Diabetes and Arrhythmias: Pathophysiology, Mechanisms and Therapeutic Outcomes

REVIEW
published: 26 November 2018

doi: 10.3389/fphys.2018.01669
Diabetes and Arrhythmias:

Pathophysiology, Mechanisms and
Therapeutic Outcomes
Laurel A. Grisanti*
Department of Biomedical Sciences, College of Veterinary Medicine, University of Missouri, Columbia, MO, United States
The prevalence of diabetes is rapidly increasing and closely associated with

cardiovascular morbidity and mortality. While the major cardiovascular complication
associated with diabetes is coronary artery disease, it is becoming increasingly
apparent that diabetes impacts the electrical conduction system in the heart, resulting
in atrial fibrillation, and ventricular arrhythmias. The relationship between diabetes
and arrhythmias is complex and multifactorial including autonomic dysfunction, atrial
and ventricular remodeling and molecular alterations. This review will provide a
comprehensive overview of the link between diabetes and arrhythmias with insight into
the common molecular mechanisms, structural alterations and therapeutic outcomes.
Keywords: diabetes mellitus, arrhythmia, atrial fibrillation, cardiac fibrosis, autonomic dysregulation
Edited by:
Laurent Metzinger,
University of Picardie Jules Verne,
France
INTRODUCTION
Reviewed by: Diabetes mellitus is a group of metabolic disorders where there are high blood sugar levels over
Firdos Ahmad,
time. Prolonged elevations in sugar levels lead to a number of health complications including
University of Sharjah, United Arab
cardiovascular disease and kidney disease (Forbes and Cooper, 2013). There are two main forms
Emirates
Martin Bishop, of diabetes mellitus including type 1, which has an unknown etiology and is characterized by
King’s College London, a loss of insulin-producing β-cells in the pancreas resulting in the inability of the pancreas to
United Kingdom produce enough insulin (van Belle et al., 2011). Type 1 diabetes is often juvenile in onset, insulin
*Correspondence: dependent, and comprises roughly 10% of the diabetic patient population. Type 2 diabetes results
Laurel A. Grisanti from insulin resistance and the body’s inability to respond to insulin (Kahn et al., 2014). It is
grisantil@missouri.edu generally adult-onset and is a result of genetics and lifestyle choices including excessive body
weight, lack of exercise and poor diet. Type 2 diabetes is rapidly increasing in incidence (Centers
Specialty section: for Disease C and Prevention, 2008). As of 2015 there were an estimated 415 million people with
This article was submitted to diabetes worldwide (Federation, 2014).
Cardiac Electrophysiology,
Cardiac arrhythmia is a group of conditions where the heart beats too fast (tachycardia), too
a section of the journal
slow (bradycardia) or irregularly (Roberts-Thomson et al., 2011). While most arrhythmias are not
Frontiers in Physiology
serious acutely, prolonged arrhythmic episodes increase an individual’s likelihood of stroke, heart
Received: 19 June 2018
failure and cardiac arrest (Nattel et al., 2014). Arrhythmias arise due to a problem in the electrical
Accepted: 06 November 2018
conduction of the heart however, the cause of these complications is not fully defined. Atrial
Published: 26 November 2018
fibrillation is the most common type of arrhythmia and is associated with significant morbidity
Citation:
and mortality (Kannel et al., 1983). It is becoming increasingly apparent that diabetes mellitus is a
Grisanti LA (2018) Diabetes and
Arrhythmias: Pathophysiology,
significant promoter of cardiac arrhythmias (Kannel et al., 1998).
Mechanisms and Therapeutic While diabetes likely contributes to multiple types of cardiac arrhythmias, the connection
Outcomes. Front. Physiol. 9:1669. between diabetes and atrial fibrillation has been the most extensively studied to date. Observational
doi: 10.3389/fphys.2018.01669 studies looking at the association between diabetes mellitus and atrial fibrillation have been
Frontiers in Physiology | www.frontiersin.org 1 November 2018 | Volume 9 | Article 1669

Grisanti Diabetes and Arrhythmias
inconclusive and inconsistent (Benjamin et al., 1994; Psaty causes or all-cause death in multiple large trials (Group et al.,
et al., 1997; Wilhelmsen et al., 2001; Nichols et al., 2009; 2008; Duckworth et al., 2009) and has been associated with
Pallisgaard et al., 2016; Dahlqvist et al., 2017). The incidence increased mortality in another (Action to Control Cardiovascular
of diabetes is most commonly associated with coronary artery Risk in Diabetes Study et al., 2008). Duration of pharmacological
disease however, electrical conduction complications are also an treatment (Dublin et al., 2010) and poorly controlled diabetes
important cardiovascular problem associated with both type 1 have also been linked to increased incidence of atrial fibrillation
and type 2 diabetes (Huxley et al., 2011; Dahlqvist et al., 2017). (Huxley et al., 2012). However, in a prospective study of the
In a 38 year follow up of Framingham heart study patients, Action to Control Cardiovascular Risk in Diabetes (ACCORD)
diabetes mellitus was identified as an independent risk factor of trial cohort of patients, intensive glycemic control did not impact
atrial fibrillation (Benjamin et al., 1994). However, other studies the rate of new-onset atrial fibrillation (Fatemi et al., 2014).
