The tional class and the prevalence of frailty is not clear as some studies
deficit model is a more comprehensive instrument than the frailty found a poor association4,19,23 while others a linear correlation.18,24
phenotype. According to a multidimensional (holistic) approach, This can be probably related to the methods used for the assess-
it assesses the accumulation of health deficits across multiple ment of frailty.
domains, such as cognition, activities of daily living, co-morbid dis- The overlap between frailty and HF is complex and each syn-
eases, deficits of social relations and social support, or abnormal drome may mimic the other. Although the precise mechanisms of
laboratory results. All these health deficits interact with each other, frailty in HF have not been fully elucidated, HF patients share with
with still not adequately understood mechanisms, to determine the frail patients pathophysiological, clinical and non-clinical aspects,
occurrence of frailty. The frailty index is expressed as a ratio of which have important consequences for their prognosis and man-
health deficits present to the total number of deficits considered; agement.
the greater the number of health deficits, the higher the degree of
frailty.
Although both the Fried phenotype and the cumulative index
Pathophysiology
definitions have been widely used and have demonstrated their Pathophysiological pathways common to both HF and frailty
predictive value, their routine use in the daily practice is limited appear to involve a multisystem cascade that includes disorders
by major weaknesses. Among these, the difficulty in defining the and dysregulation in neuro-hormonal, metabolic, inflammatory,
unintentional weight loss in patients taking diuretics or the possible and immunologic pathways. This cascade leads to an enhanced
floor effect related to the instrument focused on physical frailty can catabolic state, energy failure, oxidative stress, and release of
be particularly relevant in patients with HF (Table 1). pro-inflammatory signals.25–27 The up-regulation of inflammatory
In an attempt to overcome these weaknesses, several other biomarkers impairs hormones, such as cortisol and growth hor-
instruments have been developed over time, through changing, mone, which contributes to downstream effects and leads to
omitting or adding criteria to one or the other of these two an enhanced catabolic state, thus favouring the occurrence of
conceptual definitions or using single components of the physical frailty.
frailty phenotype.2–17 The main characteristics and limitations of The imbalance between anabolic and catabolic state in HF may
the main frailty assessment instruments used in HF patients are also exacerbate the decline in muscle mass and strength, favouring
shown in Table 1. the occurrence of sarcopenia, cachexia, and frailty.
Recently, Sze et al.,18 comparing three of the main frailty instru- However, the multiple complex and interrelated pathogenic
ments (Fried phenotype, Deficit Index and Edmonton Frailty Score) mechanisms that adversely affect frailty and HF remain poorly
used in HF, found that fewer than half of those patients classified understood and cannot be limited only to the physical conse-
as frail with one of the frailty instruments were similarly classified quences of frailty.
as frail when all the three different instruments were used simul-
taneously. This reinforces the need for a new instrument to better
Clinical aspects
identify frail patients with HF.
The typical clinical aspects of HF, especially in its advanced stages,
overlap considerably with the manifestations of ‘physical’ frailty:
Frailty in heart failure exercise intolerance, weakness, fatigue, and exhaustion. Reduced
lean muscle mass (sarcopenia) and sometimes cachexia may be
Frailty is more prevalent in HF than the general population. The associated with both conditions.28
estimated overall prevalence of frailty in HF is around 45%, with a Nevertheless, physical impairment, often considered a synony-
lower prevalence in studies using the physical frailty assessment mous of frailty, is only one of the aspects characterising frailty and
tool compared to those using the cumulative deficit approach several other clinical and non-clinical conditions, such as depres-
(42.9% vs. 47.4%).19 Patients with HF are up to six times more sion, cognitive impairment, malnutrition, anaemia, dependency, iso-
likely to be frail, and frail people have a significantly increased risk lation and/or lack of social support are commonly found in both HF
of developing HF.20,21 and frail patients.
Although both frailty and HF are common in older adults, the
prevalence of frailty in patients with HF is independent of age, as
frailty can be experienced also by younger (<60 years) patients with Prognosis
HF.20 This suggests that frailty in HF patients is not solely related The presence of frailty has a negative impact on the prognosis of
to, and it is in fact additive to, the progressive age-related decline patients with HF. Frailty accelerates the progression of HF and
in physiological reserve. increases morbidity and mortality in these patients.24,29–31 Frailty
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Table 1 Main instruments to identify frailty in heart failure
Frailty assessment instrument Characteristics Limitations in HF patients

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Physical frailty
Fried’s Frailty Phenotype (FP)4 Five physical components of frailty: weakness (handgrip - Only focus on physical frailty
dynamometer); slow walking speed (5 m gait speed); - Need of dynamometer
exhaustion; unintentional weight loss; - Possible floor effect in HF patients
low physical activity - Difficulty in assessing unintentional weight
loss in HF patients taking diuretics
Single item or modified version - Single-item components of the FP - Only focus on physical frailty
of FP9–11 - Modified FP: i.e. 3 m gait speed, self-reported measures of - Possible need of dynamometer
appetite instead of weight loss - Possible floor effect in HF patients
- High misclassification rate
Short Physical Performance Encompasses slowness, weakness, and balance measured by a - Only focus on physical frailty
Battery (SPPB)12,13 series of three timed physical performance tests (gait speed, - Possible floor effect in HF patients
chair stand test, and tandem balance)
Multidimensional frailty
Frailty Index of Accumulative - Assessed through the accumulation of health deficits across - Time consuming for routine use
Deficits (FI-CD) (Rockwood’s multiple domains, such as cognition, activities of daily living, - Value expressed as a ratio of health deficits
approach)6 co-morbid diseases, deficits of social relations and social present to the total number of deficits
FI-CGA14 support, or abnormal laboratory results considered
- Frailty index derived from clinical records or the Comprehensive
Geriatric Assessment (FI-CGA) performed in elderly people
Canadian Study of Health and Seven-point frailty scale with a written description of frailty based - Semi-quantitative and based on clinical
Aging Clinical Frailty Scale on disability for basic and instrumental activities of daily living, judgement
(CSHA-CFS)6,15 mobility, activity, energy, and disease-related symptoms and - Heavily influenced by the patient’s level of
complemented by a visual chart to assist with the classification disability
of frailty based on clinical judgement - Possible floor effect in HF patients
Edmonton Frailty Scale (EFS)16 Contains nine components: cognition (clock test), general health - Low sensitivity
status (number of hospitalisation in the last year), functional - Risk of misclassification
independence, social support, medication use, nutrition
(weight loss), mood, continence, functional performance
(timed get up and go)
- It is a simplified multidimensional frailty assessment tool
HF, heart failure.
contributes to a higher risk of mortality at 1 year, increased HF shown in patients referred for heart transplantation or left ventric-
...........................................................
hospitalisations with longer bed days in hospital, and a decreased ular assist device implantation.11,35–38
probability of surviving more than 10 years. Therefore, frailty is a strong and independent predictor of nega-
In addition, frailty reduces the resistance of patients with HF tive outcomes and is associated with greater healthcare utilisation
to myocardial ischaemia, pressure and volume overload, and it in HF patients.39
also increases the risk of arrhythmias, causing decompensation and The addition of the frailty score to the Meta-analysis Global
rapid functional deterioration.32,33 Group in Chronic HF (MAGGIC) risk score, one of the most
The physical components of frailty are not the only recognised as predictive scores in HF,40 results in a significant improvement in risk
negatively affecting the outcomes of HF patients. The OPERA-HF classification of HF patients,41 thus suggesting that frailty defines a
(Observational registry to assess and PrEdict the in-patient course, risk not yet captured by traditional risk scores.
risk of Re-Admission and mortality for patients hospitalized for
or with Heart Failure) study has shown that psycho-social factors,
such as depression or anxiety, cognitive impairment and living alone Treatment
are all strongly associated with negative near-term outcomes in The presence of frailty in patients with HF, especially in those with
patients with HF, such as unplanned recurrent readmissions, 30-day advanced HF, has an unfavourable impact on the range of possible
outcome after an admission for HF, and mortality following an treatments and interventional options. Due to the increased risk
admission to hospital for HF.34 of adverse events and negative outcomes, some interventions
Furthermore, in advanced HF, frailty is an independent pre- (i.e. devices, transplantation, etc.) can become under-utilised for
dictor of increased all-cause mortality and adverse outcomes those patients with advanced HF that are frail. In this perspec-
(longer recovery time and increased risk for rehospitalisation), as tive, similar to ageism,42 a diagnosis of frailty may become a
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discriminative factor (‘frailtyism’ – definable as a stereotyping, parameters that are modifiable or reversible may improve the out-
........................................................................................................................................................................
prejudice, and discrimination against people on the basis of the comes of frail HF patients.
presence of frailty) in the management of these patients, who are Physical frailty is only one of the domains of frailty and in
more likely to receive less standard HF treatments as a result. This patients with HF the use of this sole approach can result in patient
risk is also increased by the lack of evidence-based criteria to help misclassification due to a so-called floor effect. Functional lim-
and guide the management of HF patients with frailty. itations, due to decreased exercise tolerance and shortness of
Therefore, the use of an objective and easy to apply measure- breath, are common in HF patients and are influenced by HF
ment of frailty in clinical practice, rather than a ‘vague’ clinician’s severity and aging. As not all HF patients with reduced func-
subjective ‘doorway assessment’, will help clinicians to better iden- tional capacity are frail, other clinical and non-clinical domains
tify those HF patients that being effectively frail may face a higher require consideration to correctly identify those HF patients with
risk of negative outcomes. frailty.
Therefore, due to its prognostic and therapeutic implications, Therefore, the HFA Frailty Score has been built on four main
the identification of frailty is of uttermost importance in the daily domains – clinical, functional, psycho-cognitive and social – that
assessment and management of patients with HF. are considered the determinants of frailty in HF patients
(Figure 1).
The clinical domain takes into consideration the number and
Requirement for a new definition type of co-morbidities, as in HF patients some co-morbidities can
and a tailored assessment score have a higher prognostic weight than others and, therefore, greater
influence on the therapeutic decisions (i.e. use of class 1 drugs such
of frailty in heart failure as renin–angiotensin system inhibitors in some patients with severe
In patients with HF, frailty is perceived as a reversible/dynamic renal dysfunction, use of implantable cardioverter-defibrillator,
state of increased vulnerability to stressors in one or more clinical etc.).1 Co-morbidities, in turn, are associated with poly-therapy,
and non-clinical domains, with consequential negative outcomes increased risk of inappropriate prescribing, higher risk of adverse
and dire prognosis. The occurrence of a stressor (acute/chronic, events, falls, and hospitalisations. Therefore, as mentioned in the
internal/external), even though apparently insignificant for a healthy latest ESC HF guidelines the ‘management of co-morbidities is a
person, such as a minor acute infection, an imbalance in a ‘chronic’ key component of the holistic care of patients with HF’.1
disease, a new medication or a minor procedure,43 could poten- Although the presence of cognitive impairment and mood dis-
tially alter the precarious equilibrium within one or more domains turbances, such as depression, could have been generically con-
of the HF patients’ health status. This results in a disproportion- sidered as co-morbidities, due to their consequences on health
ate individual response or decompensation associated with nega- status, prognosis and weight in determining a frail status, they have
tive outcomes, such as increased morbidity, increased healthcare been included in a separate domain (psycho-cognitive domain). Both
use (hospitalisation, prolonged recovery, institutionalisation, etc.), cognitive impairment and depression may also contribute to poor
greater dependency, and higher risk of mortality. adherence, poor prognosis, and social isolation.
Although both frailty and HF are common in elderly patients In parallel physical impairment, often associated in HF patients
with prevalence increasing with age, frailty must not be considered with a global imbalance between the anabolic and catabolic state
neither as a ‘progressive age-related decline in physiological reserve that may lead to sarcopenia and, eventually, body wasting with
and function’ (according to the World Health Organisation)44 cachexia, can cause dependency, incapacity to perform activities of
nor as a ‘geriatric syndrome’. This is supported by the lack of daily living and/or instrumental activities of daily living, and higher
any unidirectional correlation between the prevalence of frailty in risk of falls. Therefore, the functional status of HF patients has been
HF patients and their age.7 All patients with HF, independent of identified as a separate domain (functional domain).
their chronological age, are at risk of frailty, but not all elderly Although the clinical and functional factors may have negative
patients with HF are inevitably frail. Consequently, chronological consequences on the social aspect of life, it is also true that
age cannot represent a parameter to guide the assessment of frailty, the presence of isolation and the lack of support (caregiver)
and all patients with HF should be evaluated for the presence of interfere with the access to care and can influence the progno-
frailty, independently of their age, in order to better stratify their sis of frail patients. Therefore, it has been identified as a social
risk. domain.
Therefore, the HFA suggest that frailty should be defined in The variables included in the four main domains, in turn, cause
patients with HF as a multidimensional dynamic state, independent a complex cascade of factors such as poly-therapy, dependency,
of age, that makes the individual with HF more vulnerable to the effect higher risk of hospitalisations, negative outcomes, and with some
of stressors. The dynamic interrelations of clinical and non-clinical variables overlapping across the four main domains. This overlap
conditions (multidimensional), that can be reversible (treatable) or reflects the holistic nature of frailty, involving the individual in all
irreversible (supportive care), interact each other to determine its entirety and suggests the possibility that the treatment of single
a state of vulnerability (frailty). This definition reflects two key variables can potentially reverse the status of vulnerability. This is
concepts: first in patients with HF, frailty can be better identified supported by the finding that the composite elements of the frailty
using a holistic multidimensional approach than the physical phe- phenotype have an incremental value in predicting mortality than
notype approach; second the identification and treatment of those the individual elements of frailty.41
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Frailty is a dynamic and partially reversible state, consist-
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Table 2 Characteristics of the proposed Heart Failure
ing of four main domains, some modifiable components beyond
Association Frailty Score
non-reversible ones. Recognising these components may guide
management and improve HF outcomes. An accurate assessment is
• Easy to use in busy clinical settings the first and crucial step for a tailored and individualised healthcare
• Quick to perform management programme in patients with HF and frailty.
Routine frailty assessment for HF patients should be included in
• No need for special equipment
daily clinical practice as the identification of frailty could help in risk
• Cheap
stratification, decision-making, design of an individualised patient
• Reliable: able to accurately identify heart failure patients that care plan, reduce/prevent negative outcomes, reduce health costs.
are frail in daily practice The HFA Frailty Score will be the first score specifically designed
• With minimal distress or concern caused to the patient for and validated within a HF population.
• Predictive: able to correlate with prognosis and predict
Conflict of interest: none declared.
adverse clinical outcomes
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doi:10.1002/ejhf.1673
European Society of Cardiology/Heart Failure

Association position paper on the role and
safety of new glucose-lowering drugs in
patients with heart failure
Petar M. Seferović1,2*, Andrew J.S. Coats3, Piotr Ponikowski4,
Gerasimos Filippatos5,6, Martin Huelsmann7, Pardeep S. Jhund8,
Marija M. Polovina1,9, Michel Komajda10, Jelena Seferović1,11, Ibrahim Sari12,
Francesco Cosentino13, Giuseppe Ambrosio14, Marco Metra15, Massimo Piepoli16,
Ovidiu Chioncel17,18, Lars H. Lund19, Thomas Thum20, Rudolf A. De Boer21,
Wilfried Mullens22,23, Yuri Lopatin24, Maurizio Volterrani25, Loreena Hill26,
Johann Bauersachs27, Alexander Lyon28, Mark C. Petrie29, Stefan Anker30,
and Giuseppe M.C. Rosano31
1 Faculty of Medicine, University of Belgrade, Belgrade, Serbia; 2 Serbian Academy of Sciences and Arts, Belgrade, Serbia; 3 Pharmacology, Centre of Clinical and Experimental
Medicine, IRCCS San Raffaele Pisana, Rome, Italy; 4 Centre for Heart Diseases, Wrocław Medical University, Wrocław, Poland; 5 University of Cyprus Medical School, Nicosia,
Cyprus; 6 Athens University Hospital Attikon, National and Kapodistrian University of Athens, Athens, Greece; 7 Division of Cardiology, Department of Medicine II, Medical
University of Vienna, Vienna, Austria; 8 British Heart Foundation, Cardiovascular Research Centre, University of Glasgow, Glasgow, UK; 9 Department of Cardiology, Clinical
Centre of Serbia, Belgrade, Serbia; 10 Institute of Cardiometabolism and Nutrition (ICAN), Pierre et Marie Curie University, Paris VI, La Pitié-Salpétrière Hospital, Paris, France;
11 Clinic for Endocrinology, Diabetes and Metabolic Disorders, Clinical Centre, Belgrade, Serbia; 12 Department of Cardiology, Faculty of Medicine, Marmara University, Istanbul,
Turkey; 13 Cardiology Unit, Department of Medicine, Karolinska Institute and Karolinska University Hospital, Stockholm, Sweden; 14 Division of Cardiology, University of Perugia,
Perugia, Italy; 15 Cardiology, Department of Medical and Surgical Specialties, Radiological Sciences, and Public Health, University of Brescia, Brescia, Italy; 16 Heart Failure Unit,
Cardiology, G. da Saliceto Hospital, Piacenza, Italy; 17 University of Medicine Carol Davila, Bucharest, Romania; 18 Emergency Institute for Cardiovascular Diseases, Bucharest,
Romania; 19 Department of Medicine, Karolinska Institutet, and Heart and Vascular Theme, Karolinska University Hospital, Stockholm, Sweden; 20 Hannover Medical School,
Institute of Molecular and Translational Therapeutic Strategies, Hannover, Germany; 21 Department of Cardiology, University Medical Center Groningen, University of Groningen,
Groningen, The Netherlands; 22 Faculty of Medicine and Life Sciences, BIOMED - Biomedical Research Institute, Hasselt University, Diepenbeek, Belgium; 23 Department of
Cardiology, Ziekenhuis Oost, Genk, Belgium; 24 Regional Cardiology Centre Volgograd, Volgograd State Medical University, Volgograd, Russia; 25 Department of Cardiology, IRCCS
San Raffaele Pisana, Rome, Italy; 26 School of Nursing and Midwifery, Queen’s University Belfast, Belfast, UK; 27 Department of Cardiology and Angiology, Medical School Hannover,
Hannover, Germany; 28 National Heart and Lung Institute, Imperial College London and Royal Brompton Hospital, London, UK; 29 Institute of Cardiovascular and Medical Sciences,
British Heart Foundation Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow, UK; 30 Department of Cardiology (CVK), Berlin Institute of Health Center
for Regenerative Therapies (BCRT), German Centre for Cardiovascular Research (DZHK) partner site Berlin, Charité Universitätsmedizin Berlin, Berlin, Germany; and
31 Department of Medical Sciences, IRCCS San Raffaele Pisana, Rome, Italy
Received 1 August 2019; revised 9 October 2019; accepted 16 October 2019 ; online publish-ahead-of-print 9 December 2019
Type 2 diabetes mellitus (T2DM) is common in patients with heart failure (HF) and associated with considerable morbidity and mortality.
Significant advances have recently occurred in the treatment of T2DM, with evidence of several new glucose-lowering medications
showing either neutral or beneficial cardiovascular effects. However, some of these agents have safety characteristics with strong practical
implications in HF [i.e. dipeptidyl peptidase-4 (DPP-4) inhibitors, glucagon-like peptide-1 receptor agonists (GLP-1 RA), and sodium–glucose
co-transporter type 2 (SGLT-2) inhibitors].
*Corresponding author. University of Belgrade, Faculty of Medicine and Heart Failure Center, Belgrade University Medical Centre, 8 Koste Todorovića, 11000 Belgrade, Serbia.
Tel/Fax: +381 11 3614738, Email: seferovic.petar@gmail.com
© 2019 The Authors

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Role and safety of new glucose-lowering drugs in HF 197
Regarding safety of DPP-4 inhibitors, saxagliptin is not recommended in HF because of a greater risk of HF
hospitalisation. There is no compelling evidence of excess HF risk with the other DPP-4 inhibitors. GLP-1 RAs have an
overall neutral effect on HF outcomes. However, a signal of harm suggested in two small trials of liraglutide in patients
with reduced ejection fraction indicates that their role remains to be defined in established HF. SGLT-2 inhibitors
(empagliflozin, canagliflozin and dapagliflozin) have shown a consistent reduction in the risk of HF hospitalisation
regardless of baseline cardiovascular risk or history of HF. Accordingly, SGLT-2 inhibitors could be recommended to
prevent HF hospitalisation in patients with T2DM and established cardiovascular disease or with multiple risk factors.
The recently completed trial with dapagliflozin has shown a significant reduction in cardiovascular mortality and HF
events in patients with HF and reduced ejection fraction, with or without T2DM. Several ongoing trials will assess
whether the results observed with dapagliflozin could be extended to other SGLT-2 inhibitors in the treatment of
HF, with either preserved or reduced ejection fraction, regardless of the presence of T2DM. This position paper
aims to summarise relevant clinical trial evidence concerning the role and safety of new glucose-lowering therapies
in patients with HF.
..........................................................................................................
Keywords Heart failure • Type 2 diabetes mellitus • Cardiovascular risk • Hospitalisation •
Sodium–glucose co-transporter type 2 inhibitor • Glucagon-like peptide-1 receptor agonist •
Dipeptidyl peptidase-4 inhibitor • Clinical trial
Introduction humans are unclear and are under assessment in several mecha-
.........................................................................................................
nistic studies. However, the results from large CV outcome trials

Type 2 diabetes mellitus (T2DM) is common (∼20–40%) in patients (CVOTs) have shown a comprehensive CV risk reduction with
with heart failure (HF),1 and is associated with worse symptoms some of the new glucose-lowering agents, in particular with GLP-1
and quality of life, a greater burden of HF hospitalisation, and higher RA and SGLT-2 inhibitors, in patients with T2DM and established
mortality rates compared to patients without T2DM.2–7 Increased CV disease or with multiple risk factors. However, clinically rel-
levels of glycosylated haemoglobin (HbA1c ) have been associated evant issues have been raised about the effectiveness and safety
with increased morbidity and mortality in patients with T2DM of these medications relevant for HF outcomes. Therefore, the
and HF not receiving treatment with glucose-lowering drugs.8,9 purpose of this position paper is to summarize clinical trial data
However, once treatment of T2DM has been initiated, this rela- on the role and safety of these new evidence-based therapies for
tionship may no longer be linear. Most data suggest that mortality the treatment of T2DM in patients with HF.
risk in patients with HF is lowest with moderate glycaemic con-
trol (i.e. HbA1c levels 7.0–7.9%).10–14 Therefore, the 2016 Euro-
pean Society of Cardiology (ESC) guidelines for the diagnosis and Heart failure outcomes
treatment of HF stipulate that adequate glycaemic control should
be achieved gradually and leniently, with agents shown to be safe in cardiovascular outcome trials
and effective.15 A holistic approach to T2DM management in HF with new glucose-lowering
should also include blood pressure, body weight, and lipid control,
while avoiding hypoglycaemia, which is associated with a greater
medications
risk of death16 and may be a cause of increased mortality in dia- Since 2008 and 2012, the Food and Drug Administration (FDA) and
betic patients with HF on insulin therapy.17 However, this may be the European Medicines Agency (EMA), respectively, have required
challenging in clinical practice, as older age, frailty and multiple that CVOTs investigating novel glucose-lowering medications are
co-morbidities, including coronary artery disease and chronic kid- designed to evaluate CV safety. To minimize potential confounding
ney disease (CKD),6,18 increase the vulnerability to adverse drug by differences in glycaemic control between the treatment groups,
effects in many patients with T2DM and HF. CVOTs promoted a concept of ‘glycaemic equipoise’ (i.e. main-
New glucose-lowering medications [i.e. dipeptidyl peptidase-4 tenance of similar glycaemic levels during the trial) between the
(DPP-4) inhibitors,19 glucagon like peptide-1 receptor ago- treatment arms. In the majority of CVOTs, primary outcome has
nists (GLP-1 RA),20 and sodium–glucose co-transporter type 2 been a composite of the three major adverse CV events (3-point
(SGLT-2) inhibitors21 ] may have effects beyond glycaemic control MACE) comprising CV death, non-fatal myocardial infarction
pertinent to cardiovascular (CV) risk reduction in T2DM. Figure 1 (MI) and non-fatal stroke. Two trials also included hospitalisation
provides a summary of several proposed pleiotropic mechanisms for unstable angina (4-point MACE),23,24 and one trial had two
that extend the benefits of new glucose-lowering medications co-primary outcomes (the 3-point MACE and a composite of CV
beyond glycaemic control to include positive metabolic, renal, mortality and HF hospitalisation).25 Most patients had a history of
vascular and haemodynamic effects.22 At present, the exact mech- long-standing T2DM and established atherosclerotic CV disease
anism(s) underlying favourable CV effects of these medications in (or alternatively were at high CV risk) and, therefore, the evidence
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Figure 1 Proposed mechanisms of pleiotropic effects of new glucose-lowering medications. DPP-4 i, dipeptidyl peptidase-4 inhibitor; FFA,
free fatty acid; GI, gastrointestinal; GLP-1 RA, glucagon-like peptide-1 receptor agonist; SGLT-2 i, sodium–glucose co-transporter type 2
inhibitor.
derived from these trials is most compelling for secondary pre- DAPA-HF (Effect of Dapagliflozin on the Incidence of Worsening
.............................................
vention of CV events. Despite the undisputed relevance of HF in Heart Failure or Cardiovascular Death in Patients With Chronic
patients with T2DM, none of these trials included HF events as Heart Failure) has shown a significant reduction in CV mortality
a component of the primary outcome. However, hospitalisation and HF events with dapagliflozin vs. placebo among patients with
for HF was a pre-specified secondary outcome in all trials, and a HF and reduced ejection fraction (HFrEF), regardless of T2DM
co-primary composite outcome in one of the trials with SGLT-2 status, suggesting that these medications could be beneficial in
inhibitors.25 Until recently, the generalisation of trial results to the treatment of HF.26 Furthermore, observational and registry
individuals with HF was hampered by the relatively modest num- data suggest similar efficacy and safety characteristics of the new
ber of patients with a history of HF enrolled, ranging 9–28% glucose-lowering drugs in ‘real-world’ settings (compared with
(Tables 1–3) and limited characterisation of HF in terms of left ven- CVOTs),27,28 but current data are still limited.
tricular (LV) ejection fraction (LVEF), aetiology, functional class or
biomarker levels, either at baseline, or during the follow-up, with
a possible exception, to some extent, of DECLARE–TIMI 58 trial
Dipeptidyl peptidase-4 inhibitors
(Dapagliflozin Effect on Cardiovascular Events – Thrombolysis The CVOTs with DPP-4 inhibitors (saxagliptin, alogliptin, sitagliptin,
in Myocardial Infarction 58).25 However, recently completed and linagliptin) have demonstrated non-inferiority to placebo in
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Table 1 Risk of heart failure hospitalisation in cardiovascular outcome trials with dipeptidyl peptidase-4 inhibitors
Medication Trial Patients, Patient characteristics Follow-up HF hospitalisation P-value

HbA1c History
n (mean or (HR, 95% CI)a(mean) of HF
median)
...........................................................................................................................................
Saxagliptin SAVOR-TIMI 5329,30 16 492 Established CVD; multiple 8.0% 2105 (13%) 2.1 years 1.27 (1.07–1.51) 0.007
CV risk factors
Alogliptin EXAMINE31 5380 Recent acute coronary 8.0% 1533 (28%) 1.5 years 1.07 (0.79–1.46) 0.66
syndrome
Sitagliptin TECOS23 14 671 Established CVD 7.2% 2643 (18%) 3 years 1.00 (0.83–1.20) 0.98
Linagliptin CARMELINA32 6991 High CV and renal risk ∼7.9% 1876 (27%) 2.2 years 0.90 (0.74–1.08) 0.26
CI, confidence interval; CV, cardiovascular; CVD, cardiovascular disease; HbA1c , glycated haemoglobin; HF, heart failure; HR, hazard ratio.
a Treatment vs. placebo.
Table 2 Risk of heart failure hospitalisation in cardiovascular outcome trials with glucagon-like peptide-1 receptor
agonists
Medication Trial Patients, Patient characteristics HbA1c History Follow-up HF hospitalisation P-value
n (mean) of HF (mean (HR, 95% CI)a
or median)
...........................................................................................................................................
Lixisenatide ELIXA24 6068 Recent acute coronary ∼7.7% 1358 (22%) 2.1 years 0.96 (0.75–1.23) 0.75
syndrome
Liraglutide LEADER41 9340 Age ≥50 years and 8.7% 1667 (18%) 3.8 years 0.87 (0.73–1.05) 0.14
established CVD Age
≥60 years and CV risk
factors
Semaglutide SUSTAIN-642 3297 Age ≥50 years and 8.7% 777 (24%) 2.1 years 1.11 (0.77–1.61) 0.57
(subcutaneous) established CVD Age
factors
Semaglutide (oral) PIONEER 639 3183 Age ≥50 years and 8.2% 388 (12%) 1.3 years 0.86 (0.48–1.55) –
established CVD; Age
factors
Exenatide EXSCEL40 14 752 Established CVD (73%) 8.0% 2389 (16%) 3.2 years 0.94 (0.78–1.13) –
CV risk factors (37%)
Albiglutide Harmony 9463 Established CVD ∼8.7% 1922 (20%) 1.5 years 0.85 (0.70–1.04)b 0.11
Outcome44
Dulaglutide REWIND45 9901 Established CVD (31.5%) ∼7.3% 853 (8.6%) 5.4 years 0.93 (0.77–1.12)c 0.46
CV risk factors (68.5%)
CI, confidence interval; CV, cardiovascular; CVD, cardiovascular disease; HbA1c , glycated haemoglobin; HF, heart failure; HR, hazard ratio.
b A composite of CV death or HF hospitalisation.
c HF hospitalisation or urgent HF visit.
respect to primary 3-point MACE, but they have not shown supe- interval (CI) 1.07–1.53].30 The EXAMINE trial (Examination of
..............................
riority. A summary of CVOT results with DPP-4 inhibitors is pre- Cardiovascular Outcomes vs. Standard of Care in Patients with
sented in Figure 2. Despite a consistently neutral effect on the Type 2 Diabetes and Acute Coronary Syndrome) demonstrated
primary composite outcome, the rates of HF hospitalisation were a non-significant trend towards increased risk of HF hospitalisa-
different among the DPP-4 inhibitors (Table 1). In the SAVOR-TIMI tion with alogliptin vs. placebo (3.1% vs. 2.9%; HR 1.07; 95% CI
53 trial (Saxagliptin Assessment of Vascular Outcomes Recorded 0.79–1.46).31 In TECOS (Trial Evaluating Cardiovascular Outcome
in patients with diabetes mellitus – Thrombolysis In Myocardial with Sitagliptin), sitagliptin demonstrated no effect on the risk of
Infarction 53),29 a statistically significant increase of 27% in hospital- HF hospitalisation compared to placebo (3.1% vs. 3.1%; HR 1.00;
isation for HF was observed in patients randomised to saxagliptin 95% CI 0.84–1.20).23 In the most recent trial investigating this class
vs. placebo [3.5% vs. 2.8%; hazard ratio (HR) 1.27; 95% confidence of agents, CARMELINA (Effect of Linagliptin vs. Placebo on Major
© 2019 The Authors

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Table 3 Risk of heart failure hospitalisation in cardiovascular outcome trials with sodium–glucose co-transporter
type 2 inhibitors
Medication Trial Patients, Patient HbA1c Follow-up HF hospitalisation P-value

