JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY VOL. 70, NO.

16, 2017

ª 2017 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION ISSN 0735-1097/$36.00

PUBLISHED BY ELSEVIER http://dx.doi.org/10.1016/j.jacc.2017.08.044

Cardiac MR With Late Gadolinium

Enhancement in Acute Myocarditis
With Preserved Systolic Function
ITAMY Study

Giovanni Donato Aquaro, MD,a Matteo Perfetti, MD,a Giovanni Camastra, MD,b Lorenzo Monti, MD,c
Santo Dellegrottaglie, MD,d,e Claudio Moro, MD,f Alessia Pepe, MD,a Giancarlo Todiere, MD,a Chiara Lanzillo, MD,g
Alessandra Scatteia, MD,h Mauro Di Roma, MD,i Gianluca Pontone, MD,j Martina Perazzolo Marra, MD, PHD,k
Andrea Barison, MD,a Gianluca Di Bella, MD, PHD,l on behalf of the Cardiac Magnetic Resonance Working Group of
the Italian Society of Cardiology

ABSTRACT

BACKGROUND The prognostic role of cardiac magnetic resonance (CMR) and late gadolinium enhancement (LGE)
has not been clarified in acute myocarditis (AM) with preserved left ventricular (LV) ejection fraction (EF).

OBJECTIVES This study sought to evaluate the role of CMR and LGE in the prognosis of AM with preserved LVEF.

METHODS This study analyzed data from ITAMY (ITalian multicenter study on Acute MYocarditis) and
evaluated CMR results from 386 patients (299 male; mean age 35
15 years) with AM and preserved LVEF.
Clinical follow-up was performed for a median of 1,572 days. A clinical combined endpoint of cardiac
death, appropriate implantable cardioverter-defibrillator firing, resuscitated cardiac arrest, and hospitalization
for heart failure was used.

RESULTS Among the 374 patients with suitable images, LGE involved the subepicardial layer inferior and
lateral wall in 154 patients (41%; IL group), the midwall layer of the anteroseptal wall in 135 patients
(36%; AS [anteroseptal] group), and other segments in 59 patients (16%; other-LGE group), and it was absent in
26 patients (no-LGE group). The AS group had a greater extent of LGE and a higher LV end-diastolic volume index
than other groups, but levels of inflammatory markers were lower than in the other groups. Kaplan-Meier curve
analysis indicated that the AS group had a worse prognosis than the other groups (p < 0.0001). Finally, in
multivariable analysis, AS LGE was the best independent CMR predictor of the combined endpoint (odds ratio: 2.73;
95% confidence interval: 1.2 to 5.9; p ¼ 0.01).

CONCLUSIONS In patients with AM and preserved LVEF, LGE in the midwall layer of the AS myocardial segment is
associated with a worse prognosis than other patterns of presentation. (J Am Coll Cardiol 2017;70:1977–87)
© 2017 by the American College of Cardiology Foundation.

From the aGabriele Monasterio Foundation, Tuscan Region, Pisa, Italy; bCardiac Department, Vannini Hospital Rome, Rome, Italy;
c
Radiology Department, Humanitas Research Hospital, Hospital Care and Research Institution (IRCCS), Rozzano, Milan, Italy;
Listen to this manuscript’s d
Division of Cardiology, Villa dei Fiori, Acerra, Naples, Italy; eMount Sinai School of Medicine, New York, New York; fDepartment
audio summary by of Cardiology and Coronary Intensive CareUnit, ASST Monza, Desio Hospital, Desio Monza e Brianza, Italy; gCardiology Depart-
JACC Editor-in-Chief ment, Casilino Polyclinic, Rome, Italy; hDepartment of Advanced Biomedical Sciences, Federico II University, Naples, Italy; iRa-
Dr. Valentin Fuster. diological Department, European Hospital, Rome, Italy; jCardiac Department, Monzino Cardiology Center, Milano, Italy; kDivision
of Cardiology, Department of Cardiac, Thoracic, and Vascular Sciences, University of Padua, Padua, Italy; and the lClinical and
Experimental Department of Medicine, University of Messina, Messina, Italy. Dr. Pontone has received institutional grants and
fees from GE Healthcare, Medtronic, Bracco, Bayer, and Heartflow. All other authors have reported that they have no relationships
relevant to the contents of this paper to disclose.

Manuscript received May 11, 2017; revised manuscript received July 19, 2017, accepted August 8, 2017.
1978 Aquaro et al. JACC VOL. 70, NO. 16, 2017

CMR and Prognosis in Acute Myocarditis With Preserved Systolic Function OCTOBER 17, 2017:1977–87