failed to see a connection between atrial fibrillation and diabetes Animal studies investigating the involvement diabetes in atrial
(Wilhelmsen et al., 2001). Discrepancies in these studies may fibrillation suggest it may be due to glucose fluctuations rather
be a result of the populations examined since differences in the than hyperglycemia (Saito et al., 2014). In a streptozotocin-
association of diabetes and atrial fibrillation appear to be variable induced rat model, glucose fluctuations increased incidence of
depending on age (Pallisgaard et al., 2016), gender (Nichols et al., atrial fibrillation, atrial fibrosis, and reactive oxygen species (Saito
2009; Dahlqvist et al., 2017) and ethnicity (Lipworth et al., 2012; et al., 2014).
Dewland et al., 2013; Rodriguez et al., 2016; O’Neal et al., 2017). There is increasing evidence that hypoglycemic states may
In a comprehensive meta-analysis, diabetic patients were found contribute to atrial fibrillation. Several reports of hypoglycemic
to have an ∼40% greater risk for developing atrial fibrillation triggered atrial fibrillations have been reported clinically (Odeh
compared to non-diabetic patients (Huxley et al., 2011) and a et al., 1990; Celebi et al., 2011; Ko et al., 2018) and information
more recent meta-analysis, identified a 20% increase in the risk of gathered from the Framingham Heart Study suggests insulin
developing atrial fibrillation for prediabetic patients whereas in resistance does not play a role (Fontes et al., 2012). Severe
patients with diabetes, this number was elevated to 28% greater hypoglycemia in type 2 diabetics was associated with a range of
change of atrial fibrillation development (Aune et al., 2018). adverse clinical outcomes including death from cardiovascular
Furthermore, this meta-analysis identified a dose dependent cause (Chow et al., 2014) and in patients from the Outcomes
relationship between increased blood glucose levels and atrial Reduction with an Initial Glargine Intervention (ORIGIN)
fibrillation suggesting that rises in glucose may be an important trial, severe hypoglycemia was associated with greater risk
contributor to atrial fibrillation. In a large study, over 845,000 for all-cause mortality and arrhythmic death (Investigators
patients, diabetes was found to be a strong, independent risk et al., 2013). In a study using 30 patients with type 2
factor for atrial fibrillation and other cardiovascular diseases diabetes and known cardiovascular disease, glucose monitoring
mellitus (Movahed et al., 2005). However, obesity, which is in conjunction with electrocardiograms showed patients taking
common in patients with diabetes mellitus is independently insulin and/or sulfonylurea had a high incidence of severe (<3.1
associated with atrial fibrillation and might also be a contributing mmol/L) but asymptomatic hypoglycemia whereas patients
factor (Grundvold et al., 2015; Baek et al., 2017). Levels of taking metformin and/or dipeptidyl peptidase-4 inhibitors did
pericardial fat have been linked to atrial fibrillation in humans (Al not and patients with severe hypoglycemia had more ventricular
Chekakie et al., 2010). Though not as extensively characterized, arrhythmias (Stahn et al., 2014). In a separate but similar
diabetes likely also contributes to ventricular arrhythmias since study, type 2 diabetic patients with a history or risk of
there is electrocardiographic evidence of this in humans and the cardiovascular disease were monitored for interstitial glucose
underlying mechanisms linking diabetes with atrial fibrillation and ambulatory electrocardiogram simultaneously (Chow et al.,
would apply to other types of arrhythmias (Cardoso et al., 2003). 2014). Bradycardia and atrial and ventricular ectopic counts
Table 1 summarizes the clinical studies examining the correlation were higher during episodes of nocturnal hypoglycemia further
between diabetes and arrhythmias. While there is a clear link suggesting a role for hypoglycemia in arrhythmic events.