History
n characteristics (mean)(mean or (HR, 95% CI)a
of HF
median)
...........................................................................................................................................
Empagliflozin EMPA-REG 7020 Established CVD 8.1% 10% 3.1 years 0.65 (0.50–0.85) 0.002
OUTCOME56
Canagliflozin CANVAS 10 142 Established CVD (66%) 8.2% 14% 3.2 years 0.67 (0.52–0.87) –
Program60 CV risk factors (34%)
Canagliflozin CREDENCE62 4401 Albuminuric chronic 8.3% ∼15% 2.62 years 0.61 (0.47–0.80) <0.001
kidney diseaseb
Dapagliflozin DECLARE–TIMI 17 160 Established CVD (41%) 8.3% 10% 4.2 years 0.73 (0.61–0.88) –
5863 CV risk factors (59%)
Dapagliflozin DAPA-HF26 4744 Symptomatic HF (NYHA A history of 100% 1.5 years 0.70 (0.59–0.83) –
class II–IV), T2DM: 42%
NT-proBNP ≥600
pg/mL (or ≥400 pg/mL
if hospitalised for HF
within the previous 12
months; if AF/AFl ≥900
pg/mL).
AF, atrial fibrillation; AFl, atrial flutter; CI, confidence interval; CV, cardiovascular; CVD, cardiovascular disease; HbA1c , glycated haemoglobin; HF, heart failure; HR, hazard
ratio; NT-proBNP, N-terminal pro-B-type natriuretic peptide; NYHA, New York Heart Association; T2DM, type 2 diabetes mellitus.
b Estimated glomerular filtration rate: 30 to <90 mL/min/1.73 m2 and albuminuria: albumin-to-creatinine ratio >300 to 5000 mg/g.
Figure 2 Summary of clinical trial results with new glucose-lowering medications in patients with type 2 diabetes mellitus. CV, cardiovascular;
HF, heart failure; MACE, major adverse cardiovascular events; DPP-4, dipeptidyl peptidase-4; GLP-1 RA, glucagon-like peptide-1 receptor
agonist; SGLT-2, sodium–glucose co-transporter type 2. *In the co-primary efficacy analyses, dapagliflozin did not reduce the risk of 3-point
MACE (hazard ratio 0.93; 95% confidence interval 0.84–1.03; P = 0.17) but did result in a lower risk of CV death or hospitalization for HF
(hazard ratio 0.83; 95% confidence interval 0.73–0.95; P = 0.005).
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Cardiovascular Events in Adults With Type 2 Diabetes and High outcome. There was no effect of lixisenatide (4.2% vs. 4.0%; HR
........................................................................................................................................................................
Cardiovascular and Renal Risk), there was no significant effect of 0.96; 95%CI 0.75–1.23) or exenatide (3.0% vs. 3.1%; HR 0.94; 95%
linagliptin vs. placebo treatment on the risk of HF hospitalisation CI 0.78–1.13) vs. placebo on the risk of HF hospitalisation.24,40
(2.8% vs. 3.0%; HR 0.90; 95% CI 0.74–1.08),32 as well as other HF Conversely, CVOTs with liraglutide, semaglutide and albiglutide
outcomes, including CV death or HF hospitalisation (HR 0.94; 95% have shown a reduction in CV outcomes compared with placebo. A
CI 0.82–1.08), or recurrent HF hospitalisation events (326 vs. 359 summary of CVOT outcomes with GLP-1 RA is shown in Figure 2.
events, respectively; rate ratio, 0.94; 95% CI 0.75–1.20).33 In LEADER (Liraglutide and Cardiovascular Outcomes in Type
Whether DPP-4 inhibitors increase the risk of HF in general, or 2 Diabetes), liraglutide treatment led to a decrease of 13% in the
exhibit within-class differences, is not completely understood. A risk of primary endpoint MACE, as well as significantly lower risks
post hoc analysis of SAVOR-TIMI 53 has suggested a higher risk of CV mortality, all-cause mortality and microvascular events com-
with saxagliptin in patients with a history of HF, renal dysfunction pared to placebo.41 There was a non-significant 13% reduction in
[estimated glomerular filtration rate (eGFR) <60 mL/min34 ) and the risk of HF hospitalisation (4.7% vs. 5.3%; HR 0.87; 95% CI
higher baseline levels of N-terminal pro-B-type natriuretic peptide 0.73–1.05).41 In SUSTAIN-6 (Semaglutide and Cardiovascular Out-
(NT-proBNP).30 However, this was not observed with alogliptin in comes in Patients with Type 2 Diabetes), subcutaneous semaglutide
a post hoc analysis of EXAMINE, in which the risk of HF hospital- led to a 26% lower risk of the primary endpoint MACE, mainly
isation was unaffected by the above-mentioned factors.31 Notably, driven by a reduction in the rate of stroke.42 The relative risk of
the higher incidence of HF hospitalisation has not resulted in HF hospitalisation was unaffected by semaglutide treatment (3.6%
excess all-cause or CV mortality in the group treated with either vs. 3.3%; HR 1.11; 95% CI 0.77–2.78).42 Recently, the PIONEER
saxagliptin in SAVOR-TIMI 53, or alogliptin in EXAMINE.29,35 In 6 trial (Peptide Innovation for Early Diabetes Treatment) explored
a pre-specified sub-analysis of CARMELINA, linagliptin was safe CV safety of the first oral GLP-1 RA compared with placebo. The
for HF outcomes in patients with or without prior HF, irrespec- trial demonstrated no excess in the risk of 3-point MACE (2.9% vs.
tive of LVEF, and across a spectrum of renal impairment.33 In the 3.7%; HR 0.79; 95% CI 0.57–1.11) and no increase in HF hospi-
smaller VIVIDD study (Effects of Vildagliptin on Ventricular Func- talisation (1.3% vs. 1.5%; HR 0.86; 95% CI 0.48–1.55) with oral
tion in Patients with Type 2 Diabetes Mellitus and Heart Failure), semaglutide compared with placebo.39 Furthermore, the results
vildagliptin had no significant effect on LVEF, B-type natriuretic pep- of PIONEER 7 (Efficacy and safety of oral semaglutide with flex-
tide levels, or HF status in patients with HFrEF.36 However, treat- ible dose adjustment versus sitagliptin in type 2 diabetes) suggest
ment with vildagliptin resulted in an increase in LV volumes and that flexible dose-adjusted oral semaglutide can provide superior
more deaths compared with placebo (8.6% vs. 3.2%), albeit with glycaemic control and weight loss compared with sitagliptin, with
no consistent pattern and not reaching statistical significance.36 The safety characteristics similar to subcutaneous GLP-1 RAs.43 These
clinical significance of these findings remains to be determined. results open a possibility to further explore oral GLP-1 RA as an
Several meta-analyses of these trials have indicated either a alternative to the injectable form of these medications.
higher risk of HF in patients with established CV disease,37 or Recently, in Harmony Outcomes (Albiglutide and Cardiovascular
a higher HF risk associated with saxagliptin, but not with other Outcomes in Patients with Type 2 Diabetes and Cardiovascular
DPP-4 inhibitors.38 A recently presented CAROLINA trial (Car- Disease) there was a 22% lower risk of the primary composite
diovascular Outcome Study of Linagliptin versus Glimepiride in outcome with albiglutide compared with placebo, driven by a
Patients with Type 2 Diabetes) demonstrated no difference in significant reduction in the rate of MI.44 Also, a trend was observed
the 3-point MACE outcome and no increase in the risk of HF towards a lower risk of the composite outcome of CV death or
hospitalisation (3.7% vs. 3.1%; HR 1.21; P = 0.176) between hospital admission for HF with albiglutide compared with placebo
linagliptin and an active comparator, glimepiride, but patients (4.0% vs. 5.0%; HR 0.85; 95% CI 0.70–1.04).44 In addition, the
treated with glimepiride experienced more hypoglycaemia com- REWIND trial (Researching Cardiovascular Events with a Weekly
pared with those receiving linagliptin (Rosenstock J., unpublished Incretin in Diabetes) demonstrated a 12% risk reduction for the
data; NCT01243424). 3-point MACE with the long-acting dulaglutide vs. placebo (12.0%
vs. 13.4%; HR 0.88; 95% CI 0.79–0.99), primarily due to a significant
reduction in the risk of non-fatal stroke.45 Again, there was no
Glucagon like peptide-1 receptor difference between the two treatment arms with respect to HF
events (4.3% vs. 4.6%; HR 0.93; 95% CI 0.77–1.12).45
agonists A metanalysis of the four trials with a GLP-1 RA has suggested
Six CVOTs have assessed the CV safety profile of the subcutaneous that these medications can reduce the rate of 3-point MACE,
GLP-1 RA class of agents (lixisenatide, liraglutide, semaglutide, albeit to a varying degree for individual drugs.20 The discrepant
exenatide, albiglutide and dulaglutide) and one trial has evaluated responses may be related to differences in molecular structure
the first orally active form of the GLP-1 RA, oral semaglutide39 and pharmacokinetic properties (long-acting vs. short-acting) of
(Table 2). Two of these CVOTs, ELIXA (Lixisenatide in Patients different GLP-1 RA, or, perhaps, to a heterogeneity in patient
with Type 2 Diabetes and Acute Coronary Syndrome)24 and risk profiles, and study design of particular CVOTs.46 Improve-
EXSCEL (Effects of Once-Weekly Exenatide on Cardiovascular ment in CV outcomes emerged late (after 12–18 months) in the
Outcomes in Type 2 Diabetes),40 found that lixisenatide and exe- setting of modest glucose-lowering effects and mainly due to a
natide, respectively, had a neutral effect on the primary composite reduction in vascular events (either stroke or MI) suggesting that
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non-haemodynamic mechanisms beyond glycaemic control, possi- HF-related hospitalisation and mortality (2.8% vs. 4.5%; HR 0.61;
........................................................................................................................................................................
bly related to anti-atherosclerotic effects, underpin the benefits of 95% CI 0.47–0.79)57 and reduced the need for introduction of loop
GLP-1 RA (Figure 1). diuretics, which is in concert with the observed lower incidence
Thus far, GLP-1 RA have shown a neutral effect on the risk of HF hospitalisation.57,58 The beneficial effect of empagliflozin on
of HF hospitalisation, with a favourable trend observed with HF hospitalisation was consistent across pre-defined subgroups,
liraglutide, albiglutide and oral semaglutide. An observed increase including patients with and without a history of HF (HR 0.75; 95%
in heart rate (by a mean of ∼3–9 bpm) may conceivably be CI 0.48–1.19; and HR 0.59; 95% CI 0.43–0.82, respectively).57 The
partly accountable for the lack of an effect on HF.47,48 In the favourable effects on HF events occurred within the first 6 months
recent LIVE study (Effect of liraglutide, a glucagon-like peptide-1 after treatment initiation with an even earlier divergence of the
analogue, on left ventricular function in stable chronic heart failure Kaplan–Meier curves, suggesting improvement in haemodynamic
patients with and without diabetes), liraglutide had a neutral effect status and reduced congestion as putative mechanisms (Figure 1).
on LVEF in patients with chronic stable HFrEF (with or without Of note, compared with placebo, empagliflozin had no effect on
T2DM), but led to an increase in heart rate and more adverse CV the risk of MI, but there was a numerical increase in the risk of
events compared with placebo.49 A similar signal has come from stroke (HR 1.18; 95% CI 0.89–1.56).56 A subsequent sub-analysis
the FIGHT trial (Functional Impact of GLP-1 for Heart Failure showed that this difference could be explained by events occurring
Treatment) in which a trend towards higher risk of death and >90 days after the last dose of the drug, whereas there was no
rehospitalisation for HF was observed with liraglutide compared difference in events occurring on-treatment or within 90 days after
with placebo in HFrEF patients (with or without T2DM).50 In a the last dose (HR 1.08; 95% CI 0.81–1.45; P = 0.60).59 Subsequent
small randomised trial, no significant effect was documented with CVOTs with other SGLT-2 inhibitors have not shown an increase
albiglutide on cardiac function or myocardial glucose utilisation in risk of stroke.
in patients with symptomatic HFrEF, but there was a modest The CANVAS Program (Canagliflozin Cardiovascular Assess-
increase in peak oxygen consumption, the importance of which ment Study) comprised the CANVAS and CANVAS-R trials
remains to be determined.51 The suggested safety signal with
enrolling T2DM patients with established atherosclerotic CV dis-
some of the GLP-1 RA in patients with HFrEF merits further
ease (66%), or at high CV risk (34%).60 Treatment with canagliflozin
investigation.
resulted in a significant 14% relative risk reduction in the primary
composite outcome compared with placebo, with the individual
components demonstrating a statistically non-significant trend
Sodium–glucose co-transporter towards benefit. This study also showed a substantial 33% reduc-
type 2 inhibitors tion in the risk of HF hospitalisation (5.5% vs. 8.7%; HR 0.67; 95%
CI 0.52–0.87), although this finding was not considered statisti-
SGLT-2 inhibitors (empagliflozin, canagliflozin, dapagliflozin,
cally significant based on the pre-specified sequence of hypothesis
ertugliflozin) have a unique glucose-lowering effect via inhibit-
testing.60 An ancillary analysis of the CANVAS trial with a ret-
ing glucose reabsorption in the proximal renal tubule.52 Due
to the favourable outcomes in recent trials, SGLT-2 inhibitors rospective review of medical records to obtain data on LVEF at
are assumed to have cardioprotective properties, via several the time of HF hospitalisation demonstrated that the prevailing
mechanisms, as reviewed.22,53–55 Beneficial effects of SGLT-2 inhi- phenotype of HF was HFrEF, defined as admission LVEF <50%
(122 cases of 276 HF events), followed by HF with preserved
ejection fraction (HFpEF), defined as LVEF ≥50% (101 cases of
bition on CV outcomes have been shown in the recent landmark
CVOTs with empagliflozin, canagliflozin and dapagliflozin (Table 3),
while ertugliflozin is being assessed in an ongoing VERTIS trial 276 HF events), while the rest had HF event with unknown LVEF.61
(NCT01986881). Notably, SGLT-2 inhibitors are the first class of Patients with HFpEF were more likely to be female, hypertensive
glucose-lowering medications that have demonstrated a positive and to have high body mass index or microvascular disease in
effect on risk reduction for HF hospitalisation (Figure 2). In the comparison with patients with HFrEF. Importantly, canagliflozin
EMPA-REG OUTCOME (Empagliflozin Cardiovascular Outcome reduced the risk of all HF events, with no distinct difference in
Event Trial in Type 2 Diabetes Mellitus Patients Removing Excess effects on HFrEF vs. HFpEF events.61
Glucose), empagliflozin treatment in patients with T2DM and Further support of the therapeutic benefit with canagliflozin
established CV disease has resulted in a significant 14% relative comes from the CREDENCE trial (Canagliflozin and Renal Events in
risk reduction for the primary composite outcome, driven by a Diabetes with Established Nephropathy Clinical Evaluation), show-
38% risk reduction in CV mortality (3.7% vs. 5.9%; HR 0.62; 95% ing a 34% relative risk reduction in cardiorenal outcomes compared
CI 0.49–0.77).56 The trial also reported a 35% risk reduction of with placebo in patients with T2DM and kidney dysfunction (albu-
hospitalisation for HF (2.7% vs. 4.1%, HR 0.65; 95% CI 0.5–0.85) minuria and eGFR 30 to <90 mL/min/1.73 m2 ) already on optimal
and a 32% lower all-cause mortality with empagliflozin compared doses of angiotensin-converting enzyme inhibitors or angiotensin
with placebo (5.7% vs. 8.3%; HR 0.68; 95% CI 0.57–0.82).56 In a receptor blockers.62 Importantly, this trial has confirmed a robust
sub-analysis of HF outcomes in this trial, empagliflozin reduced the attenuation in the composite risk of CV death or HF hospitalisation
composite risk of HF hospitalisation or CV death (5.7% vs. 8.5%; (HR 0.69; 95% CI 0.57–0.83), including a significant risk reduction
HR 0.66; 95% CI 0.55–0.79), as well as its individual components for HF hospitalisation. On that basis, SGLT-2 inhibition may be a
compared to placebo.57 In addition, empagliflozin also reduced novel approach to improve cardiorenal protection and reduce the
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risk of HF hospitalisation among high-risk patients with T2DM and A suggested approach
........................................................................................................................................................................
mild-to-moderate CKD.
Recently, the DECLARE–TIMI 58 trial assessed the effects of to glucose-lowering therapy
dapagliflozin vs. placebo on CV outcomes in the predominantly in patients with type 2 diabetes
(59%) primary prevention population of T2DM patients. Despite
a neutral effect on the 3-point MACE outcome, dapagliflozin was
and heart failure
superior compared with placebo in reducing a composite of CV Recent CVOTs provide a perspective on the role and safety profile
death or HF hospitalisation (4.7% vs. 5.8%; HR 0.83; 95% CI of new glucose-lowering medications for the treatment of T2DM
0.73–0.95).63 This effect was due to a significant 27% risk reduction in patients with HF.
for HF hospitalisation (HR 0.73; 95% CI 0.61–0.88), whereas There is currently insufficient evidence on the safety profile
the risk of CV death was unaffected.63 Further insights into the of DPP-4 inhibitors in patients with established HF. Based on
effects of dapagliflozin according to baseline HF status (with or the available data, saxagliptin, and, possibly, vildagliptin should not
without a history of HF) and LVEF came from a sub-analysis of be used in those patients, while caution is recommended with
DECLARE–TIMI 58, demonstrating consistent reduction in the alogliptin. There is no evidence of adverse HF outcomes with
risk of HF hospitalisation in all patients, regardless of baseline linagliptin, or sitagliptin.
HF status or LVEF.64 However, the largest risk reduction in HF In the general population of T2DM patients, DPP-4 inhibitors
hospitalisation was observed in patients with HFrEF (3.9% in are well tolerated, weight-neutral and associated with a low risk of
patients with baseline LVEF <45%), in whom dapagliflozin also hypoglycaemia (Figure 3). The recommended doses, dose modifica-
attenuated all-cause and CV mortality.64 By contrast, in non-HFrEF tions and important precautions relevant for DPP-4 inhibitor use
patients (either without known HF or without known reduced are presented in Figure 3.
LVEF), HF risk reduction was lower compared with HFrEF patients GLP-1 RA demonstrated a neutral effect on the risk of HF,
and there was no effect on mortality. Yet another sub-analysis and a trend towards a lower risk was observed with liraglutide,
of the same trial has demonstrated a reduction in hospitalisation
albiglutide and oral semaglutide. However, a signal of harm detected
irrespective of baseline CV risk profile (established CV disease or
in smaller trials of GLP-1 RA in patients with HFrEF warrants
multiple risk factors), albeit individuals with prior MI derived the
caution. Therefore, this concerning safety issue needs further
greatest benefit, including a reduction in the risk of 3-point MACE
investigation prior to defining the role of GLP-1 RA for T2DM
with dapagliflozin.65
treatment in patients with established HF.
Several haemodynamic and metabolic mechanisms (not mutu-
The risk of hypoglycaemia is not increased with GLP-1 RA
ally exclusive) have been proposed to explain the salutary CV
monotherapy but may be aggravated in combined treatment with
effects of SGLT-2 inhibitors (Figure 1),22 but they await confir-
other glucose-lowering drugs, in particular insulin or insulin sec-
mation from clinical trials. In a recent exploratory analysis of
retagogues. The therapy with GLP-1 RA increases postpran-
EMPA-REG OUTCOME, changes in markers of plasma volume
dial satiety that may have favourable effect on weight loss. The
(haematocrit and haemoglobin) had the largest impact on rela-
most frequent side-effects of subcutaneous GLP-1 RA include
tive risk reduction of CV death (51.8% and 48.9%, respectively).66
(transient) gastrointestinal intolerance, and increased frequency
These changes were likely haemodynamic in origin, reflecting a sus-
of gall bladder disease.70 Gastrointestinal intolerance is also the
tained effect on plasma volume contraction owing to increased
diuresis and natriuresis with SGLT-2 inhibitors. SGLT-2 inhibitors most frequent side-effect of oral semaglutide.39 There may be
exert renal protection,56,60,63 which could also contribute to CV an increased risk of acute pancreatitis, whereas a higher risk
protection. Furthermore, in a mechanistic experimental study, of C-cell hyperplasia/medullary thyroid carcinoma has not been
empagliflozin has been associated with an improvement in myocar- confirmed in human studies.70 The recommended doses, dose
dial diastolic stiffness in isolated human cardiomyocytes, most modifications, and precautions relevant for GLP-1 RA use in
likely due to enhanced phosphorylation of myofilament regulatory the general population of patients with T2DM are presented in
proteins.67 Figure 4.
A sub-analysis of a small number of patients from EMPA-REG The three CVOTs with SGLT-2 inhibitors have consistently
OUTCOME has shown early and significant reduction in LV mass demonstrated that treatment with these agents is associated with
index and improvement in diastolic function without changes lower risk of HF hospitalisation in patients with T2DM and estab-
in LV systolic function or volumes with empagliflozin compared lished atherosclerotic CV disease or with multiple risk factors,
with placebo.68 Most recently, the EMPA-HEART CardioLink-6 with the strongest effects in individuals with established CV dis-
study has shown a reduction in LV mass index on cardiac mag- ease. These results were corroborated by a recent meta-analysis
netic resonance following 6 months of empagliflozin treatment of these CVOTs, demonstrating a significant 23% risk reduction
(compared with placebo) among diabetic patients with stable for CV death or HF hospitalisation (HR 0.77; 95% CI 0.71–0.84),
coronary artery disease, normal LVEF and without a history of as well as a reduction in HF hospitalisation by 31% (HR 0.69; 95%
HF.69 Although intriguing, these concepts require further confir- CI 0.61–0.79) with SGLT-2 inhibitors.71 Importantly, these findings
mation from larger studies.54 The results of DAPA-HF suggest were consistent regardless of CV disease burden, or a prior history
that SGLT-2 inhibitors may indeed benefit the treatment of HF, as of HF, suggesting that SGLT-2 inhibitors may have a beneficial effect
discussed below. on HF prevention in a broad spectrum of T2DM patients.71
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Figure 3 Dipeptidyl peptidase-4 (DPP-4) inhibitors: dosing, dose adjustment and precautions. CrCl, creatinine clearance; eGFR, estimated
glomerular filtration rate; ESRD, end-stage renal disease; NA, not available.
Figure 4 Glucagon-like peptide-1 receptor agonists (GLP-1 RA): dosing, dose adjustment and precautions. eGFR, estimated glomerular
filtration rate.
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Figure 5 Sodium–glucose co-transporter type 2 (SGLT-2) inhibitors: dosing, dose adjustment and precautions. eGFR, estimated glomerular
filtration rate.
This beneficial effect has already been acknowledged for reduced in patients with T2DM (HR 0.75; 95% CI 0.63–0.90)
.......................................................................................
empagliflozin in the 2016 ESC guidelines for the diagnosis and and in those without T2DM (HR 0.73; 95% CI 0.60–0.88). Both
treatment of HF15 and in the guidelines for CV prevention,72 components of the primary outcome (CV mortality and HF
which have recommended its use in patients with T2DM to delay events) were significantly reduced with dapagliflozin treatment (by
the onset of HF. In line with emerging clinical trial data, the 2019 18% and 30%, respectively) and there were no interactions with
expert consensus report from the ESC Heart Failure Associ- respect to demographic/clinical characteristics or HF treatment.26
ation has extended this recommendation to all three SGLT-2 Further information is awaited from trials with other SGLT-2
inhibitors.73 Likewise, the 2018 American Diabetes Associa- inhibitors, including patients with either HFrEF or HFpEF, with or
tion/European Association for the Study of Diabetes (ADA/EASD) without T2DM (Table 4).
consensus statement has positioned SGLT-2 inhibitors as the In addition, a clinical trial with sotagliflozin, a unique, dual
preferred treatment of T2DM in patients with known HF or at SGLT-2 and 1 inhibitor, is underway to investigate CV mortal-
risk of HF.70 Accordingly, SGLT-2 inhibitors have been recom- ity and HF hospitalisation in patients recently hospitalised for
mended as an add-on therapy in patients who have not achieved worsening HF (NCT03521934). Inhibition of both SGLT-2- and 1
adequate glucose control with metformin (or in whom met- may increase glycosuria beyond the effect observed with SGLT-2
formin is contraindicated/not tolerated).70 In patients with HF inhibitors and to reduce intestinal glucose absorption. However,
receiving dual or multiple glucose-lowering medications, not unlike SGLT-2, SGLT-1 is also expressed in various other organs,
including SGLT-2 inhibitors, a switch to an SGLT-2 inhibitor including the heart, where it may have an effect on glucose
has been recommended.70 A similar recommendation has been uptake. There is currently a paucity of data to indicate whether
issued from the American College of Cardiology,74 however in these effects could have incremental therapeutic value in patients
the absence of prospective data in patients with prevalent HF with T2DM.75
(Figure 5). SGLT-2 inhibitors are associated with a low risk of hypogly-
Clinical trials specifically investigating a potential benefit of this caemia and can be safely and effectively combined with other
class of drugs in patients with prevalent HF, independent of the glucose-lowering drugs in order to achieve optimal glucose
presence of T2DM, are currently ongoing (Table 4). The first control.76 However, adverse effects need to be considered. The
completed among those trials, DAPA-HF reported a significant most frequently observed adverse events are genital mycotic infec-
risk reduction in the primary endpoint comprising CV mortal- tions, usually mild and non-recurring after treatment.56,60,63 Rarely,
ity/HF hospitalisation/urgent HF visit (HR 0.74; 95% CI 0.65–0.85) ‘euglycaemic’ ketoacidosis may occur (characterised by lower
in patients with HFrEF (LVEF ≤40% and elevated natriuretic than typical blood glucose levels), possibly caused by increased
peptides).26 The primary composite outcome was consistently glucagon release and decreased renal ketone body excretion in
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Table 4 Selected ongoing randomized clinical trials of sodium–glucose co-transporter type 2 inhibitors in patients
with heart failure
Clinical trial Brief description of the trial

...........................................................................................................................................
Empagliflozin
EMPA-RESPONSE-AHF (NCT03200860) Effects of Empagliflozin on Clinical Outcomes in Patients With Acute Decompensated Heart Failure
• Study population: acute decompensated HF
• Estimated enrolment: n = 80
• Treatment: empagliflozin vs. placebo
• Primary outcome: change in NT-proBNP. Secondary outcome: all-cause mortality or HF
readmission
EMPEROR-Reduced (NCT03057977) Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Reduced Ejection Fraction
• Study population: HFrEF, with or without T2DM
• Treatment: empagliflozin vs. placebo on top of guideline-based medical therapy
• Primary outcome: CV death or HF hospitalization (time frame: up to 38 months)
EMPEROR-Preserved (NCT03057951) Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Preserved Ejection Fraction
• Study population: HFpEF, with or without T2DM
• Primary outcome: CV death or HF hospitalization (time frame: up to 38 months)
Empire HF (NCT03198585) Empagliflozin in Heart Failure Patients With Reduced Ejection Fraction
• Study population: HFrEF, with or without T2DM
• Primary outcome: change in plasma concentrations of NT-proBNP (time frame: 90 days) as a
measure of treatment impact on HF
EMPERIAL-Reduced (NCT03448419) Empagliflozin in Patients With HFrEF: aiming to assess how far patients can walk in 6 min and their
symptoms
• Study population: HFrEF (LVEF <40%), with or without T2DM
• Primary outcome: change from baseline to week 12 in exercise capacity as measured by the
distance walked in 6 min in standardised conditions
EMPERIAL-Preserved (NCT03448406) Empagliflozin in Patients With HFpEF: aiming to assess how far patients can walk in 6 min and their
symptoms
• Study population: HFrEF (LVEF ≥40%), with or without T2DM
• Primary outcome: change from baseline to week 12 in exercise capacity as measured by the
distance walked in 6 min in standardised conditions
Canagliflozin
Canagliflozin (NCT02920918) Treatment of Diabetes in Patients With Systolic Heart Failure
• Study population: HFrEF with T2DM
• Treatment: canagliflozin vs. sitagliptin
• Primary outcome: change in aerobic exercise capacity and ventilator efficiency (time frame:
baseline and 12 weeks)
Dapagliflozin
DEFINE-HF (NCT02653482) Dapagliflozin Effect on Symptoms and Biomarkers in Diabetic Patients With Heart Failure
• Study population: HFrEF with T2DM
• Treatment: dapagliflozin vs. placebo
• Primary outcome: change in plasma concentrations of NT-proBNP (time frame: 12 weeks)
as a measure of treatment impact on HF
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Table 4 (Continued)
Clinical trial Brief description of the trial

...........................................................................................................................................
DELIVER (NCT03619213) Dapagliflozin Evaluation to Improve the Lives of Patients with Preserved Ejection Fraction Heart
Failure
• Study population: HFpEF
• Primary outcome: composite of CV death, hospitalisation for HF or urgent HF visit.
Secondary outcome: hospitalisations for HF and CV death, worsened NYHA class
DETERMINE-Reduced (NCT03877237) Dapagliflozin Effect on Exercise Capacity Using a 6-min Walk Test in Patients With Heart Failure
With Reduced Ejection Fraction
• Study population: HFrEF, EF ≤40%; NYHA class II–IV
• Primary outcome: change from baseline in 6-min walking distance at week 16
DETERMINE-Preserved (NCT03877224) Dapagliflozin Effect on Exercise
Capacity Using a 6-min Walk Test in Patients With Heart Failure With Preserved Ejection Fraction
• Study population: HFpEF, EF >40%; NYHA class II–IV
• Primary outcome: change from baseline in 6-min walking distance at week 16
PRESERVED-HF (NCT03030235) Dapagliflozin Effect on Symptoms and Biomarkers in patients HFpEF
• Study population: HFpEF with T2DM or pre-diabetes
• Primary outcome: change in plasma concentrations of NT-proBNP (time frame: baseline to
week 6 and 12) as a measure of treatment impact on HF
SOLOIST-WHF NCT03521934) Effect of Sotagliflozin on Cardiovascular Events in Patients With Type 2 Diabetes Post Worsening
Heart Failure
• Study population: a) T2DM, HF and LVEF <50% after admission for worsening HF; b) T2DM,
HF, regardless of LVEF after admission for worsening HF
• Treatment: sotagliflozin vs. placebo
• Primary outcome: time to first occurrence of either CV death or hospitalisation for HF in
patients with LVEF <50%, as well as in the total patient population (regardless of LVEF)
CV, cardiovascular; EF, ejection fraction; HF, heart failure; HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; LVEF, left
ventricular ejection fraction; NT-proBNP, N-terminal pro-B-type natriuretic peptide; NYHA, New York Heart Association; T2DM, type 2 diabetes mellitus.
the face of enhanced glycosuria in insulin deficient patients (i.e. amputations, or fractures was observed with canagliflozin in
.....................................................
patients receiving insulin therapy).77 Although ketoacidosis has CREDENCE. Of note, in DAPA-HF, among the high-risk HFrEF
not been more frequently observed in EMPA-REG OUTCOME patients with or without T2DM, no significant excess in seri-
or CANVAS trials, it occurred more frequently with dapagliflozin ous adverse events was noted with dapagliflozin vs. placebo
in DECLARE–TIMI 58 (HR 2.18; 95% CI 1.10–4.30).63 Hospital- (including fractures, amputations, or ketoacidosis in patients
isation for an acute illness or surgery may exacerbate the risk of with T2DM).26
ketoacidosis, and it may be prudent to temporarily discontinue The three SGLT-2 inhibitors (empagliflozin, canagliflozin or
SGLT-2 inhibitors under those circumstances.78,79 Reinitiating dapagliflozin) can be considered in patients with eGFR ≥30 mL/min/
SGLT-2 inhibitors following the episode of ketoacidosis is not 1.73 m2 .80 They are not recommended/should be discontinued
recommended because of an increased risk of recurrence.78,79 In in patients with severe CKD; i.e. eGFR <30 mL/min/1.73 m2
addition, safety analyses of the CANVAS Program have suggested (Figure 5). Considering a predilection for worsening renal
a greater risk of bone fractures and lower limb amputations function in patients with HF, an emphasis should be given
with canagliflozin. The most prominent increase in the absolute on regular eGFR monitoring in patients treated with SGLT-2
risk was observed among patients with previous amputations inhibitors.
or peripheral arterial disease, possibly explained by volume Dosing and precautions pertinent to SGLT-2 inhibitor therapy
depletion and greater vulnerability to ischaemic complications.60 in the general population of patients with T2DM are presented in
By contrast, no significant increase in the risk of lower limb Figure 5.
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Safety aspects of combining new in Mortality and morbidity) have suggested a higher risk of HF
........................................................................................................................................................................
and worse outcomes in patients receiving insulin compared to
and traditional glucose-lowering those treated with oral glucose-lowering agents.97 Conversely, in
medications UKPDS (UK Prospective Diabetes Study) there was no difference
in the incidence of HF between patients receiving insulin and
Although metformin has not been evaluated in a randomized trial those receiving sulphonylurea.92 In the ORIGIN trial (Outcome
in the HF population, a substantial body of observational data indi- Reduction With Initial Glargine Intervention), among 12 537
cates that it is safe and associated with a reduction in all-cause patients with different levels of dysglycaemia (impaired glucose
mortality and rehospitalisation for HF, compared with sulpho- tolerance, impaired fasting glucose, or T2DM) and CV risk factors,
nylureas or insulin.81–85 These benefits extend to patients with randomized to basal insulin glargine or placebo, there were no
advanced HFrEF,81 as well as to patients with moderate renal differences in CV outcomes, including HF hospitalisation.98 In the
or hepatic dysfunction,85,86 in whom aggravated risk of lactic aci- recent CVOTs with SGLT-2 inhibitors, about 40–50% of patients
dosis with metformin has not been confirmed.85 Severe CKD were already treated with insulin and subgroup analyses of all trials
(eGFR <30 mL/min/1.73 m2 ) remains a contraindication for met- have demonstrated no interaction with CV outcomes in patients
formin use, and dose adjustment is advised in patients with eGFR with or without insulin. However, insulin therapy may increase
<45 mL/min/1.73 m2 . A favourable impact on CV outcomes, cou- the risk of hypoglycaemia, and dose adjustment is necessary
pled with a low risk of hypoglycaemia, a neutral effect on body in individuals treated concomitantly with new glucose-lowering
weight, and low cost, have led to the current recommendation agents. In addition, insulin has an intrinsic anti-natriuretic effect,99
that metformin should be considered in T2DM in HF patients with unaffected by insulin resistance in other tissues.100 Although fluid
stable eGFR >30 mL/min/1.73 m2 .80 It is also the preferred choice retention is usually mild, it may contribute to weight gain, and
in the combined treatment with SGLT-2 inhibitors, intending to lead to worsening HF. Of note, data from an observational cohort
achieve both optimal glycaemic control and risk reduction of HF including patients with HFrEF and advanced HF, suggest that
hospitalisation.70 insulin therapy has been associated with significantly higher 1-year
Earlier clinical trials with thiazolidinediones (pioglitazone, rosigli- mortality.101
tazone) have consistently demonstrated an increased risk of HF Although available data suggest mostly neutral effect of insulin
compared with placebo.87–89 Furthermore, a meta-analysis includ- on the risk of HF, further research is required to address
ing 20 191 patients from seven trials reported a significantly higher risks and benefits of different insulin regimens in patients
risk of HF with thiazolidinediones.90 with HF.
The possible underlying mechanisms include increased renal Although all new glucose-lowering agents carry a low risk of
fluid reabsorption and increased vascular permeability leading to hypoglycaemia when used as a monotherapy or in combination
oedema formation and weight gain.91 Hence, thiazolidinediones are with metformin, this risk may be potentiated when combined
contraindicated in patients with HF, or at high risk of developing HF, with insulin or insulin secretagogues (i.e. sulphonylureas, glinides).
and there are insufficient data to indicate that this risk is mitigated Current recommendations from the ADA and EASD stipulate
by the combined treatment with novel glucose-lowering agents. dose adjustment or even discontinuation of some of antihyper-
Similar to metformin, sulfonylureas (gliclazide, glimepiride, glip- glycaemic agents to prevent hypoglycaemia when initiating a new
izide, and glibenclamide92 ) and glinides (repaglinide and nateglinide) glucose-lowering medication in patients already receiving insulin
have not been prospectively evaluated for CV safety. Data on HF and/or insulin secretagogues.70 In addition, decompensated HF,
outcomes are sparse and difficult to generalize to all sulphony- worsening renal function, infection and other critical conditions,
lureas/glinides. A recent propensity score-matched analysis of 130 may exacerbate the risk of hypoglycaemia. Hence, a multidis-
000 patients (6% with a history of HF) has suggested a greater ciplinary team management (cardiologists, diabetologists, and
risk of HF hospitalisation or CV death with sulfonylureas com- HF nurses) should be considered in patients receiving complex
pared with metformin.93 A recent cohort study of almost 500 glucose-lowering regimens (two or more drugs). Even in T2DM
000 patients reported a higher all-cause mortality in patients patients principally managed by the cardiologists, periodic consul-
receiving sulphonylurea monotherapy or a combination therapy tation with a diabetologist would be important. Future long-term
with insulin, whereas the risk was not increased when sulpho- follow-up studies with concomitant assessment of adherence
nylureas were combined with metformin, thiazolidinediones, or should consider the potential risks of polypharmacy, in terms of
DPP-4 inhibitors.94 There are limited data to indicate a heterogene- adverse reactions, and drug to drug interactions, especially among
ity in CV benefits of the new glucose-lowering drugs in combination vulnerable patients with HF and T2DM, such as the elderly, frail
with sulphonylureas or glinides, but a dose adjustment of the latter and associated multi-co-morbid conditions.
drugs may be needed to avoid the risk of hypoglycaemia. As the
risk of hypoglycaemia with sulphonylureas tends to escalate with
declining renal function, these medications are not recommended
Conclusions
in patients with severe CKD (eGFR <30 mL/min/1.73 m2 ).70,95,96 Over the last decade, management of T2DM has evolved from
Insulin therapy is widely used in patients with T2DM, but only optimising glycaemic control with the primary aim of prevent-
a few studies have investigated its association with HF. Data from ing the development or progression of microvascular complica-
CHARM (Candesartan in Heart failure: Assessment of Reduction tions (retinopathy, nephropathy and neuropathy), to using new
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glucose-lowering medications for improving CV outcomes, includ- personal fees from Novartis, during the conduct of the study. M.H.
........................................................................................................................................................................
ing prevention of HF hospitalisation. Recent CVOTs have shown reports grants from Roche Diagnostics, and personal fees from
a heterogeneity with respect to risk of HF among the classes Boerhinger, AstraZeneca during the conduct of the study. P.S.J.
of new glucose-lowering drugs. Specifically, important safety con- reports other from AstraZeneca, personal fees from Novartis,
cerns have been raised regarding the risk of HF hospitalisation with grants from Boehringer Ingelheim, during the conduct of the study;
some of these classes of agents. Accordingly, a DPP-4 inhibitor, personal fees from Cytokinetics, outside the submitted work. M.K.
saxagliptin should not be prescribed to patients with HF, whilst cau- reports personal fees from Novartis, Servier, BMS, Torrent, Sanofi,
tion is advised with alogliptin and vildagliptin. Although sitagliptin AstraZeneca, MSD, Novo Nordisk, outside the submitted work.
and linagliptin do not increase HF risk, they have no clear effect on Y.L. reports personal fees from Servier, Novartis, Boehringer
CV outcomes, so their use needs to be compared with benefits Ingelheim, during the conduct of the study. L.H.L. reports per-
demonstrated with other classes, including several of the GLP-1 sonal fees from Merck, Sanofi, Bayer, Pharmacosmos, Abbott,
RA and SGLT-2 inhibitors. Based on published CVOTs, GLP-1 Medscape; grants from Boehringer Ingelheim, Boston Scientific;
RA have demonstrated a neutral effect on HF risk in the gen- grants and personal fees from Vifor-Fresenius, AstraZeneca,
eral population of T2DM patients with established CV disease or Relypsa, Novartis, Mundipharma, outside the submitted work. A.L.
with multiple risk factors. In addition, their beneficial effects on reports personal fees from Servier; grants and personal fees from
weight and prevention of atherosclerotic events (MI and stroke) Pfizer; personal fees from Novartis, Roche, Takeda, Boehringer
deserve consideration in T2DM patients deemed to have high Ingelheim, Amgen, Clinigen Group, Ferring Pharmaceuticals, Eli
CV risk. However, a signal of harm with liraglutide suggested by Lily, BMS, Eisai Ltd, outside the submitted work. M.M. reports
two small randomised trials of patients with reduced LVEF, indi- grants from European Community during the conduct of the study
cates that the role GLP-1 RA remains to be defined in individuals and personal fees from Bayer, Novartis, and Servier outside the
with established HF. The three SGLT-2 inhibitors (empagliflozin, submitted work. W.M. has nothing to disclose. M.C.P. reports
canagliflozin and dapagliflozin) have consistently demonstrated a personal fees and other from AstraZeneca; personal fees from
substantial reduction in the risk of HF hospitalisation across the Novartis, Novo Nordisk, Lilly, Bayer; grants and personal fees
spectrum of CV risk and regardless of a history of HF. On that from Beohringer Ingelheim, during the conduct of the study.;
basis, SGLT-2 inhibitors could be recommended to prevent HF personal fees from Maquet, Takeda, null, outside the submitted
hospitalisation in patients with T2DM and high CV risk. Impor- work. M.P. has nothing to disclose. M.M.P. has nothing to disclose.
tantly, this class of medications has a favourable safety profile, with P.P. has nothing to disclose. G.M.C.R. has nothing to disclose.
low risk of hypoglycaemia and beneficial effect on weight con- I.S. has nothing to disclose. J.S. has nothing to disclose. P.M.S.
trol, while serious adverse events (e.g. ketoacidosis, bone fracture received grants/research supports: Ministry of Education, Science
or limb amputations) occur infrequently and could be avoided by and Technological Development of Republic of Serbia; receipt
appropriate patient selection and monitoring. Despite encouraging of honoraria or consultation fees from Servier, Boehringher
results with dapagliflozin, it remains to be determined in ongo- Ingelheim, Hemofarm, Novartis, AstraZeneca; participation in a
ing clinical trials whether SGLT-2 inhibitors could be used for company sponsored speaker’s bureau: Fondazione Internazionale
the treatment of HF, with or without reduced LVEF, and whether Menarini. T.T. reports personal fees from Cardior Pharmaceuticals
their beneficial CV effects could be extended to HF patients GmbH, outside the submitted work. M.V. reports personal fees
without T2DM. from Servier during the conduct of the study.
Conflict of interest: G.A. reports personal fees from Angelini,
Behring, Menarini, outside the submitted work. S.A. reports
grants and personal fees from Vifor Int, Abbott Vascular, and
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doi:10.1002/ejhf.1678
Imaging in patients with suspected acute heart

failure: timeline approach position statement
on behalf of the Heart Failure Association of
the European Society of Cardiology
Jelena Čelutkienė1,2*†, Mitja Lainscak3,4†, Lisa Anderson5, Etienne Gayat6,
Julia Grapsa7, Veli-Pekka Harjola8,9, Robert Manka10,11, Petros Nihoyannopoulos12,
Pasquale Perrone Filardi13, Rosa Vrettou14, Stefan D. Anker15,
Gerasimos Filippatos16, Alexandre Mebazaa17, Marco Metra18, Massimo Piepoli19,
Frank Ruschitzka20, Jose Luis Zamorano21, Giuseppe Rosano22,
and Petar Seferovic23
1 Clinic of Cardiac and Vascular Diseases, Institute of Clinical Medicine, Faculty of Medicine, Vilnius University, Vilnius, Lithuania; 2 State Research Institute Centre For Innovative
Medicine, Vilnius, Lithuania; 3 Department of Cardiology and Department of Research and Education, General Hospital Celje, Celje, Slovenia; 4 Faculty of Medicine, University of
Ljubljana, Ljubljana, Slovenia; 5 Department of Cardiology, Royal Brompton Hospital, Imperial College London, London, UK; 6 Department of Anesthesiology, Burn and Critical
Care Medicine, AP-HP, Saint Louis and Lariboisière University Hospitals, Paris, France; 7 Barts Heart Center, St Bartholomew’s Hospital, London, UK; 8 Emergency Medicine,
Helsinki University, Helsinki, Finland; 9 Department of Emergency Medicine and Services, Helsinki University Hospital, Helsinki, Finland; 10 Institute of Diagnostic and Interventional
Radiology, University Hospital Zurich, Zurich, Switzerland; 11 Department of Cardiology, University Heart Center Zurich, Zurich, Switzerland; 12 Unit of Inherited Cardiovascular
Diseases/Heart Center of the Young and Athletes, First Department of Cardiology, Hippokration General Hospital, National and Kapodistrian University of Athens, Greece;
National Heart and Lung Institute, Imperial College London, London, UK; 13 Department of Advanced Biomedical Sciences, Federico II University, Naples, Italy; 14 Department of
Clinical Cardiology, Attikon University Hospital, National and Kapodistrian University of Athens, Athens, Greece; 15 Department of Cardiology (CVK); and Berlin-Brandenburg
Center for Regenerative Therapies (BCRT); German Centre for Cardiovascular Research (DZHK) Partner Site Berlin, Charité Universitätsmedizin Berlin, Berlin, Germany;
16 Department of Clinical Cardiology, Attikon University Hospital, National and Kapodistrian University of Athens, Athens, Greece; 17 Department of Anesthesiology, Burn and
Critical Care Medicine, AP-HP, Saint Louis and Lariboisière University Hospitals, Paris, France; 18 Cardiology, Department of Medical and Surgical Specialties, Radiological Sciences,
and Public Health, University of Brescia, Brescia, Italy; 19 Cardiac Department, Guglielmo da Saliceto Polichirurgico Hospital AUSL Piacenza, Piacenza, Italy; 20 Department of
Cardiology, Heart Failure Clinic and Transplantation, University Heart Center Zurich, Zurich, Switzerland; 21 Department of Cardiology, Hospital Ramon y Cajal, Madrid, Spain;
22 Clinical Academic Group, St George’s Hospitals NHS Trust, London, UK; Department of Medical Sciences, IRCCS San Raffaele, Rome, Italy; and 23 Faculty of Medicine,
University of Belgrade, Belgrade, Serbia
Received 30 March 2019; revised 15 October 2019; accepted 24 October 2019 ; online publish-ahead-of-print 9 December 2019
Acute heart failure is one of the main diagnostic and therapeutic challenges in clinical practice due to a non-specific clinical
manifestation and the urgent need for timely and tailored management at the same time. In this position statement, the Heart
Failure Association aims to systematize the use of various imaging methods in accordance with the timeline of acute heart fail-
ure care proposed in the recent guidelines of the European Society of Cardiology. During the first hours of admission the
point-of-care focused cardiac and lung ultrasound examination is an invaluable tool for rapid differential diagnosis of acute dys-
pnoea, which is highly feasible and relatively easy to learn. Several portable and stationary imaging modalities are being increas-
ingly used for the evaluation of cardiac structure and function, haemodynamic and volume status, precipitating myocardial ischaemia
or valvular abnormalities, and systemic and pulmonary congestion. This paper emphasizes the central role of the full echocardio-
graphic examination in the identification of heart failure aetiology, severity of cardiac dysfunction, indications for specific heart fail-
ure therapy, and risk stratification. Correct evaluation of cardiac filling pressures and accurate prognostication may help to prevent
.
*Corresponding author. Clinic of Cardiac and Vascular Diseases, Institute of Clinical Medicine, Faculty of Medicine, Vilnius University, Santariškiu¸ 2, LT-08661, Vilnius, Lithuania.
Tel: +370 61600180, Fax: +370 5 2501742, Email: jelena.celutkiene@santa.lt
† These authors contributed equally to the study.
© 2019 The Authors

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182 J. Čelutkienė et al.
unscheduled short-term readmission. Alternative advanced imaging modalities should be considered to assist patient
management in the pre- and post-discharge phase, including cardiac magnetic resonance, computed tomography,
nuclear studies, and coronary angiography. The Heart Failure Association addresses this paper to the wide spectrum
of acute care and heart failure specialists, highlighting the value of all available imaging techniques at specific stages
and in common clinical scenarios of acute heart failure.
..........................................................................................................
Keywords Imaging • Heart failure • Echocardiography • Stress echocardiography • Cardiac magnetic
resonance • Computed tomography • Global longitudinal strain • Nuclear imaging •
Hybrid imaging
Introduction reported to reveal the aetiology of hypotension in 48% of inten-
.................................................................................................................................
sive care patients and change therapy in 60–80% of patients in
Acute heart failure (AHF) has various clinical presentations the pre-hospital setting.6 Thus, we suggest echocardiography is
and it is a common cause to seek medical assistance.1 Many a first-choice test in the differential diagnosis of AHF since it
co-existing or alternative conditions with different pathophysi- enables to promptly detect essential structural abnormalities,
ology can induce similar clinical picture, making the differential systolic and/or diastolic dysfunction, and to facilitate time-sensitive
diagnosis of underlying pathology challenging but crucial for timely decision-making.2–4
and tailored management. Along with the initial routine assess- As recently recommended, focused echocardiography is needed
ment (clinical examination, electrocardiogram) and laboratory in a case of haemodynamic instability in pre-hospital or at hospital
parameters (natriuretic peptides, troponins, D-dimer, inflam- admission to identify or eliminate cardiac cause(s)2,4 (Figure 1).
mation markers), imaging modalities are pivotal for fast triage FoCUS7–9 represents a rapid problem-oriented point-of-care
and accurate diagnosis in emergency departments, as well as for protocol for the emergency department usually limited to sub-
subsequent clinical decisions during the stabilization phase.2–4 This costal long-axis and inferior vena cava views, parasternal long and
document aims to systematize the use of imaging examinations short-axis and apical four-chamber views. FoCUS is possible to
according to the patient care timeline, as indicated in the latest carry out with portable or handheld devices as an adjunct to phys-
heart failure (HF) guidelines of the European Society of Cardi- ical examination, utilizing two-dimensional and colour-Doppler
ology (ESC).2 The diagnostic yield of bedside focused cardiac methods.
ultrasound (FoCUS) and lung ultrasound, providing the shortest The main diagnostic targets, ultrasonic signs and clinical sce-
path to life-saving therapies during first 2 h after admission, is narios in FoCUS echocardiography important for AHF settings
described. As witnessed in recent years, portable ultrasound are listed in Table 1. Simplified ultrasound examination allows
devices are an excellent time-saving tool in the emergency set- to quickly differentiate the type of shock (obstructive, cardio-
tings, representing an extension of the physical examination genic, hypovolaemic or distributive) through the identification
of the chest. of cardiac tamponade, right or left ventricular (LV) dysfunc-
Comprehensive echocardiography has the central role in the tion, lung B-lines, severe valvular dysfunction, or hyperdynamic
assessment of HF type and aetiology, indications for medical and small heart with a small inferior vena cava8,10–12 (Figure 2; online
interventional treatment, and stratification of patients’ risk. Main supplementary Videos S1 and S2).
ultrasound parameters of cardiac structure and function with Detection of regional wall motion abnormalities and absence
abnormality criteria, clinical meaning and practical recommenda- of signs of chronic LV disease typically suggests acute myocardial
tions are summarized in this paper. Correct evaluation of cardiac infarction. Global systolic LV dysfunction usually indicates a diag-
filling pressures and accurate prognostication may help to prevent nosis of cardiogenic pulmonary oedema, though in the substantial
unscheduled short-term readmission. Alternative advanced imag- proportion of patients this condition may be caused by diastolic
ing modalities should be considered to assist patient management dysfunction, hypertensive crisis, acute valvular disease, or atrial
in the pre- and post-discharge phase according to the most com- fibrillation. Early identification of severe LV dysfunction (online
mon scenarios in AHF. supplementary Video S3) and massive mitral regurgitation may
change the prognosis of AHF patients.13 A large jet of mitral regur-
gitation and a clear structural abnormality (such as a flail leaflet)
Imaging in the urgent phase: are typical for severe valvular dysfunction. In the absence of signs
heart failure-oriented focused of right ventricular (RV) failure, FoCUS can rule out an extensive
pulmonary embolism, which involves more than half of the pul-
cardiac ultrasound examination monary vascular bed. When spectral Doppler mode is available,
It has been shown that if the diagnosis of AHF is based on a proposed stepwise algorithm of Cardiopulmonary Assessment
medical history and physical examination only, misdiagnosis in Real-time to Determine Diastolic and Systolic function with
rates may be as high as 33%.5 Meanwhile echocardiography was Sonography (CARDDSS) exam may be utilized to assess pulmonary
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Imaging in acute heart failure 183
Figure 1 Use of imaging modalities in consecutive phases of acute heart failure. FoCUS, focused cardiac ultrasound.
oedema, central venous congestion, and elevated LV end-diastolic over- and under-diagnosis of serious cardiac pathology. There-
....................................................
pressure.7 fore, frequently FoCUS triggers subsequent imaging tests such as