I
ABBREVIATIONS n the last 10 years, cardiac magnetic in 10 Italian hospitals. CMR was performed in
AND ACRONYMS resonance (CMR) has significantly patients with suspected AM and different clinical
improved diagnosis in patients with sus- presentations: new onset of chest pain, dyspnea, or
AM = acute myocarditis
pected acute myocarditis (AM). The clinical ventricular arrhythmic events (ventricular tachy-
AS = anteroseptal
presentation of AM is heterogeneous, and it cardia, resuscitated cardiac arrest, or new-onset
CMR = cardiac magnetic
may begin as recent-onset heart failure, third-degree atrioventricular block).
resonance
with arrhythmic events, or with infarct-like In the current study, we excluded patients with
CRP = C-reactive protein
symptoms (1–3). Systolic function is usually heart failure or arrhythmic events at presentation,
ECG = electrocardiographic
preserved in patients with infarct-like pre- decreased systolic function (EF <50%), and hemo-
EDV = end-diastolic volume
sentation, who are considered to have a dynamic instability (Figure 1). For the diagnosis of
EDVi = end-diastolic volume good prognosis. In the subsets of hemody- AM, we applied the diagnostic algorithm reported in
index
namically stable AM with preserved systolic Figure 2, which was modified from the algorithm of
EF = ejection fraction
function, endomyocardial biopsy may not the European Society of Cardiology guidelines (3).
ESR = erythrocyte
be indicated (4), and CMR is considered the Briefly, clinically suspected AM was diagnosed
sedimentation rate
best noninvasive imaging modality for a def- when symptomatic patients with chest pain (peri-
ICD = implantable
cardioverter-defibrillator
inite diagnosis of AM. carditis or pseudoischemic pain) fulfilled 1 or more
CMR can detect signs of myocardial dam- diagnostic criteria (new electrocardiographic [ECG]
IL = inferolateral
age such as myocardial edema, hyperemia, modification, elevated troponin, wall motion ab-
LGE = late gadolinium
enhancement and late gadolinium enhancement (LGE) in normalities with preserved LVEF at echocardiogra-
LV = left ventricular
patients with preserved left ventricular (LV) phy) or in asymptomatic patients with 2 or more
ejection fraction (EF) (5). Preserved systolic diagnostic criteria. A definite diagnosis of AM was
RV = right ventricular
function is a good predictor of survival in all then made in the event of 2 or more CMR Lake
SSFP = steady-state free
precession cardiac disease, and previous studies Louise criteria (myocardial edema, hyperemia, and
demonstrated that impairment of EF in AM is LGE) (5).
the strongest predictor of worse prognosis (6,7). In Endomyocardial biopsy was performed when CMR
many heart diseases, the presence of myocardial LGE results were inconclusive (#1 CMR criterion). To
is associated with an increased risk for adverse car- exclude obstructive coronary artery disease, coronary
diovascular events in patients with preserved systolic artery angiography was performed on all patients
function (8,9), but in AM, most patients have positive with the exception of those younger than 30 years of
LGE (10). age with a low risk of coronary artery disease. The
final population included 386 patients (299 male;
SEE PAGE 1988
mean age 35
15 years) with a CMR diagnosis of
In nonselected patients with AM, Mahrholdt et al. stable AM and preserved systolic function (LVEF
(11) demonstrated 2 main patterns of LGE presenta- >50%). At hospital admission, all patients underwent
tion: 1 involving the subepicardial layer of the lateral clinical evaluation and laboratory testing, including
wall and 1 involving the midwall layer of the ante- leukocytes, C-reactive protein (CRP), erythrocyte
roseptal wall. The latter was associated with ven- sedimentation rate (ESR), and troponin T. Informed
tricular remodeling and EF impairment at follow-up consent was obtained from all patients at the time of
CMR. The main indication for CMR in AM is in CMR examination.
hemodynamically stable patients with preserved
CMR ACQUISITION PROTOCOL. CMR imaging was
EF. The aim of this multicenter study was to evaluate
performed with 1.5-T systems (CVi, HD release, GE
the prognostic role of LGE in a large sample of
Healthcare, Milwaukee, Wisconsin; Magnetom Avanto,
patients with hemodynamically stable AM and pre-
Siemens Medical Systems, Erlangen, Germany;
served EF.
Gyroscan NT, Philips Healthcare, Amsterdam, the
METHODS Netherlands) using dedicated cardiac software, a
phased-array surface receiver coil, and vectocardio-
ITAMY (ITalian multicenter study on Acute MYocar- gram triggering. According to the protocols recom-
ditis) is a multicenter investigation of the prognostic mended by the Society for Cardiovascular Magnetic
value of CMR in AM of the Cardiac Magnetic Reso- Resonance, we acquired cine steady-state free preces-
nance Working Group of the Italian Society of Cardi- sion (cine-SSFP) images, T2-weighted imaging, and
ology. The ITAMY registry includes 415 consecutive LGE at 10 min after gadolinium injection in the
inpatients with a definite CMR diagnosis of AM who short-axis (9 to 13 images covering the entire LV),
were enrolled from January 2006 to January 2013 2-chamber, and 4-chamber planes. Short-axis
JACC VOL. 70, NO. 16, 2017 Aquaro et al. 1979
OCTOBER 17, 2017:1977–87 CMR and Prognosis in Acute Myocarditis With Preserved Systolic Function

cine-SSFP images were acquired immediately after

F I G U R E 1 Study Population
gadolinium injection for hyperemia assessment.
CMR ANALYSIS. All CMR studies were analyzed off-
n = 462 patients with Clinically Suspected Acute Myocarditis
line using a workstation with dedicated cardiac soft-
ware with consensus among 3 experienced observers
n = 16 excluded for claustrophobia,
who were blinded to the clinical presentation results. contraindications, no Gd injection
To evaluate LV global and regional function and
calculate LV mass, the endocardial and epicardial n = 31 other diagnosis by CMR
borders were manually drawn in the end-diastolic
and end-systolic short-axis cine-SSFP images. Papil- n = 415 patients with CMR and definite diagnosis of myocarditis
lary muscles and trabeculae were not included in the
myocardium. LV end-diastolic volume (EDV), LV n = 29 excluded for LVEF <50%
end-systolic volume, LVEF, and LV mass were
determined. n = 386 patients with definite diagnosis of myocarditis and preserved LVEF
On T2-weighted images, edema was considered
present when the ratio of signal intensity between the n = 12 excluded for sub-optimal LGE images
myocardium and the mean signal intensity of the
skeletal muscle was $2 (5,12). LGE was qualitatively n = 374 patients with acute myocarditis and LVEF >50%
evaluated and manifested as a nonischemic pattern of
distribution (i.e., subepicardial or midventricular n = 154 Infero-Lateral LGE n = 26 no LGE

enhancement) (13,14). Myocardial hyperemia was

n = 135 Anteroseptal LGE n = 59 other LGE
evaluated, as previously reported (13), using the post-
contrast SSFP cine images. The occurrence of edema,
hyperemia, or LGE was evaluated in each of the 17 LV Flow chart visualizing the derivation of the study population. CMR ¼ cardiac magnetic
segments (13,14). Furthermore, each LV wall (septal, resonance; Gd ¼ gadolinium; LGE ¼ late gadolinium enhancement; LVEF ¼ left

anterior, inferior, and lateral) was considered to ventricular ejection fraction.