between diabetes and cardiac arrhythmias, the mechanisms
underlying these changes are not fully elucidated. Potential
causes include changes in glucose levels, the autonomic nervous AUTONOMIC DYSFUNCTION
system, structural and electrical remodeling, mitochondrial
alterations and inflammation will be reviewed herein (Figure 1). The autonomic nervous system is an important regulator
of heart rhythm through innervation by sympathetic and
parasympathetic nerves. Dysfunction of the autonomic nervous
BLOOD GLUCOSE LEVELS system is recognized as a risk for development of atrial fibrillation
and a contributing factor to disease progression (Agarwal et al.,
Meta-analysis of clinical populations suggests a dose-dependent 2017). A link between type 2 diabetes and autonomic dysfunction
relationship between blood glucose levels and atrial fibrillation, has also been well established and is recognized as a complication
implying that glucose levels may be an important contributor to that damages multiple organs including the heart (Mäkimattila
atrial fibrillation onset (Aune et al., 2018). However, this may et al., 1997; Oberhauser et al., 2001). While the etiology of diabetic
not be the case since intensive glucose control has not been autonomic neuropathy is not fully understood, it is thought
shown to be beneficial in reducing death from cardiovascular that metabolic insult, neurovascular insufficiency, autoimmune

TABLE 1 | Characterization of studies evaluating the correlation between diabetes and arrhythmias. Statistics are reported as [risk ratio (95% confidence interval)].
Study Location Duration Population characteristics Findings
Benjamin et al., 1994 United States 38 years 2090 males Follow-up from the Framingham Heart Study, diabetes was
2641 females significantly associated with the development of atrial fibrillation
55-94 years old (1.4 for men, 1.6 for women)
Dahlqvist et al., 2017 Sweden 10.2 years 179,980 non-diabetics Slight increased risk in males [1.13 (1.01–1.25)] and greater
(non-diabetics) 35.4±14.5 years old increased risk [1.50 (1.30–1.72)] in females
9.7 years 36,253 type 1 diabetics
(diabetics) 35.6±14.6 years old
Dublin et al., 2010 United States N/A 2203 control Increased risk of developing atrial fibrillation in pharmacologically
68 years median age treated diabetic patients [1.40 (1.15–1.71)] compared with control
1410 atrial fibrillation (1.00) whereas non-treated diabetics had no difference [1.04
74 years median age (0.75–1.45)]
Fatemi et al., 2014 United States 4.68 years 5042 diabetic-standard glycemic Intensive glycemic control had no impact on atrial fibrillation
and Canada control incidence compared with standard therapy in diabetic patients
5040 diabetic-intensive glycemic
control
Fontes et al., 2012 United States ∼10 years 3023 59.2±6.9 years old Insulin resistance was no associated with risk of atrial fibrillation
Huxley et al., 2011 Multiple N/A 1,686,097 Meta-analysis associated diabetes with atrial fibrillation [1.39
Countries (1.10–1.75)]
Huxley et al., 2012 United States N/A 13,025 Pre-diabetic and untreated diabetes were not associated with
increased risk for atrial fibrillation. Type 2 diabetics had an
increased risk of atrial fibrillation [1.35 (1.14–1.60)]. No association
was observed between fasting glucose or insulin and atrial
fibrillation but there was a positive association between HbA1c
levels and atrial fibrillation in both diabetic and non-diabetic
subjects.
Ko et al., 2018 Korea 8.5 years 1,509,280 Severe hypoglycemia was associated with increased risk of atrial
30-75 years old fibrillation [1.10 (1.01–1.19)]
Lipworth et al., 2012 United States 9 years 3026 white Diabetes was associated with an increased risk for atrial fibrillation
5810 black in both white [1.38 (1.15–1.66)] and black [1.25 (0.98–1.59)]
>65 years old subjects with an elevated incidence in white subjects.