Portable handheld echocardiographs are excellent bedside tools comprehensive echocardiography, computed tomography (CT), or
for a fast patient triage,14 which are expected to be widely cardiac catheterization (Figure 1).
disseminated in the emergency departments, outreach clinics,
coronary and intensive care units. Battery-operated pocket-size
Key points
imaging devices have a very short start-up time, permit prompt
identification of serious structural and/or functional links to
• In haemodynamically unstable patients with suspected AHF,
patient symptoms, leading to faster clinical decisions. The FoCUS
FoCUS combined with lung ultrasound examination helps to
approach, providing a limited number of evidence-based targets
differentiate the type of shock.
(Table 1), requires less training and expertise than full echocar-
• In the early phase of AHF, FoCUS examination is useful to
diography study.14–16 Moreover, recent prospective studies show detect structural and functional abnormalities of the ventricles
that paramedics were successful in obtaining point-of-care cardiac and valves.
ultrasound scans in the field.17,18 • When dyspnoea is accompanied by chest pain, FoCUS as
In an urgent situation with minimal time, critically ill patients initial test can help to distinguish pulmonary embolism, aortic
and challenging conditions, it is difficult to completely avoid both dissection and acute coronary syndrome.
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Table 1 Main diagnostic targets and clinical scenarios in focused cardiac ultrasound examination
Diagnostic targets Ultrasonic signs Clinical scenarios Pitfalls/tricks

...........................................................................................................................................
LV global contractile Visually estimated global LV Myocardial ischaemia, myocarditis, Rare causes: sepsis-related
dysfunction hypokinesia myocardial toxicity, cardiogenic dysfunction, myocardial contusion
shock
LV regional contractile Regional wall motion abnormalities MI, myocarditis, Takotsubo CMP Use contrast agent; wall thickness is
dysfunction (dyssynergy) preserved in acute conditions
Abnormalities of LV size and Dilatation; spherical shape; regional Ischaemic or non-ischaemic CMP; Be aware of apical, mid-ventricular
shape ballooning Takotsubo CMP or basal ballooning
Dynamic LV outflow tract Hyperdynamic motion of the HOCM, Takotsubo CMP; May be haemodynamically unstable,
obstruction outflow tract myocardium; SAM treatment with inotropic agents cause systolic murmur
RV dysfunction, RV pressure RV dilatation, hypokinesia; systolic Massive pulmonary embolism; RV Thrombi in transit may be detected
and/or volume overload or diastolic septal flattening MI; decompensation of chronic in right-side cavities or IVC
RV failure; pulmonary
hypertension
Severe native or prosthetic Leaflet flail, masses, disruption of Acute valvular regurgitation or Think about post-MI papillary muscle
valve dysfunction the valvular apparatus, turbulent obstruction; chronic valvular rupture, chest trauma,
flow, thickened leaflets, reduced disease; thrombosis endocarditis
mobility
Ventricular septal defect or Irregular discontinuity, systolic flow Complications of MI; may be Keep high index of clinical suspicion;
free-wall rupture across the ventricular septum; haemodynamically unstable; check for a new holosystolic
pericardial effusion signs of tamponade murmur; use multiple views
Pericardial effusion; signs of Echo-free space around the heart; Pericarditis; haemopericardium in Accompanied by IVC plethora; viral
tamponade atrial systolic, ventricular aortic dissection; malignancies; or tuberculous aetiology;
diastolic collapse; ‘swinging constrictive pericarditis differentiate from pericardial fat
heart’
Additional cardiac masses Globular echogenic masses may be Thrombi; tumours (myxoma, Do not miss apical LV thrombus due
attached by stalk to interatrial fibroelastoma) in atria and to foreshortening; do not mix
septum or ventricular apex; ventricles with Chiari’s network in RA
assess size, mobility
Aortic dilatation, aneurysm, Dissection membrane or flap; Central aortic regurgitation, Think about reverberation and other
dissection bicuspid aortic valve increased bleeding into pericardial space is artefacts
risk seen frequently
IVC size and respiratory Small end-expiratory size; dilated Hypovolaemia; hypervolaemia and Constrictive pericarditis; restrictive
variations non-collapsing IVC increased RA pressure CMP; tricuspid regurgitation; RV
failure
CMP, cardiomyopathy; HOCM, hypertrophic obstructive cardiomyopathy; IVC, inferior vena cava; LV, left ventricular; MI, myocardial infarction; RA, right atrium; RV, right
ventricular; SAM, systolic anterior motion of the mitral valve.
Imaging in the early phase oedema between emergency physicians and radiologists has been
.................................................
found less than 50%.23,24

Workup for lung congestion and other For differentiation of acute breathlessness, point-of-care bed-
pulmonary conditions: chest X-ray side lung ultrasound has become increasingly available and is a
and lung ultrasound useful tool in the emergency and even pre-hospital settings,25
recommended for diagnosis of pulmonary oedema by an inter-
Though chest X-ray remains a recommended diagnostic method national consensus panel.26 The findings of lung ultrasound are
in patients presenting with acute dyspnoea,2 it requires radiology highly feasible and reproducible, easy to learn, equally reliable in
facilities and specific reading expertise. Chest roentgenograms the hands of experienced and novice sonographers, while patients
are helpful in identification of pulmonary congestion as well as for may be scanned in their position of comfort in 1–5 min. Arte-
alternative pathology, especially pneumonia, pleural effusion and facts caused by the interaction of water-rich and air structures,
pneumothorax. However, published values of sensitivity and speci- called B-lines, represent non-time-consuming ultrasound signs of
ficity of the chest radiograph for detection of pulmonary oedema pulmonary congestion (Figure 3; online supplementary Video S2).
range from 14% to 68% and 53% to 96%, respectively; therefore, When B-lines are widely detected on the anterolateral thoracic
the absence of radiographic sign of congestion does not rule out zones, the diffuse alveolar-interstitial syndrome can be diagnosed
HF.19–22 Notably, the agreement in interpretation of pulmonary with high probability.25 A rapid anterior two-region scan may be
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Figure 2 Echocardiographic images of a young female patient presenting with acute shortness of breath: (A) parasternal short-axis view
showing massive pericardial effusion (blue arrow); (B) four-chamber view revealing a dilated and hypertrophied right ventricle (yellow arrow)
and circumferential pericardial effusion with right atrial collapse (blue arrow). The primary diagnosis was systemic lupus erythematosus.
Figure 3 Two windows of B-lines, positive for interstitial congestion.
sufficient; a positive region is determined by the presence of three disease and acute respiratory distress syndrome,26 but in such
........................................
or more B-lines, two or more positive areas represent a positive cases it is accompanied by pleural, subpleural abnormalities and
exam for interstitial syndrome.27 non-homogeneous distribution of B-lines.
The ability of lung ultrasound to rule in and rule out significant The proposed Bedside Lung Ultrasound in Emergency (BLUE)
interstitial syndrome is superior compared to chest X-ray26,28 and protocol enables differentiation between pulmonary oedema,
may potentially improve patient outcomes.10 Observational stud- emboli, pneumonia, chronic obstructive disease or pneumotho-
ies and systematic reviews, which evaluated the quality of avail- rax, based on the detection of A-, B-lines, lung sliding and lung
able data as average to excellent, have shown the moderately high point10 (online supplementary Video S2). The number of B-lines
(80–90%)29–31 accuracy of lung ultrasound in detection of pul- increases with the severity of congestion and facilitates monitoring
monary oedema, though study populations most frequently had an of response to treatment.26,31 A recent systematic review suggests
increased proportion of AHF and small number of non-cardiogenic that large number of B-lines in AHF patients at discharge identifies
dyspnoea. It is important to note that interstitial syndrome may residual congestion and high risk of HF readmission or death.32
be also caused by interstitial pneumonia, diffuse parenchymal lung Pleural effusion (online supplementary Video S3), pneumonia and
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Figure 4 Echocardiography of a patient with acute onset of chest and back pain: (A) parasternal long-axis view demonstrates aortic dissection
tear (flap showed with yellow arrow, aortic wall with green arrow); (B) parasternal short-axis view on the level of the aortic cusps (blue arrow)
and dissection flap (yellow arrow).
pneumothorax can be also reliably detected with lung ultrasound Direct visualization of the coronary arteries either with inva-
................................................................................................................
(preferably using higher frequency transducer), with very good sive coronary angiography or non-invasively with CT angiography
performance33 and detection threshold that is much better than enables early detection of acute coronary syndrome, which may be
a classical chest X-ray. Looking for latter conditions, the ultra- a precipitating factor of cardiac decompensation. Emergency coro-
sound probe is placed in multiple rib interspaces over the anterior nary angiography and revascularization is the treatment of choice
chest, in the axillary lines and sometimes more posteriorly. Imme- for patients with an acute coronary syndrome and cardiogenic
diate information, provided by thoracic ultrasound, has potentially shock, irrespective of the time onset of ischaemic symptoms.
a positive impact on initial patient care, before the radiographic or New generations of multidetector CT scanners are able to
laboratory results are available. differentiate the diagnoses of the three most common acute con-
ditions in one non-invasive procedure: concurrent coronary, aortic
Key point and pulmonary angiography. This so-called “triple rule-out” (TRO)
CT protocol is probably the most appropriate for patients having
• Lung ultrasound is a fast, reliable and easy-to-learn method for low to intermediate risk for acute coronary syndrome,36 although
detecting interstitial syndrome. it requires a higher dose of radiation. The sensitivity of TRO CT
is reported to be 86–100%, 71% and 94% for detecting acute
coronary syndrome, pulmonary embolism and aortic dissection,
Differentiation with coronary or aortic respectively.37
syndromes and pulmonary embolism: Computed tomography images are also valuable for demonstra-
invasive and computed tomography tion of cardiogenic pulmonary oedema with consistently posterior
angiography involvement of the interstitium, dilated pulmonary veins and unaf-
fected bronchi.38
Fast and accurate triage of patients with AHF, which is accompanied
by potentially life-threatening chest pain, is one of the most
important tasks in the emergency department. We suggest starting Key point
from FoCUS imaging in cases of simultaneous dyspnoea and chest
pain. The initial bedside ultrasound exam may show a thin mobile • In the early hours of AHF differentiation from other acute
dissection membrane or flap attached to the wall of the aorta conditions, CT and coronary angiography are often necessary.
(Figure 4), or remarkable RV dysfunction.
On the next steps, CT is most commonly performed to confirm
or exclude the diagnosis, determine the type and complications
Stabilization phase:
of aortic dissection; though less available, cardiac magnetic res- comprehensive echocardiographic
onance (CMR) has excellent performance in aortic syndromes.34
CT pulmonary angiography is the method of choice to visualize
examination
the pulmonary vascular tree and exclude pulmonary thromboem- In haemodynamically stable patients who are able to lie in decubitus
bolism in haemodynamically stable patients.35 Transoesophageal position, a structured comprehensive echocardiographic examina-
echocardiography (TOE) is equally reliable to CT and CMR for tion is preferable within the first 48 h after admission and should be
the diagnosis of aortic dissection and may help when searching for performed at least before discharge in most patients with a diagno-
emboli in the main pulmonary arteries.34,35 sis of AHF. Additional subcostal, suprasternal or right parasternal
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projections may be necessary in critically ill patients or in patients depends on load conditions, inotropic medications and is not well
........................................................................................................................................................................
under mechanical ventilation. The standards for adequate training studied during ventilatory support.6,11
and education of physicians performing emergency echocardiogra- Global longitudinal strain is recommended by EACVI for the
phy are proposed by the European Association of Cardiovascular evaluation of cardiac performance in all AHF patients, indicat-
Imaging (EACVI),39 highlighting the mandatory supervision by a ing mild and severe dysfunction if reduced ≤16% and ≤10%,
competent independent expert in every single emergency case. respectively6 (online supplementary Video S5).
Appropriate documentation and recording of studies should be Acute dysfunction of the right ventricle, assessed by quantitative
ensued by continuous quality control, correction of errors and sys- systolic parameters, is an indicator of worse prognosis in HF
tematic education. A full echocardiographic investigation generally patients and requires appropriate adjustment of therapy43 (Table 2;
includes cardiac chamber quantification, evaluation of systolic and Figures 5 and 6). In case of RV infarction due to reduced preload, the
diastolic ventricular function, haemodynamic and valvular assess- degree of LV dysfunction can be underestimated. Typical evidence
ment (Table 2). of RV pressure overload is the systolic D-shape deformation of
the ventricular septum and diastolic septal bounce towards the left
(online supplementary Video S6).
Chamber quantification Calculated isovolumetric ventricular time, based on Doppler
Echocardiography is the first-line technique for detection of con- measurements of transmitral and transaortic blood flow, may be
centric or eccentric patterns of ventricular remodelling. The pre- useful for monitoring of myocardial performance during inotrope
dictive value of the presence and severity of LV hypertrophy and infusions.11 Namely, prolongation of total isovolumetric time with
dilatation have been shown in patients with HF.13 A LV diastolic an increase in the dose of inotropes may reflect the direct negative
diameter >55 mm and a diastolic volume index >97 mL/m2 are effect of catecholamines on myocardial function.
characteristic for systolic, while left atrial volume index >34 mL/m2
for diastolic HF. Some acute myocarditis cases may be present Key point
with non-dilated dysfunctional left ventricle. Tachyarrhythmias,
myocardial ischaemia or acute mitral regurgitation due to chordal • Cardiac chamber size, type of hypertrophy, ejection fraction
rupture can trigger AHF in patients with hypertrophic cardiomy- and global longitudinal strain are fundamental measurements
opathy. Cases of hypertrophic left ventricle with restrictive filling of AHF syndrome.
pattern require differentiation with infiltrative cardiomyopathies,
such as amyloidosis or Anderson–Fabry disease. Ratio of RV/LV
diameters >1.0 in apical four-chamber view is typical for acute Haemodynamic and volume status
RV failure. assessment
Echocardiography can be used for the estimation of LV
end-diastolic, pulmonary pressure and pulmonary vascular resis-
Evaluation of ventricular function tance. Although pulmonary pressure parameters have been
A dilated hypokinetic left ventricle may be seen in acute decom- validated against invasive haemodynamics,44 obtaining a qualitative
pensated HF, as well as in acute coronary syndrome, espe- spectrum of tricuspid regurgitation as a requisite for Doppler
cially in those with prior infarctions (online supplementary Video analysis may be challenging in a stressful situation. Measuring LV
S4). Thin, bright, dyssynergic myocardial wall is typical for the outflow tract diameter and velocity–time integral, stroke volume
scar of old infarction. Systolic bulging of the ventricular septum and cardiac output can be accurately calculated.45
toward the RV cavity may be an indirect sign of septal rupture A restrictive pattern of LV filling46 and a short E wave
after myocardial infarction. Regional wall motion abnormalities deceleration47 time are powerful predictors of mortality, and
may be observed not only in coronary syndromes, but also in if irreversible, should prompt consideration of advanced HF ther-
left bundle branch block, LV pre-excitation, paced rhythm, and apies. It is unlikely to find normal e′ in AHF patients, and E/e′
cardiomyopathies. ratio (Figure 7) in most cases provides reliable estimation of LV
A good visualization of the endocardium is crucial for accurate filling pressure,48 except conditions markedly affecting the mitral
assessment of cardiac size and performance. Use of contrast agents annulus.
in critically ill patients may facilitate rapid distinction of systolic In cardiac tamponade due to ventricular interdependence,
and diastolic dysfunction,39 greatly improves the detection rate of left-sided filling significantly drops during inspiration (decrease of
intracardial masses and complications of myocardial infarction.40,41 transmitral E wave velocity of more than 25%) with concomitant
The latter are frequently diagnosed late and require higher level increase of right-sided filling (increase in tricuspid E wave velocity
of suspicion as well as knowledge of specific risk factors, such as of more than 40%). If pericardial effusion (Figure 8) causes car-
older age, female gender, first myocardial infarction, hypertension, diac compression, transient invagination of the walls of atria and
and other.42 right ventricle at the time of the lowest intracavitary pressure is
A well-pumping left ventricle may be combined with dyspnoea observed.49
or pulmonary oedema in hypertensive crisis, atrial fibrillation with The diameter and collapsibility of inferior vena cava allows esti-
rapid heart rate, acute aortic regurgitation, or constrictive peri- mation of right atrial pressure and has been validated in mechani-
carditis. Importantly, in acute settings, ejection fraction particularly cally ventilated patients as a marker of fluid responsiveness.44,50
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188
Table 2 Diagnostic parameters of comprehensive echocardiography relevant in acute heart failure settings
Diagnostic parameter Criterion for abnormality Clinical meaning Recommendations/tricks

...................................................................................................................................................................................................................
Increased LV size LV diastolic diameter >5.2 cm (F), >5.8 cm (M); LV Substantial myocardial damage; dilatative remodelling; Volumes should be routinely assessed; 3D method is preferable
end-diastolic/end-systolic volume index 2D: increased risk of cardiac death, thrombus formation due to better reproducibility, especially for device candidates
>61/24 mL/m2 (F), >74/31 mL/m2 (M); 3D:
>72/29 mL/m2 (F), >80/33 mL/m2 (M)
Increased ventricular wall LV wall: >0.9 cm (F), >1.0 cm (M); RV wall: >0.5 mm Different types of LV hypertrophy; chronic RV pressure Linear method is fast and accurate; 3DE avoids geometric
thickness, LV mass Relative wall thickness > 0.42 LV mass: > 95 g/m2 (F), overload; LV mass is a strong predictor of assumptions, can be most accurate in abnormally shaped
>115 g/m2 (M) cardiovascular events ventricle
Reduced ventricular ejection 2D biplane method of disks is recommended; reduced Increased morbidity and mortality; guidelines direct Should be reported with ventricular volumes for assessment
fraction LVEF <50%; mildly reduced LVEF 40–49%; 3D LVEF treatment for medications and devices of cardiac output; 3DE has superior accuracy, suitable for RV
<57% (F), <54% (M) 3D RVEF <45%
Reduced GLS LV GLS <20%; RV free wall GLS <23%; GLS <15% Impaired longitudinal function in various types of Adds incremental predictive value regardless of ejection fraction
associated with worse outcomes remodelling
Increased WMSI Reduced or absent wall thickening and endocardial motion Abnormal regional myocardial function, frequently 16 or 17-segment models, 4-grade scoring are used to assess
of myocardial segment; semiquantitative WMSI >1 related to coronary perfusion territories stress-induced ischaemia
E/A ratio of mitral inflow E/A ≤ 0.8 along with E ≤ 50 cm/s is consistent with normal Identifies filling patterns, which correlate better with Mitral annular velocities are needed to differentiate normal from
LA pressure; E/A ≥ 2 means elevated LA pressure; in filling pressures and prognosis than LVEF pseudonormal pattern
‘gray zone’ E/e’ ratio, LA volume index and TR jet
velocity are necessary
Increased mitral E/e′ ratio Resting E/e’ >13 is a criterion for HFpEF diagnosis; Elevated LV filling pressures; normal e’ is unusual for Stress E/e’ >14 increases the sensitivity of HFpEF diagnosis
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e’ < 9 cm/s in diastolic dysfunction HF
Shortened early filling E wave deceleration time <150 ms is associated with poor Increased LV chamber stiffness; predictor of cardiac Highly accurate both in sinus rhythm and atrial fibrillation; think
deceleration time prognosis mortality about cardiac transplant
Reduced RV function TAPSE <1.7 cm; tricuspid annular S′ <9.5 cm/s; fractional Markers of global RV dysfunction with established Reflect interaction of RV contractility and load; indicators
area change <35% prognostic value of poor prognosis
Increased systolic pulmonary Estimated using peak tricuspid regurgitant jet velocity Pre- or post-capillary pulmonary hypertension Left-sided disease and pulmonary embolism are the most frequent
artery pressure >2.8 m/s decrease survival causes
LVOT TVI LVOT TVI <15 cm Reduced LV stroke volume and cardiac output Susceptibility to hypotension and pump failure
Significant MR Effective regurgitant orifice area ≥20 mm2 and regurgitant Correction may improve survival; may be papillary Look for tenting of mitral leaflets, central turbulent or eccentric
volume ≥30 mL for secondary MR; vena contracta muscle dysfunction or rupture jet; assess carefully eccentric jet
≥0.7 cm
Severe tricuspid regurgitation Effective regurgitant orifice area ≥40 mm2 ; tricuspid Most often caused by RV dysfunction, pressure/volume Severe leaflet tethering is seen; other causes: infective endocarditis,
annulus ≥40 mm2 or >21 mm2 /m2 is an indication to overload, has dynamic nature thoracic trauma
consider surgery as an adjunct to left-sided surgery
Increased LA volume index LA volume index >34 mL/m2 is a predictor of death, atrial Reflects LV diastolic dysfunction, disease chronicity Is seen in significant mitral valve disease, arrhythmias
fibrillation, HF
Cardiac compression or Increased transmitral and aortic flow reduction during Ventricular interdependence in cardiac tamponade, Right atrium and ventricle may collapse at lowest intracavitary
constriction inspiration >25%; interventricular septum shift to the left constrictive pericarditis pressures; decrease in left-sided filling
2D, two-dimensional; 3D, three-dimensional; 3DE, three-dimensional echocardiography; A, A wave velocity; CMP, cardiomyopathy; E, E wave velocity; GLS, global longitudinal strain; HF, heart failure; HFpEF, heart failure with preserved ejection fraction; LA, left atrial; LV,
left ventricular; LVEF, left ventricular ejection fraction; LVOT, left ventricular outflow tract; MR, mitral regurgitation; RV, right ventricular; TAPSE, tricuspid annular plane systolic excursion; TVI, time–velocity integral; WMSI, wall motion score index.
© 2019 The Authors

J. Čelutkienė et al.

mitral regurgitation mechanism, for example, either dilatation of
........................................................................................................................................................................
the mitral annulus or structural abnormality of the valvular appa-
ratus including chordal rupture or leaflet prolapse, is necessary
for therapeutic decision. The characteristic signs of severe mitral
regurgitation include wide vena contracta (Table 2), large repro-
ducible proximal acceleration zone on the ventricular side, systolic
retrograde flow in the pulmonary veins, high transmitral E wave
and increased pulmonary artery pressure; meanwhile size of colour
Doppler jet might underestimate severity because of rapid equal-
ization of pressures.
In patients with AHF complicating severe aortic stenosis, the
prognosis is extremely poor, with all-cause mortality reach-
ing 62% within 5 years.51 Given the high (41%) prevalence of
low-flow, low-gradient aortic stenosis in AHF patients,51 low-dose
dobutamine echocardiography can often be used to differentiate
pseudo- and true stenosis.
Prosthetic valves should be evaluated for possible obstruction
by inspection of disk motion (which is also feasible with cineflu-
oroscopy) and Doppler technique. A reduced or absent leaflet
motion coupled with twice as high transvalvular gradient as that
given for normal prosthetic model is the hallmark of prosthetic
valve thrombosis.52 Vegetations may be seen as mobile irregu-
lar masses attached to prosthetic structures most frequently on
low-pressure side: atrial and ventricular side in mitral and aortic
prostheses, respectively.
Role of transoesophageal
echocardiography
Transoesophageal echocardiography is an accurate tool in case
of poor image quality and in providing adequate visualization of
thoracic aorta (to rule out aortic dissection), pulmonary artery,
native and prosthetic heart valves. TOE may be the best echocar-
diographic method to determine the principal reason of patient’s
haemodynamic instability, particularly if there is a high clinical sus-
picion of myocardial infarction complication or the patient remains
Figure 5 Echocardiographic signs of right ventricular dysfunc- unstable despite revascularization. TOE is also beneficial in urgent
tion and pulmonary hypertension: (A) reduced tissue Doppler S′ cases when after transthoracic examination uncertainty persists
velocity of tricuspid valve (7 cm/s); (B) reduced tricuspid annular regarding papillary muscle or chordal rupture, infective endocardi-
plane systolic excursion (TAPSE) up to 1.1 cm; (C) systolic gradi- tis or acute prosthetic dysfunction, and cardiac tumours. This
ent between the right ventricle and the right atrium ranges from modality is recommended when urgent electrical or pharmacolog-
30 to 50 mmHg depending on cardiac cycle in irregular rhythm. ical cardioversion is needed to rule out intracavitary thrombi.2
Key point
Imaging before or after discharge
• Comprehensive echocardiography enables to non-invasively Magnetic resonance imaging
assess cardiac filling pressures, pulmonary hypertension, and Once the patient is stabilized, CMR has an important comple-
volaemic status. mentary role to echocardiography for the evaluation of HF aeti-
ology. In addition, CMR is the gold standard for the assessment
of ejection fraction and cardiac chamber volumes as it offers
Valvular abnormalities the highest reproducibility among all imaging modalities. Further-
A specific target for evaluation should be the presence and sever- more, CMR uniquely enables myocardial tissue characterization,
ity of mitral regurgitation as an important marker of adverse ischaemia/viability assessment, and confirmation of LV thrombus
prognosis. Not only quantification but also identification of the formation in one examination.2,53–55
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Figure 6 Two-dimensional speckle tracking of the right ventricle showing moderately reduced deformation with regional differences. AVC,
aortic valve closure; GS, global strain.
In patients with AHF, segmented k-space acquisitions that idiopathic dilated cardiomyopathy whereas a patchy distribution
.......................................................................................
require a regular cardiac rhythm and multiple breath holds may be is found in cardiac sarcoidosis and lateral wall enhancement is
difficult to perform (Figure 9). Parallel imaging and partial Fourier seen in Anderson–Fabry disease and mitochondrial cardiomy-
techniques decrease breath hold time and real-time cine imag- opathy. Due to the need for a specific therapy, CMR should
ing enables functional assessment even without electrocardiogram be performed at the earliest opportunity in patients with AHF
gating.56 Single-shot late gadolinium enhancement (LGE) enables and cardiac amyloidosis and in suspected cardiac iron over-
fibrosis and scar assessment of the heart in one heartbeat without load (using T2* imaging) to expedite definitive diagnosis and
breath holding57,58 (Figure 10). treatment.63,64
In acute coronary syndrome wall motion abnormalities, oedema
and endo-to-transmural LGE related to coronary territories are
observed. In Takotsubo cardiomyopathy, the patient presents with Stress and nuclear imaging
wall motion abnormalities, myocardial oedema with raised T2 Stress imaging may be considered if ischaemic aetiology or an
values, but no LGE. In contrast, in myopericarditis, wall motion underlying valvular pathology in AHF are suspected to assess
abnormalities, sub-epicardial to transmural oedema and LGE are the presence and severity of these conditions. Depending on the
found (Figure 11; online supplementary Video S7), with diffuse LGE availability and expertise in imaging modalities and the patient
and oedema in giant cell myocarditis. characteristics, the clinician may choose stress echocardiography,
Importantly, despite normal coronary angiography, in >10% of CMR, or nuclear imaging.2,65,66
patients with ‘non-ischaemic dilated cardiomyopathy’ CMR shows Complementary assessment of coronary flow, contractile
typical ischaemic LGE distribution.59 Myocardial perfusion assess- reserve, myocardial deformation and interstitial lung fluid during
ment with adenosine vasodilator stress is well established and stress echocardiography, in addition to conventional evaluation of
safe.60 wall motion abnormalities, has a potential to increase its diagnos-
For dilated cardiomyopathy patients, LGE predicts all-cause tic and prognostic value.67 Microvascular integrity evaluated by
mortality and hospitalization for HF, sudden cardiac death, myocardial contrast echocardiography and response to low-dose
ventricular arrhythmias, and appropriate defibrillator shocks.61 dobutamine infusion may be used for prediction of functional
Myocardial inflammation and oedema are detected with T2 recovery after acute myocardial damage.
mapping and T2-weighted CMR, whereas myocardial infiltra- Stress–rest myocardial perfusion single photon emission com-
tion and fibrosis are detected with T1-weighted LGE and T1 puted tomography (SPECT) is an option for assessing severity and
mapping, which has an evolving role for detection of intersti- extent of ischaemia in patients presenting with AHF who have
tial myocardial fibrosis.62 Mid-wall LGE is a typical finding in coronary artery disease and no angina.68,69 Stress–rest perfusion
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........................................................................................................................................................................
Figure 8 Echocardiographic long parasternal image discerning
a difference between pericardial and pleural effusion. LA, left
atrium; LV, left ventricle; MV, mitral valve; RV, right ventricle.
Reprinted from Goodman et al.49
positron emission tomography (PET), with quantitative measure-

ment of myocardial blood flow and flow reserve, has higher accu-
racy to detect coronary artery disease compared with relative
regional perfusion analysis, reducing the number of false negative
and false positive tests.70 PET with 18-FDG and 13N-ammonia pro-
vides a reliable evaluation of myocardial viability.71,72 In patients
with AHF, combining anatomical and functional imaging, hybrid
SPECT/PET-CT might be useful to identify quickly the aetiology
of the disease and, in the presence of obstructive coronary artery
disease, to indicate and guide revascularization.73
In the diagnostic workup of cardiac amyloidosis, nuclear imaging
with bone tracers, including [99mTc]-DPD and [99mTc]-PYP,
may reliably detect ATTR amyloidosis and discern it from
AL type.74
Labelling of metaiodobenzylguanine with radioactive 123-iodine
(123I-MIBG) enables scintigraphic visualization of the pre-synaptic
sympathetic nerve endings and depicts the status of cardiac inner-
vation, which is associated with the prognosis of HF patients.75–77
Of note, according to 123I-MIBG imaging, a temporary decrease
of norepinephrine uptake in the myocardium is typical for an exac-
erbation of HF and may be a potential therapeutic target.78,79 How-
ever, additional radiation exposure should be weighed against the
impact on clinical decisions in HF patients who are at increased risk
of developing cancer.
Computed tomography and invasive

imaging
Guidelines of the European Society of Cardiology on HF diagnosis
and treatment2 recommend that coronary angiography should be
considered in patients suffering from angina, as well as those with a
Figure 7 (A) Transmitral blood flow, E wave velocity 70 cm/s. (B) history of symptomatic ventricular tachycardia or aborted cardiac
Medial mitral annular tissue velocity e’ 4 cm/s. (C) Lateral mitral arrest. In the absence of angina symptoms, the reasonable approach
annular tissue velocity e’ 5 cm/s. is to perform invasive imaging in patients with intermediate to high
probability of coronary artery disease depending on the results of
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Figure 9 Cardiac magnetic resonance: single end-diastolic frame from a segmented k-space cine (A) and real-time cine (B) scan of
four-chamber view.
Figure 10 Cardiac magnetic resonance: single end-diastolic frame from a segmented k-space late gadolinium enhancement (A) and single-shot
late gadolinium enhancement (B) scan in a patient with atrial fibrillation and inability to breath hold; two-chamber view.
non-invasive stress tests (Figure 1). When results of stress tests Conclusions
................................
are equivocal or pre-test probability low to intermediate, in the

absence of contraindications non-invasive visualization of coronary The entire spectrum of non-invasive and invasive imaging modal-
anatomy by CT may be preferred. ities is increasingly being used to identify the underlying causes,
confirm or differentiate diagnosis and make clinical decisions in
patients with suspected AHF. The integration of focused car-
Key point diac and lung ultrasound into acute care at an early stage
makes it possible to revolutionize the urgent workup provid-
• After the AHF patient has stabilized, advanced imaging tech- ing a prompt correct diagnosis and immediate life-saving ther-
niques help in determining HF aetiology, assessing myocardial apy. Detailed expert level echocardiography is of paramount
blood flow and risk stratification. importance for reviewing the need for specific HF therapy and
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Supplementary Information
........................................................................................................................................................................
Additional supporting information may be found online in the
Supporting Information section at the end of the article.
Video S1. Echocardiographic four-chamber view of an elderly
female patient with dyspnoea who lost consciousness in the emer-
gency department; multiple large mobile thrombi are seen in the
severely dilated dominating right chambers.
Video S2. Lung ultrasound: multiple laser-like B-lines are consis-
tent with pulmonary oedema.
Video S3. A 72-year-old female complaining of dyspnoea in the
last few days. (A) Left-side hydrothorax with pleural carcinomatosis
masses, causing compression of the heart. (B) Non-collapsing
dilated inferior vena cava, hyperaemic hepatic veins.
Video S4. Remarkable left ventricular systolic dysfunction with
akinesis and wall thinning in inferior and posterior walls: (A)
parasternal short-axis view at the mid left ventricle; (B) parasternal
long-axis view.
Video S5. Two-dimensional speckle tracking of the left ventricle
showing severely reduced deformation with substantial difference
between four-chamber (A) and two-chamber (B) views, indicating
regional wall motion abnormalities.
Video S6. Signs of right ventricular dysfunction and pressure
overload: (A) marked right ventricular dilatation, septal shift and D
shape of the left ventricle; (B) severely diminished right ventricular
contractility.
Video S7. Cardiac magnetic resonance: patient with chest pain
and mildly reduced ejection fraction showing regional wall motion
abnormalities in the anterior wall; (A) two-chamber view; (B)
cineloop of the entire left ventricle in short axis.
Conflict of interest: none declared.
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JOINT PUBLICATIONS
FROM European Society
of Cardiology Registries
& The Heart Failure

Association
Published in the European Journal of Heart Failure
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doi:10.1002/ejhf.1492
Acute heart failure congestion and perfusion