be involved if at least 1 segment with LGE was

observed (15).
CLINICAL FOLLOW-UP. After the CMR examination,
follow-up was performed for all patients by the in-
vestigators of the 10 Italian hospitals in the registry. A
F I G U R E 2 Diagnostic Algorithm
clinical questionnaire was compiled by a clinical
physician during periodic ambulatory visitations in
Clinically suspected acute myocarditis:
each hospital, by contacting the patients’ relatives by
• In patients with acute chest pain (pericarditic or pseudo-ischemic) and
telephone, by a general practitioner, or by consulting ≥1 Diagnostic Criteria:
the office of vital statistics at a patient’s place of - New ECG abnormalities (ST elevation or non ST elevation, T wave
inversion, new I-III degree AV-block)
residence. The clinical questionnaire included the
- Myocardiocytolysis markers (elevated Troponin T/I)
definition of the following major events: cardiac - Wall motion abnormalities at echocardiography (with preserved LVEF)
death, resuscitated cardiac arrest, ventricular assist
• In patients with no chest pain and ≥2 diagnostic criteria
device, transplantation, and appropriate implantable Plus
cardioverter-defibrillator (ICD) shock, as well as mi- Absence of angiographically detectable coronary artery disease (or age <30 y
and low risk of CAD) and absence of known pre-existing cardiovascular
nor events (heart failure hospitalization). A complete disease or secondary conditions
analysis of the ICD was performed by the referring
physician to confirm the appropriateness of the
Definite diagnosis of acute myocarditis:
shock.
In clinically suspected myocarditis + ≥2 tissue abnormalities at CMR
STATISTICAL ANALYSIS. Values are presented as the (edema, hyperemia, LGE)
mean
SD or as the median (interquartile range In presence of ≤1 CMR tissue abnormality, diagnosis confirmed by
endomyocardial biopsy
[IQR]) for variables with normal and non-normal
distributions, respectively. Values with non-normal
distribution according to the Kolmogorov-Smirnov Diagnostic algorithm for the diagnosis of acute myocarditis used in the current study.
test were logarithmically transformed for parametric AV ¼ atrioventricular; CAD ¼ coronary artery disease; ECG ¼ electrocardiographic; other
analysis. Qualitative data are expressed as abbreviations as in Figure 1.

percentages.
1980 Aquaro et al. JACC VOL. 70, NO. 16, 2017

CMR and Prognosis in Acute Myocarditis With Preserved Systolic Function OCTOBER 17, 2017:1977–87

T A B L E 1 Patient Characteristics T A B L E 2 Diagnostic Characteristics of the Population

Males 299 (73) Chest pain

Age, yrs 35
15 Yes 368 (95)
Height, cm 175
10 No 18 (5)
Weight, kg 76
14 Diagnostic criteria
Hypertension 44 (11) Troponin elevation þ new ECG abnormalities 304 (79)
Hyperlipidemia 15 (4) Troponin elevation þ new ECG abnormalities þ 67 (17)
Diabetes 9 (4) wall motion abnormalities at echocardiography

Smoking 55 (13) Troponin elevation þ wall motion abnormalities at 15 (4)

echocardiography
Family history of CAD 48 (12)
Other clinical symptoms/signs
Obesity 19 (5)
Recent fever 225 (58)
Pericardial effusion 48 (12)
Respiratory or GI symptoms 68 (18)
Chest pain 368 (95)
Elevated ERS/CRP 385 (99)
Fever (2 weeks from symptoms onset) 225 (58)
Pericardial effusion 48 (12)
Palpitations 20 (5)
Coronary angiography
ECG abnormalities 371 (96)
Performed (no obstructive CAD) 365 (95)
Wall motion abnormalities at echocardiography 82 (21)
Not performed (age <30 yrs, low risk of CAD) 21 (5)
Coronary artery angiography performed 365 (95)
Cardiac magnetic resonance
Endomyocardial biopsy performed 18 (5)
$2 tissue abnormalities (edema, hyperemia, LGE) 368 (95)
Laboratory tests
3
1 tissue abnormality 18 (5)
Leukocytes, 10 cells/ml 10.7
3.8
Edema þ hyperemia þ LGE 85 (22)
ERS, mm/h 21
19
Edema þ LGE 261 (68)
CRP, ng/ml 5.5 (1.8–15.5)
Edema only 16 (4)
Abnormal ERS and/or CRP 385 (99)
LGE only 2 (1)
Troponin T, peak ng/ml 1.85 (0.002–7.6)
Endomyocardial biopsy
Elevated troponin T 386 (100)
Positive 18 (5)
CMR parameters
LVEDVi, ml/m2 83
23
Values are n (%). Data refer to the entire population of 386 patients.
LVEF, % 61
9 GI ¼ gastrointestinal; other abbreviations as in Table 1.
LV mass index, g/m2 73
16
WMSI 1.07
0.27
RVEDVi, ml/m2 82
17
RVEF, % 52
21 A p value lower than 0.05 was considered statistically
Wall motion abnormalities 92 (24) significant.
No. of segments with edema 2 (1–4)
No. of segments with hyperemia 2 (0–3)
RESULTS
No. of segments with LGE 2 (1–4)