Movahed et al., 2005 United States 10 years 552,624 non-diabetic There was a significant association between type 2 diabetes and
293,124 diabetic development of atrial fibrillation [2.13 (2.10–2.16)] and atrial flutter
Primarily male [2.20 (2.15–2.26)]
65 year old average
Nichols et al., 2009 United States 7.2 years 7159 non-diabetics Positive association of diabetes with atrial fibrillation among
10,213 diabetics women [1.26 (1.08–1.46)] but not men [1.09 (0.96–1.24)]
58.4±11.5 years old
O’Neal et al., 2017 United States 10 years 8611 white Diabetes was associated with a slightly elevated risk for atrial
5077 black fibrillation in white subjects [1.21 (1.01–1.45)] but not black
63 year old average subjects [1.06 (0.79–1.43)]
Psaty et al., 1997 United States 3.28 years 4844 combined gender Elevated blood glucose was associated with atrial fibrillation [1.10
>65 years old (1.04–1.17)]
Pallisgaard et al., 2016 Denmark 16 years 4,827,713 non-diabetics Diabetes is associated with incidence of atrial fibrillation,
253,374 diabetics particularly in young patients 2.34 relative risk with a 1.52–3.60
(95% confidence level) in 18–39 year olds, 1.52 (1.47–1.56) in
40–64 year olds, 1.20 (1.19–1.23) in 65–74 year olds and 0.99
(0.97–1.01) in 75–100 year olds
Investigators et al., Multiple 6.2 year 12,537 Severe hypoglycemia was associated with risk of arrhythmic death
2013 Countries median 50+ years old [1.77 (1.17–2.67)]
Rodriguez et al., 2016 United States 13.7 years 114,083 non-Hispanic white Diabetes was associated with a slightly elevated risk for atrial
11,876 African American fibrillation in women (1.33 for non-Hispanic whites, 1.42 for African
5174 Hispanic American, 1.25 for Hispanic, 1.42 for Asian) with no notable
3803 Asian difference dependent on ethnicity
63 year old average age
Females
Wilhelmsen et al., 2001 Sweden 25.2 years 7495 males No association
47-55 years old

FIGURE 1 | The complex relationship between diabetes and cardiac arrhythmias. Potential contributors to the induction of cardiac arrhythmias including
hypoglycemia, hyperglycemia or glucose fluctuations and autonomic dysfunction activate multiple mechanisms to contribute to the development of cardiac
arrhythmias. Structural remodeling including changes in the electrical conduction of the heart and fibrosis promote and potentiate the progression of the disease.
Mitochondrial dysfunction leads to changes in cardiomyocyte function and metabolism and contributes to disease progression through oxidative stress. Inflammation
is present and may arise as a result of oxidative stress and structural changes.
damage and deficiency in neurohormonal growth factors may be major cardiovascular events including arrhythmias (Valensi
contributing factors to the damage or loss of nerves (Vinik et al., et al., 2001). The recurrence of atrial fibrillation is increased
2003). Despite the fact that cardiovascular autonomic neuropathy in diabetic patients with autonomic neuropathy, which was
has been extensively studied, it remains largely overlooked and determined by Ewing’s test. Electrocardiographic measurements
serious complication of diabetes (Vinik et al., 2003). from diabetic patients with autonomic neuropathy had a longer
In a study of nearly 2,000 men and women from the P-wave duration and dispersion compared to control patients
Framingham Offspring Study, heart rate variability, an indicator or diabetic patients, suggesting that autonomic neuropathy is
of autonomic nervous system function, was associated with causing inhomogeneous atrial depolarization to trigger atrial
plasma glucose levels and reduced in diabetic and patients with fibrillation (Bissinger et al., 2011). In a study investigating
impaired fasting glucose levels (Singh et al., 2000). In healthy, the changes in autonomic function and repolarization that
non-diabetic adults, impaired heart rate recovery, another occurring during prolonged hypoglycemia in type 2 diabetic
measure of autonomic dysfunction, and a predictor of all cause patients, twelve type 2 diabetic patients and eleven age and
death in diabetic patients (Wheeler et al., 2002; Cheng et al., body mass index-matched control patients had their glucose
2003), was more common in participants with abnormal fasting levels maintained by hyperinsulinemic clamps at euglycemia
plasma glucose levels, which was also true in diabetic patients (6 mmol/L) or hypoglycemia (2.5 mmol/L; Chow et al.,
(Panzer et al., 2002). A closer examination of the link between 2017). Differences in autonomic regulation during periods of
diabetes and autonomic neuropathy using heart rate recovery hypoglycemia, as indicated by heart rate, heart rate variability
as measure of autonomic dysfunction also associated diabetes and blood pressure, occurred between patients with type 2
and autonomic dysfunction with new-onset atrial fibrillation and diabetes and controls during hypoglycemia, suggesting that
heart failure independent of other cardiovascular risk factors changes in cardiac autonomic regulation in diabetic patients
(Negishi et al., 2013). Interestingly, this study demonstrated an may occur during hypoglycemic episodes and may contribute to
incremental and predictive association between diabetes, heart arrhythmias (Chow et al., 2017).