status – impact of the clinical classification on
in-hospital and long-term outcomes; insights
from the ESC-EORP-HFA Heart Failure
Long-Term Registry
Ovidiu Chioncel1*, Alexandre Mebazaa2, Aldo P. Maggioni3,4, Veli-Pekka Harjola5,
Giuseppe Rosano6,7, Cecile Laroche8, Massimo F. Piepoli9, Maria G. Crespo-Leiro10,
Mitja Lainscak11, Piotr Ponikowski12,13, Gerasimos Filippatos14,15,
Frank Ruschitzka16, Petar Seferovic17, Andrew J.S. Coats18, and Lars H. Lund19,20,
on behalf of the ESC-EORP-HFA Heart Failure Long-Term Registry Investigators†
1 Emergency Institute for Cardiovascular Diseases ‘Prof. C.C.Iliescu’, University of Medicine Carol Davila, Bucharest, Romania; 2 University of Paris Diderot, Hôpitaux
Universitaires Saint Louis Lariboisière, APHP, Paris, France; 3 ANMCO Research Center, Florence, Italy; 4 EURObservational Research Programme, European Society of
Cardiology, Sophia-Antipolis, France; 5 Emergency Medicine, University of Helsinki, Helsinki University Hospital, Helsinki, Finland; 6 Cardiovascular Clinical Academic Group,
St George’s Hospitals NHS Trust University of London, London, UK; 7 IRCCS San Raffaele Roma, Rome, Italy; 8 EURObservational Research Programme, European Society of
Cardiology, Sophia-Antipolis, France; 9 Cardiology Department, Polichirurgico Hospital G. da Saliceto, Cantone del Cristo, Piacenza, Italy; 10 Unidad de Insuficiencia Cardiaca y
Trasplante Cardiaco, Complexo Hospitalario Universitario A Coruna (CHUAC), INIBIC, UDC, CIBERCV, La Coruna, Spain; 11 Department of Internal Medicine, and Department
of Research and Education, General Hospital Murska Sobota, Murska Sobota, Slovenia; 12 Department of Heart Diseases, Wroclaw Medical University, Wroclaw, Poland;
13 Cardiology Department Centre for Heart Diseases, Military Hospital, Wroclaw, Poland; 14 National and Kapodistrian University of Athens, Athens, Greece; 15 University of
Cyprus, Nicosia, Cyprus; 16 Universitäts Spital Zürich, Zürich, Switzerland; 17 University of Belgrade, Faculty of Medicine, Belgrade, Serbia; 18 IRCCS San Raffaele Pisana, Rome,
Italy; 19 Heart and Vascular Theme, Karolinska University Hospital, Stockholm, Sweden; and 20 Department of Medicine, Karolinska Institutet, Stockholm, Sweden
Received 21 February 2019; revised 7 April 2019; accepted 23 April 2019 ; online publish-ahead-of-print 24 May 2019
Aims Classification of acute heart failure (AHF) patients into four clinical profiles defined by evidence of congestion and per-
fusion is advocated by the 2016 European Society of Cardiology (ESC)guidelines. Based on the ESC-EORP-HFA Heart
Failure Long-Term Registry, we compared differences in baseline characteristics, in-hospital management and out-
comes among congestion/perfusion profiles using this classification.
.....................................................................................................................................................................
Methods We included 7865 AHF patients classified at admission as: ‘dry-warm’ (9.9%), ‘wet-warm’ (69.9%), ‘wet-cold’ (19.8%)
and results and ‘dry-cold’ (0.4%). These groups differed significantly in terms of baseline characteristics, in-hospital management
and outcomes. In-hospital mortality was 2.0% in ‘dry-warm’, 3.8% in ‘wet-warm’, 9.1% in ‘dry-cold’ and 12.1%
in ‘wet-cold’ patients. Based on clinical classification at admission, the adjusted hazard ratios (95% confidence
interval) for 1-year mortality were: ‘wet-warm’ vs. ‘dry-warm’ 1.78 (1.43–2.21) and ‘wet-cold’ vs. ‘wet-warm’
1.33 (1.19–1.48). For profiles resulting from discharge classification, the adjusted hazard ratios (95% confidence
interval) for 1-year mortality were: ‘wet-warm’ vs. ‘dry-warm’ 1.46 (1.31–1.63) and ‘wet-cold’ vs. ‘wet-warm’
2.20 (1.89–2.56). Among patients discharged alive, 30.9% had residual congestion, and these patients had higher
1-year mortality compared to patients discharged without congestion (28.0 vs. 18.5%). Tricuspid regurgitation,
diabetes, anaemia and high New York Heart Association class were independently associated with higher risk of
congestion at discharge, while beta-blockers at admission, de novo heart failure, or any cardiovascular procedure
during hospitalization were associated with lower risk of residual congestion.
*Corresponding author. Institute of Emergency for Cardiovascular Diseases ‘Prof. C.C. Iliescu’, University of Medicine and Pharmacy Carol Davila, Bucuresti 950474, Romania. Tel:
+40 745400498, Fax: +40 21 3175224, Email: ochioncel@yahoo.co.uk
† Listed in Appendix 1.
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Impact of congestion and hypoperfusion classification on outcomes 1339
Conclusion Classification based on congestion/perfusion status provides clinically relevant information at hospital admission
and discharge. A better understanding of the clinical course of the two entities could play an important role towards
the implementation of targeted strategies that may improve outcomes.
..........................................................................................................
Keywords Acute heart failure • Congestion • Perfusion • Forrester classification • Registry •
Outcomes
Introduction and outcomes associated with each clinical profile, defined at both
.............................................................................................................................................
admission and discharge.
Acute heart failure (AHF) includes a wide spectrum of clinical
conditions with varied aetiologies and triggers.1 The pathophysi-
ology of AHF is also diverse, and involves various haemodynamic Methods
abnormalities related to elevated ventricular filling pressure and/or
reduced cardiac output, clinically manifesting as congestion and Study design
hypoperfusion.2 – 6 The ESC-EORP-HFA HF-LT Registry is an ongoing, prospective,
Classification of AHF patients by evidence of congestion and per- multinational, multicentre, observational study of patients present-
fusion was introduced by the 2016 European Society of Cardiology ing to 211 cardiology centres from 21 European and Mediterranean
(ESC) heart failure (HF) guidelines with recommended treatment countries.9 – 11 Centre selection took into account the population of
approaches for each category.1 This classification scheme is based each country (one centre/2 million people) and representation of each
on bedside evaluation and categorization by clinical signs of con- category of hospitals and hospital facilities according to the distribu-
tion of the different types of medical centres in the individual country,
gestion (‘wet’ vs. ‘dry’ if present vs. absent) and hypoperfusion
approximately 20% of centres providing cardiac surgery, 30% that do
(‘cold’ vs. ‘warm’ if present vs. absent),1 to allow differentiation
not provide cardiac surgery but do provide interventional cardiology,
into four distinct profiles: ‘wet-warm’ – patients demonstrating
and 50% community centres providing neither cardiac surgery nor
congestion and adequate peripheral perfusion; ‘wet-cold’ – with interventional cardiology. Patients were included one day per week.
congestion and hypoperfusion; ‘dry-cold’ – free of congestion but Ethics approvals were obtained for all sites and written informed con-
with hypoperfusion; and ‘dry-warm’ – free of either congestion or sent was provided by all patients. The EORP Department of the ESC
hypoperfusion. The classification was originally proposed by For- was appointed to coordinate the project operationally, provide support
rester and Waters3 and then clinically adapted by Nohria et al.4 to the committees, national coordinators, and participating centres,
Although invasive haemodynamic data could refine classification and to oversee the methodological concepts of the survey and statis-
based on clinical examination and would improve guiding of intra- tical analysis.
venous (i.v.) therapies, the results of the ESCAPE trial7 showed
no benefit in terms of mortality and HF readmissions from inva-
sive assessment of haemodynamics by pulmonary artery catheter Patients and data
compared to rigorous clinical assessment. All patients admitted to hospital for AHF (either pre-existing or
Previous studies4,8 have yielded conflicting evidence about the new-onset HF) were included, and age < 18 years was the only
reliability of congestion/hypoperfusion profiling to offer prognos- exclusion criterion. A diagnosis of AHF was made by the
clinician-investigators at initial presentation and required the presence
tic information. However, these studies had small sample size,
of signs and symptoms of HF, evidence of cardiac dysfunction, and the
enrolling less than 500 patients, and selectively included only
need for therapy.1
those patients with advanced HF and very low ejection fraction.4,8 In the ESC-EORP-HFA HF-LT Registry, data from a comprehen-
Although proposed by the recent ESC guidelines,1 this classifica- sive clinical examination were collected at both admission and dis-
tion has never been validated in an unselected ‘real-world’ AHF charge. Based on the findings from clinical examination at admission,
population including patients from the entire continuum of clini- patients were retrospectively classified into four profiles according
cal severity and with any range of left ventricular ejection fraction to the 2016 ESC guidelines1 : no congestion and no hypoperfusion
(LVEF). (‘dry-warm’), congestion without hypoperfusion (‘wet-warm’), hypop-
The ESC-EURObservational Research Programme erfusion without congestion (‘dry-cold’), and congestion and hypoper-
(EORP)-Heart Failure Association (HFA) Heart Failure Long-Term fusion (‘wet-cold’).
(HF-LT) Registry is the largest pan-European cohort with sys- To categorize as congestion, at least one of the following clinical
signs collected in the case report form should be present: pulmonary
tematic collection of baseline, discharge and 1-year follow-up
rales, peripheral bilateral oedema, jugular venous distension > 6 cm,
data, providing contemporary information about the whole
hepatomegaly, hepatojugular reflux. Hypoperfusion was defined by the
spectrum of AHF patients, from all regions of Europe and affili- presence of either cold extremities or other peripheral hypoperfusion
ated countries at a mix of primary, secondary and tertiary care signs (oliguria or mental confusion).
centres.9 – 11 The objectives of this analysis were to use the Patients who survived during hospitalization were again re-classified
congestion/hypoperfusion classification in ESC-EORP-HFA HF-LT into the same four profiles, based this time on clinical signs collected
Registry, and to describe the baseline features, treatment patterns at discharge.
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1340 O. Chioncel et al.
Statistical analysis ‘wet-cold’ (57.8%), but also as ‘wet-warm’ (13.0%), ‘dry and cold’
........................................................................................................................................................................
(26.4%), and even ‘dry and warm’ (2.8%).
All results were summarized overall and then stratified by the
four clinical profiles. Baseline continuous variables were reported
as mean ± standard deviation or median and interquartile range (IQR),
as appropriate. Comparisons among groups were made using t-test
Baseline characteristics
and Kruskal–Wallis test, as appropriate. Categorical variables were by congestion/hypoperfusion
reported as percentages and compared using chi-square test, or classification
Fisher’s exact test if any expected cell count was less than five.
In-hospital and 1-year outcomes were reported stratified by conges- Detailed baseline characteristics stratified by congestion/perfusion
tion/hypoperfusion classification. Plots of the Kaplan–Meier curves for at admission are presented in Table 1. Patients classified as
time to all-cause death and time to first all-cause death or HF hospital- ‘dry-warm’ were younger and more frequently male and had
ization were performed for clinical profiles identified at admission and more commonly a history of percutaneous coronary interven-
discharge, and survival distributions were compared using the log-rank tion/coronary artery bypass graft or device implants. Overall,
test. In addition to unadjusted Kaplan–Meier curves, the associations 86.9% of patients classified as ‘wet-warm’ presented at admis-
between clinical profiles and in-hospital and 1-year all-cause mortality sion with NYHA class III and IV, compared to only 47% for
were assessed using Cox proportional hazard models with multivari- ‘dry-warm’ patients. SBP < 90 mmHg at admission was reported
able adjustment for baseline relevant variables: age, gender, New York
in 6.4% of ‘wet-cold’ and 1.6% of ‘wet-warm’ patients. The low-
Heart Association (NYHA) class, systolic blood pressure (SBP), LVEF,
est haemoglobin levels were reported in ‘wet-warm’ patients.
serum sodium, serum creatinine, and blood urea nitrogen (BUN).
For AHF patients who survived during hospitalization, a multivari-
‘Wet-cold’ patients had more frequently diabetes (41.3%) and base-
able logistic regression analysis was performed to identify independent line renal dysfunction (creatinine > 1.5 mg/dL) (35.4%) and had the
predictors associated with congestion at discharge. All variables at highest levels of B-type natriuretic peptide (BNP) or N-terminal
entry with at least 70% of available data, which were statistically sig- proBNP (NT-proBNP).
nificant at univariate analysis (P < 0.10) were included, and variables Echocardiography was obtained during hospitalization in 79.8%
considered of relevant clinical interest were forced into the multi- of patients. On the basis of LVEF categories, HF with reduced
variable model, even if P-value was not <0.10 in univariate analysis. (HFrEF), mid-range (HFmrEF) and preserved ejection fraction
A significance level of 0.05 was required to enter a variable into the (HFpEF) was present in 51.1%, 25.1% and 23.8% of patients,
model (SLENTRY = 0.05) and a significance level of 0.05 was required respectively. When AHF patients were stratified by LVEF cate-
for a variable to stay in the model (SLSTAY = 0.05). Missing values were
gories, the ‘wet-warm’ profile was identified in 67.3% of HFrEF
not imputed.
patients, in 72.7% of HFmrEF patients and in 73.4% of HFpEF
A two-sided P-value <0.05 was considered statistically significant.
All analyses were performed using SAS statistical software version 9.4 patients (online supplementary Figure S2). The ‘wet-cold’ profile
(SAS Institute, Inc., Cary, NC, USA). was more common in HFrEF patients (22.7%).
Moderate to severe mitral and tricuspid regurgitation were
reported in 65.7% and 50.6% of ‘wet-cold’ patients, respectively.
Results
Clinical profile classification In-hospital therapies and procedures
The registry enrolled 8290 patients hospitalized for AHF, of whom Utilization of i.v. treatments, interventional procedures and car-
7865 had detailed physical examination to allow classification into diovascular therapies is presented in Table 2. The proportion of
four clinical profiles, thus the study population included 7865 patients treated with i.v. diuretics varied among the four groups,
patients hospitalized for AHF. between 30% and 88%. Overall, inotropes and vasopressors were
Classifying patients with AHF by clinical signs of conges- used in 11.7% of patients, and the highest proportion was observed
tion/hypoperfusion collected at admission yielded four mutu- in the ‘wet-cold’ profile (27.8%). Interestingly, invasive procedures
ally exclusive categories: ‘dry-warm’ (9.9%), ‘wet-warm’ (69.9%), were not more common among the cold profiles. Utilization of car-
‘wet-cold’ (19.8%), and ‘dry-cold’ (0.4%) (Figure 1). During hospi- diovascular therapies increased during hospitalization in the warm
talization, 417 patients died (5.3%) and classification at discharge profiles, and decreased in the cold profiles. During hospitaliza-
was performed in the remaining of 7448 patients who survived. tion, the highest implant rates of cardiac resynchronization ther-
Classification at discharge differed from admission, and patients apy (CRT) and implantable cardioverter-defibrillator (ICD) was in
classified at admission in one of the four clinical profiles fre- ‘dry-warm’ patients.
quently had migrated by the time of discharge into other cate-
gories (Figure 1). The distribution of patients classified at admission
by congestion/hypoperfusion status according to the two classifi- In-hospital course
cation systems recommended by previous guidelines (i.e. clinical During hospitalization, 417 (5.3%) patients died, and classification
phenotypes11,12 and SBP categories at admission13 ) is presented performed at discharge in alive patients showed that 30.9% of dis-
in the online supplementary Figure S1. The ‘wet-warm’ category charged patients still had signs of residual congestion (Figure 1).
was the most prevalent in all clinical profiles, except for cardio- Using a multivariable logistic regression model (Table 3), moder-
genic shock (CS). Patients with CS presented most commonly as ate to severe tricuspid regurgitation, diabetes and worse NYHA
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Figure 1 Classification based on congestion/hypoperfusion status assessed by clinical examination performed at admission and discharge.
Classification at discharge was used in 7448 patients discharged alive.
class were independent risk markers for congestion at discharge. ‘wet-warm’ patients had higher mortality than ‘dry-warm’ patients,
......................................................
In contrast, beta-blocker at admission, high haemoglobin levels at mortality rates did not differ significantly by pairwise comparison
admission, de novo HF and any procedure during hospitalization in the adjusted model. In both unadjusted and adjusted models,
were associated with lower risk of residual congestion. in-hospital mortality of ‘wet-cold’ patients was significantly higher
During hospitalization, body weight decreased in 65.2% of compared to other groups.
patients and 24.4% were discharged with NYHA class III and IV
(Table 4). In-hospital all-cause mortality was 5.3%, and the high-
est rate was noted in ‘wet-cold’ patients (12.1%) vs. 9.1%, 2.0% Clinical profiles and one-year outcomes
and 3.8% in the ‘dry-cold’, ‘wet-warm’ and ‘dry-warm’ categories, Figure 3 shows the Kaplan–Meier curves for all-cause mortality, and
respectively (Table 4). Of the total number of deaths occurring the composite event of all-cause mortality and HF hospitalization
during hospitalization, the ‘wet-warm’ profile was associated with for AHF patients stratified by clinical profiles assessed at admission
50.3% of deaths and the ‘wet-cold’ profile with 45.1% of deaths and discharge (again excluding the ‘dry-cold’ profile because of the
(online supplementary Figure S3). For the deaths collected between few patients in this group). One-year all-cause mortality ranged
discharge and 1-year follow-up, 82.1% of deaths were associated from 12.1% in ‘dry-warm’ to 26.4% in ‘wet-cold’ patients, and
with the ‘wet-warm’ profile and 11.2% were associated with the most of deaths were due to cardiovascular causes (Table 4). AHF
‘wet-cold’ profile. patients presenting as ‘wet-warm’ and ‘wet-cold’ had the highest
Cox proportional hazard model for in-hospital all-cause mor- 1-year HF hospitalization rate. Patients free of congestion at
tality (Figure 2) showed that although in the unadjusted model discharge had a significantly lower 1-year mortality compared to
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Table 1 Epidemiology and baseline characteristics by congestion and hypoperfusion status at admission
Overall Dry-warm Wet-warm Dry-cold Wet-cold P-value

(n = 7865) (n = 785) (n = 5492) (n = 33) (n = 1555)
...........................................................................................................................................
Age (years) 69.0 ± 12.9 65.8 ± 12.2 69.2 ± 13.2 70.8 ± 11.9 70.1 ± 12.1 <0.001
Male sex 62.9 67.3 62.8 57.6 61.2 0.033
History
Diabetes 39.0 31.6 39.4 36.4 41.3 <0.001
Previous MI 53.4 54.8 51.4 81.8 59.1 <0.001
PCI 20.3 30.2 18.8 36.4 20.3 <0.001
CABG 10.0 10.6 9.8 6.1 10.5 0.629
PM 6.4 6.7 6.4 3.0 6.4 0.865
CRT-P 0.7 0.9 0.7 3.0 0.6 0.353
CRT-D 2.9 4.4 2.5 0.0 3.7 0.004
ICD 4.7 9.5 4.0 0.0 4.9 <0.001
Valvular surgery 5.6 3.8 6.1 6.1 4.6 0.014
PAD 15.1 7.3 12.1 6.1 30.1 <0.001
Stroke/TIA 12.6 8.3 10.7 12.1 21.6 <0.001
VTE 5.3 4.0 3.3 3.0 12.9 <0.001
CKD 26.3 11.4 25.8 21.2 35.4 <0.001
Hepatic dysfunction 7.7 1.7 6.7 3.0 14.5 <0.001
Cancer 4.9 1.8 4.8 0.0 6.8 <0.001
COPD 20.2 8.8 18.2 24.2 33.1 <0.001
Sleep apnoea 3.0 1.0 3.1 3.0 3.5 0.007
Parkinson’s disease 1.2 0.6 0.7 3.0 3.2 <0.001
Depression 7.8 2.6 5.9 12.1 17.5 <0.001
Primary aetiology
Ischaemic heart disease 56.6 58.1 54.4 75.8 63.5 <0.001
Hypertension 8.1 7.8 8.9 6.1 5.2 <0.001
Dilated cardiomyopathy 13.6 15.0 13.1 12.1 14.7 0.266
Valve disease 12.0 7.6 13.0 6.1 10.6 <0.001
Other 9.7 11.5 10.6 0.0 6.0 <0.001
Precipitants
ACS 18.6 19.4 16.2 45.5 26.0 <0.001
Myocardial ischaemia 30.9 34.1 27.3 42.4 41.7 <0.001
AF 31.1 21.9 30.3 18.2 38.8 <0.001
Ventricular arrhythmias 8.0 9.2 4.7 12.1 18.8 <0.001
Bradyarrhythmias 3.9 3.6 2.8 9.1 7.6 <0.001
Infection 19.7 6.8 19.6 12.1 26.7 <0.001
Uncontrolled HTN 17.6 9.6 16.4 15.2 26.0 <0.001
Noncompliance 5.5 1.0 5.8 3.0 6.6 <0.001
Renal dysfunction 18.6 7.8 16.7 15.2 31.1 <0.001
Anaemia 15.4 6.8 14.8 18.2 21.7 <0.001
Iatrogenic 1.3 1.5 1.1 0.0 1.8 0.191
Clinical presentation
New onset (%) 29.7 31.5 31.2 18.2 23.6
<0.001
Worsening 70.3 68.5 68.8 81.8 76.4
NYHA class <0.001
II 16.4 53.3 13.0 51.5 9.3
III 52.1 38.3 57.3 33.3 41.1
IV 31.5 8.4 29.6 15.2 49.6
CS 2.8 2.8 1.3 15.2 7.8 <0.001
SBP < 90 mmHg 2.5 1.1 1.6 0.0 6.4
SBP 90–140 mmHg 67.1 73.9 66.7 69.7 65.1 <0.001
SBP > 140 mmHg 30.4 25.0 31.7 30.3 28.5
Pulse pressure (mmHg) 50.0 [40.0–65.0] 50.0 [40.0–60.0] 50.0 [40.0–66.0] 49.0 [40.0–70.0] 35.0 [30.0–55.0] <0.001
Proportional pulse pressure (%) 39.8 [33.6–45.5] 40.0 [35.7–45.6] 40.0 [34.6–45.5] 33.7 [26.0–46.2] 28.8 [23.3–41.4] <0.001
HR (b.p.m.) 87.0 [72.0–104.0] 76.0 [65.0–90.0] 88.0 [73.0–104.0] 80.0 [72.0–88.0] 90.0 [75.0–110.0] <0.001
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Table 1 Continued

(n = 7865) (n = 785) (n = 5492) (n = 33) (n = 1555)
...........................................................................................................................................
Pulmonary rales 74.6 0.0 82.8 0.0 85.0 <0.001
Peripheral oedema 55.0 0.0 60.8 0.0 63.5 <0.001
JVD > 6 cm 34.4 0.0 35.4 0.0 50.3 <0.001
Hepatomegaly 24.6 0.0 25.2 0.0 35.7 <0.001
Hepatojugular reflux 22.8 0.0 24.8 0.0 32.3 <0.001
Cold extremities 18.3 0.0 0.0 75.7 91.0 <0.001
Other hypoperfusion signsa 16.4 0.0 0.0 45.4 82.1 <0.001
Biology
Creatinine (mg/dL) 1.2 [0.9–1.5] 1.0 [0.9–1.2] 1.2 [0.9–1.5] 1.2 [0.9–1.5] 1.3 [1.0–1.7] <0.001
BUN (mg/dlL) 25.0 [19.0–39.0] 23.0 [19.0–35.0] 25.0 [18.3–36.0] 18.3 [15.6–20.9] 28.1 [21.0–46.0] 0.022
Sodium (mmol/L) 139 [135–141] 139.0 [137–141] 139 [135–141] 137 [135–140] 138.0 [135.0–141.0] <0.001
Glycaemia (mg/dL) 110 [92–150] 101 [89–123] 111 [93–150] 107 [96–156] 115 [93–161] <0.001
Haemoglobin (g/dL) 12.8 [11–14] 13.7 [12–15] 12.6 [11–14) 12.7 [10–14] 12.8 [11–14] <0.001
BNP (pg/mL) (available 745 [339–1374] 527 [168–869] 756 [354–1315] 339 [246–532] 898 [415–2145] <0.001
for 822 patients)
NT-proBNP (pg/mL) (available 3937 [1736–8839] 1639 [582–3701] 4144 [1837–9429] 3200 [2500–8270] 5000 [2500–10 590] <0.001
for 1769 patients)
Troponin (mg/L) (available 0.1 [0.0–0.4] 0.1 [0.0–0.5] 0.1 [0.0–0.3] 0.1 [0.0–0.3] 0.1 [0.0–1.2] <0.001
for 3564 patients)
ECG
AF 32.3 21.0 33.2 21.4 34.8 <0.001
QRS duration 110.2 ± 31.0 116.6 ± 31.4 109.1 ± 30.6 100.6 ± 35.4 111.2 ± 31.8 <0.001
QT duration 380.4 ± 71.8 397.8 ± 58.1 374.6 ± 75.0 377.1 ± 58.4 391.2 ± 63.9 <0.001
LBBB 15.0 13.2 14.3 3.7 18.3 <0.001
Echo
LVEF 39.8 ± 14.8 38.9 ± 14.1 39.8 ± 14.4 44.6 ± 15.0 40.4 ± 16.4 0.165
LVEF < 40% 51.0 54.4 50.5 40.0 51.2
LVEF 40–49% 25.1 26.5 26.0 15.0 21.5 <0.001
LVEF ≥ 50% 23.8 19.1 23.5 45.0 27.2
LVEDD (mm) 58.7 ± 11.2 58.3 ± 11.9 58.7 ± 11.2 59.3 ± 12.5 59.2 ± 10.7 0.431
LA volume (mL) 69.4 ± 40.7 73.1 ± 36.6 74.4 ± 44.3 42.2 ± 14.5 57.4 ± 28.6 <0.001
Mitral regurgitation, 52.5 38.2 50.9 63.6 65.7 <0.001
moderate-severe
Tricuspid regurgitation, 36.3 19.3 34.8 50.0 50.6 <0.001
moderate-severe
Values are expressed as mean ± standard deviation, percentages, or median [interquartile range].
ACS, acute coronary syndrome; AF, atrial fibrillation; BNP, B-type natriuretic peptide; BUN, blood urea nitrogen; CABG, coronary artery bypass graft; CKD, chronic kidney
disease; COPD, chronic obstructive pulmonary disease; CRT, cardiac resynchronization therapy; CRT-D, cardiac resynchronization therapy with defibrillator; CRT-P, cardiac
resynchronization therapy with pacemaker; CS, cardiogenic shock; ECG, electrocardiogram; ICD, implantable cardioverter-defibrillator; HTN, hypertension; JVD, jugular
venous distension; LA, left atrial; LBBB, left bundle brunch block; LVEDD, left ventricular end-diastolic diameter; LVEF, left ventricular ejection fraction; MI, myocardial infarction;
NT-proBNP, N-terminal pro-B-type natriuretic peptide; NYHA, New York Heart Association; PAD, peripheral arterial disease; PCI, percutaneous coronary intervention; PM,
pacemaker; SBP, systolic blood pressure; VTE, venous thromboembolism; TIA, transient ischaemic attack.
a Oliguria < 30 mL/h or mental confusion.
patients with residual congestion (18.5 vs. 28.0%; P < 0.001) (online followed by the ‘wet-warm’ profile and with the ‘dry-warm’ profile
..............................
supplementary Table S1). having the lowest risk. All these pairwise differences were highly
Since there were significant differences in baseline characteristics statistically significant.
among clinical profiles, Cox proportional hazard models with
multivariable adjustment were performed, and 1-year mortality
rates of each profile resulting from both admission and discharge Discussion
classification, were pairwise compared by adjusted Cox regression In the ESC-EORP-HFA HF-LT Registry, classification of patients
analysis (again excluding ‘dry-cold’ patients) (Figure 2). Comparing hospitalized for AHF based on clinical signs obtained at bed-
1-year mortality of each profile resulting from admission and side physical examination can be used to detect four distinct
discharge classifications, the ‘wet-cold’ profile had the highest risk, phenotypes with different baseline characteristics, different
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Table 2 Intravenous vasoactive therapies, interventions and cardiovascular oral therapies during hospitalization
according to profile at admission

(n = 7865) (n = 785) (n = 5492) (n = 33) (n = 1555)
...........................................................................................................................................
Intravenous therapies
Inotropes 11.7 5.0 8.2 9.1 27.8 <0.001
Vasodilators 19.3 7.0 20.6 28.1 20.7 <0.001
Diuretics 81.1 30.5 87.7 54.5 83.8 <0.001
Interventions
Coronary angiography 21.7 41.5 20.2 15.2 17.0 <0.001
PCI/CABG 10.1 17.9 9.3 12.1 8.6 <0.001
EPS 0.6 1.2 0.6 0.0 0.2 0.029
Transcatheter ablation 0.7 1.5 0.6 0.0 0.3 0.006
Right heart catheterization 1.9 2.5 1.9 0.0 1.9 0.610
IABP 0.9 1.2 0.7 6.1 1.4 0.001
CRT 3.8 5.4 3.2 3.0 4.9 0.001
ICD 6.4 11.9 5.3 0.0 7.5 <0.001
Oral CV therapies
BB admission 72.4 82.8 71.8 60.6 69.8 <0.001
BB discharge 73.9 84.6 74.0 63.6 68.2 <0.001
ACEi/ARB admission 77.7 84.5 78.7 75.8 71.3 <0.001
ACEi/ARB discharge 79.1 84.6 78.7 69.7 69.5 <0.001
MRA admission 55.9 53.0 57.2 27.3 53.6 <0.001
MRA discharge 54.7 53.9 56.1 27.3 50.8 <0.001
Ivabradine admission 3.2 1.3 3.2 3.0 4.0 0.05
Ivabradine discharge 3.1 1.4 3.3 3.0 3.4 0.033
Diuretics admission 80.3 71.6 81.9 54.5 79.8 <0.001
Diuretics discharge 83.2 73.1 86.3 54.5 77.8 <0.001
Digoxin admission 25.9 16.8 25.6 15.2 31.5 <0.001
Digoxin discharge 23.7 15.7 24.3 18.2 25.7 <0.001
Values are expressed as percentages.

ACEi, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; BB, beta-blocker; CABG, coronary artery bypass graft; CRT, cardiac resynchronization
therapy; CV, cardiovascular; EPS, electrophysiological study; IABP, intra-aortic balloon pump; ICD, implantable cardioverter-defibrilator; MRA, mineralocorticoid receptor
antagonist.
Table 3 Independent predictors of residual congestion at discharge in multivariable analysis
OR (95% CI) P-value

...........................................................................................................................................
Tricuspid regurgitation, moderate-severe (hospital entry) 2.085 (1.850;2.350) <0.001
Diuretics i.v. 1.601 (1.357;1.889) <0.001
Diabetes 1.270 (1.129;1.429) <0.001
NYHA class
NYHA class IV vs. II 2.563 (2.103;3.124) <0.001
NYHA class III vs. II 1.702 (1.412;2.052) <0.001
PCI/CABG/CRT/ICD at discharge 0.706 (0.605;0.824) <0.001
Beta-blockers (hospital entry) 0.711 (0.624;0.810) <0.001
Haemoglobin (g/dL) (hospital entry) 0.931 (0.907;0.956) <0.001
HF status (new onset vs. worsening) 0.621 (0.546;0.706) <0.001
CABG, coronary artery bypass graft; CI, confidence interval; CRT, cardiac resynchronization therapy; HF, heart failure; ICD, implantable cardioverter-defibrillator; i.v.,
intravenous; NYHA, New York Heart Association; OR, odds ratio; PCI, percutaneous coronary intervention.
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Table 4 In-hospital and 1-year adverse outcomes by classification at admission

(n = 7865) (n = 785) (n = 5492) (n = 33) (n = 1555)
...........................................................................................................................................
In-hospital outcomes
All-cause death 5.3 2.0 3.8 9.1 12.1 <0.001
Cardiac 80.6 62.5 75.2 100.0 87.8
Vascular 5.0 6.3 4.3 0.0 5.9
Non-cardiovascular 10.6 25.0 14.8 0.0 4.8
Unknown 3.8 6.3 5.7 0.0 1.6 –
Hospital length of stay (days) 10.7 ± 25.4 8.6 ± 17.9 10.6 ± 26.5 8.2 ± 4.1 12.0 ± 24.6 <0.001
Admitted in ICCU (%) 47.7 38.5 45.4 45.5 60.0 <0.001
ICCU length of stay (days) 2.6 ± 4.6 2.0 ± 4.4 2.5 ± 4.6 3.0 ± 4.3 3.2 ± 4.4 <0.001
NYHA class III/IV at discharge 24.4 18.7. 22.9 20.0 33.4 0.063
Body weight at discharge
Decrease >3 kg 22.5 8.0 23.5 6.7 27.0 <0.0001
Decrease 0–3 kg 42.7 29.8 43.3 50.0 47.6
Stable 29.3 56.9 28.2 23.3 17.9
Increase 5.5 5.4 5.0 20.0 7.5
WRF at dischargea 14.5 9.9 15.2 7.4 13.9 0.008
Hyponatremia at dischargeb 17.2 16.7 17.0 17.2 18.0 0.845
Decrease ≥ 40% BNP 38.2 26.3 42.0 16.7 31.3 0.163
Decrease ≥ 25% NT-proBNP 56.3 45.9 57.0 50.0 57.1 0.600
1-year outcomes
1-year all-cause death 22.2 12.1 22.6 28.0 26.4 <0.001
Cardiac 47.8 46.4 43.4 71.4 63.2
Vascular 3.4 6.0 3.1 0.0 3.6
Non-cardiovascular 13.2 6.0 14.4 14.3 10.7
Unknown 35.7 41.7 39.1 14.3 22.5 –
1-year all-cause hospitalization 43.6 37.0 43.6 41.7 47.2 <0.001
1-year HF hospitalization 25.6 14.2 26.3 16.7 29.4 <0.001
1-year all-cause death and/or HF hospitalization 44.7 26.2 44.7 48.1 54.1 <0.001
Values are expressed as percentages, or mean ± standard deviation.

BNP, B-type natriuretic peptide; eGFR, estimated glomerular filtration rate (Modification of Diet in Renal Disease formula); HF, heart failure; ICCU, intensive coronary care
unit; NT-proBNP, N-terminal pro-B-type natriuretic peptide; NYHA, New York Heart Association; WRF, worsening renal function.
a Hyponatremia: Na < 135 mEq/L.
b Creatinine (discharge) – Creatinine (baseline) ≥ 0.3 or [1-eGFR (discharge)]/eGFR (baseline) ≥ 0.25.
in-hospital therapies and significantly different outcomes. An or emergency department treatments, as well as differences in the
........................................................
additional strength of the present analysis is the re-classification methodologies of the two studies.
at discharge. Using classification at admission, hypoperfusion, Similarly to previous studies,4,8 ‘dry-warm’ patients were less
but not congestion, was associated with in-hospital mortality, symptomatic compared to other phenotypes. Since physical assess-
while for discharge classification, hypoperfusion but also con- ment can only detect a moderate to high level of congestion,5
gestion were associated with 1-year mortality, suggesting that it cannot be excluded that these patients may have mild signs of
congestion at discharge is a particularly important treatment congestion, potentially undetected at initial evaluation but caus-
target. ing sufficient symptoms for patients to seek acute care and to
This classification scheme was used more than 15 years ago in be admitted to hospital. Also, some ‘dry-warm’ patients may
two previous studies that classified AHF patients prospectively4 be treated with vasoactive drugs before hospitalization in the
and retrospectively.8 In both studies, the distribution of the four ambulance or in the emergency department with resolution of
clinical profiles was similar to the present analysis, with a majority signs/symptoms of HF by the time they were enrolled in the reg-
of patients ascertained as ‘wet-warm’ and only a small minority istry. In ESC-EORP-HFA HF-LT Registry, ‘dry-warm’ patients had
classified as ‘dry-cold’. the highest rate of CRT/ICD implants, suggesting that some of
The ‘dry-warm’ category represented 9.9% of the study pop- these patients are ‘suitcase’ patients with a planned but expe-
ulation in the present analysis, compared to 27.2% and 16.6%, dited procedure during acute admission, since elective admissions
respectively, in the two previous studies.4,8 These differences may for procedures are excluded from the registry. Of note, AHF
reflect changes in medical care patterns over time with an increas- patients classified as ‘dry-warm’ have a similar echocardiographic
ing threshold for hospital admission in favour of ambulatory visits pattern as ‘wet -warm’ patients, in terms of LVEF, left ventricular
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Figure 2 Forest plot of clinical outcomes, in-hospital mortality (A) and 1-year mortality using classification at admission (B) and at discharge
(C). ‘Dry-warm’, ‘wet-warm’ and ‘wet-cold’ profiles were pairwise compared by Cox regression analysis in unadjusted and adjusted model
(adjusted for age, gender, New York Heart Association class, systolic blood pressure, left ventricular ejection fraction, serum sodium, serum
creatinine and blood urea nitrogen). CI, confidence interval; HR, hazard ratio.
end-diastolic diameter and left atrial volume, suggesting compa- The ‘wet-cold’ profile represented 19.9% of patients enrolled in
.................................................................
rable cardiac structural abnormalities, but with different clinical the ESC-EORP-HFA HF-LT Registry. The ‘wet-cold’ group includes
presentations. more diverse entities, with CS at the end-spectrum of severity, rep-
In the ESC-EORP-HFA HF-LT Registry, ‘wet-warm’ representing only 7.8% of ‘wet-cold’ patients. This suggests that hypop-
resented the largest category (69.9%), similar to previous erfusion signs are not completely specific to CS, being reported in
reports.4,8 This category of patients had a dynamic in-hospital other clinical phenotypes such as pulmonary oedema and decom-
course, 39% presented residual congestion at discharge, whereas pensated HF. Also, utilization of i.v. inotropes in ‘wet-cold’ patients
59.2% were free of congestion. Furthermore, they had the is lower than in patients with CS,11 suggesting that the two enti-
ties are not equivalent, and in ‘wet-cold’ patients hypoperfusion
highest in-hospital decrease in natriuretic peptides (NPs), but
is not always accompanied by SBP < 90 mmHg or by markers of
the highest proportion of in-hospital worsening renal function
end-organ injury.14
(WRF).
Alternatively, CS patients have diverse clinical presentations
Patients classified at admission as ‘dry-cold’ represented a minor-
varying from ‘wet-cold’ (57.8%) to ‘dry-warm’ (2.8%), demonstrat-
ity of those admitted with AHF in the ESC-EORP-HFA HF-LT Reg-
ing the existence of the diverse sub-phenotypes within CS, rather
istry (0.4%). Additionally, when considering discharge classification, than a singular clinical presentation.15 Our results are similar to
only 1.6% of patients were categorized as ‘dry-cold’. ‘Dry-cold’ those obtained in the SHOCK trial,16 where CS patients have been
was also poorly represented in previous studies with proportions classified as: ‘wet-cold’ (64%), ‘dry-cold’ (28%), ‘wet-warm’ (6%)
ranging from 3.5% to 4.1%.4,8 This phenotype may represent some and ‘dry-warm’ (3%).
hypovolemic patients as a result of dehydration or pre-hospital One novel aspect of our work is the assessment by LVEF (HFrEF,
vasoactive therapies. Some patients may fit into the ‘wet-cold’ phe- HFmrEF and HFpEF) categories. These LVEF categories presented
notype when clinical signs of congestion at admission are obscure at admission with similar proportion of congestion, suggesting
and unnoticed. that high filling pressure is a common finding in these phenotypes
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A B
C D
Figure 3 Kaplan–Meier (K-M) curves for 1-year all-cause death and all-cause death or heart failure (HF) hospitalization by clinical profile
classification performed at admission (A, B) and at discharge (C, D). FU, follow-up.
despite the diverse cardiac abnormalities. Similar proportions of patients had signs of congestion at discharge, and in particu-
..................................................................
patients free of congestion at discharge, among the three pheno- lar had higher mortality and rehospitalization rates at 60 days.19
types, suggest that i.v. vasoactive therapies are equally effective in Ensuring decongestion is an essential goal during AHF hospital-
decreasing filling pressures, regardless of baseline LVEF. ization, but there is no standardized method for evaluating con-
More surprisingly, the considerable prevalence of hypoperfusion gestion before discharge and what defines adequate deconges-
in the HFpEF group suggests that LVEF has a low accuracy to iden- tion is currently unclear.20 Although clinical trials17,21 proposed
tify a specific clinical phenotype. Of note, peripheral hypoperfusion a ‘definition for decongestion’, assessment of decongestion based
is much closer related to stroke volume and vascular resistance strictly on trial pre-defined clinical signs may be non-sensitive and
rather than LVEF. In clinical practice, various HFpEF pathologies non-specific, and has not been investigated in real-life clinical prac-
such as hypertrophic cardiomyopathy, acute mitral regurgitation or tice. Furthermore, clinicians often limit decongestion interventions
massive pulmonary embolism, may clinically manifest with clinical due to fear of WRF, but growing evidence suggests that appar-
hypoperfusion as a consequence of low stroke volume. ent WRF that is due to decongestion is both reversible and not
associated with harm.22,23 In addition, very few studies described
the factors associated with residual congestion that may con-
tribute to the understanding of clinical course of congestion during
In-hospital outcomes hospitalization.
Despite a relatively long in-hospital stay, a high proportion (30.9%) In the present study, multivariable analysis identified the pres-
of patients from the ESC-EORP-HFA HF-LT Registry were dis- ence of moderate to severe tricuspid regurgitation as the most
charged with clinical signs suggestive of persistent congestion, important independent predictor of residual congestion. Since the
which confers a significant risk of 1-year death, similar to the right ventricle is preload-dependent and afterload-sensitive, the
EVEREST17 and PROTECT18 trials. Also, in a post-hoc analysis presence of functional tricuspid regurgitation signifies a dilated and
including patients from DOSE-AHF and CARESS-HF, 48% of dysfunctional right ventricle or severe pulmonary hypertension.24
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The association between beta-blocker use at admission and lower will develop CS and require mechanical circulatory assistance or
........................................................................................................................................................................
risk of residual congestion is not clearly understood. However, specific organ function support.
these patients may represent a lower-risk group with less con- Previous studies yielded conflicting information about the relia-
traindications to therapy and more clinically stable over time.25 bility of the congestion/hypoperfusion classification to predict out-
Low haemoglobin was also associated with residual congestion. In comes. Our results are similar to those reported by Nohria et al.4
the EVEREST analysis,26 anaemic patients had more clinical signs of revealing significant differences in outcomes by clinical profiles.
fluid overload (jugular vein distension and higher level of NPs) and In another study,8 although outcomes did not differ significantly
a higher rate of HF readmissions, suggesting that anaemia may be a among the four profiles, the trend for survival was similar to that
reflection of haemodilution (or lack of haemoconcentration).22,23,26 seen in the present analysis.
As an effect of hyperinsulinaemia or insulin treatment,27 diabetes is Notably, similar to the classification obtained at admission,
associated with weight gain, sodium and fluid retention, account- phenotyping alive AHF patients based on clinical signs at dis-
ing for the increased probability of residual congestion observed in charge identified significant differences in mortality among groups.
our study. Kaplan–Meier curves based on discharge classification showed that
The lowest and highest in-hospital mortality rates were reported ‘wet-cold’ patients had an abrupt increase in mortality in the early
in the ‘dry-warm’ and ‘wet-cold’ groups, respectively, in both months post-discharge. Furthermore, comparing 1-year mortality
unadjusted and adjusted models. When pairwise compared in an rates in Cox proportional hazard model, patients with congestion
adjusted Cox proportional hazard model, in-hospital mortality of at discharge (‘wet-warm’) had significantly higher 1-year mortality
‘wet-warm’ patients did not differ significantly from mortality of than patients without congestion (‘dry-warm’). In terms of residual
‘dry-warm’ patients, suggesting that congestion may be an impor- clinical congestion, our results are similar to other studies,17 – 19
tant target of therapy and alleviating congestion during hospitaliza- indicating residual congestion as a factor associated with higher
tion is associated with improved outcomes. rehospitalization and mortality rates, and supporting the risk strat-
ifying properties of congestion at discharge. Indeed, the clinical
profile classification at the time of planned discharge will both
One-year outcomes
identify patients at distinctly higher risk and alert clinicians to resid-
The Kaplan–Meier curves showed that the highest rates of both ual congestion. Persisting congestion should be more aggressively
1-year death and the composite of 1-year death and HF read- addressed prior to discharge, perhaps even at the expense of delay-
missions were observed in patients classified at admission as ing discharge. Also, these patients should be more closely followed
‘wet-cold’. When pairwise compared in the adjusted Cox model, up during the post-discharge period. Furthermore, other biolog-
1-year mortality differed significantly by each profile. Patients ical variables as surrogate markers of haemodynamic congestion,
classified at admission as ‘wet-warm’ had higher 1-year mortal- a < 30% change in NP concentrations28 or decreased haemat-
ity than ‘dry-warm’ patients, in contrast to in-hospital mortal- ocrit during hospitalization,29 add significant prognostic informa-
ity. ‘Wet-warm’ patients may have been inadequately decongested tion beyond residual clinical congestion. This underscores the need
during hospitalization, or even if decongested they may experi- to integrate all data available from in-hospital monitoring acquired
ence a recurrence of congestion during post-discharge follow-up, with different tools.30
which may trigger subsequent deaths or readmissions in the Clinical phenotyping of AHF patients, in conjunction with biolog-
post-discharge phase. These findings may account for the asso- ical variables, may facilitate early decision-making regarding appro-
ciation between congestion at admission and 1-year mortality, priate triage, novel targeted treatment of high-risk populations and
despite of lack of association with in-hospital mortality. In a pre- may mediate improvements in quality of care and outcomes. How-
vious study, 65% of decongested AHF patients had recurrence of ever, the impact of AHF classification on current clinical practice
congestion at 60-day follow-up,19 suggesting that the clinical ben- should be further evaluated in prospective studies.
efit of in-hospital decongestive therapies does not extend beyond
hospitalization. Taken together, our findings suggest that although it
is crucial to achieve adequate decongestion during hospitalization,
medical efforts should not be only limited to decongestion, and is
Limitations
further important to treat co-morbidities, to optimize therapies This analysis retrospectively evaluated physical examinations per-
and to follow up patients after discharge. formed as part of an observational study. Because of the vari-
Analysis of the specific contribution of each clinical profile to the ety of type of centres and participating investigators, the degree
total number of deaths and the Kaplan–Meier curves showed that of clinical acumen in the examination may have varied. Although a
the vast majority of ‘wet-cold’ patients died during hospitalization training meeting was organized for all clinical investigators, the diag-
or within the first few months after discharge. In order to improve nosis and classification were made at the point of care by each
outcomes in this category, medical therapies, including vasoactive clinician-investigator and this process may not have been readily
agents and invasive procedures, should be initiated early in the reproducible or may have resulted in inconsistent classification. The
course of decompensation and these patients should be closely very low prevalence of in-hospital utilization of pulmonary artery
monitored during hospitalization. Early recognition of hypoperfu- catheter reflects real-life practice typical for an observational study,
sion signs, even in the absence of hypotension, may help to identify and consequently these data were not used to validate the clinical
in an appropriate therapeutic window the ‘high-risk’ patients who classification.
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Other potentially important variables, with well-known prog- (2011–2019), Daiichi Sankyo Europe GmbH (2011–2020), The
........................................................................................................................................................................
nostic importance, such as NP levels, were not selected in the Alliance Daiichi Sankyo Europe GmbH and Eli Lilly and Com-
multivariable models or in adjusted analyses, as data were not avail- pany (2014–2017), Edwards (2016–2019), Gedeon Richter Plc.
able in many patients. (2014–2016), Menarini Int. Op. (2009–2012), MSD-Merck &
Finally, the limited number of patients with a ‘dry-cold’ profile Co. (2011–2014), Novartis Pharma AG (2014–2020), ResMed
precluded meaningful statistical analysis of this category. (2014–2016), Sanofi (2009–2011), Servier (2009–2021), Vifor
(2019–2022).
Conflict of interest: O.C. reports grants from Servier, Vifor,
Conclusions Novartis outside the submitted work. A.M. reports personal fees
from Novartis, Orion, Roche, Servier, Cardiorentis, grants and per-
Classifying AHF patients based on evaluation of clinical signs
sonal fees from Adrenomed, grants from MyCartis and Critical
of congestion/perfusion at baseline and discharge identified signif-
diagnostics, personal fees from Zs Pharma outside the submitted
icant differences in 1-year mortality and rehospitalizations among
work. A.P.M. reports personal fees from Bayer, Novartis, Fresenius
groups. ‘Wet-cold’ patients had the worst outcomes, confirming
outside the submitted work. M.G.C.L. reports grants and personal
that hypoperfusion is a marker of severity of HF and is associated
fees from Novartis, grants from Cibercv-Feder Funds, personal
with poor prognosis. ‘Wet-warm’ was not worse than ‘dry-warm’
fees from Abbott, MSD, outside the submitted work. P.P. reports
for in-hospital mortality, suggesting congestion can be addressed
grants, personal fees and other from Vifor Pharma, grants, per-
in hospital. However, at discharge, ‘wet-warm’ had a higher 1-year
sonal fees and other from Servier, personal fees and other from
mortality than ‘dry-warm’, suggesting residual congestion is asso-
Novartis, personal fees and other from Bayer, other from BMS,
ciated with poor outcomes. Assessment of congestion and hypop-
personal fees and other from Boehringer Ingelheim, Coridea, per-
erfusion status is therefore important throughout hospitalization,
sonal fees and other from Cardiorentis, personal fees and other
and a better understanding of the clinical course of the two entities
from AstraZeneca, grants from Singulex, other from Fresenius, per-
could play an important role towards the implementation of tar-
sonal fees and other from Cibiem outside the submitted work.
geted strategies that may improve outcomes.
G.F. reports that he was Committee Member of trials and reg-
istries sponsored from Bayer, Novartis, Servier, Vifor, Medtronic,
Supplementary Information BI outside the submitted work. F.R. before 2018 reports grants
and personal fees from SJM/Abbott, grants and personal fees from
Additional supporting information may be found online in the Servier, personal fees from Zoll, AstraZeneca, Sanofi, grants and
Supporting Information section at the end of the article. personal fees from Novartis, personal fees from Amgen, BMS,
Figure S1. Classification of clinical phenotypes and systolic blood Pfizer, Fresenius, Vifor, Roche, Cardiorentis, grants and personal
pressure categories by congestion/hypoperfusion status at admis- fees from Bayer, personal fees from Boehringer Ingelheim, other
sion. from Heartware, grants from Mars, outside the submitted work.
Figure S2. Distribution of clinical profiles at admission and dis- P.S. reports grants/research supports from the Ministry of Edu-
charge by ejection fraction categories. cation, Science and Technological Development of Republic of
Figure S3. Proportional contribution of each clinical profile Serbia; receipt of honoraria or consultation fees from Servier,
assessed at admission to in-hospital and 1-year mortality. Boehringher Ingelheim, Hemofarm, Novartis, AstraZeneca; par-
Table S1. One-year outcome according to binary classification at ticipation in a company sponsored speaker’s bureau: Fondazione
discharge: congestion vs. free of congestion. Internationale Menarini. A.J.S.C. reports personal fees from Vifor,
Servier, Respicardia, Nutricia, Novartis, Menarini, Gore, Faraday,
Acknowledgements AstraZeneca, Actimed outside the submitted work. L.H.L. reports
EORP Oversight Committee, Registry Executive and Steering grants and other from Novartis, other from Merck, Boehringer
Committees of the EURObservational Research Programme Ingelheim, Sanofi, grants and other from Vifor Pharma, other from
(EORP). Data collection was conducted by the EORP Department AstraZeneca, grants and other from Relypsa, other from Bayer,
of the European Society of Cardiology by Emanuela Fiorucci grants from Boston Scientific outside the submitted work. The
as Project Officer, Gérard Gracia and Maryna Andarala as Data other authors have nothing to disclose.
Managers. Statistical analyses were performed by Cécile Laroche.
Overall activities were coordinated and supervised by Dr. Aldo P.
Maggioni (EORP Scientific Coordinator).
Appendix 1
Funding EORP Oversight Committee
Since the start of EORP, the following companies have supported Christopher Peter Gale, Chair, GB, Branko Beleslin, RS, Andrzej
the programme: Abbott Vascular Int. (2011–2021), Amgen Car- Budaj, PL, Ovidiu Chioncel, RO, Nikolaos Dagres, DE, Nicolas
diovascular (2009–2018), AstraZeneca (2014–2021), Bayer AG Danchin, FR, David Erlinge, SE, Jonathan Emberson, GB, Michael
(2009–2018), Boehringer Ingelheim (2009–2019), Boston Scien- Glikson, IL, Alastair Gray, GB, Meral Kayikcioglu, TR, Aldo Mag-
tific (2009–2012), The Bristol Myers Squibb and Pfizer Alliance gioni, IT, Klaudia Vivien Nagy, HU, Aleksandr Nedoshivin, RU,
© 2019 The Authors