Values are n (%), mean
SD, or median (interquartile range). The data refer to the entire pop- Baseline characteristics of the entire population and
ulation of 386 patients.
groups are summarized in Table 1. The population
CAD ¼ coronary artery disease; CMR ¼ cardiac magnetic resonance; CRP ¼ C-reactive protein;
ECG ¼ electrocardiographic; ERS ¼ erythrocyte sedimentation rate; LGE ¼ late gadolinium was composed of young adults with a low prevalence
enhancement; LV ¼ left ventricular; LVEDVi ¼ left ventricular end-diastolic volume index;
of risk factors for coronary heart disease. The most
LVEF ¼ left ventricular ejection fraction; RVEDVi ¼ right ventricular end-diastolic volume index;
RVEF ¼ right ventricular ejection fraction; WMSI ¼ wall motion score index. commonly reported symptom was chest pain (95%),
and fever was present in 58% of patients. All patients
were in New York Heart Association functional class I
Categorical variables were compared by the chi- because of the exclusion of patients with heart failure
square test or the Fisher exact test when appro- presentation. ECG abnormalities were found in 371
priate. Continuous variables were compared by the (96%) of the subjects (ST-segment elevation in 73%,
Student independent t test and analysis of variance or ST-segment depression in 15%, and negative T-wave
by the Wilcoxon nonparametric test when appro- in 8%). Increased troponin T was found in all pa-
priate. The Kaplan-Meier time-to-event method was tients, and abnormal values of ESR or increased CRP
used to calculate and compare longitudinal curves were found in 385 patients (99%). Regional wall mo-
among groups. Logistic regression analysis was used tion abnormalities were found in 82 patients by using
to explore the impact of each significant variable in echocardiography (21%).
univariate analysis to predict the occurrence of car- Coronary artery angiography was performed in 365
diac events evaluated as a combined endpoint (car- patients (95%), who all showed no obstructive coro-
diac death, appropriate ICD firing, resuscitated nary artery disease (patients with obstructive disease
cardiac arrest, and hospitalization for heart failure). were excluded from the study). Coronary artery
JACC VOL. 70, NO. 16, 2017 Aquaro et al. 1981
OCTOBER 17, 2017:1977–87 CMR and Prognosis in Acute Myocarditis With Preserved Systolic Function

F I G U R E 3 Example of IL LGE

Cardiac magnetic resonance images of a case of acute myocarditis with the anteroseptal (AS) pattern of late gadolinium enhancement (LGE).
SSFP ¼ steady-state free precession; STIR ¼ short tau inversion recovery.

angiography was not performed in 21 patients effusion was found in 48 patients (12%), and signs of
younger than 30 years of age (mean age of these pa- pericardial inflammation (post-contrast enhance-
tients was 22
9 years), patients who had a low risk ment) were found in 11 (3%). Regional wall motion
of coronary artery disease, and patients with signs of abnormalities were found in 92 patients (22%). In
inflammation (fever preceding chest pain, increase of T2–short tau inversion recovery (STIR) images, signs
ESR and CRP, or signs of viral infection). The definite of myocardial edema were detected in 362 patients
diagnosis of AM was made using endomyocardial bi- (94%). Hyperemia was found in 85 patients (23%).
opsy in 18 patients (5%) with only 1 tissue abnor- In 12 cases, LGE images were of suboptimal quality
mality in CMR. In the remaining patients, clinically as a result of artifacts. LGE images of 374 patients
suspected myocarditis was made confirmed by the were visually analyzed, among which 4 main clusters
evidence of 2 or more tissue abnormalities in CMR. of distribution were found: in 154 patients (41%),
The diagnostic criteria are shown in Table 2. the subepicardial layer of the inferior and lateral
segments was constantly involved with variable dis-
CMR RESULTS. LV dilation was found in 33 patients tribution in other segments, except the anteroseptal
(8%; 28 male) by using recently published reference segments (IL cluster); in 135 patients (36%), the mid-
values of normality (16). Right ventricular (RV) dila- wall layer of the basal anteroseptal wall was
tion was found in 42 patients (10%). Pericardial constantly involved with various other segments,
1982 Aquaro et al. JACC VOL. 70, NO. 16, 2017

CMR and Prognosis in Acute Myocarditis With Preserved Systolic Function OCTOBER 17, 2017:1977–87

F I G U R E 4 Example of AS LGE

Cardiac magnetic resonance images of a case of acute myocarditis with the inferolateral (IL) pattern of LGE. Abbreviations as
in Figures 1 and 3.

except the inferior or inferolateral walls (AS cluster); in the no-LGE and other-LGE patients. Myocardial
and in 59 cases (16%), LGE images were positive but edema and hyperemia had the same regional distri-
did not involve the inferolateral basal or the ante- bution of LGE.
roseptal walls (other-LGE cluster). Finally, in 26
patients (7%), LGE images were negative (no-LGE CLINICAL FOLLOW-UP. During the median follow-up
cluster). On the basis of these clusters, the population of 1,572 days (25th to 75th percentile: 1,122 to 2,923),
was subdivided into 4 groups: the IL group, AS group, ICDs were inserted in 6 patients (2 patients for epi-
other-LGE group, and no-LGE group (Figure 1). sodes of nonvasovagal syncope associated with non-
Examples of LGE images from these groups are sustained ventricular tachycardia during 24-h ECG
shown in Figures 3 and 4. Holter monitoring and in 4 patients for evidence of
As evident in Table 3, patients in the AS group had sustained ventricular tachycardia during Holter
lower ESR and CRP values than did other groups. In monitoring). There were 30 patients who had >5%
addition, the AS group had a higher LV EDV index worsening of LVEF according to echocardiography
(LVEDVi) and more myocardial segments with LGE during follow-up. The average decrease of LVEF in
than the IL group. LVEF and wall motion score index these 30 patients was 10
5%. In 26 of these patients,
were not different among groups, but patients in the coronary angiography was repeated during follow-up
AS group had a lower RVEF than others. The no-LGE and confirmed the absence of obstructive coronary
and other-LGE groups showed higher RVEF than artery disease. The worsening of LV function was
other patients. The number of myocardial segments more prevalent in the AS group than in the IL group
with edema was higher in the AS and IL groups than (20 vs. 10; p ¼ 0.022).
JACC VOL. 70, NO. 16, 2017 Aquaro et al. 1983
OCTOBER 17, 2017:1977–87 CMR and Prognosis in Acute Myocarditis With Preserved Systolic Function