rate recovery and new-onset atrial fibrillation. There is some Animal models of diabetes show alterations in cardiac
evidence that the presence of cardiac autonomic neuropathy in innervation (Gando et al., 1993; Otake et al., 2009; Švíglerová
asymptomatic type 1 and type 2 diabetes patients could predict et al., 2011; Thaung et al., 2015). In a streptozotocin-induced

diabetic rat model, diabetic rats had increased heterogeneity of

sympathetic nerves as measure by immunohistochemistry
for tyrosine hydroxylase (sympathetic nerves) and
acetylcholinesterase (parasympathetic nerves; Otake et al.,
2009). This study also found that sympathetic nerve stimulation
increased incidence of atrial fibrillation in diabetic rats. Zucker
diabetic fatty rats have elevated resting cardiac sympathetic nerve
activity (Thaung et al., 2015). Signs of chronic β-adrenergic
stimulation were observed in hearts from these rats including
impaired responses to dobutamine stimulation, downregulation
of β1-adrenergic receptors and increases in Gαi proteins. These
studies demonstrate dysfunction of the autonomic nervous
system in diabetes, confirming the findings from human studies.
STRUCTURAL REMODELING
FIGURE 2 | Normal and fibrotic cardiac tissue highlights the structural
Structural remodeling likely plays a large role in which changes that occur with fibrosis (Red=cardiomyocytes, Blue=fibrosis).
diabetes mellitus and obesity promote cardiac arrhythmias. Atrial Structural changes that occur with diabetes contribute to the pathogenesis of
arrhythmias through disrupting the normal architecture of the heart. Fibrosis
hypertrophy, fibrosis and fat deposits are observed in the hearts
and fat deposits slow the electrical conduction and disrupt the direction.
of obese and type II diabetes patients (Tadic and Cuspidi, 2015). Furthermore, they serve as a source of paracrine signaling molecules including
Extensive atrial fibrosis is a hallmark of atrial fibrillation and cytokines/chemokines, adipokines and pro-fibrotic that exasperate the
is thought to play a role in both initiating and perpetuation disease.
the arrhythmia. Fibrotic tissue in the myocardium disrupts the
geometry of the heart and alters the mechanical, electrical and
chemical composition (Figure 2). There is extensive evidence
of cardiac fibrosis in both type 1 Sutherland et al., 1989 and diabetic heart. AGEs and RAGEs are increased in streptozotocin-
type 2 diabetes (Regan et al., 1977; Fischer et al., 1984; Nunoda induced diabetic rat atrial and inhibition of AGE formation
et al., 1985; van Hoeven and Factor, 1990; Shimizu et al., 1993; significantly reduced elevated levels of connective tissue growth
Kawaguchi et al., 1997) however, the contribution of fibrosis factor and atrial fibrosis observed in the diabetic rats (Kato
to atrial fibrillation is not fully understood in the context of et al., 2008). Elevated RAGE has been associated with atrial
diabetes. Structural remodeling is particularly relevant in diabetic fibrillation in humans, however the link between RAGE and
cardiomyopathy where architectural changes including fibrosis diabetes was not observed in this study (Lancefield et al., 2016).
and cardiomyocyte length changes as a result of cardiac dilation However, other mechanisms likely also contribute to the fibrosis
increased axial resistance in cardiomyocytes which exasperates seen in the diabetic heart. Studies using fasudil, a Rho-kinase
conduction dysfunction (Aromolaran and Boutjdir, 2017). (ROCK) inhibitor, and a high-fat/low dose streptozotocin rat
Animal models of diabetes also exhibit signs of increased model of diabetes, implemented the RhoA/ROCK pathway in
cardiac fibrosis (Kato et al., 2006; Liu et al., 2012). In Goto- cardiac fibrosis through decreasing RhoA, ROCK and collagen
Kakizaki rats, a genetic non-overweight type 2 diabetes model expression (Chen et al., 2014).