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Anna-Sonia Petronio, IT, Jolien Roos-Hesselink, NL, Lars Wallentin, (Baranya): R. Halmosi; Israel Hadera: J. Elber, I. Alony, A. Shotan, A.
........................................................................................................................................................................
SE, Uwe Zeymer, DE. Vazan Fuhrmann; Haifa: O. Amir; Italy Atri: S. Romano, S. Marcon,
M. Penco, M. Di Mauro, E. Lemme; Brescia: V. Carubelli, R. Rovetta,
M. Metra, M. Bulgari, F. Quinzani, C. Lombardi; Cotignola: S. Bosi,
Executive Committee
G. Schiavina, A. Squeri, A. Barbieri; Cremona: G. Di Tano, S. Pirelli;
M. Crespo-Leiro, ES, S. Anker, DE, A. Mebazaa, FR, A. Coats, GB, Ferrara: R. Ferrari, A. Fucili; Foggia: T. Passero, S. Musio, M. Di
G. Filippatos, GR, R. Ferrari, IT, A.P. Maggioni, IT, M.F. Piepoli, IT. Biase, M. Correale, G. Salvemini; Lumezzane: S. Brognoli, E. Zanelli,
A. Giordano; Milano: P. Agostoni, G. Italiano, E. Salvioni; Modena:
Steering Committee S. Copelli, M.G. Modena, L. Reggianini, C. Valenti, A. Olaru; Mon-
(National Coordinators): A. Goda, AL; M. Diez, AR; A. Fernandez, serrato: S. Bandino, M. Deidda, G. Mercuro, C. Cadeddu Dessalvi;
AR; F. Fruhwald, AT; E. Fazlibegovic, BA; P. Gatzov, BG; A. Kurlian- Novara: P.N. Marino, M.V. Di Ruocco, C. Sartori, C. Piccinino;
skaya, BY; R. Hullin, CH; T. Christodoulides, CY; J. Hradec, CZ; Palermo: G. Parrinello, G. Licata, D. Torres, S. Giambanco, S.
O. Wendelboe Nielsen, DK; R. Nedjar, DZ; T. Uuetoa, EE; M. Has- Busalacchi, S. Arrotti, S. Novo, R.M. Inciardi, P. Pieri, P.R. Chirco,
sanein, EG; J.F. Delgado Jimenez, ES; V-P. Harjola, FI; D. Logeart, FR; M. Ausilia Galifi, G. Teresi, D. Buccheri, A. Minacapelli; Passirana
V. Chumburidze, GE; D. Tousoulis, GR; D. Milicic, HR; B. Merkely, di Rho (Milano): M. Veniani, A. Frisinghelli; Pavia: S.G. Priori, S.
HU; E. O’Donoghue, IE; O. Amir, IL; A. Shotan, IL; D. Shafie, IR; M. Cattaneo, C. Opasich, A. Gualco; Roma: M. Pagliaro, M. Mancone,
Metra, IT; A. Matsumori, JP; E. Mirrakhimov, KG; A. Kavoliuniene, F. Fedele, A. Cinque, M. Vellini, I. Scarfo, F. Romeo, F. Ferraiuolo,
LT; A. Erglis, LV; E. Vataman, MD; M. Otljanska, MK; E. Srbinovska D. Sergi; San Bonifacio (Verona): M. Anselmi; Sassuolo: F. Melandri, E.
Kostovska, MK; D. Cassar DeMarco, MT; J. Drozdz, PL; C. Fon- Leci, E. Iori; Torino: V. Bovolo, S. Pidello, S. Frea, S. Bergerone, M.
seca, PT; O. Chioncel, RO; M. Dekleva, RS; E. Shkolnik, RU; U. Botta, F.G. Canavosio, F. Gaita; Trieste: M. Merlo, M. Cinquetti, G.
Dahlstrom, SE; M. Lainscak, SI; E. Goncalvesova, SK; A. Temizhan, Sinagra, F. Ramani, E. Fabris, D. Stolfo; Udine: J. Artico, D. Miani, C.
TR; V. Estrago, UY; G. Bajraktari, XK. Fresco, C. Daneluzzi, A. Proclemer; Verona: M. Cicoira, L. Zanolla,
G. Marchese, F. Torelli, C. Vassanelli; Latvia Jelgava: N. Voronina;
Riga: A. Erglis; Lithuania Kaunas: V. Tamakauskas, V. Smalinskas, R.
Investigators Karaliute, I. Petraskiene, E. Kazakauskaite, E. Rumbinaite, A. Kavoli-
Austria Braunau: J. Auer; Graz: K. Ablasser, F. Fruhwald, T. Dolze, uniene; Marijampole: V. Vysniauskas, R. Brazyte-Ramanauskiene, D.
K. Brandner; Innsbruck: S. Gstrein, G. Poelzl; Sankt Poelten: D. Petraskiene; Poland Biala: S. Stankala, P. Switala, Z. Juszczyk; Byd-
Moertl; Vienna: S. Reiter, A. Podczeck-Schweighofer; Bosnia goszcz: W. Sinkiewicz, W. Gilewski, J. Pietrzak; Chelmza: T. Orzel,
Herzegovina Mostar: A. Muslibegovic, M. Vasilj, E. Fazlibegovic, P. Kasztelowicz; Czestochowa: P. Kardaszewicz, M. Lazorko-Piega,
M. Cesko, D. Zelenika, B. Palic, D. Pravdic, D. Cuk; Bulgaria Sofia: J. Gabryel; Gdansk: K. Mosakowska, J. Bellwon, A. Rynkiewicz, G.
K. Vitlianova, T. Katova, T. Velikov, T. Kurteva, P. Gatzov; Vidin: Raczak, E. Lewicka, A. Dabrowska-Kugacka; Kielce: R. Bartkowiak,
D. Kamenova; Varna: M. Antova, V. Sirakova; Czech Republic B. Sosnowska-Pasiarska, B. Wozakowska-Kaplon; Kluczbork: A.
Brno: J. Krejci, M. Mikolaskova, J. Spinar; Prague: J. Krupicka, F. Krzeminski; Krakow: M. Zabojszcz, E. Mirek-Bryniarska, A. Grze-
Malek, M. Hegarova; Olomouc: M. Lazarova; Znojmo: Z. Monhart; gorzko, K. Bury, J. Nessler, J. Zalewski, A. Furman; Lodz: M. Broncel,
Egypt Alexandria: M. Hassanein, M. Sobhy, F. El Messiry, A.H. El A. Poliwczak, A. Bala, P. Zycinski, M. Rudzinska, L. Jankowski, J.D.
Shazly, Y. Elrakshy; Assiut: A. Youssef; Benha: A.A. Moneim; Cairo: Kasprzak, L. Michalak, K. Wojtczak Soska, J. Drozdz, I. Huziuk, A.
M. Noamany, A. Reda, T.K. Abdel Dayem, N. Farag, S. Ibrahim Retwinski; Lublin: P. Flis, J. Weglarz, A. Bodys; Poznan: S. Grajek,
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doi:10.1002/ejhf.1532
Sacubitril/valsartan eligibility and outcomes

in the ESC-EORP-HFA Heart Failure
Long-Term Registry: bridging between
European Medicines Agency/Food and Drug
Administration label, the PARADIGM-HF trial,
ESC guidelines, and real world
Chris J. Kapelios1, Mitja Lainscak2, Gianluigi Savarese3, Cécile Laroche4,
Petar Seferovic5, Frank Ruschitzka6, Andrew Coats7, Stefan D. Anker8,
Maria G. Crespo-Leiro9, Gerasimos Filippatos10, Massimo F. Piepoli11,
Giuseppe Rosano12, Luisa Zanolla13, Carlos Aguiar14, Jan Murin15,
Przemyslaw Leszek16, Theresa McDonagh17, Aldo P. Maggioni4,18,
and Lars H. Lund3*, on behalf of the Heart Failure Long-Term Registry
Investigators†
1 Department of Cardiology, Laiko General Hospital, Athens, Greece; 2 Division of Cardiology, Murska Sobota, Murska Sobota and Faculty of Medicine, University of Ljubljana,
Ljubljana, Slovenia; 3 Division of Cardiology, Department of Medicine, Karolinska Institutet, Stockholm, Sweden; Heart and Vascular Theme, Karolinska University Hospital,
Stockholm, Sweden; 4 EURObservational Research Programme, European Society of Cardiology, Sophia-Antipolis, France; 5 Clinical Center of Serbia, Cardiology II, Department
for Heart Failure, University of Belgrade, Belgrade, Serbia; 6 Department of Cardiology, Heart Failure Clinic and Transplantation, University Heart Centre Zurich, Zurich,
Switzerland; 7 IRCCS San Raffaele, Rome, Italy; 8 Division of Cardiology and Metabolism; Department of Cardiology (CVK); and Berlin-Brandenburg Center for Regenerative
Therapies (BCRT); German Centre for Cardiovascular Research (DZHK) partner site Berlin; Charité Universitätsmedizin Berlin, Germany & Department of Cardiology and
Pneumology, University Medicine Göttingen (UMG), Göttingen, Germany; 9 Unidad de Insuficiencia Cardiaca Avanzada y Trasplante Cardiaco, Complexo Hospitalario
Universitario A Coruna, La Coruna, Spain; 10 Heart Failure Unit, Department of Cardiology, University Hospital Attikon, Athens, Greece; 11 Heart Failure Unit, Cardiac
Department, Guglielmo da Saliceto Hospital, Piacenza, Italy; 12 Cardiovascular Clinical Academic Group St George’s Hospitals NHS Trust University of London, Cranmer Terrace,
London, IRCCS San Raffaele, Rome, Italy; 13 Ospedale Civile Maggiore, Verona, Italy; 14 Unidade de Insuficiência Cardíaca Avançada e Transplantação Cardíaca, Hospital de Santa
Cruz, Carnaxide, Portugal; 15 University Hospital Bratislava, Bratislava, Slovakia; 16 The Cardinal Stefan Wyszynski Institute of Cardiology, Warsaw, Poland; 17 King’s College
Hospital, London, UK; and 18 ANMCO Research Centre, Heart Care Foundation, Florence, Italy
Received 30 April 2019; revised 15 May 2019; accepted 17 May 2019 ; online publish-ahead-of-print 18 June 2019
Aims To assess the proportion of patients with heart failure and reduced ejection fraction (HFrEF) who are eligible for sacu-
bitril/valsartan (LCZ696) based on the European Medicines Agency/Food and Drug Administration (EMA/FDA) label,
the PARADIGM-HF trial and the 2016 ESC guidelines, and the association between eligibility and outcomes.
.....................................................................................................................................................................
Methods Outpatients with HFrEF in the ESC-EORP-HFA Long-Term Heart Failure (HF-LT) Registry between March 2011
and results and November 2013 were considered. Criteria for LCZ696 based on EMA/FDA label, PARADIGM-HF and ESC
guidelines were applied. Of 5443 patients, 2197 and 2373 had complete information for trial and guideline eligibility
assessment, and 84%, 12% and 12% met EMA/FDA label, PARADIGM-HF and guideline criteria, respectively.
Absent PARADIGM-HF criteria were low natriuretic peptides (21%), hyperkalemia (4%), hypotension (7%) and
sub-optimal pharmacotherapy (74%); absent Guidelines criteria were LVEF>35% (23%), insufficient NP levels (30%)
*Corresponding author. Karolinska Institutet, Solna, S1:02, 171 76 Stockholm; Sweden. Tel: +46 8 51770000, Fax: +46 8 311044, Email: lars.lund@alumni.duke.edu
† Listed in Appendix.
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1384 C.J. Kapelios et al.
and sub-optimal pharmacotherapy (82%); absent label criteria were absence of symptoms (New York Heart
Association class I). When a daily requirement of ACEi/ARB ≥ 10 mg enalapril (instead of ≥ 20 mg) was used, eligibility
rose from 12% to 28% based on both PARADIGM-HF and guidelines. One-year heart failure hospitalization was higher
(12% and 17% vs. 12%) and all-cause mortality lower (5.3% and 6.5% vs. 7.7%) in registry eligible patients compared
to the enalapril arm of PARADIGM-HF.
.....................................................................................................................................................................
Conclusions Among outpatients with HFrEF in the ESC-EORP-HFA HF-LT Registry, 84% met label criteria, while only 12% and 28%
met PARADIGM-HF and guideline criteria for LCZ696 if requiring ≥ 20 mg and ≥ 10 mg enalapril, respectively.
Registry patients eligible for LCZ696 had greater heart failure hospitalization but lower mortality rates than
the PARADIGM-HF enalapril group.
..........................................................................................................
Keywords Sacubitril/valsartan • LCZ696 • Angiotensin receptor–neprilysin inhibitor • Eligibility •
Registry • Prognosis
Introduction ESC guideline criteria, and compared outcomes in registry vs. trial
....................................................................................................................... patients.
Sacubitril/valsartan (LCZ696) is the first agent of the
angiotensin receptor–neprilysin inhibitor (ARNI) drug class.1
In PARADIGM-HF (Prospective Comparison of ARNI with ACEI Methods
to Determine Impact on Global Mortality and Morbidity in Heart
Failure), LCZ696 compared to enalapril reduced the risk of the ESC-EORP-HFA HF-LT Registry HFrEF
primary outcome [cardiovascular death or heart failure (HF) cohort: baseline characteristics
hospitalization] by 20%. Notably, the risks of all-cause and cardio- and comparability with the
vascular mortality and of HF hospitalization were also significantly PARADIGM-HF population
reduced by ARNI.2
The ESC-EURObservational Research Programme (EORP)-Heart Fail-
Following the results of the PARADIGM-HF trial, both the U.S.
ure Association (HFA) Heart Failure Long-Term (HF-LT) Registry has
Food and Drug Administration (FDA) and European Medicines
been previously described.5,6 Briefly, it is a prospective, multicentre,
Agency (EMA) approved LCZ696 for symptomatic patients with observational study enrolling patients presenting with HF to a broad
HF and reduced ejection fraction (HFrEF). The EMA guidance ref- range of cardiology centres. In this analysis, 28 countries were included.
erenced the inclusion/exclusion criteria of PARADIGM-HF which Chronic HF outpatients and acute HF inpatients requiring intravenous
some may interpret as suggesting patients offered LCZ696 should HF therapy are included. The only exclusion criterion for enrolment
also meet PARADIGM-HF criteria. Interestingly, the FDA permit- in the registry is age < 18 years. Patients are followed up in accor-
ted a more liberal use of LCZ696 compared with the EMA.3 The dance with the usual practice of the centres, except for a mandatory
inclusion criteria in PARADIGM-HF were complex, requiring symp- follow-up visit, or telephone follow-up for those unwilling or unable to
tomatic HF [New York Heart Association (NYHA) class II–IV], attend a visit, at 1 year performed to collect information on morbidity
left ventricular ejection fraction (LVEF) ≤ 40% (later amended to and mortality.
≤ 35%), but also elevated plasma levels of natriuretic peptides In the current analysis, only outpatients with HFrEF registered
between March 2011 and November 2013 were considered. The index
(NPs), a dose of angiotensin-converting enzyme inhibitor (ACEi)
or angiotensin receptor blocker (ARB) equivalent to ≥ 10 mg of
date was defined as the baseline outpatient visit where data on baseline
enalapril daily for the run-in and ≥ 20 mg of enalapril daily for

characteristics, laboratory tests and medications were collected. We
compared the baseline characteristics of the ESC-EORP-HFA HF-LT
randomization, and therapy with a beta-blocker (BB) as tolerated Registry outpatients with HFrEF according to the availability of data
according to guidelines. Thus, the 2016 European Society of Car- for assessment of eligibility and the presence/absence of eligibility for
diology (ESC) guidelines on HF, considering the single trial and LCZ696 with those of the PARADIGM-HF population.2,7
strict inclusion criteria of PARADIGM-HF, recommended ARNI as
a replacement for an ACEi only in outpatients with LVEF ≤ 35% who
remain symptomatic (NYHA class II–IV) despite optimal treatment Patient eligibility for LCZ696 based
with an ACEi/ARB (at equivalent of 20 mg enalapril daily dose), a BB on EMA/FDA label, PARADIGM-HF
and an MRA as tolerated and with NP levels above those required and 2016 ESC guidelines
in PARADIGM-HF (class I, level B).4
Eligibility for LCZ696 in the ESC-EORP-HFA HF-LT Registry was
Given the efficacy of LCZ696 and the potential implications assessed based on EMA/FDA label, the PARADIGM-HF eligibility crite-
of widespread implementation, for both improved HF outcomes ria and the 2016 ESC HF guidelines.2,4 According to the EMA label,
and increased costs, we assessed in a large and unselected, LCZ696 is indicated for ‘adult patients with symptomatic chronic
European-wide real-world HF population eligibility for LCZ696 HFrEF”, while according to the FDA label, LCZ696 is indicated for
according to EMA and FDA labels, the PARADIGM-HF and the ‘chronic HF (NYHA class II–IV) and reduced ejection fraction’. Thus,
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Sacubitril/valsartan eligibility in the ESC HF-LT Registry 1385
patients were considered eligible for LCZ696 based on the EMA/FDA use. Outcome risk was compared vs. the enalapril arm of the
........................................................................................................................................................................
label if they were outpatients (inpatients were not included in any anal- PARADIGM-HF population (we did not use the LCZ696 arm since
ysis in this manuscript) with LVEF ≤ 40% and NYHA class II–IV. In this none in the registry were treated with LCZ696) in order to inves-
study, for PARADIGM-HF, patients were considered eligible if they had: tigate differences in outcomes occurrence in trial vs. real-world
(i) symptomatic HF (NYHA class II–IV); (ii) LVEF ≤ 40%; (iii) elevated setting.7
plasma levels of NPs [B-type natriuretic peptide (BNP) ≥ 150 pg/mL or
N-terminal pro-B-type natriuretic peptide (NT-proBNP) ≥ 600 pg/mL;
or alternatively BNP ≥ 100 pg/mL or NT-proBNP ≥ 400 pg/mL if they Statistical analysis
had been hospitalized for HF within the previous 12 months]; (iv) a
dose of ACEi/ARB equivalent to ≥ 10 mg of enalapril daily for run-in
Design and statistical analyses were performed by EORP. For baseline
and ≥ 20 mg of enalapril daily for randomization, and therapy with a BB
characteristics as well as outcome variables, numerical data are pre-
sented as mean ± standard deviation or median [interquartile range]
according to guidelines. MRAs were not required, but the trial protocol
and categorical data are presented as numbers (percentages). All anal-
specified that an MRA should also be considered in all patients, taking
yses were performed with SAS statistical software version 9.4 (SAS
account of renal function, serum potassium, and tolerability. Therefore,
Institute, Inc., Cary, NC, USA).
MRA use was not considered a criterion for LCZ696 eligibility in our
analysis, though proportions of patients with and without MRA receipt
were reported. Furthermore and uniquely, the registry records all the
details required to assess PARADIGM-HF criteria, even including his- Results
tory of angioedema. Thus, the exclusion criteria in PARADIGM-HF that
were considered as ineligibility criteria in the present analysis included ESC-EORP-HFA HF-LT Registry HFrEF
(i) severe chronic kidney disease (estimated glomerular filtration rate cohort: baseline characteristics
< 30 mL/min/1.73 m2 ), (ii) intolerance to ACEi due to angioedema, (iii) according to eligibility and comparability
a current or recent (within the last 3 months) cardiovascular medical
condition (myocardial infarction, stroke, transient ischaemic attack) or with the PARADIGM-HF trial population
surgical (including heart surgery and vascular surgery) or interventional The baseline characteristics of the 5443 HFrEF outpatients of the
procedure (percutaneous coronary intervention or carotid angio- ESC-EORP-HFA HF-LT registry are shown in Table 1. Mean age
plasty), (iv) hyperkalaemia (serum potassium > 5.2 mmol/L for screen- was 64 ± 13 years, 22% female, approximately half had a history of
ing or > 5.4 mmol/L for run-in and randomization), or (v) symptomatic
hypertension and one third had diabetes.
hypotension and/or systolic blood pressure < 100 mmHg for screen-
Patients in the registry were similar to those in PARADIGM-HF
ing and < 95 mmHg for run-in and randomization. When not explicitly
regarding age, gender distribution, body mass index, prevalence
stated otherwise, in this study the criteria for randomization were used
for parameters that were different for screening, run-in and random- of diabetes, systolic blood pressure and LVEF (Table 1). Notably,
ization. The registry captures not only use and dosing of drugs, but also ischaemic heart disease was the most common underlying cause
reasons for non-use. Thus, uniquely, tolerability and contraindications, of HF in both populations (48% in the registry vs. 60% in
even history of angioedema, were available for our analyses. PARADIGM-HF). Fewer patients in the registry were in NYHA
In this study, for ESC guidelines, patients were considered eligible if class II–IV compared with the PARADIGM-HF trial (84% vs.
they had: (i) symptomatic HF (NYHA class II–IV), (ii) LVEF ≤ 35%, (iii) 95%). Indeed, 16% in the registry were in NYHA class I, which
(current or prior, not tolerated) use of an ACEi/ARB, (iv) (current or was an exclusion criterion for the PARADIGM-HF trial run-in
prior, not tolerated) use of a BB, (v) (current or prior, not tolerated) but not for randomization, when 5% in PARADIGM-HF has
use of an MRA, (vi) elevated NPs (same levels as above), and (vii) daily
dose of an ACEi/ARB equal to an enalapril equivalent of ≥ 20 mg.
improved to NYHA class I. Regarding HF pharmacotherapy,
in the ESC-EORP-HFA HF-LT HFrEF outpatient population vs.
As PARADIGM-HF run-in required only 10 mg daily, in the present
study, a daily dose of an ACEi/ARB ≥ 10 mg of enalapril equivalent PARADIGM-HF trial, patients were less likely to use an ACEi, more
was also evaluated as potential alternative to the last criterion for likely to use an MRA and a loop diuretic, whereas no differences
PARADIGM-HF and ESC eligibility. existed in use of BBs and ARBs (Table 1).
We analysed the study population with no missing data for the
detailed variables required to assess eligibility. We compared baseline
characteristics of the entire population vs. the population of patients ESC-EORP-HFA HF-LT Registry patient
with complete information on eligibility to evaluate any potential eligibility for LCZ696 based on EMA/FDA
differences due to data not missing at random. Finally, we analysed
the impact of the individual criteria on eligibility and the impact of all
label, PARADIGM-HF and 2016 ESC
criteria when applied one after the other in a sequential manner. guideline criteria
Among the 5443 outpatients with HFrEF, 84% where symptomatic
Risk of outcomes in PARADIGM-HF vs. (NYHA class II–IV) and thus met the regulatory criteria. Complete
ESC-EORP-HFA HF-LT Registry data for variables needed to define LCZ696 eligibility according
We calculated crude risk during the 1-year follow-up for HF hos- to PARADIGM-HF and the 2016 ESC HF guidelines were available
pitalization and all-cause mortality in the overall HFrEF cohort in 2197 (40%) and 2373 (44%) patients, respectively (Tables 2
of the ESC-EORP-HFA HF-LT Registry, as well as in the sub- and 3).
groups, defined by the fulfilment or not of EMA/FDA label, ESC Eligible patients based on PARADIGM-HF and the ESC guide-
guidelines and PARADIGM-HF eligibility criteria for LCZ696 lines had similar characteristics (Table 1). Baseline characteristics
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Table 1 Baseline characteristics in ESC-EORP-HFA HF-LT Registry outpatients with heart failure with reduced ejection fraction and in PARADIGM-HF
1386
patients
ESC-EORP-HFA HF-LT Registry population PARADIGM-HF

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . populationb
Missing HFrEF Complete Eligible Eligible
data (% of overall information according to according to
outpatient (PARADIGM-HF 2016 ESC PARADIGM-HF
HFrEF cohort) criteria) guidelinesa run-in criteria
.........................................................................................................................................................................................
Baseline, n 5443 2197 (40% of overall) 282 (12% of complete info 616 (28% complete info on 8399
on ESC guideline criteria) PARADIGM-HF criteria)
Age (years) 0% 63.8 ± 12.6 63.4 ± 12.8 62.4 ± 12.4 65.0 ± 11.6 63.8 ± 11.4
Age ≤ 65 years 0% 53% 54% 56% 50% –
BMI (kg/m2 ) 0% 27.8 ± 4.9 27.8 ± 4.9 29.0 ± 4.9 28.4 ± 4.8 28.2 ± 5.5
Female sex 0% 22% 20% 17% 21% 22%
Diabetes 0% 32% 34% 40% 37% 35%
Chronic obstructive 0% 15% 16% 17% 17% 13%
pulmonary disease
Hypertension 0% 56% 58% 66% 64% 71%
NYHA class 0%
I 16% 14% 0% 0% 5%
II 55% 59% 70% 71% 70%
III 26% 25% 30% 27% 24%
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IV 2% 2% 0% 2% 1%
Unknown 0% 0% 0% 0% 0%
LVEF 0%
≤ 15% 5% 6% 6% 5% 29.5 ± 6.2
15–20% 13% 14% 16% 15%
21–25% 18% 18% 24% 18%
26–30% 28% 27% 30% 31%
31–35% 24% 24% 24% 22%
36–40% 12% 11% 0% 9%
Primary aetiology 0%
IHD 48% 47% 51% 46% 60%
Hypertension 4% 4% 4% 5% –
DCM 35% 39% 36% 39%
Valve disease 4% 4% 3% 4% –
Tachycardia-related 1% 1% 0% 1% –
myopathy
Other 7% 6% 6% 5% –
eGFR (mL/min/1.73 m2 ) 11%
≥ 60 56% 58% 64% 62% 70.0 ± 20.0
45–59 23% 22% 22% 24%
30–44 15% 14% 12% 14%
< 30 7% 6% 2% 0%
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C.J. Kapelios et al.

Table 1 Continued
ESC-EORP-HFA HF-LT Registry population PARADIGM-HF

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . populationb
Missing HFrEF Complete Eligible Eligible
© 2019 The Authors

data (% of overall information according to according to
outpatient (PARADIGM-HF 2016 ESC PARADIGM-HF
HFrEF cohort) criteria) guidelinesa run-in criteria
.........................................................................................................................................................................................
Serum K+ 12% 4.5 ± 0.5 4.5 ± 0.5 4.5 ± 0.5 4.5 ± 0.5 4.5 ± 0.5
BNP (pg/mL) 88% 348 [128–862] 343 [128–862] 545 [290–935] 422 [236–836] –
NT-proBNP (pg/mL) 68% 1608 [646–3939] 1614 [650–3982] 2181 [1073–3853] 2054 [1055–4534] 1631 (885–3154)
for LCZ696
1594 [886–3305]
for enalapril
SBP (mmHg) 0% 120.8 ± 19.8 120.7 ± 19.8 123.9 ± 21.3 126.2 ± 18.5 121 ± 15
Sacubitril/valsartan eligibility in the ESC HF-LT Registry
Implantable 0% 23% 24% 31% 22% 15%

cardioverter-defibrillator
Cardiac 0% 18% 19% 22% 21% 7%
resynchronization
therapy
Haemoglobin 16% 13.5 ± 1.8 13.7 ± 1.7 13.8 ± 1.6 13.8 ± 1.7 –

HbA1c 72% 6.8 ± 1.5 6.7 ± 1.5 6.7 ± 1.4 6.7 ± 1.5 –
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Non-CV drugs, n 38% 2.2 ± 1.6 2.3 ± 1.6 2.2 ± 1.7 2.2 ± 1.6 –
HF pharmacotherapy
ACEi 0% 69% 70% 92% 81% 78%
ACEi according to 32% 42% 44% 88% 73% –
PARADIGM-HF run-inc
ARB 0% 21% 22% 10% 19% 23%
ARB according to 79% 11% 10% 7% 16% –
PARADIGM-HF run-inc
BB 0% 90% 91% 95% 97% 93%
MRA 0% 63% 65% 83% 68% 56%
Loop diuretics 17% 96% 97% 96% 96% 80%
Thiazide 17% 11% 10% 10% 13% –
Continuous data presented as mean ± standard deviation or median [interquartile range], as appropriate. Categorical data presented as proportions.
ACEi, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; BB, beta-blocker; BMI, body mass index; BNP, B-type natriuretic peptide; CV, cardiovascular; DCM, dilated cardiomyopathy; eGFR, estimated
glomerular filtration rate; EORP, EURObservational Research Programme; ESC, European Society of Cardiology; HbA1c , glycated haemoglobin; HF, heart failure; HFA, Heart Failure Association; HF-LT, Heart Failure Long-Term; HFrEF,
heart failure with reduced ejection fraction; IHD, ischaemic heart disease; K+ , potassium; LCZ696, sacubitril/valsartan; LVEF, left ventricular ejection fraction; MRA, mineralocorticoid receptor antagonist; NT-proBNP, N-terminal
pro-B-type natriuretic peptide; NYHA, New York Heart Association; SBP, systolic blood pressure.
a Patients with (i) LVEF ≤ 35%, (ii) NYHA class II–IV, (iii) plasma BNP ≥ 150 pg/mL (or NT-proBNP ≥ 600 pg/mL) or a BNP ≥ 100 pg/mL (or NT-proBNP ≥ 400 pg/mL) and a hospitalization for HF within the last 12 months, (iv)
current or prior treatment with an ACEi/ARB at minimum ESC guideline dose equivalent to enalapril 20 mg daily and BB and MRA (or contraindicated or not tolerating BB and/or MRA).
b Data adapted from McMurray et al.2
c Minimum daily dose equivalent to 10 mg of enalapril.
1387
Table 2 The individual and sequential impact of each eligibility criterion according to PARADIGM-HF in
ESC-EORP-HFA HF-LT Registry outpatient population with complete information for eligibility assessment
ESC-EORP-HFA HF-LT Registry population with complete

information on PARADIGM-HF criteria
........................................................................
Individually, n (%) Sequentially, n (cum. %)
...........................................................................................................................................
ESC-EORP-HFA HF-LT Registry HFrEF outpatient population with 2197 (100) 2197 (100)
complete data on eligibility
Inclusion criteria
1 Age ≥ 18 years 2197 (100) 2197 (100)
2 LVEF ≤ 40% 2197 (100) 2197 (100)
3 NYHA class II–IV 1881 (86) 1881 (86)
4 Plasma BNP ≥ 150 pg/mL (or NT-proBNP ≥ 600 pg/mL) or a 1732 (79) 1542 (70)
BNP ≥ 100 pg/mL (or NT-proBNP ≥ 400 pg/mL) and a
hospitalization for HF within last 12 months
Exclusion criteria
1 eGFR < 30 mL/min/1.73 m2 2066 (94) 1427 (65)
2 Patients with acute HF 2197 (100) 1427 (65)
3 Patients with angioedema or history of angioedema 2193 (100) 1425 (65)
4 Patients with a current or recent (within last 3 months) CV 1970 (90) 1247 (57)
medical condition (MI, stroke, TIA) or surgical (including heart
surgery, carotid, vascular surgery) and interventional procedure
(PCI or carotid angioplasty)
5 Patients with hyperkalaemia (serum K+ > 5.4 mmol/L) 2110 (96) 1200 (55)
6 Symptomatic hypotension and/or a SBP < 95 mmHg 2039 (93) 1109 (50)
Pharmacotherapy
1 Current or prior treatment with an ACEi/ARB + BB 1936 (88) 985 (45)
a Current or prior treatment with an ACEi/ARB + BB + MRA 1407 (64) 751 (34)
2 Current or prior treatment with minimum PARADIGM-HF dose 1236 (56) 616 (28)
of an ACEi/ARB equivalent to enalapril 10 mg/day + BB
a Current or prior treatment with minimum PARADIGM-HF dose 874 (40) 461 (21)
of an ACEi/ARB equivalent to enalapril 10 mg/day + BB + MRA
3 Current or prior treatment with a stable dose of an ACEi/ARB 565 (26) 259 (12)
equivalent to enalapril 20 mg/day + BB
a Current or prior treatment with a stable dose of an ACEi/ARB 388 (18) 189 (9)
equivalent to enalapril 20 mg/day + BB + MRA
Adult HFrEF outpatients are used as denominator for all percentage calculation.
ACEi, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; BB, beta-blocker; BNP, B-type natriuretic peptide; CV, cardiovascular; eGFR, estimated
glomerular filtration rate; EORP, EURObservational Research Programme; ESC, European Society of Cardiology; HF, heart failure; HFA, Heart Failure Association; HF-LT, Heart
Failure Long-Term; HFrEF, heart failure with reduced ejection fraction; K+ , potassium; LVEF, left ventricular ejection fraction; MI, myocardial infarction; MRA, mineralocorticoid
receptor antagonist; NT-proBNP, N-terminal pro-B-type natriuretic peptide; NYHA, New York Heart Association; PCI, percutaneous coronary intervention; SBP, systolic
blood pressure; TIA, transient ischaemic attack.
were also similar between patients who had no missing data for began) treatment with an ACEi/ARB and a BB. When the crite-
................................
the variables required to assess eligibility and the entire population rion for a minimum daily dose of ACEi/ARB equivalent to enalapril
(Table 1). 10 mg daily and a BB was included, 1236 (56%) patients met this
Eligibility based on the EMA/FDA label is shown in Figure 1. criterion, whereas when a minimum daily dose of ACEi/ARB equiv-
The individual and sequential impact of each eligibility criterion alent to enalapril 20 mg was considered, 565 (26%) patients met
according to PARADIGM-HF is shown in Table 2 and Figure 1. Of the criterion. Finally, when all the PARADIGM-HF criteria for eli-
HFrEF outpatients with complete data to assess eligibility, the vast gibility were simultaneously considered, only 259 (12%) patients
majority met criteria for NYHA class II–IV and NPs, estimated were candidates for LCZ696 if a minimum dose of ACEi/ARB
glomerular filtration rate, potassium and systolic blood pressure at least equivalent to enalapril 20 mg daily was considered as a
levels. Regarding HF pharmacotherapy, 1936 (88%) of HFrEF out- requirement and 616 (28%) if a dose at least equal to 10 mg daily
patients were receiving (or had received when the outpatient visit was required.
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Table 3 The individual and sequential impact of each eligibility criterion according to the 2016 ESC guideline criteria
in the ESC-EORP-HFA HF-LT Registry population with complete information for eligibility assessment
ESC-EORP-HFA HF-LT Registry population with

complete information on 2016 ESC guideline criteria
.............................................................
Individually, Sequentially,
n (%) n (cum. %)
...........................................................................................................................................
ESC-EORP-HFA HF-LT Registry HFrEF outpatient population 2373 2373
ESC guideline inclusion criteria