T A B L E 3 Clinical Differences Among the Groups

AS Group IL Group Other-LGE Group No-LGE Group Global

(n ¼ 135) (n ¼ 154) (n ¼ 59) (n ¼ 26) p Value

Age, yrs 33
12 32
12 33
12 38
15*†‡ 0.02

Hypertension 11 (8) 23 (15) 7 (12) 3 (12) 0.50
Hyperlipidemia 5 (4) 6 (4) 1 (2) 1 (4) 0.80
Diabetes 2 (2) 2 (1) 3 (5) 2 (7) 0.09
Smoking 15 (11) 27 (17) 10 (17) 3 (12) 0.50
Family history of CAD 13 (9) 24 (15) 9 (15) 2 (7) 0.60
Obesity 7 (5) 7 (4) 3 (6) 2 (7) 0.80
ECG abnormalities 131 (97) 152 (98) 56 (95) 24 (92) 0.12
Laboratory results
Leukocytes, 103cells/ml 10.1
3.2 10.3
3.9 10.8
4.2 10.1
3.8 0.60
Troponin T, ng/ml 1.5 (1–4)‡§ 1.4 (0.9–1.8) 1.0 (0.9–1.7) 0.9 (0.4–1.2) 0.02
ERS, mm/h 12 (1–27)†‡ 20 (4–40) 23 (7–46) 12 (1–26)†‡ 0.005
CRP, mg/l 7.2 (2.9–32.2)† 8.1 (4.3–36.8) 7.7 (2.2–33) 4.7 (2.3–11)*†‡ 0.002
CMR results
LVEDVi, ml/m2 84
18† 79
16 84
27 81
19 0.004
LVEF, % 62
7 62
6 62
7 62
9 0.30
LV mass index, g/m2 74
17 72
16 72
15 72
15 0.70
WMSI 1.02
0.23 1.03
0.19 1.04
0.18 1.01
0.03 0.11
RVEDVi, ml/m2 82
16 81
16 81
17 76
14 0.16
RVEF, % 50
16†‡§ 52
20 56
8 58
8 0.001
No. of segments with edema 4 (1–8)†‡§ 3 (1–5) 2 (1–4) 2 (1–3) 0.01
No. of segments with hyperemia 2 (1–4) 2 (2–4) 2 (2–4) 2 (1–3) 0.70
No. of segments with LGE 5 (3–7)†‡§ 2 (1–3) 2 (1–3) 0 <0.001

Values are mean
SD, n (%), or median (interquartile range). The data refer to the population of 374 patients with LGE images of sufficient image quality. *p significant vs.
AS-group. †p significant vs. IL group. ‡p significant vs. other-LGE group. §p significant vs. no-LGE group.
AS ¼ anteroseptal; IL ¼ inferolateral; other abbreviations as in Tables 1 and 2.

As reported in Table 4, there were 8 major car- among IL, other-LGE, and no-LGE groups. The char-
diac events (4 sudden cardiac deaths; 2 resuscitated acteristics of patients with and without cardiac
cardiac arrests, 2 appropriate ICD firings) and 21 events are summarized in Table 5. A logistic regres-
hospitalizations for heart failure. Major cardiac sion analysis was carried out using the combined
events occurred more frequently in the AS group endpoint as the dependent variable and the AS group
than in the IL group (AS: 6; IL: 0; p < 0.01), and troponin peak as independent variables.
whereas no differences were found with other Belonging to the AS group was the best predictor of
groups (2 events in the other-LGE group and none the combined endpoint (AS group: odds ratio: 2.73;
in the no-LGE group). The AS group also had more 95% confidence interval: 1.20 to 5.90; p ¼ 0.01; and
frequent hospitalizations for heart failure than did
the IL group (15 vs. 4; p ¼ 0.004). Fifteen patients
had recurrence of AM with clinical manifestation of T A B L E 4 Incidence of Cardiac Events During Follow-Up
chest pain, troponin increase, and evidence of 2 or
Other-LGE No-LGE
more signal abnormalities in the CMR evaluation. AS Group IL Group Group Group
The prevalence of recurrence was not significantly (n ¼ 135) (n ¼ 154) (n ¼ 59) (n ¼ 26)

different among the groups (5 for AS, 6 for IL, and 4 Combined endpoint 21 (16)*† 4 (3) 4 (7) 0 (0)

for other-LGE). Sudden cardiac death 4 (3)* 0 (0) 0 (0) 0 (0)

Appropriate ICD shock 2 (2) 0 (0) 0 (0) 0 (0)
Overall, the combined endpoint of major cardiac
Resuscitated cardiac arrest 0 (0) 0 (0) 2 (4) 0 (0)
events and hospitalization for heart failure occurred
Hospitalization for heart 15 (11)* 4 (3) 2 (4) 0 (0)
in 21 patients (16%) in the AS group, 4 (3%) in the IL failure
group, and 4 (5%) in other-LGE group, whereas no 3-yr event probability 0.14 (0.05–0.24) 0.04 (0–0.07) 0.04 (0–0.08) 0
event occurred in the no-LGE group. In the Kaplan- 5-yr event probability 0.36 (0.20–0.52) 0.03 (0–0.06) 0.08 (0–0.09) 0

Meier curve analysis, the AS group had worse event-

Values are n (%) or hazard ratio (95% confidence interval). *Significant vs. IL group. †Significant vs. no-LGE.
free survival rates than did the other groups (Central ICD ¼ implantable cardioverter-defibrillator; other abbreviations as in Tables 2 and 3.
Illustration). No prognostic differences were found
1984 Aquaro et al. JACC VOL. 70, NO. 16, 2017

CMR and Prognosis in Acute Myocarditis With Preserved Systolic Function OCTOBER 17, 2017:1977–87

C E NT R AL IL L U STR AT IO N Prognostic Role of Different LGE Patterns in Patients With AM and Preserved EF

Aquaro, G.D. et al. J Am Coll Cardiol. 2017;70(16):1977–87.