with slight impairments of glucose tolerance, Goto-Kakizaki rats While not as extensively investigated as fibrosis, increases in
had significantly greater atrial arrhythmogenicity and increased epicardial and pericardial fat is associated with type 2 diabetes
atrial fibrosis compared with control rats (Kato et al., 2006). (Rosito et al., 2008; Noyes et al., 2014; Levelt et al., 2016) and are
However, this study did not examine the progression of the correlated with left atrial enlargement, cardiac structural changes,
disease making it difficult to determine if arrhythmias arose and has been associated with increased atrial fibrillation risk
due to atrial fibrosis or if fibrosis is a contributing factor to (Al Chekakie et al., 2010; Batal et al., 2010; Wong et al., 2011).
atrial fibrillation. In a rabbit alloxan-induced diabetic model, Increased epicardial fat is associated with adipocyte infiltration
diabetic rabbits had increased atrial interstitial fibrosis and into the myocardium, which contributes to changes in the
electrophysiological changes including a prolonged inter-atrial electrical conduction between cardiomyocytes due to physical
conduction time and increased atrial effective refractory period disruption and slowing of the conduction time (Friedman et al.,
which increased the inducibility of atrial fibrillation (Liu et al., 2014; Mahajan et al., 2015; Haemers et al., 2017). Epicardial
2012). and pericardial fat is also an abundant source of adipokines and
Advanced glycation end products (AGEs) are proteins or cytokines which have pro-fibrotic and pro-inflammatory effects
lipids that become glycated as a result of sugar exposure and on the heart. Studies have shown that the secretome from human
have become recognized as a major contributor to complications epicardial fat, including TGF-β family members and matrix
from diabetes (Ramasamy et al., 2011). AGEs and AGE receptors metalloproteinases, produces a pro-fibrotic response in rat atrial
(RAGEs) may contribute to the structural remodeling seen in the myocardium (Venteclef et al., 2015). Additionally, pericardial

and epicardial fat have increased markers of inflammation changes in electrical conduction since animal models often have
including C-reactive protein, IL-6, IL-1β, and TNF-α, which are a number of alterations in metabolism including hyperglycemia
associated with increased incidence, severity and reoccurrence of and hyperlipidemia. However, studies using a cardiac-specific
atrial fibrillation (Abe et al., 2018). Furthermore, inflammatory insulin receptor knockout mouse model, several K+ channel
mediator production is not reversed by standard therapies components that are important for ventricle repolarization were
including angiotensin converting enzyme (ACE) inhibitors or identified as being decreased, in particular components of the
angiotensin II receptor blockers (Mazurek et al., 2003). transient outward K+ current fast component, which were also
associated with a reduction in the current (Lopez-Izquierdo et al.,
2014). Similar with what is seen in other diabetic models and
ROLE OF ELECTRICAL CONDUCTION human patients, cardiac-specific insulin receptor knockout mice
also had a longer ventricular action potential duration due to a
Studies consistently demonstrate prolonged action potentials prolonged QT interval, substantiating the role of insulin signaling
in diabetic patients and animal models. Type 1 (Sivieri et al., in diabetes-induced arrhythmias.
1993) and type 2 (Jermendy et al., 1990; Veglio et al., 2002; Contrarily, not all research implicates K+ currents in action
Ramirez et al., 2011) diabetic patients have been identified as potential changes with diabetes. In a fructose-fat fed rat model of
having slowed conduction velocity and an increased prevalence pre-diabetes, QRS prolongation was present, slower conduction
of prolonged QT interval. In some cases, this has been linked velocity, and increased propensity for ventricular fibrillation
with autonomic neuropathy (Ewing and Neilson, 1990). This (Axelsen et al., 2015). There were no changes in Na+ or
is also observed in numerous animal models of type 1 and K+ currents, fibrosis or gap junctions, suggesting another
type 2 diabetes (Xu et al., 2002; Lengyel et al., 2007; Huang mechanism for dysfunction. In an alloxan-induced diabetic
et al., 2013). Studies in Goto-Kakizaki (Howarth et al., 2008) rabbit model, no changes in action potential duration were
and Zucker Diabetic Fatty rats (VanHoose et al., 2010) also observed, but there was a reduction in conduction velocity
identified prolonged QT intervals with additional changes in the (Stables et al., 2014). A reduction in cell capacitance and Na+