2035 (86) 2035 (86)
LVEF ≤ 35%
1 NYHA class II–IV 1827 (77) 1827 (77)
2
1897 (80) 1703 (72)
3 Current or prior treatment with an ACEi/ARB
1865 (79) 1674 (71)
4 Current or prior treatment with an ACEi/ARB + BB (or contraindicated or not
tolerating BB)
1539 (65) 1392 (59)
5 Current or prior treatment with an ACEi/ARB + BB + MRA (or contraindicated
or not tolerating BB and/or MRA)
Plasma BNP ≥ 150 pg/mL (or NT-proBNP ≥ 600 pg/mL) or a BNP ≥ 100 pg/mL
1667 (70) 1150 (48)
6
(or NT-proBNP ≥ 400 pg/mL) and a hospitalization for HF within last 12 months
942 (40) 669 (28)
7 Current or prior treatment with an ACEi/ARB at minimum PARADIGM-HF dose
equivalent to enalapril 10 mg daily + BB + MRA (or contraindicated or not
tolerating BB and/or MRA)
152 (6) 139 (6)
a Current treatment with an ACEi/ARB not reaching minimum PARADIGM-HF
dose equivalent to enalapril 10 mg daily but who are in up-titration + BB + MRA
(or contraindicated or not tolerating BB and/or MRA)
419 (18) 282 (12)
8 Current or prior treatment with an ACEi/ARB at minimum ESC guideline dose
equivalent to enalapril 20 mg daily + BB + MRA (or contraindicated or not
tolerating BB and/or MRA)
332 (14) 302 (13)
a Current treatment with an ACEi/ARB not reaching minimum ESC guideline dose
equivalent to enalapril 20 mg daily but who are in up-titration + BB + MRA (or
contraindicated or not tolerating BB and/or MRA)
Adult HFrEF outpatients are used as denominator for all percentage calculation.
ACEi, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; BB, beta-blocker; BNP, B-type natriuretic peptide; EORP, EURObservational Research
Programme; ESC, European Society of Cardiology; HF, heart failure; HFA, Heart Failure Association; HF-LT, Heart Failure Long-Term; HFrEF, heart failure with reduced
ejection fraction; LVEF, left ventricular ejection fraction; MRA, mineralocorticoid receptor antagonist; NT-proBNP, N-terminal pro-B-type natriuretic peptide; NYHA, New
York Heart Association.
The respective impact of eligibility criteria according to the ESC Risk of outcomes in PARADIGM-HF vs.
........................................................
guidelines is shown in Table 3 and Figure 1 . Of 2373 HFrEF patients ESC-EORP-HFA HF-LT Registry
with complete data to assess ESC criteria, a vast majority again
met clinical criteria, somewhat fewer met concomitant therapy Among the 5443 HFrEF outpatients of the registry, 139 (2.6%)
criteria, and only a small minority met the ACEi/ARB dose criteria. were lost to follow-up leaving 5304 (97%) patients for outcomes
Indeed, only 419 (18%) patients were on current treatment or had analysis.
been previously treated with ACEi/ARB at a daily dosage ≥ 20 mg In the enalapril (control) arm of the PARADIGM-HF trial,2,7 the
enalapril, whereas in 332 (14%) up-titration was still ongoing. 1-year HF hospitalization rate was 12%. HF hospitalization rates
When a minimum daily dose of ACEi/ARB equal to enalapril were higher in the overall outpatient HFrEF cohort and in all the
10 mg was considered, 942 (40%) patients met this criterion, with outpatient sub-categories of the ESC-EORP-HFA HF-LT Registry
additional 152 (6%) patients in the up-titration phase. Finally, when (Figure 2A). The corresponding risk was 13%, 15%, 17%, 15%,
all the ESC guideline criteria for eligibility were simultaneously 12%, and 14% for HFrEF outpatients overall, EMA/FDA label eli-
considered, only 282 (12%, same as for PARADIGM-HF eligibility) gible, ESC eligible and ineligible, and PARADIGM-HF eligible and
patients were candidates for LCZ696 if a dose of ACEi/ARB ineligible, respectively. The 1-year all-cause mortality rate in the
at least equivalent to enalapril 20 mg daily was considered as a enalapril arm of PARADIGM-HF was 7.7%.2 The rate of death
requirement and 669 (28%, same as for PARADIGM-HF eligibility) in the overall HFrEF cohort was 8.8% but differed considerably
if a dose of ACEi/ARB at least equal to enalapril 10 mg daily was across outpatient sub-categories of the ESC-EORP-HFA HF-LT
required. Registry (Figure 2B). Namely, all-cause mortality rates were 8.7%,
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Figure 1 Fulfilment of (A) drug label, (B) 2016 ESC guidelines on heart failure and (C) PARADIGM-HF criteria for sacubitril/valsartan (LCZ696)
eligibility among ESC-EORP-HFA HF-LT Registry heart failure with reduced ejection fraction outpatients: individual and sequential impact of
criteria. Proportions of 28% and 12% for both PARADIGM-HF and ESC guidelines represent the main findings based on requiring 10 or
20 mg enalapril daily, respectively. ACEi, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; BB, beta-blocker; CV,
cardiovascular; eGFR, estimated glomerular filtration rate; LVEF, left ventricular ejection fraction; MRA, mineralocorticoid receptor antagonist;
NT-ProBNP, N-terminal pro-B-type natriuretic peptide; NYHA, New York Heart Association; SBP, systolic blood pressure.
6.5%, 9.0%, 5.3%, and 8.7% in EMA/FDA label eligible, ESC guide- alternatively considered, then 28% of patients were eligible by both
.......................................................................
line eligible and ineligible, and PARADIGM-HF eligible and ineligi- PARADIGM-HF and ESC criteria.
ble, respectively. Among registry patients considered ineligible for Heart failure trials are selective, and patients are generally
LCZ696 based on PARADIGM-HF criteria, the ones considered younger and have better outcomes compared to real-world
ineligible due to low levels of NPs had considerably lower HF hos- patients.8 However, the HFrEF outpatient cohort of the
pitalization (4.9% vs. 18%) and all-cause mortality rates (1.8% vs. ESC-EORP-HFA HF-LT Registry was comparable to the
12%) compared with patients ineligible due to all other criteria PARADIGM-HF population. This suggests that the PARADIGM-HF
(Figure 3). population was relatively representative of real-world HFrEF
patients, although the ESC-EORP-HFA HF-LT Registry is more
selective than many real-world registries and cohorts because
Discussion it is voluntary and investigators tend to have a greater research
interest, even though centres are selected to represent a broad
Real-world outpatients with HFrEF enrolled in the large, multi-site
range of HF care.5,6
ESC-EORP-HFA HF-LT Registry were overall comparable to those
randomized in the PARADIGM-HF trial. In the registry, 84% The exact proportion of real-world HFrEF outpatients who
met the EMA/FDA drug label criteria. Most criteria for LCZ696 are eligible for LCZ696 based on the PARADIGM-HF and ESC
eligibility set by PARADIGM-HF and the ESC guidelines were guideline criteria remains debatable, as only 4 out of 10 patients
individually met. However, when all criteria were considered of the ESC-EORP-HFA HF-LT Registry had complete entries for
simultaneously, only 12% of HFrEF outpatients were eligible, the detailed variables required for defining eligibility (although
based on either the PARADIGM-HF or ESC criteria. Notably, most other cohorts miss many of the criteria completely, e.g.
the most difficult criterion was the use of ACEi/ARB at a history of angioedema). However, the baseline characteristics of
minimum daily dose equivalent to 20 mg of enalapril (required patients with complete entries were similar to those of the entire
for randomization in PARADIGM-HF). If the criterion of 10 mg ESC-EORP-HFA HF-LT Registry HFrEF population, suggesting that
enalapril daily dose (required for run-in in PARADIGM-HF) was data were missing reasonably at random and thus that our results
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Figure 2 One-year heart failure hospitalization rates (A) and all-cause mortality rates (B) among different groups of heart failure with reduced
ejection fraction (HFrEF) outpatients enrolled in the ESC-EORP-HFA HF-LT Registry and in patients enrolled in PARADIGM-HF.
may be representative of the entire registry population. Among were analysed, 75.5% of patients prescribed enalapril ≥ 10 mg or
equivalent and 77.4% of patients prescribed enalapril ≥ 20 mg or
............................................................
HFrEF patients in the registry, only 12% were eligible for LCZ696
when the ESC guideline criteria were applied. This percentage was equivalent fulfilled all criteria for LCZ696.12 This underscores the
identical when the PARADIGM-HF criteria were used. When the potential for better integration of evidence-based treatment in
ACEi/ARB dose criterion (20 mg daily), which was most rare to HFrEF and it has been shown that enrolment in the Swedish Heart
be met, was set to half dose, the proportion of patients eligi- Failure Registry is associated with considerably improved mortal-
ble significantly increased to 28% with either the PARADIGM-HF ity, and that this improvement is precisely explained by better use
or the ESC guideline criteria. Low rates of eligibility have been of HF therapy.13
previously reported in smaller studies with fewer and less gen- Regulatory authorities (both EMA and FDA) do not consider NP
eralizable centres: the proportion of patients considered suitable levels for LCZ696 eligibility. Several criteria in PARADIGM-HF and
for LCZ696 according to the FDA drug label ranged between other trials are simply for enrichment and do not necessarily sug-
50% and 71% of patients, whereas the respective proportion gest lack of efficacy outside these criteria or lack of generalizability.
when the PARADIGM-HF criteria (20 mg daily ACEi/ARB dose) However, for LCZ696, NP levels were used in the trial, in guide-
were applied decreased to 21–39%.1,9 – 11 However, if the 10 mg lines and by some countries and payers, so they are still relevant
ACEi/ARB dose criterion was alternatively used, rates of eligibil- for stakeholders trying to interpret real-world implementation.
ity again significantly rose.9 – 11 The only exception seems to come Furthermore, and considering the big difference that we showed
from the Swedish Heart Failure Registry12 ; symptomatic (NYHA in outcome rates among patients fulfilling the NP vs. all other
class II–IV) HFrEF patients were prescribed enalapril ≥ 10 mg or exclusion criteria, it is conceivable that the risk/benefit ratio is dif-
equivalent in 74.4% and enalapril ≥ 20 mg or equivalent in 50.0% ferent in patients not having sufficiently high NP criteria, and even
of cases. When patients with complete data to assess eligibility probable that cost-effectiveness is quantitatively different.11 NPs do
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Figure 3 One-year heart failure (HF) hospitalization and all-cause mortality rates of ESC-EORP-HFA HF-LT Registry outpatients ineligible
for PARADIGM-HF due to low natriuretic peptides (NPs) vs. other criteria.
not appear to be routinely measured in real-world HFrEF outpa- the results of a sub-analysis that suggests the superiority of LCZ696
............................................................................................................
tients once the diagnosis has been established, as demonstrated by over enalapril at lower than their target doses,18 have sprouted
the high number of missing entries in the present study and other significant controversy regarding the optimal timing of LCZ696
registries.14 Eight out of 10 patients with NP entries in the registry initiation. Some experts have advocated that LCZ696 should be
fulfilled the guideline (and PARADIGM-HF) criteria, and expand- initiated in all patients with HFrEF who can tolerate an ACEi/ARB,
ing the indication of LCZ696 to patients with lower NP levels, irrespective of the dose.19 The need for presence of symptoms
as permitted by the EMA/FDA label, may not be cost-effective,11 as a prerequisite for drug initiation has also been downplayed on
even though the efficacy of LCZ696 appears to be potentially and the grounds that one of the most significant effects of LCZ696 is
counterintuitively greater in NYHA class I–II vs. NYHA class III–IV the decreased risk of sudden cardiac death,19 which often affects
patients, the NYHA class sub-groups representing the only statis- asymptomatic or oligosymptomatic HF patients. Although the effi-
tically significant interaction in PARADIGM-HF.2 cacy of LCZ696 was the same regardless of dose of LCZ696 vs.
The ESC guideline criterion, which was most rare to be enalapril achieved, the 20 mg dose was, nevertheless, required for
met, was the requirement of an ACEi/ARB use at a minimum randomization in PARADIGM-HF.
daily dose equal to enalapril 20 mg daily. Indeed, only 18% of In PARADIGM-HF there was considerable and similar drop-out
patients were on current or prior treatment with a BB, an MRA in both parts of the run-in, but the run-in began with enalapril and
and an ACEi/ARB at this dose. When minimum daily dose of was not randomized. Thus, those eliminated during the enalapril
ACEi/ARB equal to enalapril 10 mg was considered, 40% of run-in phase may have been frailer or less suitable trial subjects than
patients fulfilled it. When these two criteria were considered on those eliminated during LCZ696 run-in, who had already demon-
top of all the other eligibility criteria, the proportion of HFrEF strated tolerance to enalapril 20 mg daily. Furthermore, there was
patients suitable for LCZ696 was 12% and 28%, respectively, a greater risk of symptomatic hypotension in the LCZ696 arm
similar to that observed also in smaller populations.9,11 The than in the enalapril arm.2 Although LCZ696 dose titration to
respective rates when all PARADIGM-HF criteria were assessed the target dose seemed to be feasible in the majority (> 80%)
were identical. This may raise concerns regarding the repre- of patients with systolic blood pressure > 100 mmHg enrolled in
sentativeness and generalizability of the PARADIGM-HF trial. another randomized study,20 more than 90% of the study partic-
The run-in period (which was not randomized) was designed ipants had tolerated an ACEi/ARB prior to screening, whereas
to minimize patient drop-out but may have limited eligibil- an open-label 5-day run-in phase of LCZ696 50 mg twice daily
ity based on the trial criteria and the subsequent guideline was also included. Another randomized trial assessing the feasi-
recommendations. bility and safety of pre-discharge vs. post-discharge initiation of
Importantly, ACEi/ARB are not always tolerated and rarely LCZ696 in HFrEF patients hospitalized for HF decompensation was
used at their maximum recommended doses,15 thus hinder- recently presented.21 Importantly, 24% of the study patients were
ing the guideline-recommended introduction of LCZ696. Mul- ACEi/ARB naïve. Although no significant differences were reported
tiple retrospective analyses of the PARADIGM-HF trial have between the two study groups during the 10-week follow-up
demonstrated associations between LCZ696 use and favourable period regarding the incidence of hyperkalaemia, hypotension,
secondary outcomes, such as renal function preservation in heart failure, dizziness or renal impairment, a trend towards higher
patients with HF and diabetes and reduced risk of hyperkalaemia rates of tolerating LCZ696 at high doses of 100 or 200 mg twice
during treatment with MRAs.16,17 These findings, combined with daily was noted with post-discharge vs. pre-discharge initiation
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of the medication (68 vs. 62.5%, P = 0.07). This could raise con- lower risk in PARADIGM-HF could potentially be explained by the
........................................................................................................................................................................
cern as to whether pressure for earlier or wider administration stricter selection that inevitably occurs in trials, the higher risk pro-
of the drug could ultimately result in sub-optimal dosing regimens. file (i.e. higher prevalence of end-stage renal disease and more use
However, concerns that LCZ696 may be unsafe in hospitalized or of loop diuretics) and the less regular follow-up in the registry vs.
ACEi/ARB naïve patients were dispelled by the recently published the PARADIGM-HF and other trial populations.30 However, this
PIONEER-HF trial,22 and it is possible that guideline indications consideration is not supported by the fact that the sub-populations
and reimbursement for LCZ696 will be soon expanded. Although of HFrEF patients enrolled in the ESC-EORP-HFA HF-LT Registry
LCZ696 led to significantly greater decrease in NPs post-discharge that were eligible for LCZ696 both by PARADIGM-HF and ESC
and in significant decrease in the incidence of the exploratory com- guideline criteria had better outcome in terms of survival com-
posite endpoint (including death, rehospitalization for HF, implan- pared to patients in the enalapril arm of PARADIGM-HF, although
tation of a left ventricular assist device, and inclusion on the list of they had similar baseline characteristics. This could be possibly
patients eligible for heart transplantation) compared with enalapril, explained either by the effect of unrecognized confounders or,
PARADIGM-HF remains the only LCZ696 outcomes trial and there although it is far-fetched, by the under-reporting of adverse events
may be delays before PIONEER-HF affects guidelines, reimburse- (such as hospitalizations), which has been recognized as a significant
ment and practice. drawback of clinical trials.31
Debate regarding extrapolation of trial results continues. As The risk of outcomes in the HFrEF outpatient cohort of the
history has shown, what is logically hypothesized is not always ESC-EORP-HFA HF-LT Registry was also higher than in other reg-
correct; for example, all traditional HF medications have been istry populations.32 This may be explained by the different risk of
proven ineffective in patients with HFpEF,23 whereas the use of outcomes across the countries participating in the registry (i.e.
BB or digoxin in patients with HF and/or atrial fibrillation is also risk of all-cause mortality ranged from 6.9% in Southern Europe to
currently challenged.24,25 Moreover, potential safety issues related 15.6% in North Africa), and thus by geographical differences in HF
to long-term LCZ696 use should also be highlighted.26 Finally, severity, pharmacotherapy use and clinical practice.6 Since baseline
many argue that data pertaining to the post-market, non-trial set- characteristics were similar to PARADIGM-HF, it may be expected
ting use of LCZ696 should also be examined, even though this that if LCZ696 were administered to eligible patients from coun-
would be non-randomized data, prior to considering use of the tries and centres such as those enrolled in the ESC-EORP-HFA
drug in a wider population. This piece of information may be HF-LT Registry, the benefits may be similar to those observed in
greatly valued as the observed proportion of HF patients eligi- the trial.
ble for LCZ696 is very close to the theoretical estimate of 10%
among all HF patients.27 We should also look into contemporary
registry data to evaluate penetration of LCZ696 into clinical prac-
tice, with particular emphasis on eligibility criteria (if information
Limitations
available), safety and drug discontinuation. We do not make an Our study included only centres which had elected to partici-
argument regarding who should receive LCZ696, or whether clin- pate in the ESC-EORP-HFA HF-LT Registry, and thus results may
icians should follow the label, the trial, or guidelines, or what are not be generalizable to those seen in different units or cen-
appropriate payer restrictions. The aim of our study was com- tres. Furthermore, although baseline characteristics of patients
pletely different: LCZ696 is beneficial to patients but has been with no missing data for relevant variables needed for our analysis
variably implemented worldwide and poorly implemented in cer- did not differ from those of the entire cohort, non-randomness
tain areas. We hypothesized that the trial criteria and guidelines in missing data, leading to bias, cannot be excluded. Although
may explain the extent of implementation, and therefore the eli- the ESC-EORP-HFA HF-LT Registry is generalizable, it had low
gibility numbers in our analyses may be helpful in understanding representation of women, as is common also in clinical trials.
LCZ696 implementation and HF quality of care more generally.
However, poor implementation may also be due to complex reim-
bursement schemes or other administrative hurdles. A major pur-
pose of a quality registry is to assess use of and potential reasons
Conclusion
for poor use of evidence-based interventions. There is indeed evi- Real-world HFrEF patients enrolled in the ESC-EORP-HFA HF-LT
dence that HF registries can improve survival by improving use Registry had similar demographic and clinical characteristics, but
of treatment,13 and there are studies assessing in detail reasons different use of HF treatment and different outcomes compared
for non-use of MRAs and cardiac resynchronization therapy.28,29 with those randomized in the PARADIGM-HF trial. Of these HFrEF
Actual implementation of ARNI will be assessed in the current patients, 84% met regulatory criteria for LCZ696, whereas only
ongoing ESC HF III Registry. The present analysis is intended to 12% were eligible for LCZ696 if 20 mg enalapril equivalent was
assess but by no means justify or reinforce potential reasons for required (28% if only 10 mg enalapril equivalent was required),
LCZ696 underuse. based on either the PARADIGM-HF or the ESC guideline criteria.
The risk of outcomes in the HFrEF population enrolled in The most difficult criterion was the use of ACEi/ARB at a daily dose
the ESC-EORP-HFA HF-LT Registry was heterogeneous among equivalent to ≥ 20 mg of enalapril. Our findings highlight the need
groups. Risk of HF hospitalization in the registry was distinctly for better strategies to integrate evidence-based treatments in a
higher than in the enalapril arm of the PARADIGM-HF trial. This real-world HF setting.
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Acknowledgements personal fees from Boehringer Ingelheim, Vifor-Fresenius, Relypsa,
........................................................................................................................................................................
Novartis, Mundipharma; grants from Boston Scientific, outside the
EORP Oversight Committee, Registry Executive and Steering
submitted work. The other authors have no conflicts of interest to
Committees of the EURObservational Research Programme
disclose.
(EORP). Data collection was conducted by the EORP Department
of the European Society of Cardiology by Emanuela Fiorucci
as Project Officer, Gérard Gracia and Maryna Andarala as Data
Managers. Statistical analyses were performed by Cécile Laroche.
Appendix
Overall activities were coordinated and supervised by Dr. Aldo P. EORP Oversight Committee
Maggioni (EORP Scientific Coordinator). This study was funded in Christopher Peter Gale, Chair, GB, Branko Beleslin, RS, Andrzej
part by Novartis. Budaj, PL, Ovidiu Chioncel, RO, Nikolaos Dagres, DE, Nicolas
Danchin, FR, David Erlinge, SE, Jonathan Emberson, GB, Michael
Glikson, IL, Alastair Gray, GB, Meral Kayikcioglu, TR, Aldo P.
Funding Maggioni, IT, Klaudia Vivien Nagy, HU, Aleksandr Nedoshivin, RU,
Since the start of EORP, the following companies have supported Anna-Sonia Petronio, IT, Jolien Roos-Hesselink, NL, Lars Wallentin,
the programme: Abbott Vascular Int. (2011–2021), Amgen Car- SE, Uwe Zeymer, DE.
diovascular (2009–2018), AstraZeneca (2014–2021), Bayer AG
(2009–2018), Boehringer Ingelheim (2009–2019), Boston Scien- Executive Committee
tific (2009–2012), The Bristol Myers Squibb and Pfizer Alliance
M. Crespo-Leiro, ES, S. Anker, DE, A. Mebazaa, FR, A. Coats, GB,
(2011–2019), Daiichi Sankyo Europe GmbH (2011–2020), The
G. Filippatos, GR, R. Ferrari, IT, A.P. Maggioni, IT, M.F. Piepoli, IT.
Alliance Daiichi Sankyo Europe GmbH and Eli Lilly and Com-
pany (2014–2017), Edwards (2016–2019), Gedeon Richter Plc.
(2014–2016), Menarini Int. Op. (2009–2012), MSD-Merck & Steering Committee (National Coordinators)
Co. (2011–2014), Novartis Pharma AG (2014–2020), ResMed A. Goda, AL; M. Diez, AR; A. Fernandez, AR; F. Fruhwald, AT;
(2014–2016), Sanofi (2009–2011), Servier (2009–2021), Vifor E. Fazlibegovic, BA; P. Gatzov, BG; A. Kurlianskaya, BY; R. Hullin,
(2019–2022). CH; T. Christodoulides, CY; J. Hradec, CZ; O. Wendelboe Nielsen,
Conflict of interest: M.L. reports grants from Roche, personal DK; R. Nedjar, DZ; T. Uuetoa, EE; M. Hassanein, EG; J. F. Delgado
fees from Astra Zeneca, Vifor Pharma, Novartis, outside the sub- Jimenez, ES; V-P. Harjola, FI; D. Logeart, FR; V. Chumburidze, GE;
mitted work. G.S. reports grants and personal fees from Vifor, D. Tousoulis, GR; D. Milicic, HR; B. Merkely, HU; E. O’Donoghue,
AstraZeneca; grants and non-financial support from Boehringer IE; O. Amir, IL; A. Shotan, IL; D. Shafie, IR; M. Metra, IT; A.
Ingelheim; personal fees from SPA, Roche; grants from MSD, out- Matsumori, JP; E. Mirrakhimov, KG; A. Kavoliuniene, LT; A. Erglis,
side the submitted work. P.S. reports receipt of grants/research LV; E. Vataman, MD; M. Otljanska, MK; E. Srbinovska Kostovska,
supports from Ministry of Education, science and technologi- MK; D. Cassar DeMarco, MT; J. Drozdz, PL; C. Fonseca, PT; O.
cal development of Republic of Serbia; receipt of honoraria or Chioncel, RO; M. Dekleva, RS; E. Shkolnik, RU; U. Dahlstrom, SE;
consultation fees from Servier, Boehringer Ingelheim, Hemofarm, M. Lainscak, SI; E. Goncalvesova, SK; A. Temizhan, TR; V. Estrago,
Novartis, Astra Zeneca; participation in a company sponsored UY; G. Bajraktari, XK.
speaker’s bureau from Fondazione Internazionale Menarini. F.R.
reports grants and personal fees from SJM/Abbott, Servier, Novar-
tis, Bayer; personal fees from Zoll, AstraZeneca, Sanofi, Amgen, Investigators
BMS, Pfizer, Fresenius, Vifor, Roche, Cardiorentis, Boehringer Austria Braunau: J. Auer; Graz: K. Ablasser, F. Fruhwald, T. Dolze,
Ingelheim; grants from Mars, other from Heartware, outside the K. Brandner; Innsbruck: S. Gstrein, G. Poelzl; Sankt Poelten: D.
submitted work. A.C. reports personal fees from Novartis, dur- Moertl; Vienna: S. Reiter, A. Podczeck-Schweighofer; Bosnia
ing the conduct of the study; personal fees from AstraZeneca, Herzegovina Mostar: A. Muslibegovic, M. Vasilj, E. Fazlibegovic,
Menarini, Nutricia, Respicardia, Servier, Stealth Peptides, Vifor, M. Cesko, D. Zelenika, B. Palic, D. Pravdic, D. Cuk; Bulgaria Sofia:
Actimed, Faraday, WL Gore, outside the submitted work. S.D.A. K. Vitlianova, T. Katova, T. Velikov, T. Kurteva, P. Gatzov; Vidin:
reports grants and personal fees from Abbott Vascular, Vifor Int, D. Kamenova; Varna: M. Antova, V. Sirakova; Czech Republic
V-Wave; personal fees from Bayer, Boehringer Ingelheim, Novar- Brno: J. Krejci, M. Mikolaskova, J. Spinar; Prague: J. Krupicka, F.
tis, Servier, Brahms, outside the submitted work. M.G.C-L. reports Malek, M. Hegarova; Olomouc: M. Lazarova; Znojmo: Z. Monhart;
grants from CIBERCV, personal fees and non-financial support from Egypt Alexandria: M. Hassanein, M. Sobhy, F. El Messiry, A.H. El
Novartis; personal fees from Abbott, Astellas, MSD, outside the Shazly, Y. Elrakshy; Assiut: A. Youssef; Benha: A.A. Moneim; Cairo:
submitted work. G.F. reports that he was Committee Member M. Noamany, A. Reda, T.K. Abdel Dayem, N. Farag, S. Ibrahim
of trials and registries sponsored from Bayer, Novartis, Servier, Halawa, M. Abdel Hamid, K. Said, A. Saleh; Damanhour, El Beheira:
Vifor, Medtronic, BI, outside the submitted work. A.P.M. reports H. Ebeid; Giza Cairo: R. Hanna, R. Aziz, O. Louis, M.A. Enen,
personal fees from Novartis, Bayer, Fresenius, outside the sub- B.S. Ibrahim; Ismailya: G. Nasr; Port Said: A. Elbahry; Tanta: H.
mitted work. L.H.L. reports personal fees from Merck, Sanofi, Sobhy, M. Ashmawy; Zagazig: M. Gouda, W. Aboleineen; France
AstraZeneca, Bayer, Abbott, Pharmacosmos, Medscape; grants and Besançon: Y. Bernard, P. Luporsi, N. Meneveau, M. Pillot, M. Morel,
© 2019 The Authors

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M-F. Seronde, F. Schiele, F. Briand; Bron-Lyon: F. Delahaye; Créteil: A. Cichy; Sieradz: P. Ruszkowski, M. Splawski; Starachowice: G. Fitas,
........................................................................................................................................................................
T. Damy; Dijon: J-C. Eicher; Lille: P. de Groote, M. Fertin, N. A. Szymczyk, A. Serwicka, A. Fiega; Strzegom: D. Zysko; Szczecin:
Lamblin; Paris: R. Isnard, C. Lefol, S. Thevenin, A. Hagege, G. W. Krysiak, S. Szabowski, E. Skorek; Warszawa: P. Pruszczyk, P.
Jondeau, D. Logeart; Poitiers: V. Le Marcis, J-F. Ly, D. Coisne, B. Bienias, M. Ciurzynski, M. Welnicki, A. Mamcarz, A. Folga, T. Zielin-
Lequeux; Rennes: V. Le Moal, S. Mascle, P. Lotton, N. Behar, E. ski, T. Rywik, P. Leszek, M. Sobieszczanska-Malek, M. Piotrowska,
Donal, C. Thebault, C. Ridard, A. Reynaud, A. Basquin; Rouen: F. K. Kozar-Kaminska, K. Komuda, J. Wisniewska, A. Tarnowska,
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Tourikis, M. Stavroula, D. Tousoulis, C. Stefanadis, C. Chrysohoou, O. Mozenska, K. Byczkowska, K. Gil, A. Pawlak, A. Michalek, P.
I. Kotrogiannis, V. Matzaraki, T. Dimitroula, A. Karavidas, G. Tsitsi- Krzesinski, K. Piotrowicz, B. Uzieblo-Zyczkowska, A. Stanczyk,
nakis, C. Kapelios, J. Nanas, H. Kampouri, E. Nana, E. Kaldara, A. A. Skrobowski; Wroclaw: P. Ponikowski, E. Jankowska; Zabrze: P.
Eugenidou; Heraklion, Crete: P. Vardas, I. Saloustros, A. Patrianakos; Rozentryt, L. Polonski, E. Gadula-Gacek, E. Nowalany-Kozielska,
Volos: T. Tsaknakis, S. Evangelou, N. Nikoloulis, H. Tziourganou, A. A. Kuczaj, Z. Kalarus, M. Szulik, K. Przybylska, J. Klys; Zamosc:
Tsaroucha, A. Papadopoulou, A. Douras; Hungary Budapest: L. G. Prokop-Lewicka, A. Kleinrok; Portugal Carnaxide: C. Tavares
Polgar, B. Merkely, A. Kosztin, N. Nyolczas, A. Csaba Nagy; Pecs Aguiar, A. Ventosa; Faro: S. Pereira, R. Faria, J. Chin, I. De Jesus;
(Baranya): R. Halmosi; Israel Hadera: J. Elber, I. Alony, A. Shotan, A. Guilhufe-Penafiel: R. Santos, P. Silva, N. Moreno, C. Queirós, C.
Vazan Fuhrmann; Haifa: O. Amir; Italy Atri: S. Romano, S. Marcon, Lourenço, A. Pereira, A. Castro, A. Andrade; Lisboa: T. Oliveira
M. Penco, M. Di Mauro, E. Lemme; Brescia: V. Carubelli, R. Rovetta, Guimaraes, S. Martins, R. Placido, G. Lima, D. Brito, A.R. Francisco,
M. Metra, M. Bulgari, F. Quinzani, C. Lombardi; Cotignola: S. Bosi, R. Cardiga, M. Proenca, I. Araujo, F. Marques, C. Fonseca; Porto:
G. Schiavina, A. Squeri, A. Barbieri; Cremona: G. Di Tano, S. Pirelli; B. Moura, S. Leite, M. Campelo, J. Silva-Cardoso, J. Rodrigues, I.
Ferrara: R. Ferrari, A. Fucili; Foggia: T. Passero, S. Musio, M. Di Rangel, E. Martins, A. Sofia Correia; Santarem: M. Peres, L. Marta,
Biase, M. Correale, G. Salvemini; Lumezzane: S. Brognoli, E. Zanelli, G. Ferreira da Silva, D. Severino, D. Durao; Vila Real: S. Leao, P.
A. Giordano; Milano: P. Agostoni, G. Italiano, E. Salvioni; Modena: Magalhaes, I. Moreira, A. Filipa Cordeiro, C. Ferreira, C. Araujo,
S. Copelli, M.G. Modena, L. Reggianini, C. Valenti, A. Olaru; Mon- A. Ferreira, A. Baptista; Romania Brasov: M. Radoi; Bucharest:
serrato: S. Bandino, M. Deidda, G. Mercuro, C. Cadeddu Dessalvi; G. Bicescu, D. Vinereanu, C-J. Sinescu, C. Macarie, R. Popescu, I.
Novara: P.N. Marino, M.V. Di Ruocco, C. Sartori, C. Piccinino; Daha, G-A. Dan, C. Stanescu, A. Dan; Constanta: E. Craiu; Galati: E.
Palermo: G. Parrinello, G. Licata, D. Torres, S. Giambanco, S. Nechita; Iasi: V. Aursulesei; Timisoara: R. Christodorescu; Serbia
Busalacchi, S. Arrotti, S. Novo, R.M. Inciardi, P. Pieri, P.R. Chirco, Belgrade: P. Otasevic, P.M. Seferovic, D. Simeunovic, A.D. Ristic, V.
M. Ausilia Galifi, G. Teresi, D. Buccheri, A. Minacapelli; Passirana Celic, M. Pavlovic-Kleut, J. Suzic Lazic, B. Stojcevski, B. Pencic, A.
di Rho (Milano): M. Veniani, A. Frisinghelli; Pavia: S.G. Priori, S. Stevanovic, A. Andric; Kragujevac: V. Iric-Cupic, M. Jovic, G. Davi-
Cattaneo, C. Opasich, A. Gualco; Roma: M. Pagliaro, M. Mancone, dovic, S. Milanov; Nis: V. Mitic, V. Atanaskovic, S. Antic, M. Pavlovic,
F. Fedele, A. Cinque, M. Vellini, I. Scarfo, F. Romeo, F. Ferraiuolo, D. Stanojevic; Niska Banja: V. Stoickov, S. Ilic, M. Deljanin Ilic, D.
D. Sergi; San Bonifacio (Verona): M. Anselmi; Sassuolo: F. Melandri, E. Petrovic; Sremska Kamenica (Vojvodina): S. Stojsic, S. Kecojevic, S.
Leci, E. Iori; Torino: V. Bovolo, S. Pidello, S. Frea, S. Bergerone, M. Dodic, N. Cemerlic Adic, M. Cankovic, J. Stojiljkovic, B. Mihajlovic,
Botta, F.G. Canavosio, F. Gaita; Trieste: M. Merlo, M. Cinquetti, G. A. Radin; Zemun, Belgrade: S. Radovanovic, M. Krotin; Slovakia
Sinagra, F. Ramani, E. Fabris, D. Stolfo; Udine: J. Artico, D. Miani, C. Banovce nad Bebravou: A. Klabnik; Bratislava: E. Goncalvesova, M.
Fresco, C. Daneluzzi, A. Proclemer; Verona: M. Cicoira, L. Zanolla, Pernicky, J. Murin; Martin: F. Kovar; Presov: J. Kmec, H. Semjanova;
G. Marchese, F. Torelli, C. Vassanelli; Latvia Jelgava: N. Voronina; Slovenia Brezice: M. Strasek, M. Savnik Iskra; Izola: T. Ravnikar,
Riga: A. Erglis; Lithuania Kaunas: V. Tamakauskas, V. Smalinskas, R. N. Cernic Suligoj, J. Komel; Ljubljana: Z. Fras, B. Jug; Maribor: T.
Karaliute, I. Petraskiene, E. Kazakauskaite, E. Rumbinaite, A. Kavoli- Glavic, R. Losic, M. Bombek, I. Krajnc, B. Krunic; Murska Sobota: S.
uniene; Marijampole: V. Vysniauskas, R. Brazyte-Ramanauskiene, D. Horvat, D. Kovac, D. Rajtman; Ptuj: V. Cencic, M. Letonja; Sempeter
Petraskiene; Poland Biala: S. Stankala, P. Switala, Z. Juszczyk; Byd- pri Novi Gorici: R. Winkler, M. Valentincic, C. Melihen-Bartolic,
goszcz: W. Sinkiewicz, W. Gilewski, J. Pietrzak; Chelmza: T. Orzel, A. Bartolic; Slovenj Gradec: M. Pusnik Vrckovnik, M. Kladnik, C.
P. Kasztelowicz; Czestochowa: P. Kardaszewicz, M. Lazorko-Piega, Slemenik Pusnik, A. Marolt; Trbovlje: J. Klen, B. Drnovsek, B.
J. Gabryel; Gdansk: K. Mosakowska, J. Bellwon, A. Rynkiewicz, G. Leskovar; Spain Albacete: M.J. Fernandez Anguita, J.C. Gallego
Raczak, E. Lewicka, A. Dabrowska-Kugacka; Kielce: R. Bartkowiak, Page, F.M. Salmeron Martinez; Barakaldo (Vizcaya): J. Andres;
B. Sosnowska-Pasiarska, B. Wozakowska-Kaplon; Kluczbork: A. Barcelona: A. Bayes-Genis, S. Mirabet, A. Mendez, L. Garcia-Cosio,
Krzeminski; Krakow: M. Zabojszcz, E. Mirek-Bryniarska, A. Grze- E. Roig, V. Leon, J. Gonzalez-Costello, G. Muntane, A. Garay;
gorzko, K. Bury, J. Nessler, J. Zalewski, A. Furman; Lodz: M. Broncel, Granada: V. Alcade-Martinez, S. Lopez Fernandez, R. Rivera-Lopez,
A. Poliwczak, A. Bala, P. Zycinski, M. Rudzinska, L. Jankowski, J.D. M. Puga-Martinez, M. Fernandez-Alvarez, J.L. Serrano-Martinez;
Kasprzak, L. Michalak, K. Wojtczak Soska, J. Drozdz, I. Huziuk, A. La Coruna: M. Crespo-Leiro, Z. Grille-Cancela, R. Marzoa-Rivas,
Retwinski; Lublin: P. Flis, J. Weglarz, A. Bodys; Poznan: S. Grajek, P. Blanco-Canosa, M.J. Paniagua-Martin, E. Barge-Caballero; La
M. Kaluzna-Oleksy, E. Straburzynska-Migaj, R. Dankowski, K. Laguna - Santa Cruz de Tenerife (Canary Islands): I. Laynez Cer-
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Abdulkarim, A. Lauko-Rachocka; Przeworsk: L. Kaminski, A. Kostka, T. Soria, P. Garcia-Pavia, M. Gomez-Bueno, M. Cobo-Marcos, L.
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Alonso-Pulpon, J. Segovia Cubero, I. Sayago, A. Gonzalez-Segovia, Starling RC, Teerlink JR, Vanhaecke J, Vinereanu D, Wong RC; PARADIGM-HF
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ESC HEART FAILURE ORIGINAL RESEARCH ARTICLE
ESC Heart Failure 2019; 6: 1167–1177
Published online 9 December 2019 in Wiley Online Library (wileyonlinelibrary.com) DOI: 10.1002/ehf2.12537
Brachial pulse pressure in acute heart failure. Results

of the Heart Failure Registry
Stefano Bonapace1, Andrea Rossi2, Cécile Laroche3, Maria G. Crespo-Leiro4,5,6,7, Massimo F. Piepoli8, Andrew J.
S. Coats9, Ulf Dahlström10, Filip Malek11, Cezar Macarie12, Pier Luigi Temporelli13,
Aldo P. Maggioni3,14, Luigi Tavazzi15* and the European Society of Cardiology Heart Failure
Long-Term Registry Investigators group†
1
Unità Complessa di Cardiologia, Istituto di Ricovero e Cura a Carattere Scientifico Ospedale Sacro Cuore don Calabria, Negrar, Italy; 2Section of Cardiology, Department of
Medicine, University of Verona, Verona, Italy; 3EURObservational Research Programme Department, European Society of Cardiology, Sophia Antipolis, France; 4Unidad de
Insuficiencia Cardiaca y Trasplante Cardiaco, Complexo Hospitalario Universitario A Coruna, A Coruña, Spain; 5Instituto de Investigación Biomédica, A Coruña, Spain;
6
Universidade da Coruña, A Coruña, Spain; 7Centro de Investigación en Red en Enfermedades Cardiovasculares, A Coruña, Spain; 8Heart Failure Unit, Cardiac Department,
Guglielmo da Saliceto Hospital, AUSL Piacenza, Italy; 9San Raffaele Pisana Scientific Institute, Rome, Italy; 10Division of Cardiology, Department of Medical and Health
Sciences, Linköping University, Linköping, Sweden; 11Heart Failure and Hypertension Clinic, Na Homolce Hospital Cardiovascular Center, Prague, Czech Republic; 12Institutul
de Urgenta pentru Boli Cardiovasculare C.C. Iliescu, Bucharest, Romania; 13Division of Cardiology, Istituti Clinici Scientifici Maugeri, Istituto di Ricovero e Cura a Carattere
Scientifico, Veruno, Italy; 14ANMCO Research Center, Florence, Italy; 15Maria Cecilia Hospital, GVM Care&Research, Cotignola, Italy
Abstract
Aims To investigate the still uncertain independent prognostic impact of pulse pressure (PP) in acute heart failure (HF), in
particular across the left ventricular ejection fraction (EF) phenotypes, and the potential contribution of PP in outlining the in-
dividual phenotypes.
Methods and results We prospectively evaluated 1-year death and rehospitalization in 4314 patients admitted for acute
HF grouped by EF and stratified by their PP level on admission. In HF with reduced (< 40%) EF (HFrEF), the highest quar-
tiles of PP had the lowest unadjusted [hazard ratio (HR) 0.77, 95% confidence interval (CI) 0.61–0.98] and adjusted (HR 0.64
0.50–0.82) risk of 1 year all cause death compared to the lowest quartile. Its prognostic impact was partially mediated by
systolic blood pressure (SBP). In HF with preserved (≥ 50%) EF (HFpEF), the intermediate quartile of PP showed the lowest
1 year all cause mortality in unadjusted (HR 0.598, CI 0.416–0.858) and adjusted (HR 0.55, 95% CI 0.388-0.801) models with
no relationship with SBP. In a receiver operating characteristic analysis, a combination of PP > 60 mmHg and
SBP > 140 mmHg was associated to a preserved EF with a high performance value. No prognostic significance of PP
was found in the HF with mid-range EF subgroup.
Conclusions In acute HFrEF, there is an almost linear inverse relation between mortality and PP, partly mediated by SBP. In
HFpEF, a J-shaped relationship between mortality and PP was present with a better prognosis at the nadir. A combination of
PP > 60 mmHg with SBP > 140 mmHg may be clinically helpful as marker of a preserved left ventricular EF.
Keywords Pulse pressure; Heart Failure; Acute Heart Failure; Prognosis

Received: 14 May 2019; Revised: 23 August 2019; Accepted: 17 September 2019
*Correspondence to: Luigi Tavazzi MD, Maria Cecilia Hospital, GVM Care&Research, Via Corriera, 1, 48033 Cotignola, Ravenna, Italy.
Email: ltavazzi@gvmnet.it
Listed in Appendix 1.
when the central arteries become stiffer, in aging as in heart

Introduction failure (HF), the reflected wave arising from the peripheral ar-
terial vessels travels faster and moves from diastole to systole
Pulse pressure (PP) is the difference between systolic and di- increasing SBP (SBP), decreasing diastolic BP and widening
astolic blood pressure (BP) and reflects the complex interac- PP.2 The widening of PP imposes a greater burden on the
tion between left ventricular (LV) function and the elastic LV affecting both systolic and diastolic function, favouring
properties of the proximal large vasculature.1 Particularly, LV hypertrophy and impairing coronary blood flow.1
© 2019 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of the European Society of Cardiology
This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any me-
dium, provided the original work is properly cited and is not used for commercial purposes.
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1168 S. Bonapace et al.
Increased PP is associated with an increased risk of myocar- this registryThe registry management, the central data quality
dial infarction and cardiovascular (CV) mortality in normoten- control, and the statistical analysis were performed by the
sive, hypertensive, and high-risk patients3,4 and with EORP Department of the ESC. For a random sample of 5%
increased risk of HF in the elderly.5 Higher PP favours the de- of centres, data source verification was performed by EORP
velopment of coronary artery disease4 and is an independent monitors. There were no specific exclusion criteria, except
prognosticator of re-infarction and all-cause mortality after for age ≤ 18 years. Data were collected using a web-based
myocardial infarction (MI) in patients with LV systolic dys- system. The registry was approved by each local Institutional
function.6 Because a stiffening of the large elastic arteries de- Review Board according to the rules of each participating
termines a similar impairment in functional capacity in HF country. All patients gave written informed consent before
with reduced ejection fraction (EF) < 40% (HFrEF) and HF discharge.
with preserved EF ≥ 50% (HFpEF) LVEF,7,8 also a similar be-
haviour of PP could be expected in both EF phenotypes. How-
ever, data regarding the prognostic significance of PP in Clinical and laboratory data
patients with acute HFrEF and HFpEF are unclear.9,10 Low
PP has emerged as an independent predictor of mortality in Blood pressure was measured on hospital admission, and PP
patients with acute HFrEF,11,12 and in these patients it is be- was calculated as the difference between systolic and dia-
lieved to reflect mainly an excessive reduction in stroke vol- stolic BP. Patients were considered as having hypertension
ume rather being an index of arterial stiffening. In patients if their BP was ≥ 140/90 mmHg or if they were taking antihy-
with acute HFpEF, and even more in those with HF mid-range pertensive drugs. Biochemical blood measurements were de-
EF (HRmEF), the prognostic role of PP is far less termined using local standard laboratory procedures.
established,13,14 and inconsistent results were reported,9,13,14 According to the pure observational nature of the study,
Apart its prognostic role, we also speculated the possible the large involvement of many heterogeneous European
clinical utility of PP amplitude to discriminate the two HF phe- countries and the urgency clinical status of patients enrolled
notypes because in the acute setting they both present with the BP measurement technique was not predetermined by
similar clinical symptoms and signs.15 To address these clinical protocol. Conventional trans-thoracic echocardiography was
issues, we prospectively investigated a large multinational Eu- used to measure EF according to international standard
ropean cohort of acute HF (AHF) patients followed up for criteria. Patients were stratified according to LVEF as HF with
1 year by considering distinctly the phenotypes according to preserved ≥ 50% (HFpEF), reduced < 40% (HFrEF), and mid-
the EF value. range 40–49% EF (HFmEF).17
Statistical analyses
Methods
In the current analysis, we present the 1 year data from the
Study design ESC-EORP HF Long-Term registry concerning the rates of the
cumulative (in-hospital and post-discharge) all cause of death,
The principles and procedures of the European Society of Car- the post-discharge 1 year all cause mortality and 1 year CV-
diology (ESC)-Heart Failure Association EURObservational Re- death, 1 year all cause re-hospitalization, and 1 year CV-
search Programme (EORP) HF Long-Term Registry, a study of rehospitalization in acute HFrEF, HFmEF, and HFpEF stratified
the EORP of the ESC and the ESC-Heart Failure Association by PP on admission. Descriptive statistics were used to sum-
have been previously described.16 The enrolling network of marize frequency tabulations (%) and distributions
this prospective, multicentre, and observational study in- (mean ± standard deviation). A Cox proportional hazards
cluded 211 Cardiology centres of 21 European and Mediterra- model was used to assess the association between PP quar-
nean ESC member countries. National network coordinators tiles and outcomes. In addition to unadjusted hazard ratios
were identified by the participating National Societies of Car- (HRs), adjusted HRs were estimated after adjustment for
diology, and several training meetings were organized for the pre-specified potential confounding factors selected on the
study investigators to assure consistency in definition and basis of their clinical or biological plausibility, namely age,
data collection. A diagnosis of AHF (both de novo and wors- gender, HF aetiology (ischemic vs. non-ischemic), renal dys-
ening HF) was made by the clinician–investigators at initial function, and diabetes. The role of SBP on the prognostic im-
presentation and required the presence of signs and symp- pact of PP was also explored by dividing the population in
toms of HF, evidence of cardiac dysfunction, and the need three groups of SBP (< 100 mmHg, between 100–139 mmHg,
for intravenous therapy. From May 2011 to April 2013, all pa- and > 140 mmHg) accordingly to the results of several stud-
tients admitted for acute HF during the enrolment period (on ies.18–20 All conclusions were drawn separately by individual
1 day per week for 12 consecutive months) were included in HF phenotype. A test for trend was also planned, but no