In a population of patients with acute myocarditis (AM) and preserved ejection fraction (EF), we identified 4 main patterns of distribution of late gadolinium
enhancement (LGE) (left). The anteroseptal pattern of late gadolinium enhancement was associated with a worse prognosis than the other patterns (right).
AS ¼ anteroseptal; IL ¼ inferolateral.

troponin peak: odds ratio: 1.14; 95% confidence in- but it is less accurate for the diagnosis of myocarditis
terval: 1.03 to 1.63; p ¼ 0.12). when the initial presentation includes heart failure or
arrhythmic events.
DISCUSSION Although preserved systolic function is a good
predictor of survival in many cases of heart disease,
The main results of the present study are as follows: the presence of myocardial scar is generally associ-
1) 3 main patterns of LGE were found in patients with ated with increased risk for adverse cardiovascular
AM and preserved LVEF: IL, AS, and other-LGE; 2) the events, even in patients with preserved systolic
AS group had higher a RVEDVi and LVEDVi, higher function. In a large group of 857 patients with
troponin release, and lower inflammatory markers; ischemic and nonischemic cardiomyopathies, Cheong
3) the AS group was associated with a worse prognosis et al. (8) showed that the presence of scar tissue
according to Kaplan-Meier analysis; and 4) being in expressed by LGE predicted a worse outcome than
the AS group was the best CMR predictor of the did the absence of LGE, even in patients with EF
combined endpoint (Central Illustration). >50%. The data were confirmed in a cohort of 1,068
We selected patients with AM, preserved LVEF, consecutive patients (9), in which LGE was further
and New York Heart Association functional class I. associated with a high occurrence of hospitalization
Almost all these patients had an infarct-like for heart failure, regardless of etiology, stage of heart
presentation with chest pain and ECG abnormalities. failure, or severity of EF impairment.
Infarct-like myocarditis in patients with preserved EF Grün et al. (7) studied 203 patients with a definite
is probably 1 of the most appropriate indications for diagnosis of AM detected by endomyocardial biopsy
CMR. As demonstrated by Francone et al. (17), CMR is and found that patients with LGE had larger ventri-
very sensitive for identifying AM with infarct-like cles, lower LVEF, and a worse prognosis. Particularly,
presentation compared with endomyocardial biopsy, these investigators observed cardiac death during
JACC VOL. 70, NO. 16, 2017 Aquaro et al. 1985
OCTOBER 17, 2017:1977–87 CMR and Prognosis in Acute Myocarditis With Preserved Systolic Function

follow-up in 28 of 29 of patients with positive LGE

T A B L E 5 Characteristics of Patients With and Without Cardiac Events
and only in 1 patient with negative LGE. However, all
their patients with events had impaired EF. No Events Events
(n ¼ 345) (n ¼ 29) p Value
In 2014, Schumm et al. (18) used CMR to evaluate
Age, yrs 34
14 36
14 0.46
405 patients with suspected AM. These investigators
Hypertension 43 (12) 3 (10) 0.40
found that patients with abnormalities at CMR (with a Hyperlipidemia 14 (4) 1 (4) 0.85
final diagnosis of AM or other cardiac diseases) had a Diabetes 8 (2) 1 (4) 0.52
worse prognosis than did patients with negative CMR Smoking 53 (15) 2 (7) 0.21
findings. More recently, Sanguineti et al. (6) followed Family history of CAD 44 (13) 4 (14) 0.72

203 patients with a CMR-based diagnosis of AM for an Obesity 18 (5) 1 (4) 0.20
ECG abnormalities 315 (91) 26 (90) 0.93
average of 18.9 months. These investigators observed
Laboratory results
that the presence and extent of myocardial edema
Leukocytes, 103cells/ml 10.2
3.4 9.2
2.7 0.12
and the extent of LGE were not predictive of the Troponin T, ng/ml 1.03 (0.0–6.7) 4 (0.4–9.5) <0.0001
outcome. An impaired LVEF at the first examination ERS, mm/h 25 (14–45) 24 (19–79) 0.60
was the only independent CMR predictor of an CRP, mg/l 3.75 (1.2–7.7) 2.7 (0.8–7.4) 0.12
adverse clinical outcome (6). CMR results

In our multicenter study, we found that in AM with LVEDVi, ml/m2 81
17 85
25 0.24