R wave amplitudes and signs of autonomic neuropathy. While channel density were present in diabetic hearts however, no
prolongation of action potentials consistently occurs throughout changes in gap junctions or fibrosis were observed. In obesity-
studies, the mechanisms responsible are less clear. Potassium induced QT interval prolongation, there is extensive literature
channels have been the most widely identified change leading connecting abnormal calcium conduction with arrhythmias
to slowed action potentials in diabetic hearts. Prolongation of (Aromolaran and Boutjdir, 2017). However, this mechanism
the QT interval is observed in diet-induced obese mice, which of arrhythmogenesis is not clear in diabetes and if Na+ or
was attributed to a protein kinase D-dependent reduction in Ca+ channels play an important role in diabetes-induced
voltage gated potassium channel expression (Huang et al., 2013). arrthymias remains to be determined. Energy in the form of
Oxidative stress-induced alterations in GsH redox state, which ATP is necessary for maintaining membrane potential and
will be discussed in more detail in subsequent sections, may generating action potentials, which is mainly supplied by
regulate K+ channels, that have been shown to be decreased oxidative phosphorylation in the mitochondria, and oxidative
in myocytes isolated from diabetic rats and be reversed by phosphorylation to a lesser extent (Barth and Tomaselli,
insulin application (Xu et al., 2002). This has also been further 2009). It is likely that metabolic activity and arrhythmias are
supported in follow-up studies, corroborating the involvement of interdependent since changes in the cellular energy promotes
glucose metabolism in these changes (Xu et al., 1996). Changes arrhythmias however arrhythmias also influence metabolic
in outward K+ currents are observed early after streptozotocin activity. Whole transcriptome analysis of human atrial tissue
injection and corresponded with increases in glucose levels, revealed an upregulation of metabolic process related genes with
which were prevented by blocking hyperglycemia (Shimoni et al., atrial fibrillation (Barth et al., 2005). This was confirmed in
1994). Periodic changes in K+ ion current have been linked a study using human atrial appendages where metabolomics
to oscillations in energy metabolism in cardiomyocytes, which and proteomics were performed comparing patients with
could be modulated by changing glucose metabolism (O’Rourke sinus rhythm compared to patients that developed persistent
et al., 1994). Studies have shown that in cardiomyocytes, atrial fibrillation following cardiac surgery (Mayr et al., 2008).
glycolysis is more effective than oxidative phosphorylation at Patients with atrial fibrillation had an elevation in substrates
regulating K+ channel opening (Weiss and Lamp, 1987). These and enzymes for ketogenic metabolism and other metabolic
changes in K+ channels observed in small animals appear to processes. Additionally, mutantion or knockout of important ion
also hold true in larger, more human relevant animal species. In channel genes cause both prolonged ventricular repolarization
a type 1 diabetes model in dogs, while only slight lengthening as well as diabetes (Hu et al., 2014). Hypoglycaemia is also
in ventricular repolarization was observed, there were decreases associated with hypokalemia, which could contribute to delayed
in transient outward K+ and slow delayed rectifier potassium repolarization (Petersen et al., 1982; Heller and Robinson,
currents (Lengyel et al., 2007). In a streptozotocin-induce type 2000; Christensen et al., 2009). As mentioned above, there
1 diabetes mouse model, prolongation of the QT interval were is extensive clinical and experimental evidence to suggest
observed along with increased susceptibility to arrhythmia and that structural alterations contribute to the occurrence and
decreased K+ currents (Meo et al., 2016). Many of these studies persistence of atrial fibrillation (Nattel and Harada, 2014).
make it difficult to determine the mechanisms responsible for Changes in gap junctions, which are important for the electrical

impulse propagation and synchronization in the heart, are channel (Cav ) 3.1, Cav β3, ryanodine receptor 3 and Cav γ4
observed with fibrosis and hypertrophy and affect the electrical (Ferdous et al., 2016). This same group identified a unique
conduction of the heart (Spach et al., 1988; Saffitz and profile of ion channel alterations in the atrioventricular node
Kléber, 2004; Ten Tusscher and Panfilov, 2007; dos Santos with no changes in connexins (Howarth et al., 2017).