DOI: 10.1002/ehf2.12537
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Pulse pressure and heart failure 1169
evidence of linear trend was found in the main analysis using The baseline characteristics of the PP quartiles in HFrEF,
the quartile of PP in categories. A ROC analysis to evaluate HRmEF and HFpEF are reported in Supporting Information
the ability of PP to discriminate a preserved or a reduced EF Table S1. The patients of the highest PP quartile as compared
in AHF was also performed. A two-sided P value of < 0.05 to the patients of the lower PP quartiles were significantly
was considered as statistically significant. All analyses were and uniformly older, with higher proportion of female, higher
performed using SAS Statistical software version 9.4 (SAS Insti- BMI, and higher proportion of diabetes, hypertension, and is-
tute, Inc., Cary, NC, USA). chemic heart disease. As expected, these patients were more
likely to be treated with antihypertensive drugs as
angiotensin-converting enzyme inhibitors, angiotensin II re-
ceptor blockers, and calcium channel blockers. In contrast,
Results patients in the lowest PP quartile were shown to have lower
systolic and diastolic BP, lower sodium plasma concentration,
Baseline characteristics of heart failure with higher rate of AF and were more frequently treated with an-
reduced ejection fraction, heart failure with ticoagulant drugs, beta-blockers, aldosterone antagonists,
mid-range ejection fraction, heart failure with digitalis, and diuretics as compared to the highest quartile. In-
preserved ejection fraction groups and pulse terestingly, patients in NYHA III–IV functional class were sig-
pressure quartiles nificantly more represented in the lowest PP quartile in the
HFrEF group, whilst no difference in NYHA functional class
Among the patients enrolled in the registry, 6629 were hospi- was observed across PP quartiles in HRmEF and HFpEF.
talized with a primary diagnosis of AHF. Out of them, 6618
had PP available, but only 4314 had also the EF available;
217 died in-hospital (5%). Median follow-up time was 378 Prognostic impact of pulse pressure in ejection
(288–415) days, during which 271 (6%) patients discharged fraction subgroups
alive were lost to follow-up, then 4097 patients were in-
cluded in the present analysis. Cox proportional hazard models of PP quartiles or continuous
According to a brachial SBP classification, 26.8% of patients PP value at hospital admission with the individual endpoints
presented within the range ≤ 80–110 mmHg (< 2% with in acute HFrEF, HFmEF, and HFpEF are shown in Table 3. In
values < 85 mmHg), 42.9% with 110–140 mmHg, and HFrEF, patients in the intermediate and highest quartile com-
30.3% with >140 mmHg, respectively. Then, on admission, pared to patients in the lowest quartile had a 33.9% and
> 70% of patients had a brachial SBP > 110 mmHg. The sub- 22.6% significantly lower unadjusted relative risk of death, re-
jects distributed according to the EF-phenotypes were 2213 spectively. This association was strengthened after adjusting
(51.3%) HFrEF, 818 (19.0%) HFmEF, and 1283 (29.7%) HFpEF. for age, gender, HF aetiology, diabetes, and renal dysfunction
Main baseline characteristics of the EF-subtypes are reported with a 39.5% and 35.9% significant reduction in relative risk of
in Table 1. Age was increasing along with the increase in EF death, respectively. All the other endpoints showed similar
among the considered three EF subgroups (from 65.8 [12.8] lower event rates either in unadjusted or in adjusted models
to 71.9 [13.1] years), whereas the male gender prevalence for intermediate and higher PP quartiles. This was confirmed
was decreasing (from 76.4% to 45.1%), and the prevalence also when PP was considered as a continuous variable. In
of the New York Heart Association (NYHA) functional class both the analyses of crude 1 year events and of the PP quar-
III–IV was similar (88–83%). Ischemic aetiology was prevalent tile in categories, no evidence of linear trend was found.
in HFrEF (62.6%) and HRmEF (65.4%) and not in HFpEF The association of PP for different levels of SBP was also
(37.6%). Hypertension was highly represented in all three explored and it was found that a BP between 100 and
groups, particularly in HFpEF (76.1%), in which the atrial fibril- 139 mmHg conferred a 11.8% and 16.6% significant relative
lation (AF) rate was also high (55%) whereas the prevalence risk reduction in all-cause deaths for every 10 mmHg increase
was 38% and 44% in HFrEF and HFmEF, respectively. of PP in the unadjusted and adjusted models, respectively,
Angiotensin-converting enzyme inhibitors, angiotensin II re- whereas no relationship with outcomes was found for SBP
ceptor blockers, aldosterone antagonists, beta-blockers, below and above these thresholds (Table 3). The estimated
antiplatelets drugs, and lipid-lowering drugs were prevalent cumulative incidence of all-cause death according to PP quar-
in HFrEF and HRmEF. Oral anticoagulants were more utilized tiles in HFrEF showed an increase of probability of a fatal
in HFpEF (39.9%). The crude 1 year all-cause death, CV death, event with the decline in PP amplitude (P = 0.0006). In con-
cumulative all-cause deaths, all cause re-hospitalization, CV trast, no prognostic measurable differences among PP quar-
rehospitalisation and in-hospital death in the three groups tiles were observed in the HFmEF group. Similar neutral
are reported in Table 2. All end-point events (except the in- results were seen by combining PP and SBP (Table 4). In
hospital mortality, P 0.78) were significantly higher HFpEF, Cox proportional hazard models showed a 40.2%
(P < 0.001) in patients with HFrEF. and 44.3% significantly lower unadjusted and adjusted

DOI: 10.1002/ehf2.12537
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1170
Table 1 Baseline clinical characteristics in acute HFrEF (ejection fraction < 40%), HFmEF (40% ejection fraction 49%) and HFpEF (ejection fraction > ≥50%)
Phenotypes n All 4314 HFrEF 2213 HRmEF 818 HFpEF 1283 P value
Demographic and anthropometric
Age (years) [mean (SD)] 68.1 (13.0) 65.8 (12.8) 68.5 (12.1) 71.9 (13.1) < 0.001
Caucasian 3352 (79.3%) 1652 (76.4%) 606 (75.0%) 1094 (87.2%) < 0.001
Men 2785 (64.6%) 1690 (76.4%) 516 (63.1%) 579 (45.1%) < 0.001
NYHA class III–IV 3694 (86.0%) 1945 (88.2%) 675 (83.0%) 1074 (84.1%) < 0.001
Body Mass Index (kg/m2) Median [Q1–Q3] 27.8 [25.1; 31.6] 27.7 [24.6; 30.9] 28.4 [25.5; 32.0] 28.4 [25.4; 32.7] < 0.001
Systolic Blood Pressure (mmHg) Median [Q1–Q3] 130.0 [110.0; 150.0] 120.0 [110.0; 140.0] 130.0 [117.0; 150.0] 135.0 [120.0; 159.0] < 0.001
Diastolic Blood Pressure (mmHg) Median [Q1–Q3] 80.0 [70.0; 90.0] 75.0 [70.0; 85.0] 80.0 [70.0; 90.0] 80.0 [70.0; 90.0] < 0.001
Heart Rate (b.p.m) Median [Q1–Q3] 86.0 [72.0; 102.0] 88.0 [72.0; 100.0] 90.0 [75.0; 106.0] 83.0 [70.0; 102.0] < 0.001
Pulse pressure (mmHg) Median [Q1–Q3] 50.0 [40.0; 62.0] 47.0 [40.0; 60.0] 50.0 [40.0; 66.0] 59.0 [45.0; 70.0] < 0.001
Haemoglobin (g/l) Median [Q1–Q3] 12.6 [11.0; 14.0] 12.9 [11.3; 14.1] 12.6 [10.9; 13.9] 12.0 [10.5; 13.6] < 0.001
2
eGFR (mL/min/1.73m ) Median [Q1–Q3] 55.8 [38.8; 73.6] 56.3 [39.5; 73.6] 54.8 [38.5; 73.2] 55.1 [38.2; 73.7] 0.555
NT–proBNP (pg/dL) Median [Q1–Q3] 3801.0 [1665.0; 8612.1] 4570.0 [2088.0; 9110.0] 3250.5 [1372.0; 8505.5] 2553.0 [1200.0; 6799.0] < 0.001
Total cholesterol (mg/dL) Median [Q1–Q3] 156.0 [123.0; 190.0] 161.0 [129.3; 196.0] 156.0 [126.7; 190.0] 156.0 [126.7; 190.0] 0.029
Glycemia (mg/dL) Median [Q1–Q3] 110.0 [92.7; 150.0] 108.0 [91.0; 147.0] 111.7 [93.0; 163.3] 111.0 [95.0; 149.0] 0.008
Sodium (mEq/L) Median [Q1–Q3] 139.0 [135.0; 141.0] 138.0 [135.0; 141.0] 139.0 [136.0; 142.0] 139.0 [136.0; 141.0]
Risk factors and comorbidities
Diabetes mellitus 1766 (40.9%) 907 (41.0%) 345 (42.2%) 514 (40.1%) 0.629
Hypertension 2860 (66.3%) 1335 (60.4%) 549 (67.1%) 976 (76.1%) < 0.001
Smoking status (never) 676 (15.7%) 401 (18.1%) 143 (17.5%) 132 (10.3%) < 0.001
Ischaemic HF aetiology 2403 (55.7%) 1385 (62.6%) 535 (65.4%) 483 (37.6%)
Previous stroke 558 (12.9%) 262 (11.8%) 95 (11.6%) 201 (15.7%) 0.002
- 247 -
Previous MI/angina 2407 (55.8%) 1356 (61.3%) 522 (63.8%) 529 (41.2%) < 0.001
COPD 861 (20.0%) 412 (18.6 %) 144 (17.6%) 305 (23.8%) < 0.001
Atrial fibrillation 1916 (44.4%) 847 (38.3%) 361 (44.1%) 708 (55.2%) < 0.001
Type of atrial fibrillation
Paroxysmal 478 (11.1%) 210 (9.5%) 84 (10.3%) 184 (14.3%) < 0.001
Permanent 1167 (27.1%) 518 (23.4%) 227 (27.8%) 422 (32.9%)
Persistent 271 (6.3%) 119 (5.4%) 50 (6.1%) 102 (8.0%)
Medications
Previous revascularization (percutaneous/surgical) 973 (22.6%) 580 (26.2%) 181 (22.1%) 212 (16.5%) < 0.001
Statins 2085 (48.4%) 1148 (52.0%) 422 (51.6%) 515 (40.1%) < 0.001
ACE-Inhibitors 2425 (56.3%) 1363 (61.7%) 474 (57.9%) 588 (45.8%) < 0.001
ARBs 607 (14.1%) 259 (11.7%) 102 (12.5%) 246 (19.2%) < 0.001
Beta-blockers 2647 (61.4%) 1478 (66.9%) 499 (61.0%) 670 (52.2%) < 0.001
Aldosterone antagonists 1782 (41.4%) 1159 (52.5%) 317 (38.8%) 306 (23.9%) < 0.001
Diuretics 3117 (72.3%) 1744 (79.0%) 538 (65.5%) 837 (65.2%) < 0.001
Calcium channel blockers 668 (15.5%) 204 (9.2%) 144 (17.6%) 320 (24.9%) < 0.001
Digitalis 948 (22.0%) 576 (26.1%) 155 (18.9%) 217 (16.9%) < 0.001
Antiplatelets 2274 (52.8%) 1302 (58.9%) 443 (54.2%) 529 (41.2%) < 0.001
Anticoagulants (vitamin K antagonists/NOACs) 1547 (35.9%) 785 (35.5%) 250 (30.6%) 512 (39.9%) < 0.001
ACE: Angiotensin converting-enzyme; ARB: angiotensin II receptor blocker; COPD, chronic obstructive pulmonary disease; eGFR, estimated Glomerular Filtration Rate; HF, heart failure;
HFmEF, heart failure with mid-range ejection fraction; HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; NT-proBNP, N-terminal
prohormone of BNP; NOAC, new oral anticoagulant; NYHA, New York Heart Association; MI, myocardial infarction.
All variables were available in > 98% of the cases, except for total cholesterol (n 2883), glycemia (n 3679), Na (n 4082), and NT-proBNP (n 984).
Categorical variables are reported as n(%).

S. Bonapace et al.
DOI: 10.1002/ehf2.12537
Table 2 Outcomes at 1 year according to the left ventricular ejection fraction phenotypes
Phenotypes n HFrEF 2213 HFmEF 818 HFpEF 1283 P value

1 year all cause death 534/1944 (27.5%) 141/730 (19.3%) 244/1151 (21.2%) < 0.001
1 year cardiovascular death 270/1731 (15.6%) 68/682 (10.0%) 113/1071 (10.6%) < 0.001
Cumulative (in-hospital + 1 year) all cause death 643/2053 (31.3%) 180/769 (23.4%) 313/1220 (25.7%) < 0.001
In-hospital death 109/2212 (4.9%) 39/818 (4.8%) 69/1283 (5.4%) 0.782
1 year all cause rehospitalization (at least 1) 887/1777 (49.9%) 288/694 (41.5%) 524/1081 (48.5%) < 0.001
1 year cardiovascular rehospitalization (at least 1) 754/1744 (43.2%) 239/687 (34.8%) 386/1066 (36.2%) < 0.001
HFmEF, heart failure with mid-range ejection fraction; HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with re-
duced ejection fraction.
relative risk of death respectively in the intermediate quartile Longitudinal community studies like the Framingham Heart
of PP compared to patients in the lowest quartile, in which study21 and the Multiethnic Study of Atherosclerosis22
the probability of a fatal event is slightly more elevated. showed that the brachial PP, in particular the pulse wave ve-
(P = 0.031). This was confirmed also for the cumulative all- locity and the pulse reflection magnitude respectively, were
cause deaths. As shown in the Table 4, we did not find any strong predictors for incident HF. Several studies on the prog-
relationship between PP and different levels of SBP in both nostic role of PP in established chronic HF were conducted
unadjusted and adjusted models. As shown in the Supporting with non-consistent results.6,9–14,23–25 In acute HF, most of
Information, Tables S2 and S3, the number of patients, partic- the work focused on the prognostic impact of the SBP, a
ularly in the category of SBP < 100 mmHg in HFmEF and in meaningful indicator, and the potential prognostic role of
HFpEF, is relatively low that may have weaken the statistical PP has been less explored.26–30
power of this SBP subgroup analysis. Our data in HFrEF are in line with the results of both Vaso-
dilation in the Management of Acute-HF study11 and (Meta-
Analysis Global Group in Chronic Heart Failure) MAGGIC
Pulse pressure as marker of preserved vs. meta-analysis12 on the prognostic value of PP in acute HFrEF
reduced left ventricular ejection fraction (with a cut-off value of EF < 40% and < 50% respectively)
that found that the patients in the lowest PP had the worst
We conducted a ROC analyses to evaluate the potential role prognosis with an association more pronounced if PP was
of PP as marker of a preserved LVEF (≥ 50%), measured on measured within 24 hours after admission11 (with EF).12 Sim-
hospital admission, in individual AHF patients (Figure 1). ilarly to our results, the prognostic role of PP was interpreted
When only PP > 60 mmHg was considered and analysed as according to corresponding SBP values.12 Higher PP was asso-
a continuous variable, its ability in detecting an EF ≥ 50% ciated to higher SBP and higher LVEF suggesting that stroke
was low (the ROC area under curve was 66.6%). On the other volume and SBP are probably the major determinants of its
hand, when the highest quartile of PP > 60 mmHg was com- amplitude in this setting.11,12
bined with SBP > 140 mmHg, the ROC curve area coefficient Differently from our data, the Get With The Guidelines
was 76.1% suggesting a remarkable sensitivity and specificity (GWTG) Registry13 reported a U-shaped association between
of this combination to suggest a preserved LVEF in this clinical PP at discharge and mortality in patients with HFrEF (EF cut-
context. off at 50%) with a risk nadir at PP of 50 mmHg. Risk decreased
as PP increased up to 50 mmHg, whereas risk increased as PP
increased ≥50 mmHg suggesting that for lower PP the LV
Discussion function is the main determinant of its amplitude, whereas
for higher PP arterial stiffness plays a major role. In our pop-
The salient findings of our study, performed in patients with ulation, although intermediate quartiles of PP showed the
acute HF, are the following: (i) in HFrEF, intermediate and best prognosis, this significant positive trend was maintained
highest quartiles of PP showed a lower mortality as compared also for higher PP quartiles suggesting an almost linear rela-
to the lowest quartile with an almost inverse linear relation- tion between PP amplitude and reduced mortality further
ship, at least in part mediated by SBP; (ii) in HFmEF, PP did supporting the predominant role of LV pump in determining
not show any relationship to prognosis; (iii) in HFpEF, inter- the PP amplitude in HFrEF. No data were reported in the
mediate quartiles of PP showed a better prognostic value above studies about the role of PP in the “grey” zone of
suggesting a J-curve with a more favourable PP value at the HFmEF patients. We did not observe any relationship be-
nadir of the curve, with no relationship with SBP; (iv) the tween PP and mortality in this intermediate cohort, and even
combination of PP > 60 mmHg and SBP > 140 mmHg was as- by comparing the EF subgroups obtained by a single cut-off
sociated with a preserved LVEF suggesting a clinical relevance value of 50%, the results of PP interaction in HFrEF and HFpEF
of this combination in discriminating these HF phenotypes. did not change substantially (data not shown). The lack of

DOI: 10.1002/ehf2.12537
- 248 -
Table 3 Hazard Ratios of PP quartiles or continuous PP value at hospital admission with the individual endpoints in acute HFrEF (n 2213), HFmEF (n 818), and HFpEF (n 1283) (Cox pro- 1172
portional hazards model).
HFrEF HFmEF HFpEF

Unadjusted Adjusted Unadjusted Adjusted Unadjusted Adjusted
HR HR** HR P HR** P HR HR**
Variable Modality (95% CI) P value (95% CI) P value (95% CI) value (95% CI) value (95% CI) P value (95% CI) P value
Q1 (PP < =40) Ref .. .. .. ..
Q2 (40.0 < 0.92 0.650 0.81 (0.57-1.16) 0.251 1.00 0.982 1.11 0.637 0.72 0.067 0.68 0.030
PP < =47.0) (0.64-1.31) (0.64-1.57) (0.71-1.75) (0.509-1.023) (0.48-0.96)
1 year Q3 (47.0 < 0.66 <0.001 0.60 <0.001 1.06 0.800 1.15 0.574 0.59 0.005 0.56 0.002
all-cause PP < =60.0) (0.54-0.81) (0.49-0.74) (0.66-1.71) (0.71-1.86) (0.416-0.858) (0.39-0.80)
death
Q4 (PP > 60.0) 0.77 0.037 0.64 <0.001 0.93 0.764 0.90 0.657 0.85 0.351 0.77 0.119
(0.60-0.98) (0.50-0.82) (0.58-1.48) (0.56-1.44) (0.615-1.189) (0.55-1.07)
Continue PP value 0.99 0.016 0.98 <0.001 1.00 0.527 0.99 0.302 1.00 0.230 0.99 0.065
(0.98-0.99) (0.98-0.99) (0.99-1.00) (0.99-1.00) (0.990-1.002) (0.99-1.00)
Q1 (PP < =40) Ref .. .. .. ..
Q2 (40.0 < 0.83 0.483 0.73 0.232 0.54 0.081 0.59 0.139 0.71 0.189 0.68 0.140
PP < =47.0) (0.50-1.38) (0.44-1.22) (0.27-1.08) (0.29-1.19) (0.43-1.18) (0.41-1.13)
1 year CV Q3 (47.0 < 0.57 <0.001 0.53 <0.001 0.66 0.249 0.70 0.320 0.61 0.061 0.56 0.027
death* PP < =60.0) (0.43-0.76) (0.39-0.71) (0.32-1.34) (0.33-1.43) (0.36-1.02) (0.33-0.93)
Q4 (PP > 60.0) 0.68 0.030 0.56 0.001 0.97 0.929 0.92 0.803 0.72 0.199 0.66 0.101
(0.48-0.96) (0.39-0.80) (0.53-1.76) (0.50-1.69) (0.44-1.19) (0.40-1.08)
Continue PP value 0.99 0.009 0.99 <0.001 1.01 0.843 1.00 0.573 0.99 0.167 0.99 0.068
(0.98-0.99) (0.97-0.99) (0.99-1.01) (0.98-1.01) (0.98-1.00) (0.98-1.00)
- 249 -
Q1 (PP < =40) Ref .. .. .. ..
Q2 (40.0 < 0.88 0.432 0.78 0.142 0.97 0.889 1.08 0.707 0.68 0.011 0.65 0.005
PP < =47.0) (0.63-1.21) (0.56-1.09) (0.66-1.43) (0.73-1.60) (0.50-0.91) (0.48-0.87)
Cumulative Q3 (47.0 < 0.65 <0.001 0.60 <0.001 0.98 0.918 1.04 0.853 0.53 <0.001 0.50 <0.001
in-hospital PP < =60.0) (0.54-0.78) (0.50-0.72) (0.64-1.49) (0.68-1.60) (0.40-0.73) (0.36-0.69)
+ 1 year all
cause death
Q4 (PP > 60.0) 0.69 0.002 0.59 <0.001 0.87 0.524 0.83 0.391 0.73 0.032 0.65 0.004
(0.55-0.87) (0.46-0.74) (0.58-1.32) (0.55-1.26) (0.54-0.97) (0.49-0.88)
Continue PP value 0.99 <0.001 0.99 <0.001 1.00 0.365 0.99 0.155 0.99 0.004 0.99 <0.001
(0.98-0.99) (0.98-0.99) (0.99-1.00) (0.99-1.00) (0.98-1.00) (0.98-0.99)
Q1 (PP < =40) Ref .. .. .. ..
Q2 (40.0 < 1.02 0.895 1.01 0.969 0.95 0.748 0.93 0.693 0.94 0.659 0.95 0.698
PP < =47.0) (0.75-1.38) (0.74-1.36) (0.68-1.32) (0.67-1.30) (0.73-1.22) (0.73-1.23)
1 year all Q3 (47.0 < 0.89 0.163 0.89 0.163 1.33 0.116 1.27 0.200 0.87 0.262 0.87 0.265
cause PP < =60.0) (0.76-1.05) (0.75-1.05) (0.93-1.90) (0.88-1.84) (0.68-1.11) (0.67-1.11)
re-hospi-
talization
Q4 (PP > 60.0) 0.99 0.930 0.96 0.711 1.10 0.549 1.07 0.676 1.12 0.358 1.02 0.883
(0.81-1.21) (0.78-1.18) (0.80-1.52) (0.77-1.49) (0.89-1.43) (0.79-1.31)
Continue PP value 1.00 0.390 1.00 0.265 1.00 0.540 1.00 0.886 1.00 0.804 1.00 0.580
(0.99-1.00) (0.99-1.00) (0.99-1.00) (0.99-1.00) (0.99-1.00) (0.99-1.00)
Q1 (PP < =40) Ref .. .. .. ..
0.271 0.232 0.511 0.656 0.039 0.033
(Continues)

S. Bonapace et al.
DOI: 10.1002/ehf2.12537
A composite endpoint of cardiovascular death comprising death because of stroke, myocardial infarction (MI) or other cardiovascular aetiology, including deaths because of pulmonary
P value
CI; confidence interval; CV, cardiovascular; HFmEF, heart failure with mid-range ejection fraction; HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced
0.440
0.117
0.258
relation between PP and any of the prognostic outcomes con-
sidered in the intermediate EF group remains unexplained,
but it could be related to the very narrow range of EF and a
(0.53-0.98)
(0.68-1.18)
(0.60-1.06)
(0.99-1.00)
Adjusted
(95% CI)
too low number of patients and events.
HR**
0.72
0.90
0.80
1.00
In acute HFpEF, the prognostic impact of PP is more com-
plex. In our study and in another recent report,14 the inter-
HFpEF
mediate quartiles of PP showed a better prognosis

P value
0.685
0.347
0.671
compared to the lowest and the highest quartiles with no re-
lationship with the level of SBP. This suggests that in HFpEF
attributing the relative weight of PP amplitude to arterial
Unadjusted
(0.54-0.98)
(0.72-1.24)
(0.66-1.16)
(0.99-1.00)
stiffness or to LV systolic function may be harder than in
(95% CI)
0.73
0.94
0.87
1.00
HR
HFrEF, and probably, the better prognostic impact of inter-

mediate values of PP is associated with a more favourable
embolism. Any MI or stroke followed by death in the next 28 days (regardless of the cause) was considered to be a fatal MI or fatal stroke. ventricular–vascular coupling compared to higher or lower
values of PP. Differently from our results, in the GWTG Regis-
0.616
0.774
0.788
value
try,13 the patients with HFpEF showed increasing risk of mor-

P
tality as PP increases, and this was mediated by increasing

(0.65-1.31)
(0.61-1.34)
(0.66-1.36)
(0.99-1.00)
SBP suggesting a predominant role of arterial stiffening over

Adjusted
(95% CI)
HR**
0.90
0.92
0.95
1.00
LV systolic function. On the contrary, in the acute HFpEF pa-

tients of the MAGGIC meta-analysis,12 those in the lowest
HFmEF
quintile of PP had the worst outcome irrespective of the level

of SBP, suggesting a prevalent role of a transient alteration in
0.448
0.888
0.403
value
P
LV systolic performance during the acute episode.

The relative contribution of the single determinants of PP
Unadjusted
(0.63-1.26)
(0.58-1.27)
(0.72-1.45)
(1.00-1.01)
amplitude is dynamic and varies in relation to the clinical sit-

(95% CI)
0.86
0.90
1.02
1.00
uation and the precise timing at which the measurement is

HR
performed. In fact, changes over time of its amplitude during

hospital stay have been described.30 Of course PP measured
on admission is not the same as PP taken days after or at dis-
P value
<0.001
<0.001
0.002
charge from the initial acute episode, and PP taken early on

admission showed the worst prognostic impact.11 Our deter-
minations of PP are on hospital admission whereas in the
(0.64-0.90)
(0.60-1.13)
(0.50-0.79)
(0.98-0.99)
Covariates: age, gender, heart failure aetiology, diabetes, renal function.
GWTG Registry13 were taken at hospital discharge, and in

Adjusted
(95% CI)
HR**
0.76
0.82
0.63
0.99
both the MAGGIC meta-analysis12 and the Tokitsu study,14

data of PP were measured at variable time during hospital
HFrEF
stay. This might help to explain the apparent discrepancy ob-

served in the literature regarding its prognostic behaviour
P value
<0.001
<0.001
0.001
The fact that a lower PP is associated with a worse progno-

ejection fraction; HR, hazard ratio; PP, pulse pressure.
sis does not exclude a major role also of arterial stiffening in

determining its narrowing rather than its widening. In fact
Unadjusted
(0.64-0.89)
(0.60-1.15)
(0.50-0.79)
(0.99-1.00)
(95% CI)
under stress conditions such as during physical exercise, HFrEF

0.76
0.83
0.63
0.99
HR
patients with stiffer arteries had lower PP amplitude com-

pared to those with more distensible elastic arteries.7 Simi-
larly, in HFpEF, an altered ventricular–vascular coupling
Continue PP value
reserve may determine a lesser increase in LVEF and in PP am-

Q4 (PP > 60.0)
plitude compared to normal subjects.31 This increased burden

Modality
PP < =60.0)
PP < =47.0)
Q3 (47.0 <
Q2 (40.0 <
on the left ventricle related to a stiffer vascular system ob-

served during exercise in both HFrEF, and HFpEF may resem-
Table 3 (continued)
ble what happens during an acute episode of HF leading to a

narrower PP. This may also explain the opposite negative
prognostic behaviour of low PP and high pulse wave velocity,
Fisher’s test.
1 year CV
talization
re-hospi-
a direct measure of arterial stiffness, observed in patients with

Variable
chronic HFrEF.32 In a recent study comparing 22 hypertensive

control subjects and 98 HFpEF patients during hemodynamic
b
a

DOI: 10.1002/ehf2.12537
- 250 -
Table 4 Hazard ratios for association of pulse pressure with 1 year all-cause death in A HFrEF ( n 2213), B HFmEF ( n 818) and C HFpEF (n
1283) for different level of SBP (Cox proportional hazard models)
a
Variable SBP level, mmHg Unadjusted HR (95% CI) P value Adjusted HR (95% CI) P value
A
1 year all-cause death SBP < 100 0.95 (0.71–1.27) 0.748 0.83 (0.618–1.13) 0.241
100 ≤ SBP < 140 0.88 (0.79–0.98) 0.023 0.83 (0.748–0.93) 0.001
SBP ≥ 140 1.12 (1.00–1.25) 0.046 1.08 (0.961–1.21) 0.201
B
100 ≤ SBP < 140 1.15 (0.92–1.43) 0.230 1.16 (0.92–1.46) 0.202
SBP ≥ 140 1.10 (0.94–1.28) 0.229 0.97 (0.83–1.14) 0.711
C
100 ≤ SBP < 140 1.05 (0.90–1.21) 0.552 0.94 (0.81–1.09) 0.441
SBP ≥ 140 1.09 (0.98–1.20) 0.105 1.04 (0.94–1.15) 0.469
CI, confidence interval; HFmEF, heart failure with mid-range ejection fraction; HFpEF, heart failure with preserved ejection fraction; HFrEF,
heart failure with reduced ejection fraction; HR, hazard ratio; SBP, systolic blood pressure.
Fisher’s test.
HRs Adjusted per every 10 mmHg increase of PP.
a
Covariates: age, gender, heart failure aetiology (ischemic/non-ischemic), diabetes, renal function
exercise testing with invasively measured radial artery pres- as well as in the MAGGIC meta-analyses12 a lower PP relates
sure waveform, the HFpEF subjects displayed reduced total to higher prevalence of AF.
arterial compliance and higher effective arterial elastance at Finally, the results of our study also suggest a potential
similar mean arterial pressures in control subjects. This was di- clinical role of PP. Acute HFrEF and HFpEF present with similar
rectly correlated with higher ventricular filling pressures and clinical symptoms and signs, and only imaging techniques can
depressed cardiac output reserve.33 really differentiate the LVEF phenotipes.15 In previous stud-
Also, the presence of atrial fibrillation may at least in part ies, a low proportional PP index (PP/SBP) has shown to corre-
contribute to a narrower PP in acute HF probably because late with LV systolic performance in HFrEF.34 In our study, a
of a reduction in atrial contribution to LV filling with a conse- combination with PP > 60 mmHg and a SBP > 140 mmHg
quent further reduction in stroke volume. This may reconcile has been shown to discriminate a preserved EF providing a
the apparent discrepancy with earlier studies showing that support for a phenotypic diagnosis and some insight in the
higher PP is a predictor of incident AF whereas in our study pathogenetic pattern of these two clinical entities.
Figure 1 Receiving operator characteristics (ROC) curve of PP > 60 mmHgcombined with SBP > 140 mmHg in predicting a preserved ejection fraction
(>50%) in AHF (ROC curve area 0.761).

DOI: 10.1002/ehf2.12537
- 251 -
Study limitations (EORP). Data collection was conducted by the EORP depart-
ment from the ESC by Emanuela Fiorucci as Project Officer,
Several issues regarding our study must be acknowledged. Gerard Gracia and Maryna Andarala as Data Managers, and
First, by considering the presumable high proportion of pa- Cécile Laroche as Statistician. Overall activities were coordi-
tients needing immediate treatment at enrollment (in fact nated and supervised by Doctor Aldo P. Maggioni (EORP Sci-
88% were in NYHA functional class III–IV), and to foster the entific Coordinator).
consecutiveness of enrollment, specific modalities of BP mea- All investigators listed in the Supporting Information Ap-
surements were not mandated by protocol. This may expose pendix 1.
to some imprecision in the BP-reported values. However, the
reported level of BP was that used by the attending physi-
cians to take the clinical decisions for patients’ management. Conflicts of interest
Second, the observational, pragmatic methodology of our
large study does not allow a definite proof of a direct link be- Stefano Bonapace, Andrea Rossi, Cécile Laroche, Massimo
tween PP amplitude and outcome. Third, a recent compre- Piepoli, Philip Malek, Cezar Macarie, Pierluigi Temporelli,
hensive technical, physiopathological, and clinical review on confict of interest: none declared;
pulsatile hemodynamics in various HF conditions also outlines Maria G. Crespo-Leiro: reports grants from Centro de
the limitation of inferring the PP between two points mea- Investigación en Red en Enfermedades Cardiovasculares,
sured at the clinical bed.29 However, some information can grants and personal feed from Novartis, Other from Pfizer,
be drawn by this simple measurement, and we tried to ex- personal fees, and other from Amgen outside the submitted
plore this area of clinical knowledge. Fourth, we have only work.
one time-point measurement, and we cannot evaluate the Andrew J Coats: reports personal fees from AstraZeneca,
potential—likely relevant—prognostic role of changes over personal fees from Menarini, personal fees from Novartis,
time of PP, and we cannot exclude unmet or unknown con- personal fees from Nutricia, personal fees from Respicardia,
founding factors that may have influenced its prognostic impersonal fees from Servier, personal fees from Stealth Pep-
pact. Fifth, we do not have information about central PP, tides, personal fees from Vifor, personal fees from Actimed,
found to be a stronger prognostic marker than brachial PP personal fees from Faraday, and personal fees from W.L.
in various conditions.21,35 Sixth, we also lack of direct mea- Gore, outside the submitted work;
surements of arterial stiffness like the aortic pulse wave ve- Ulf Dahlstrӧm: reports grants from AstraZeneca, other
locity that showed prognostic impact in chronic HFrEF32,36 from Novartis, and other from AstraZeneca, outside the sub-
and HFpEF.14 However, though warranted, central PP and mitted work;
aortic pulse wave velocity have never been measured in any Aldo P. Maggioni: reports personal fees from Bayer, per-
large trial in acute HF and cannot be implemented in a large sonal fees from Novartis, and personal fees from Fresenius,
multinational setting of non-tertiary cardiology centres like outside the submitted work.
the present registry. Luigi Tavazzi: reports personal fees from Servier and per-
sonal fees from CVie Therapeutics, outside the submitted
work.
Conclusions
Brachial PP has a prognostic value and a potential contribu- Funding
tory diagnostic role in acute HF. In HFrEF, an almost linear, in-
verse relationship between mortality and PP, partly mediated Since the start of EORP, the following companies have sup-
by SBP, was shown. In HFpEF, a J-shaped relationship be- ported the programme: Abbott Vascular International
tween mortality and PP was observed with no evident rela- (2011–2021), Amgen Cardiovascular (2009–2018),
tionship to the level of SBP. A combination of PP and SBP AstraZeneca (2014–2021), Bayer AG (2009–2018), Boehringer
may result as clinically helpful to discriminate the two differ- Ingelheim (2009–2019), Boston Scientific (2009–2012), The
ent major phenotypes of HF. Bristol Myers Squibb and Pfizer Alliance (2011–2019), The Al-
liance Daiichi Sankyo Europe GmbH and Eli Lilly and Company
(2011–2017), Daiichi Sankyo Europe (2012–2020), Edwards
(2016–2019), Gedeon Richter plc (2014–2017), Menarini In-
Acknowledgements ternational Op. (2009–2012), MSD–Merck & Co. (2011–
2014), Novartis Pharma AG (2014–2020), ResMed (2014–
EORP Oversight Committee, Registry Executive and Steering 2016), Sanofi (2009–2011), Servier (2009–2021), and Vifor
Committees of the EURObservational Research Programme (2019–2022).