LVEF, % 62
6 61
7 0.39
preserved LVEF, LGE had different patterns of pre-
LV mass index, g/m2 72
15 76
15 0.17
sentation. The most frequent pattern found in 41% of
WMSI 1.03
0.2 1.06
0.08 0.42
cases involved the subepicardial layer of the inferior
RVEDVi, ml/m2 82
16 83
18 0.74
and lateral wall of the left ventricle (IL group). In 36% RVEF, % 53
20 51
21 0.60
of patients, LGE was located in the midwall of the No. of segments with edema 3 (1–5) 2 (1–3) 0.30
interventricular septum (AS group). The AS pattern of No. of segments with hyperemia 2 (0–3) 2 (1–3) 0.89
LGE was associated with a worse prognosis than in No. of segments with LGE 3 (2–4) 3 (2–6) 0.90

patients with the IL and no-LGE or other-LGE pat- AS cluster of LGE 114 (33) 21 (72) <0.0001
IL cluster of LGE 150 (43) 4 (14) 0.14
terns. Patients with the AS pattern had no significant
No-LGE 26 (7) 0 (0) 0.09
differences in LVEF from other groups, despite higher
Other site of LGE 55 (16) 4 (10) 0.77
LVEDVi and more myocardial segments with LGE.
However, the extent of LGE was not different in pa- Values are mean
SD, n (%), or median (interquartile range).
Abbreviations as in Tables 1 to 3.
tients with and without cardiac events. Moreover, the
AS pattern of LGE was the best independent predictor
of the combined endpoint. The AS group had higher
troponin release than other groups but lower levels of The difference in LGE pattern could be explained
inflammatory markers such as ESR and CPR. This by the different tropism of viruses. In fact, human
result suggests a different kind of myocarditis, with herpesvirus 6 infects not only T cells but also cells of
less inflammation but greater myocardial damage. the nervous system and the cardiac conduction sys-
These findings were concordant with those of a tem, and it can establish a latent state after primary
previous postmortem study by Shirani et al. (19) and infection (20). After a primary infection in early
with a report by Mahrholdt et al. (11), who found childhood, AM may be a reactivation of the disease,
similar distributions of LGE patterns in a nonselected with myocardial infection and damage occurring in
population of 86 patients with AM. Mahrholdt et al. the septum because of the presence of virus in the
(11) found that the IL pattern of LGE was mostly cardiac conduction system (21). Repeated viral reac-
associated with the detection of the parvovirus B19 tivation may be the cause of the most frequent pro-
genome, whereas the AS pattern was associated with gression to LV dysfunction found in patients with the
the human herpesvirus 6 genome and with the com- septal pattern of LGE than in those without it.
bined presence of both the parvovirus B19 and Moreover, reactivation of viral infection in the cardiac
herpesvirus 6 genomes. Moreover, in that study, the conduction system may be the trigger for arrhythmic
presence of LGE in the ventricular septum was the events in patients with the AS pattern. In contrast,
strongest CMR predictor of chronic ventricular parvovirus B19 is associated with polyserositis and
dysfunction, as well as ventricular dilatation at pericarditis after initial viremia (22). Thus the left
follow-up. In accord with the results of Mahrholdt lateral free wall and the inferior wall may be involved
et al. (11), we found that the AS pattern was most because of the direct contact with the pericardium.
prevalently associated with worsening of LVEF at We did not perform endomyocardial biopsy in all
follow-up than other LGE presentations. the patients in the study because our population was
1986 Aquaro et al. JACC VOL. 70, NO. 16, 2017

CMR and Prognosis in Acute Myocarditis With Preserved Systolic Function OCTOBER 17, 2017:1977–87

composed of hemodynamically stable patients with in the absence of positive LGE, whereas T2 mapping
preserved LVEF, and the invasive procedure was not would allow us to detect myocardial edema quanti-
indicated. Thus we cannot evaluate the presence of tatively. However, at the time of patients’ enrollment
different viral genomes in our patients, and we did in the study, these 2 techniques were not available in
not know whether these or other viruses were all CMR scanners, and nowadays, the pulse sequence
involved in the mechanism of damage of our patients. of T1 and T2 mapping may provide different results
However, our results strengthen the role of AS LGE in for different CMR vendors. Therefore, in the context
myocarditis by the finding of a prognostic role of this of a multicenter study, we preferred not to include
pattern during long-term follow-up of patients with these 2 new yet promising techniques.
preserved LVEF. Future studies are needed to eval-
uate whether the different patterns of LGE and CONCLUSIONS
different prognoses could be caused by different viral
tropisms or other factors. In this multicenter study, patients with AM and
STUDY LIMITATIONS. First, as mentioned, we did not preserved LVEF had different patterns of LGE. The
perform endomyocardial biopsy in all the patients, AS pattern of LGE was associated with a worse
and the diagnosis was made by the summation of prognosis and with presentations different from
clinical and CMR findings. As shown in the 2009 those the IL pattern, the no-LGE pattern, and other
white paper in the Journal, CMR criteria are highly patterns.
specific for the diagnosis of myocarditis but less
sensitive (5). Our population is almost completely ADDRESS FOR CORRESPONDENCE: Dr. Giovanni

composed of patients with infarct-like myocarditis, as Donato Aquaro, Fondazione Toscana G. Monasterio,
demonstrated by the high prevalence of chest Via Giuseppe Moruzzi, 1, 56124 Pisa, Italy. E-mail:
pain (95%), new ECG abnormalities (96%), elevations aquaro@ftgm.it.
in CRP and/or ERS (99%), and troponin increases
(100%). As a previous study demonstrated, in patients PERSPECTIVES
with infarct-like presentations, CMR is also very
sensitive for detection of AM (17). In contrast, CMR
COMPETENCY IN MEDICAL KNOWLEDGE:
has a low sensitivity in patients with heart failure
CMR enabled confirmation of AM in hemodynamically
presentations and a very low sensitivity in those with
stable patients with clinically suspected AM and
arrhythmic presentations, and for this reason we
preserved EF. In these patients the 2 most frequent
decided to exclude patients with these presentations.
patterns of LGE were the subepicardial IL and the AS
Furthermore, when compared with endomyocardial
midwall pattern. Patients presenting with LGE in the
biopsy, CMR was demonstrated to be very accurate
midwall of the AS myocardial segments had a worse
for the detection signs of myocardial damage in AM,
prognosis than did patients with other patterns of
whereas it was less sensitive for the diagnosis of
distribution.
chronic myocarditis (23). In our population of pa-
tients with clinically suspected AM and an infarct-like
TRANSLATIONAL OUTLOOK: Further research
presentation, CMR may be considered both specific
should be conducted to determine whether the
and sensitive to confirm the diagnosis of AM.
different patterns of presentation of LGE in AM are
Second, we did not perform T1 and T2 mapping in
associated with different viral causes.
our population. T1 mapping could permit the detec-
tion and quantification of microscopic fibrosis, even