DOI: 10.1002/ehf2.12537
- 252 -
Supporting information Table S2. The number of patients in each SBP category of in
the HF phenotypes.
Additional supporting information may be found online in the Table S3. Distribution of HF subgroups according to SBP
Supporting Information section at the end of the article. category
Appendix S1. List of investigators.
Table S1. Clinical characteristics of acute HFrEF, HFmEF and
HFpEF groups stratified by baseline PP quartiles.
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DOI: 10.1002/ehf2.12537
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doi:10.1002/ejhf.1645
Sex- and age-related differences in the

management and outcomes of chronic heart
failure: an analysis of patients from the ESC
HFA EORP Heart Failure Long-Term Registry
Mitja Lainščak1,2†, Ivan Milinković3,4†, Marija Polovina3,4, Marisa G. Crespo-Leiro5,
Lars H. Lund6, Stefan D. Anker7,8,9, Cécile Laroche10, Roberto Ferrari11,12,
Andrew J.S. Coats13, Theresa McDonagh14, Gerasimos Filippatos15,16,
Aldo P. Maggioni10,17, Massimo F. Piepoli18, Giuseppe M.C. Rosano19,
Frank Ruschitzka20, Dragan Simić3,4, Milika Ašanin3,4, Jean-Christophe Eicher21,
Mehmet B. Yilmaz22 and Petar M. Seferović4,23*, on behalf of the European Society
of Cardiology Heart Failure Long-Term Registry Investigators Group‡
1 Divisionof Cardiology, General Hospital Murska Sobota, Murska Sobota, Slovenia; 2 Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia; 3 Department of Cardiology,
Clinical Centre of Serbia, Belgrade, Serbia; 4 Faculty of Medicine, Belgrade University, Belgrade, Serbia; 5 Unidad de Insuficiencia Cardiaca y Trasplante Cardiaco, Complexo
Hospitalario Universitario A Coruna (CHUAC), INIBIC, UDC, CIBERCV, La Coruna, Spain; 6 Heart and Vascular Division, Department of Medicine, Karolinska Institute,
Karolinska University Hospital, Stockholm, Sweden; 7 Division of Cardiology and Metabolism, Department of Cardiology, Berlin-Brandenburg Centre for Regenerative Therapies,
Berlin, Germany; 8 German Centre for Cardiovascular Research (Berlin partner site), Charité Universitätsmedizin Berlin, Berlin, Germany; 9 Department of Cardiology and
Pneumology, University of Medicine Göttingen, Göttingen, Germany; 10 EURObservational Research Programme, European Society of Cardiology, Sophia-Antipolis, France;
11 Centro Cardiologico Universitario di Ferrara, University of Ferrara, Ferrara, Italy; 12 GVM Care and Research, Maria Cecilia Hospital, Cotignola, RA, Italy; 13 Pharmacology
Division, Centre of Clinical and Experimental Medicine, IRCCS San Raffaele Pisana, Rome, Italy; 14 Faculty of Life Sciences and Medicine, King’s College Hospital, London, UK;
15 Department of Cardiology, Heart Failure Unit, Athens University Hospital Attikon, Athens, Greece; 16 School of Medicine, National and Kapodistrian University of Athens,
Athens, Greece; 17 ANMCO Research Centre, Florence, Italy; 18 Heart Failure Unit, Guglielmo da Saliceto Hospital, Piacenza, Italy; 19 Cardiovascular and Cell Sciences Institute,
King’s College Hospital, London, UK; 20 Clinic of Cardiology, University Hospital, Zurich, Switzerland; 21 Department of Cardiology, Rhythmology and Heart Failure Unit,
University Hospital François Mitterrand, Dijon, France; 22 Department of Cardiology, Faculty of Medicine, Cumhuriyet University, Sivas, Turkey; and 23 Serbian Academy of Sciences
and Arts, Belgrade, Serbia
Received 12 May 2019; revised 20 July 2019; accepted 19 September 2019 ; online publish-ahead-of-print 20 December 2019
Aims This study aimed to assess age- and sex-related differences in management and 1-year risk for all-cause mortality and
hospitalization in chronic heart failure (HF) patients.
.....................................................................................................................................................................
Methods Of 16 354 patients included in the European Society of Cardiology Heart Failure Long-Term Registry, 9428 chronic HF
and results patients were analysed [median age: 66 years; 28.5% women; mean left ventricular ejection fraction (LVEF) 37%]. Rates
of use of guideline-directed medical therapy (GDMT) were high (angiotensin-converting enzyme inhibitors/angiotensin
receptor blockers, beta-blockers and mineralocorticoid receptor antagonists: 85.7%, 88.7% and 58.8%, respectively).
Crude GDMT utilization rates were lower in women than in men (all differences: P ≤ 0.001), and GDMT use became
lower with ageing in both sexes, at baseline and at 1-year follow-up. Sex was not an independent predictor of
GDMT prescription; however, age >75 years was a significant predictor of GDMT underutilization. Rates of all-cause
mortality were lower in women than in men (7.1% vs. 8.7%; P = 0.015), as were rates of all-cause hospitalization
(21.9% vs. 27.3%; P < 0.001) and there were no differences in causes of death. All-cause mortality and all-cause
hospitalization increased with greater age in both sexes. Sex was not an independent predictor of 1-year all-cause
mortality (restricted to patients with LVEF ≤45%). Mortality risk was significantly lower in patients of younger age,
compared to patients aged >75 years.
*Corresponding author. Koste Todorovica 8, 11 000 Belgrade, Serbia. Tel: + 381 11 361 4738, Email: seferovic.petar@gmail.com
† These authors contributed equally to the manuscript.
‡ Listed in Appendix 1.
© 2019 The Authors

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Management of chronic heart failure: sex- and age-related differences 93
Conclusions There was a decline in GDMT use with advanced age in both sexes. Sex was not an independent predictor of GDMT or
adverse outcomes. However, age >75 years independently predicted lower GDMT use and higher all-cause mortality
in patients with LVEF ≤45%.
..........................................................................................................
Keywords Age • Sex • Mortality • Hospitalization • Registry
Introduction Inclusion and exclusion criteria
..............................................................................................................................................
From the overall registry population (n = 16 354) enrolled between
Heart failure (HF) is a growing health concern affecting more than
2011 and 2016, for the purpose of the present analyses, data on ambu-
26 million patients worldwide.1,2 Despite advances in treatment, it
latory patients with HF (n = 9428 patients) were selected. Ambulatory
accounts for significant proportions of hospitalization, disability and patients included all outpatients with chronic HF diagnosed according
mortality.3–6 Chronic HF predominantly affects elderly people; its to the clinical judgement of the responsible cardiologist at the par-
incidence doubles in men and triples in women with each decade ticipating centre.22 Further details on the registry protocol have been
after the age of 65 years.2 Clinical trials and registries of chronic described elsewhere.22 The only exclusion criterion was age <18 years.
HF have provided conflicting data on age- and sex-related char- At inclusion, demographic and clinical data were collected, and
acteristics in terms of their influence on patient management and details on HF management before and after the ambulatory visit were
prognosis.7–12 Several studies have indicated a better prognosis in recorded. Patients were followed up in accordance with the standard
female than in male patients,7–9 whereas other studies have shown of care at each participating centre. A mandatory 1-year visit was set
no sex-specific differences in outcomes or a worse prognosis in up to obtain data on morbidity, mortality and treatment (before and
women.10–12 after the follow-up visit). Follow-up data were available for >95% of
patients. The registry was approved by local institutional review boards
With respect to HF treatment, a tendency for the underuti-
or ethics committees and informed consent documents were signed
lization or suboptimal dosing of guideline-directed medical ther-
by all participants. To ensure data quality and consistency, training
apy (GDMT) in women and elderly patients compared to men meetings were organized for the investigators and data sources were
and younger patients has been shown. Women with HF receive verified by EURObservational Research Programme (EORP) monitors
beta-blockers (BBs) and angiotensin-converting enzyme inhibitors in a random sample of 5% of the enrolled patients.
(ACEIs) less frequently, and at lower than recommended dosages,
than men.13–15 One study has suggested a sex-specific bias in the
choice of HF medication in relation to the health care provider’s Statistical analysis
specialty (cardiologist vs. non-cardiologist).16 In addition, subop-
Descriptive analyses were summarized and stratified by sex (male
timal dosing of ACEIs and BBs has been reported in elderly HF
and female), age group (<55 years, 55–64 years, 65–75 years, and
patients.17–19 These factors may contribute to the reported lesser >75 years) and according to left ventricular ejection fraction (LVEF)
improvements in functional status, quality of life and survival with (≤45% and >45%). Continuous variables are presented as the
GDMT in women and elderly patients with chronic HF.20,21 mean ± standard deviation (SD), median or interquartile range. For
The reasons for such age- and sex-related discrepancies in the comparisons of continuous variables, the t-test or Mann–Whitney
care of HF patients remain unresolved. They may reflect sex and U-test was used. Categorical variables are presented as percentages
age variability in HF pathophysiology, clinical phenotype, comor- and statistical analyses were performed using chi-squared or Fisher’s
bidities and response to GDMT. Particularly, there is a paucity of exact tests for counts of less than 5. For group comparisons, the
data on medium- and long-term management and outcomes in rela- non-parametric Kruskal–Wallis test was applied.
tion to patient age and sex in chronic stable HF patients. At 1-year follow-up, the prescription of GDMT [ACEIs/angiotensin
receptor blockers (ARBs), BBs, mineralocorticoid receptor antago-
Therefore, the present study aimed to assess age- and
nists (MRAs)], as well as all-cause mortality and all-cause hospitaliza-
sex-related differences in HF management, and 1-year risk
tion were assessed. For visual presentation, Kaplan–Meier curves for
for all-cause mortality and hospitalization, in 16 354 HF patients
all-cause mortality and all-cause hospitalization stratified by sex, age
from the European Society of Cardiology Heart Failure Long-Term and LVEF category (≤45% and >45%) were constructed. Log-rank tests
(ESC HF-LT) Registry. were used to compare survival distributions. In patients with LVEF
≤45%, multivariable logistic regression models stratified by age and
sex were used to assess the associations between predictor variables
Methods and GDMT prescription. For all-cause mortality at 1-year follow-up,
a stratified Cox model was used. In both cases, a stepwise proce-
Study design and participating centres dure was performed, using a P-value of <0.05 to allow entry to the
The ESC HF-LT Registry is a prospective, multicentre, multinational, model and a P-value <0.05 to remain in the updated model. No inter-
observational database of patients with acute and chronic HF.22 It action was tested. A two-sided P-value <0.05 was used as a cut-off
involves a total of 133 participating centres across 21 European and value to indicate differences of statistical significance. All analyses were
Mediterranean countries, of which 47% are university centres, 49% are performed in SAS Version 9.3 or higher (SAS Institute, Inc., Cary,
local/regional centres and 4% are based in private hospitals. NC, USA).
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94 M. Lainscak et al.
Results However, there was an evident gap in rates of prescription of
........................................................................................................................................................................
ACEIs/ARBs, BBs and MRAs in female compared to male patients
Of the 16 354 patients enrolled in the ESC HF-LT Registry between (Table 2). Similarly, age-related under-prescription of the key HF
2011 and 2016, 9428 outpatients (median age: 66 years; 28.5% medications persisted at 1-year follow-up in both sexes (online
women) with chronic HF were included in the present analysis. supplementary Tables S3 and S4).
Baseline demographic and clinical Predictors of treatment at 1-year

characteristics follow-up
The baseline characteristics of all patients and comparisons
The analysis of GDMT predictors was restricted to patients with
LVEF ≤45%, in whom this treatment has a proven outcome benefit.
between sexes are presented in Table 1. In comparison to male
patients, women with chronic HF were older (median age of
In the multivariable analysis, sex was not confirmed as an indepen-
women and men: 69 years and 65 years, respectively), and had a
dent predictor of the use of ACEIs/ARBs, BBs or MRAs. Advanced
lower body mass index (BMI), and higher mean systolic blood pres-
age (>75 years) was a significant predictor of a lower use of GDMT
sure (SBP) and heart rate (HR). Women also had higher mean LVEF
compared to younger age categories.
compared to men (41.8 ± 15.0% and 35.3 ± 12.6%, respectively)
The odds of receiving ACEIs/ARBs increased with higher
and a higher prevalence of preserved LVEF >45%. Despite a higher
BMI and the absence of lower SBP (<110 mmHg). The odds of
mean LVEF, women more frequently presented with New York
ACEI/ARB treatment were lower in patients with higher NYHA
Heart Association (NYHA) class III or IV symptoms. Ischaemic
class (III or IV), prior HF hospitalization, and renal or hepatic
heart disease (IHD), diabetes, peripheral artery disease (PAD),
dysfunction (Table 3).
chronic obstructive pulmonary disease (COPD), sleep apnoea,
Prior HF diagnosis (vs. de novo HF) was associated with higher
renal dysfunction (all P < 0.001), a history of stroke (P = 0.005)
odds for BB prescription (Table 3). Conversely, the likelihood of BB
and hepatic dysfunction (P = 0.001) were more frequent in men,
prescription was lower in patients with higher NYHA class (III or
in whom the prevalence of prior HF hospitalization was also
IV), COPD, depression and the presence of a pacemaker.
higher than in women. Women suffered more often from aortic
Mineralocorticoid receptor antagonists were more likely to be
stenosis and depression. Both sexes had similar clinical signs of HF
used in patients with lower SBP, higher NYHA class (III or IV), prior
at presentation (Table 1).
HF hospitalization, third heart sound and AF. Renal dysfunction was
Baseline characteristics stratified by age group in both sexes
associated with a lower use of MRAs (Table 3).
are presented in online supplementary Tables S1 and S2. Female
patients showed an age-related increase in the prevalences of
lower BMI, higher SBP, lower HR and higher mean LVEF. Older All-cause mortality and all-cause
female patients more often presented with NYHA class III or IV hospitalization at 1 year
symptoms, and a higher burden of comorbidities [e.g. valvular
At follow-up, 8.2% of patients had died. Cardiovascular death
disease, IHD, atrial fibrillation (AF), diabetes, hypertension, PAD,
was the most common cause of mortality (52.0%) in both sexes,
stroke and renal dysfunction]. Similar age-related characteristics
whereas non-cardiovascular and unclassified deaths were recorded
were observed in men, but, in addition, pulmonary congestion and
in 23.0% and 25.0% of patients, respectively. Hospitalization for
COPD became more prevalent in men with increasing age.
any cause occurred in 25.7% of patients and hospitalization for HF
in 12.0% (Table 4).
Baseline heart failure treatment Compared to men, women had lower rates of all-cause mortality
At baseline, high percentages of the total study population received and all-cause hospitalization, as well as a lower rate of HF hospi-
ACEIs/ARBs or BBs (85.7% and 88.7%, respectively). Overall, MRAs talization. Although mortality was lower in women, there were no
were prescribed to 58.8% of patients. Fewer women than men sex-related differences in causes of death (Table 4).
were treated with ACEIs/ARBs, BBs and MRAs (Table 1). Rates of Rates of all-cause mortality, all-cause hospitalization and HF
prescription of these medications also decreased with patient age hospitalization demonstrated significant increases with greater age
in both sexes (online supplementary Tables S1 and S2). In contrast, in both sexes (online supplementary Table S5).
the proportions of patients prescribed diuretics, oral anticoagu- Figures 1 and 2 present Kaplan–Meier survival curves for
lants, nitrates and calcium channel blockers at baseline increased all-cause death and all-cause hospitalization stratified by sex and
across the age categories (online supplementary Tables S1 and S2). LVEF (≤45% and >45%). Online supplementary Figures S1 and S2
present similar data for the cohort stratified by age category and
Treatment for heart failure at 1-year LVEF (≤45% and >45%).
follow-up
At 1-year follow-up, there was a high persistence of GDMT Predictors of 1-year all-cause mortality
utilization in the overall study population and the proportions of The analysis of the predictors of 1-year all-cause mortality was
patients receiving ACEIs/ARBs, BBs and MRAs remained compara- restricted to patients with LVEF ≤45%. In multivariable analysis,
ble with those at baseline (86.5%, 88.8% and 58.7%, respectively). sex was not an independent predictor of mortality. The hazard
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Table 1 Baseline demographic, clinical and treatment characteristics of female and male heart failure patients
Characteristic All patients Female patients Male patients P-value

(n = 9428) (n = 2684) (n = 6744)
...........................................................................................................................................
Age, years, median (IQR) 66.0 (57.0–75.0) 69.0 (59.0–78.0) 65.0 (56.0–74.0) <0.001
BMI, kg/m2 , mean ± SD 28.1 ± 5.1 27.9 ± 5.7 28.2 ± 4.9 <0.001
SBP, mmHg, mean ± SD 124.4 ± 21.0 126.2 ± 22.2 123.7 ± 20.4
SBP ≤ 110 mmHg, n (%)
<0.001
2848/9427 (30.2%) 779/2683 (29.0%) 2069/6744 (30.7%) 0.117
HR, b.p.m., mean ± SD 73.1 ± 15.6 75.1 ± 16.6 72.3 ± 15.2
HR ≥70 b.p.m., n (%)
<0.001
5278/9427 (56.0%) 1619/2683 (60.3%) 3659/6744 (54.3%) <0.001
EF, %, mean ± SD 37.1 ± 13.6 41.8 ± 15.0 35.3 ± 12.6 <0.001
EF >45%, n (%) 1938/8415 (23.0%) 850/2318 (36.7%) 1088/6097 (17.8%) <0.001
NYHA class III or IV, n (%) 2454/9403 (26.1%) 778/2677 (29.1%) 1676/6726 (24.9%) <0.001
Pulmonary or peripheral congestion, n (%) 2983/3982 (74.9%) 907/1194 (76.0%) 2076/2788 (74.5%) 0.317
Third heart sound, n (%) 548/9108 (6.0%) 137/2589 (5.3%) 411/6519 (6.3%) 0.067
Peripheral hypoperfusion/cold, n (%) 313/9123 (3.4%) 93/2594 (3.6%) 220/6529 (3.4%) 0.610
Mitral regurgitation, n (%) 2419/9127 (26.5%) 714/2594 (27.5%) 1705/6533 (26.1%) 0.164
Aortic stenosis, n (%) 373/9125 (4.1%) 140/2593 (5.4%) 233/6532 (3.6%) <0.001
Prior HF hospitalization, n (%) 3963/9356 (42.4%) 1080/2670 (40.4%) 2883/6686 (43.1%) 0.018
HF diagnosis >12 months, n (%) 4837/7808 (61.9%) 1368/2178 (62.8%) 3469/5630 (61.6%) 0.330
Ischaemic aetiology, n (%) 4021/9372 (42.9%) 742/2668 (27.8%) 3279/6704 (48.9%) <0.001
Atrial fibrillation, n (%) 3537/9427 (37.5%) 1028/2683 (38.3%) 2509/6744 (37.2%) 0.314
Diabetes mellitus, n (%) 2940/9428 (31.2%) 762/2684 (28.4%) 2178/6744 (32.3%) <0.001
PAD, n (%) 1105/9129 (12.1%) 233/2594 (9.0%) 872/6535 (13.3%) <0.001
Hypertension, n (%) 5534/9412 (58.8%) 1570/2675 (58.7%) 3964/6737 (58.8%) 0.896
COPD, n (%) 1322/9409 (14.1%) 232/2677 (8.7%) 1090/6732 (16.2%) <0.001
Sleep apnoea, n (%) 459/8933 (5.1%) 61/2536 (2.4%) 398/6397 (6.2%) <0.001
Prior stroke/TIA, n (%) 881/9419 (9.4%) 215/2679 (8.0%) 666/6740 (9.9%) 0.005
Renal dysfunction, n (%) 1772/9419 (18.8%) 443/2683 (16.5%) 1329/6736 (19.7%) <0.001
Hepatic dysfunction, n (%) 320/9138 (3.5%) 65/2597 (2.5%) 255/6541 (3.9%) 0.001
Depression, n (%) 692/9387 (7.4%) 321/2675 (12.0%) 371/6712 (5.5%) <0.001
Pacemaker, n (%) 545/9399 (5.8%) 203/2676 (7.6%) 342/6723 (5.1%) <0.001
ACEIs/ARBs, n (%) 6285/7337 (85.7%) 1587/1968 (80.6%) 4698/5369 (87.5%) <0.001
Beta-blockers, n (%) 8357/9424 (88.7%) 2274/2682 (84.8%) 6083/6742 (90.2%) <0.001
MRAs, n (%) 5542/9425 (58.8%) 1508/2683 (56.2%) 4034/6742 (59.8%) 0.001
Diuretics, n (%) 7798/9424 (82.7%) 2255/2682 (84.1%) 5543/6742 (82.2%) 0.031
Digitalis, n (%) 2149/9422 (22.8%) 632/2683 (23.6%) 1517/6739 (22.5%) 0.275
Statins, n (%) 5690/9424 (60.4%) 1413/2683 (52.7%) 4277/6741 (63.4%) <0.001
Antiplatelets, n (%) 4616/9424 (49.0%) 1094/2683 (40.8%) 3522/6741 (52.2%) <0.001
Oral anticoagulants, n (%) 4004/9423 (42.5%) 1121/2683 (41.8%) 2883/6740 (42.8%) 0.379
Amiodarone, n (%) 1282/9203 (13.9%) 290/2612 (11.1%) 992/6591 (15.1%) <0.001
Ivabradine, n (%) 768/9147 (8.4%) 224/2598 (8.6%) 544/6549 (8.3%) 0.624
Nitrates, n (%) 1770/9146 (19.4%) 472/2598 (18.2%) 1298/6548 (19.8%) 0.071
Calcium channel blockers, n (%) 1043/9146 (11.4%) 314/2597 (12.1%) 729/6549 (11.1%) 0.193
ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; BMI, body mass index; COPD, chronic obstructive pulmonary disease; EF, ejection fraction;
HF, heart failure; HR, heart rate; IQR, interquartile range; MRA, mineralocorticoid receptor antagonist; NYHA, New York Heart Association; PAD, peripheral artery disease;
SBP, systolic blood pressure; SD, standard deviation; TIA, transient ischaemic attack.
ratios for death were significantly lower in patients of younger and outcomes of chronic HF in a large, multinational cohort of
.................................
age, compared to patients aged >75 years. The likelihood of ambulatory patients included in the ESC HF-LT Registry.
death was also lower with increasing BMI. The risk for mortality
increased with lower SBP, NYHA class III or IV status, presence
of pulmonary or peripheral congestion, aortic stenosis, PAD and Baseline demographic and clinical
renal dysfunction (Table 5). characteristics of patients
The median age, 66 years, of the overall study population in
the present registry was lower than the mean ages (>70 years)
Discussion reported in most earlier registries of chronic HF23–26 and more
The present study provides important information on age- and closely corresponded to this patient characteristic in recent clinical
sex-related differences in the clinical presentation, management trials in patients with HF with reduced ejection fraction (HFrEF).27
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Table 2 Management at 1-year follow-up in female vs. male patients with heart failure
All patients Female patients Male patients P-value

(n = 9428) (n = 2684) (n = 6744)
...........................................................................................................................................
ACEIs/ARBs, n (%) 6493/7509 (86.5%) 1766/2107 (83.8%) 4727/5402 (87.5%) <0.001
Beta-blockers, n (%) 6674/7515 (88.8%) 1800/2108 (85.4%) 4874/5407 (90.1%) <0.001
MRAs, n (%) 4409/7516 (58.7%) 1183/2107 (56.1%) 3226/5409 (59.6%) 0.006
Diuretics, n (%) 6080/7518 (80.9%) 1722/2109 (81.7%) 4358/5409 (80.6%) 0.284
Digitalis, n (%) 1583/7517 (21.1%) 446/2108 (21.2%) 1137/5409 (21.0%) 0.896
Statins, n (%) 4715/7517 (62.7%) 1167/2108 (55.4%) 3548/5409 (65.6%) <0.001
Antiplatelets, n (%) 3581/7515 (47.7%) 846/2107 (40.2%) 2735/5408 (50.6%) <0.001
Oral anticoagulants, n (%) 3263/7517 (43.4%) 877/2108 (41.6%) 2386/5409 (44.1%) 0.049
Amiodarone, n (%) 1202/7517 (16.0%) 249/2108 (11.8%) 953/5409 (17.6%) <0.001
Ivabradine, n (%) 751/7515 (10.0%) 211/2108 (10.0%) 540/5407 (10.0%) 0.977
Nitrates, n (%) 1346/7330 (18.4%) 351/2056 (17.1%) 995/5274 (18.9%) 0.075
Calcium channel blockers, n (%) 840/7517 (11.2%) 261/2108 (12.4%) 579/5409 (10.7%) 0.038
ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; MRA, mineralocorticoid receptor antagonist.
This provides important information on the clinical characteristics frequent in randomized trials than in registries, and sex-related
..............................................................................................................
and management of a relatively younger HF patient population differences in T2DM are inconsistent. In the Chronic Heart Failure
drawn from real-world cardiology practice across Europe. The Analysis and Registry in Tohoku District-2 (CHART-2), T2DM
lower median age probably reflects the inclusion of patients treated was less prevalent in female than in male patients (31.7% and
by cardiologists in accordance with the registry protocol, rather 36.4%, respectively).9 In contrast, the MAGGIC database reported
than the more general patient population included in most earlier a higher frequency of T2DM in female than in male patients
registries of chronic HF.23–26 (25.4% and 22.8%, respectively).28 The Norwegian cohort showed
This registry included a significantly higher proportion of male no difference in T2DM prevalence between the sexes.23 In the
(71.5%) than female patients. The reasons for this male predomi- present registry, the prevalence of T2DM was ∼30%, and it was
nance remain unresolved. It may relate to several factors, such as less frequently observed in females than in males (28% and 32%,
women’s or doctors’ underestimation of cardiovascular symptoms respectively).
in female patients, the difficulties faced by women in participating in Similarly to T2DM, higher prevalences of renal dysfunction have
clinical trials or registries, and female under-representation caused been reported in HF patients in registries than in clinical trials,
by current study design, including the exclusion of outpatients with in which severe renal dysfunction is generally an exclusion crite-
prevalent HFrEF. Other registries and clinical trials of HF patients rion. Sex-related heterogeneity in chronic kidney disease in HF has
have also documented a male predominance among the patients also been reported, with considerable discrepancies among stud-
included.23–30 This discrepancy may be relevant in the applicability ies. In the Olmsted cohort, the prevalence of chronic renal failure
of evidence-based therapies to both sexes. was lower in women than in men with HF, regardless of LVEF.32
Compared to men, female patients were on average 4 years Conversely, in the National HF Registry under the Spanish Society
older and more symptomatic, as indicated by a greater propor- of Internal Medicine (RICA), more women than men had chronic
tion of NYHA class III or IV symptoms, despite similar clinical renal failure (59.1% and 53.0%, respectively), and it was not asso-
presentations and better LVEF. These results comply with the ciated with impaired survival.26 In the present registry, renal dys-
MAGGIC meta-analysis of 31 studies including 41 949 patients function was more often observed in men than in women (19.7%
(13 897 women), which demonstrated that women with HF were and 16.5%, respectively) and was associated with greater mortality.
on average 5 years older than men with HF (mean ± SD age: In the current registry, COPD was more frequent in male
70.5 ± 12.1 years and 65.6 ± 11.6 years, respectively). Further, pre- than in female patients, probably as a consequence of a greater
vious data indicate a greater burden of HF symptoms in women and burden of smoking among men or of underdiagnosis of COPD in
differences between the sexes in aetiology, haemodynamic adapta- women.26,33–35 In addition, and as expected, male patients more
tions and disease perception.31,32 often suffered from sleep apnoea than did females.36,37
Similarly to the present registry, the MAGGIC database has also The frequency of depression in HF in female patients was more
suggested a lower prevalence of IHD (46.3% vs. 58.7%) and a higher than double than that in male patients (12.0% and 5.5%, respec-
prevalence of hypertension (49.9% vs. 40.0%) in women than in tively). Previous data, including a meta-analysis of 27 studies of
men.28 Likewise, in a Norwegian cohort of HF patients, women patients with HF, have shown similar findings.38 The underlying
with LVEF <50% had less frequent ischaemic HF aetiology than reasons are currently unknown. Several clinical, cultural and
did men (57% and 63%, respectively).23 Type 2 diabetes mellitus societal factors have been implicated and deserve further specific
(T2DM) in HF varies in prevalence from 20% to 40% and is less investigation because depression in HF is associated with lower
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Table 3 Multivariable analysis of independent predictors of treatment in patients with left ventricular ejection
fraction of ≤45%
Odds ratio (95% CI)a P-value

...........................................................................................................................................
ACEI/ARB treatment
Female patients 0.96 (0.77–1.21) 0.7401
Age <55 years 1.93 (1.42–2.61) <0.0001
Age 55–64 years 1.98 (1.50–2.61) <0.0001
Age 65–75 years 1.36 (1.07–1.73) 0.0118
BMI 1.06 (1.04–1.08) <0.0001
SBP ≤ 110 mmHg 0.63 (0.52–0.77) <0.0001
NYHA class III or IV 0.58 (0.48–0.71) <0.0001
Prior HF hospitalization 0.74 (0.62–0.90) 0.0019
Hypertension 1.35 (1.10–1.65) 0.0035
Renal dysfunction 0.32 (0.26–0.39) <0.0001
Hepatic dysfunction 0.52 (0.36–0.75) 0.0006
BB treatment
Female 0.81 (0.64–1.03) 0.0827
Age <55 years 1.60 (1.16–2.21) 0.0038
Age 55–64 years 1.93 (1.43–2.61) <0.0001
Age 65–75 years 1.45 (1.11–1.90) 0.0062
Prior HF diagnosis 1.45 (1.18–1.79) 0.0004
COPD 0.51 (0.40–0.66) <0.0001
Depression 0.60 (0.43–0.83) 0.0021
PM 0.55 (0.38–0.79) 0.0012
MRA treatment
Female 1.09 (0.95–1.24) 0.2098
Age <55 years 2.03 (1.70–2.42) <0.0001
Age 55–64 years 1.92 (1.64–2.25) <0.0001
Age 65–75 years 1.57 (1.35–1.82) <0.0001
SBP ≤ 110 mmHg 1.55 (1.37–1.74) <0.0001
Third heart sound 1.78 (1.39–2.28) <0.0001
Prior HF hospitalization 1.55 (1.39–1.73) <0.0001
Atrial fibrillation 1.26 (1.12–1.42) 0.0001
Renal dysfunction 0.50 (0.43–0.57) <0.0001
ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; BB, beta-blocker; BMI, body mass index; CI, confidence interval; COPD, chronic obstructive
pulmonary disease; HF, heart failure; MRA, mineralocorticoid receptor antagonist; NYHA, New York Heart Association; PM, pacemaker; SBP, systolic blood pressure.
a Reference values are male for sex and age >75 years for age.
Variables included in the Cox model: age classes, gender, BMI at baseline, SBP ≤110 mmHg, heart rate ≥70 b.p.m., NYHA class III or IV status, pulmonary or peripheral
congestion, S3 gallop (third heart sound), peripheral hypoperfusion/cold, mitral regurgitation, aortic stenosis, prior HF hospitalization, HF diagnosis of >12 months, ischaemic
aetiology, atrial fibrillation, diabetes mellitus, peripheral artery disease, hypertension treatment, COPD, sleep apnoea, prior stroke/transient ischaemic attack, renal dysfunction,
hepatic dysfunction, depression, device therapy (PM).
levels of therapeutic adherence and greater risk for adverse Baseline and follow-up medical
......................................
outcomes.39–41 management
The majority of participants (77.0%) in the present registry had
LVEF ≤45%. The predominance of reduced LVEF may suggest a
Despite high GDMT uptake in the overall population, crude
prescription rates of ACEIs/ARBs, BBs and MRAs were lower in
selection bias that arises from the more severe clinical presentation women than in men. This may be related to the higher preva-
of HF typically observed in the cardiology departments and spe- lence of HF with preserved LVEF in women, which discourages
treatment in view of no real survival benefit. However, even in HF
cialized HF units that served as recruiting institutions for the ESC
patients with preserved ejection fraction, the use of ACEIs/ARBs,
HF-LT Registry. Compared to men, women had higher mean ± SD
BBs and MRAs is currently recommended for the treatment of
LVEF (35 ± 13% and 42 ± 15%, respectively) and a higher rate of associated comorbidities (i.e. hypertension, AF etc.). The present
LVEF >45%. This is consistent with previous reports and confirms study also observed a decline in GDMT prescription rates with
a lesser propensity for HFrEF in women than in men.25,28,42,43 ageing in both sexes, and an increase in the use of diuretics, oral
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Table 4 Outcomes in female and male heart failure patients at 1 year
All patients Female patients Male patients P-value

(n = 9428) (n = 2684) (n = 6744)
...........................................................................................................................................
All-cause death, n (%) 757/9198 (8.2%) 186/2613 (7.1%) 571/6585 (8.7%) 0.015
Causes of death
CV death, n (%) 394/757 (52.0%) 102/186 (54.8%) 292/571 (51.1%)
Non-CV death, n (%) 175/757 (23.1%) 38/186 (20.4%) 137/571 (24.0%) 0.565
Unknown, n (%) 188/757 (24.8%) 46/186 (24.7%) 142/571 (24.9%)
All-cause hospitalization, n (%) 2367/9198 (25.7%) 571/2613 (21.9%) 1796/6585 (27.3%) <0.001
HF hospitalization, n (%) 1030/8357 (12.3%) 257/2364 (10.9%) 773/5993 (12.9%) 0.011
CV, cardiovascular; HF, heart failure.
Figure 1 Kaplan–Meier product–limit survival estimates for all-cause death by gender and ejection fraction (EF) subtype (%).
anticoagulants, amiodarone and other ancillary therapies, indicative evidence-based medications in the ageing population regardless of
......................................................
of an age-related greater burden of congestion and comorbidities. sex, and rates of use of ACEIs/ARBs, BBs and MRAs were similar
The proportion of patients receiving oral anticoagulants exceeded in both men and women.44
the proportion of patients with AF, suggesting that other indica- Specifically, older age, higher NYHA class and impaired renal
tions or perhaps only significantly reduced LVEF influenced the function have been repeatedly reported as predictors of MRA
decision to use anticoagulants. There was no improvement in underuse. MRAs have been proven to be effective in elderly
sex- or age-related discrepancies in the prescription of GDMT
patients and in patients with moderate renal impairment (esti-
mated glomerular filtration rate ≥30 mL/min/1.73 m2 ).45 More cau-
at 1-year follow-up. Sex was not an independent predictor of
the prescription of GDMT (in a subset of patients with LVEF
≤45%). Older age (>75 years) was an independent predictor of a
tious MRA use is required in patients with high serum potas-
sium levels, even when renal function is not significantly reduced,
lower utilization of GDMT at 1-year follow-up. This implies that
advanced age is an important obstacle to the implementation of but this issue could be resolved with the use of potassium
GDMT and this may adversely impact on prognosis. binders.46 High serum potassium can also be the reason for a
These results are similar to those of the MAGGIC meta-analysis, reluctance to up-titrate ACEIs/ARBs to optimal doses, but it does
CHART 2 study and CHARM Program,9,27,28 although the not adversely impact on the beneficial effects of ACEIs/ARBs.47
overall proportion of patients receiving evidence-based thera- In addition, frailty has been identified as an obstacle to the
pies has increased compared to those in the earlier reports. In use of GDMT, in particular MRAs, although their beneficial
IMPROVE, there was a trend towards the lower prescription of effects on outcomes appears to be unaffected by frailty.48,49
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Figure 2 Kaplan–Meier product–limit survival estimates for all-cause hospitalization by gender and ejection fraction (EF) subtype (%).
Therefore, GDMT underuse cannot be justified by these clinical practice. A further limitation refers to the lack of central validation
................................................................................................
scenarios. and adjudication of diagnoses, LVEF measurements and causes

of death. Some variables with prognostic importance, such as
natriuretic peptide levels, were largely missing and therefore
Sex- and age-related differences excluded from the analysis. The proportion of patients not using
in outcomes medications for reasons of contraindications or intolerance, and
Compared to male patients, females had lower crude rates of the proportion of patients deemed eligible for treatment but not
all-cause mortality and all-cause hospitalization, as well as a lower receiving GDMT were not documented. At the time of analysis,
crude rate of HF hospitalization. Although mortality was lower in the use of devices [cardiac resynchronization therapy (CRT),
women, there were no sex-related differences in causes of death. implantable cardioverter defibrillators, CRT defibrillators] was
These results are in line with those of the CHARM trial and not widespread in several of the participating countries, and
the MAGGIC meta-analysis.27,28 A recent analysis of patients with conclusions regarding these treatment modalities could not be
adequately inferred. Finally, patients were stratified by LVEFs of
≤45% and >45% (according to an analysis plan defined at the
dilated cardiomyopathy demonstrated better survival in women
compared to men, which was explained by less severe left ventric-
ular dysfunction and a smaller scar burden.50 In addition, favourable time of registry commencement). These limitations can serve
outcomes were noticed in patients aged <60 years, whereas male as valuable reminders of how to design future research projects
patients aged >60 years demonstrated higher all-cause mortal- to more closely represent the real-world population of HF
ity and a greater propensity for non-sudden death compared to patients.
women.50 These findings are likely to reflect differences in char-
acteristics and associated comorbidities between patients with
dilated cardiomyopathy and those with chronic HF of any aetiology
included in the current study.
Conclusions
In the present study, rates of all-cause mortality, all-cause hospi- The present study has demonstrated significant differences in the
talization and HF hospitalization significantly increased with advanc- clinical characteristics and management of HF patients in rela-
ing age in both sexes.28,51,52 Sex, however, was not an independent tion to age and sex. There was a decline in GDMT prescrip-
predictor of all-cause mortality. tion with advanced age in both sexes, suggestive of an underuti-
lization of evidence-based therapies, which may have adversely
impacted prognosis. Sex was not independently associated with
Limitations either GDMT prescription or outcomes. However, older age
There are several limitations to the present analysis. The (>75 years) independently predicted a lower use of GDMT and
study population consisted of outpatients managed mostly by a higher rate of all-cause mortality. Although the reasons behind
cardiologists and hence does not completely reflect usual clinical the disparities observed may be complex, it is important to raise
© 2019 The Authors

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EORP department of the European Society of Cardiology by
........................................................................................................................................................................
Table 5 Multivariable analysis of independent
Emanuela Fiorucci as project officer, and Gérard Gracia and Maryna
predictors of all-cause death in patients with left
ventricular ejection fraction ≤45%
Andarala as data managers. Statistical analyses were performed by
Cécile Laroche. Overall activities were coordinated and supervised
Hazard ratio P-value by A.P.M. (EORP Scientific Coordinator).
(95% CI)a
................................................................
Female 0.90 (0.68–1.18) 0.4333
Funding
Age <55 years 0.48 (0.32–0.71) 0.0003 Since its initiation, the EURObservational Research Programme has
Age 55–64 years 0.70 (0.52–0.96) 0.0260 been supported by Abbott Vascular International (2011–2021),
Age 65–75 years 0.65 (0.49–0.86) 0.0025 Amgen Cardiovascular (2009–2018), AstraZeneca (2014–2021),
BMI 0.96 (0.94–0.99) 0.0025
SBP ≤110 mmHg
Bayer AG (2009–2018), Boehringer Ingelheim (2009–2019),
1.57 (1.25–1.98) 0.0001
Boston Scientific (2009–2012), the Bristol-Myers Squibb and
NYHA class III or IV status 1.98 (1.56–2.51) <0.0001
Pfizer Alliance (2011–2019), Daiichi Sankyo Europe GmbH
Pulmonary or peripheral congestion 2.15 (1.50–3.09) <0.0001
Aortic stenosis 1.58 (1.04–2.41) 0.0323 (2011–2020), the Daiichi Sankyo Europe GmbH and Eli Lilly
PAD 1.40 (1.06–1.84) 0.0184 & Company Alliance (2014–2017), Edwards (2016–2019),
Renal dysfunction 1.70 (1.34–2.16) <0.0001 Gedeon Richter (2014–2016), Menarini International Operations
(2009–2012), MSD-Merck & Co. (2011–2014), Novartis Pharma
BMI, body mass index; CI, confidence interval; HF, heart failure; NYHA, New
York Heart Association; PAD, peripheral artery disease; SBP, systolic blood
AG (2014–2020), ResMed (2014–2016), Sanofi (2009–2011),
pressure. Servier (2009–2021) and Vifor (2019–2022).
a Reference values are male for sex and age >75 years for age.
Conflicts of interest: M.G.C.-L. reports the receipt of per-
Variables included in the Cox model: age classes, gender, BMI at baseline, SBP
≤110 mmHg, heart rate ≥70 b.p.m., NYHA class III/IV, pulmonary or periph- sonal fees from Novartis, Abbott, MSD and Astellas, and grants
eral congestion, S3 gallop (third heart sound), peripheral hypoperfusion/cold, from CIBERCV outside the submitted work. L.H.L. reports the
mitral regurgitation, aortic stenosis, prior HF hospitalization, HF diagnosis of
receipt of personal fees from Merck, Sanofi, AstraZeneca, Bayer,
>12 months, ischaemic aetiology, atrial fibrillation, diabetes mellitus, PAD, hyper-
tension treatment, chronic obstructive pulmonary disease, sleep apnoea, prior Pharmacosmos and Abbott Medscape, grants and personal fees
stroke/transient ischaemic attack, renal dysfunction, hepatic dysfunction, depres- from Boehringer Ingelheim, Vifor-Fresenius, Relypsa, Novartis and
sion, device therapy (pacemaker).
Mundipharma, and grants from Boston Scientific outside the sub-
mitted work. S.D.A. reports the receipt of personal fees from
awareness among physicians of the fact that persistence in obtain- Bayer, BI, Servier, Novartis and Respicardia, grants and personal
ing the optimal management of patients with HF is of crucial fees from Vifor, and grants from Abbott Vascular outside the sub-
importance in improving outcomes.53 Further research into the mitted work. R.F. reports the receipt of grants and personal fees
causes of undertreatment of HF in elderly patients may provide from Servier International and Novartis, and personal fees from
important insights that will facilitate the improvement of treatment Merck Serono, Bayer and Boehringer Ingelheim outside the sub-
options. mitted work. A.J.S.C. reports the receipt of personal fees from
AstraZeneca, Menarini, Novartis, Nutricia, Respicardia, Servier,
Stealth Peptides, Vifor, Actimed, Faraday and WL Gore outside the
Supplementary Information submitted work. G.F. reports having served on the committees of
Additional supporting information may be found online in the trials and registries sponsored by Bayer, Novartis, Servier, Vifor,
Supporting Information section at the end of the article. Medtronic and BI outside the submitted work. A.P.M. reports the
Figure S1. Kaplan–Meier curves for all-cause death by age and receipt of personal fees from Bayer, Fresenius and Novartis out-
ejection fraction subtype (%). side the submitted work. Prior to 2018, F.R. reports the receipt of
Figure S2. Kaplan–Meier curves for all-cause hospitalization by grants and personal fees from SJM/Abbott, Servier, Novartis and
age and ejection fraction subtype (%). Bayer, and personal fees from Zoll, AstraZeneca, Sanofi, Amgen,
Table S1. Baseline demographic, clinical and treatment character- BMS, Pfizer, Fresenius, Vifor, Roche, Cardiorentis and Boehringer
istics of female patients by age category. Ingelheim, other funding from Heartware, and grants from Mars
Table S2. Baseline demographic, clinical and treatment character- outside the submitted work; since 1 January 2018 F.R. has received
istics of male patients by age category. no personal payments and all payments have been made to the
Table S3. Management at 1-year follow-up in female patients. University of Zurich. M.B.Y. reports the receipt of grants from
Table S4. Management at 1-year follow-up in male patients. Novartis, Amgen and Bayer during the conduct of the study. P.M.S.
Table S5. Outcomes at 1 year in female and male patients. reports the receipt of grants and other research support from the
Ministry of Education, Science and Technological Development of
Acknowledgements the Republic of Serbia, the receipt of honoraria or consultation
The input of the EURObservational Research Programme (EORP) fees from Servier, Boehringer Ingelheim, Hemofarm, Novartis and
Oversight Committee, and Registry Executive and Steering Com- AstraZeneca, and has participated in a company-sponsored speak-
mittees is acknowledged. Data collection was conducted by the ers’ bureau for Fondazione Internationale Menarini. M.L., I.M., M.P.,
© 2019 The Authors

- 263 -
T.M., M.F.P., G.M.C.R., D.S., M.A, J.-C.E. and C.L. have nothing to differences in patients presenting with acute heart failure. Results from EuroHeart
........................................................................................................................................................................
Failure Survey II. Eur J Heart Fail 2008;10:140–148.
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COMPENDIUM OF

From the Heart Failure

Published in the European Journal of Heart Failure

The use of diuretics in heart failure with

Only a minority of patients with acute heart failure present acutely

© 2018 The Authors

Congestion in heart failure haemodynamics.23 The diagnostic accuracy of non-invasive clinical

© 2018 The Authors

Parameter Sensitivity Specificity Comparator Comment

Adapted from Gheorghiade,22 Nagueh,24 Mullens,25 Parrinello26 and Volpicelli.27

of increased filling pressures (right atrial pressure > 7 mmHg or

© 2018 The Authors

© 2018 The Authors

diuretic resistance and loop diuretic resistance are often used

© 2018 The Authors

Table 2 Pharmacology of diuretics

Acetazolamide Loop diuretics Thiazide-like diuretics MRAa Amiloride

© 2018 The Authors

European Journal of Heart Failure © 2018 European Society of Cardiology

© 2018 The Authors

© 2018 The Authors

© 2018 The Authors

© 2018 The Authors

© 2018 The Authors

© 2018 The Authors

Table 3 Approach to electrolyte disturbances in acute heart failure

Hyponatraemia Hypokalaemia Hyperkalaemia

European Journal of Heart Failure © 2018 European Society of Cardiology

© 2018 The Authors

© 2018 The Authors

© 2018 The Authors

© 2018 The Authors

© 2018 The Authors

© 2018 The Authors

Towards better definition, quantification

Introduction different pathological processes that underlie fibrosis formation, it

Table 1 Proposed minimal dataset to describe fibrosis in animal studies

• Reparative (scarring) fibrosis vs. reactive fibrosis (quantitative or semiquantitative)

(http://regulusrx.com/programs/pipeline/). Thus, non-coding

The role of ventricular–arterial coupling in

© 2019 The Authors

physiology of cardiac and aortic mechanics, as well as in the patho-

its complexity, several invasive and non-invasive methods have

© 2019 The Authors

Pulse wave generation

Zc: proximal aortic impedance, determining

SV dec reas es syst emic perfusion,

PWV: index of arterial stiffness, determining

Reflected wave Forward wave

Aix: index of contribution of wave

Pulse wave reflection sites

© 2019 The Authors

Degradation is the task of matrix metalloproteinases. In the pres-

DBP, coronary perfusion

© 2019 The Authors

It becomes readily apparent that the advantage of the Ea/Ees ratio as

© 2019 The Authors

Table 1 Advantages and disadvantages of ventricular–arterial coupling assessment modalities

VAC assessment Advantages Disadvantages