REFERENCES

1. Aretz HT, Billingham ME, Edwards WD, et al. diagnosis, management, and therapy of myocar- myocarditis: a JACC white paper. J Am Coll Cardiol
Myocarditis: a histopathologic definition and ditis: a position statement of the European Society 2009;53:1475–87.
classification. Am J Cardiovasc Pathol 1987;1:3–14. of Cardiology Working Group on Myocardial and
6. Sanguineti F, Garot P, Mana M, et al. Cardio-
Pericardial Diseases. Eur Heart J 2013;34:
2. Leone O, Veinot JP, Angelini A, et al. 2011 vascular magnetic resonance predictors of clinical
2636–48, 2648a–d.
consensus statement on endomyocardial biopsy outcome in patients with suspected acute
from the Association for European Cardiovascular 4. Kindermann I, Barth C, Mahfoud F, et al. myocarditis. J Cardiovasc Magn Reson 2015;17:78.
Pathology and the Society for Cardiovascular Pa- Update on myocarditis. J Am Coll Cardiol 2012;
7. Grün S, Schumm J, Greulich S, et al. Long-term
thology. Cardiovasc Pathol 2012;21:245–74. 59:779–92.
follow-up of biopsy-proven viral myocarditis:
3. Caforio AL, Pankuweit S, Arbustini E, et al. 5. Friedrich MG, Sechtem U, Schulz-Menger J, predictors of mortality and incomplete recovery.
Current state of knowledge on aetiology, et al. Cardiovascular magnetic resonance in J Am Coll Cardiol 2012;59:1604–15.
JACC VOL. 70, NO. 16, 2017 Aquaro et al. 1987
OCTOBER 17, 2017:1977–87 CMR and Prognosis in Acute Myocarditis With Preserved Systolic Function

8. Cheong BY, Muthupillai R, Wilson JM, et al. hyperemia in acute myocarditis by magnetic reso- in patients with clinically suspected myocarditis.
Prognostic significance of delayed-enhancement nance. Int J Cardiovasc Imaging 2014;30:629–37. J Cardiovasc Magn Reson 2014;16:14.
magnetic resonance imaging: survival of 857 pa-
14. Hundley WG, Bluemke DA, Finn JP, et al. ACCF/ 19. Shirani J, Freant LJ, Roberts WC. Gross and
tients with and without left ventricular dysfunc-
ACR/AHA/NASCI/SCMR 2010 expert consensus semiquantitative histologic findings in mono-
tion. Circulation 2009;120:2069–76.
document on cardiovascular magnetic resonance: a nuclear cell myocarditis causing sudden death, and
9. Wong TC, Piehler KM, Zareba KM, et al. report of the American College of Cardiology implications for endomyocardial biopsy. Am J
Myocardial damage detected by late gadolinium Foundation Task Force on Expert Consensus Doc- Cardiol 1993;72:952–7.
enhancement cardiovascular magnetic resonance uments. J Am Coll Cardiol 2010;55:2614–62.
20. De Bolle L, Van Loon J, De Clercq E,
is associated with subsequent hospitalization for
15. Di Bella G, Siciliano V, Aquaro GD, et al. Scar Naesens L. Quantitative analysis of HHV6 cell
heart failure. J Am Heart Assoc 2013;2:e000416.
extent, left ventricular end-diastolic volume, and tropism. J Med Virol 2005;75:76–85.
10. Mahrholdt H, Goedecke C, Wagner A, et al. wall motion abnormalities identify high-risk pa-
21. Zerr DM, Meier AS, Selke SS. A population-
Cardiovascular magnetic resonance assessment of tients with previous myocardial infarction: a mul-
based study of primary HHV6 infection. N Engl J
human myocarditis: a comparison to histology and tiparametric approach for prognostic stratification.
Med 2005;352:768–76.
molecular pathology. Circulation 2004;109:1250–8. Eur Heart J 2013;34:104–11.
22. Young NS, Brown KE. Parvovirus B19. N Engl J
11. Mahrholdt H, Wagner A, Deluigi CC, et al. 16. Aquaro GD, Camastra G, Monti L, et al.
Med 2004;350:586–97.
Presentation, patterns of myocardial damage, and Reference values of cardiac volumes, dimensions,
clinical course of viral myocarditis. Circulation and new functional parameters by MR: a multi- 23. Lurz P, Eitel I, Adam J, et al. Diagnostic per-
2006;114:1581–90. center, multivendor study. J Magn Reson Imaging formance of CMR imaging compared with EMB in
2017;45:1055–67. patients with suspected myocarditis. J Am Coll
12. Abdel-Aty H, Boye P, Zagrosek A, et al. Diag-
Cardiol Img 2012;5:513–24.
nostic performance of cardiovascular magnetic 17. Francone M, Chimenti C, Galea N, et al. CMR
resonance in patients with suspected acute sensitivity varies with clinical presentation and
myocarditis: comparison of different approaches. extent of cell necrosis in biopsy-proven acute
J Am Coll Cardiol 2005;45:1815–22. myocarditis. J Am Coll Cardiol Img 2014;7:254–63.
KEY WORDS acute myocarditis, cardiac
13. Perfetti M, Malatesta G, Alvarez I, et al. A fast 18. Schumm J, Greulich S, Wagner A, et al. Car- magnetic resonance, late gadolinium
and effective method to assess myocardial diovascular magnetic resonance risk stratification enhancement, prognosis