et al., 2016). In the adult heart, connexin-43 is the main
cardiac gap junction component and changes in expression,
distribution or post-translational modifications contribute to ROLE OF MITOCHONDRIA AND
heart rhythm disturbances (Boengler et al., 2006). Therapies to OXIDATIVE STRESS
restore connexin levels are capable of improving conduction
disturbances in atrial fibrillation models, further supporting the The contribution of oxidative stress to the pathogenesis of
importance of connexins in the pathogenesis of atrial fibrillation cardiac arrhythmias is becoming increasingly recognized (Yang
(Igarashi et al., 2012). and Dudley, 2013; Samman Tahhan et al., 2017). There are
There may be alterations in gap junctions in the heart with a number of signs of oxidative stress with atrial fibrillation
diabetes. Decreases in phosphorylated and overall connexin- including increased levels of superoxide and hydrogen peroxide
43 levels, a major gap junction protein which has been linked (Dudley et al., 2005; Kim et al., 2005; Reilly et al., 2011; Zhang
with atrial fibrillation, have been shown in a streptozotocin- et al., 2012), decreased nitric oxide bioavailability (Cai et al.,
induced diabetes model (Mitasíková et al., 2009) which may 2002; Bonilla et al., 2012), changes in the ratio of oxidized
occur through protein kinase Cε-dependent mechanisms (Lin glutathione disulfide to reduced glutathione and differences in
et al., 2006). These changes were associated with a decreased the ratio of oxidized cysteine to reduced cysteine (Neuman
in connexin-43 phosphorylation and ventricular conduction et al., 2007). There is also known to be increased oxidative
abnormalities. However, in a different study that also used stress in diabetes, which contributes to the damage of multiple
a streptozotocin-induced diabetes model, connexin-43 levels tissue types throughout the body including the heart (Giacco
were elevated and distribution changes were evident (Hage and Brownlee, 2010; Rochette et al., 2014). In diabetes, there is
et al., 2017). Other studies using diabetic (db/db) mice show a known increase in superoxide production, which contributes
decreased connexin-43 expression that can be reversed with to a reduction in vascular nitric oxide bioactivity through
exercise (Veeranki et al., 2016). In this study, exercise resulted in increased NADPH oxidases and dysfunction endothelial nitric
improvements in mitochondrial oxygen consumption rate, tissue oxide synthase (Guzik et al., 2002) which is similar decreases in
ATP levels and reduced cardiac fibrosis with diabetes. Further endothelial nitric oxide synthase and nitric oxide bioavailability
convoluting the involvement of cardiac connexin-43 in diabetes- are associated with atrial fibrillation (Cai et al., 2002).
induced arrhythmias, an obese diabetic (db/db) mouse model Changes in oxidative stress that are present in the heart
of diabetes showed was atrial hypertrophy and fibrosis without during diabetes are likely mitochondrial in origin since in
alterations in connexin-43 staining (Hanif et al., 2017). No diabetic human atrial tissue, where mitochrondrial changes in
alterations in connexin-43 levels were also observed in a Zucker metabolism of multiple substrates are observed (Anderson et al.,
Diabetic Fatty rat model of type 2 diabetes, where the conduction 2009). Hydrogen peroxide emissions are increased regardless of
velocity was significantly slower in diabetic rats, but levels of the substrate, suggesting alterations in the electron transport
connexin-43 were unchanged (Olsen et al., 2013). However, this system or antioxidant capacity (Anderson et al., 2009). In
study did observe distribution changes in connexin-43, which permeabilized myofibers from right atrial appendages obtained
may contribute to functional changes. from non-diabetic and type 2 diabetic patients, mitochondria
Changes in other connexins may also contribute to the from diabetic patients had a decreased capacity for glutamate and
pathogenesis of cardiac arrhythmia with diabetes. In a fatty acid-supported respiration, increased content of myocardial
streptozotocin-induced diabetic rat model where connexin- triglycerides and increased mitochondrial hydrogen peroxide
40, 43, and 45 mRNA expression was measured in the sinoatrial emission during oxidation of carbohydrate and lipid based
node, right ventricle and right atrium, connexin-45 expression substrates (Anderson et al., 2009). There is some evidence
was significantly elevated in the sinoatrial node with no changes that oxidative stress contributes to the atrial remodeling and
seen in the atrial or ventricles (Howarth et al., 2007). Using inflammation seen with atrial fibrillation. In a rabbit alloxan-
a streptozotocin-induced diabetic rat model, the duration induced diabetes model, Langendorff perfused diabetic hearts
of atrial tachyarrhythmia induced by atrial stimulation was had greater induction of atrial fibrillation following burst
extended in diabetic rats while the conduction velocity was pacing, which was decreased with use of the antioxidant
decreased (Watanabe et al., 2012). Increased atrial fibrosis was probucol (Fu et al., 2015). Antioxidant administration also
also observed in diabetic rats compared with controls and had attenuated atrial interstitial fibrosis and signs of decreased
decreased connexin 40 expression with no significant differences oxidative stress including reductions in serum and tissue
in connexin 43. A separate study examining mRNA changes in malonaldehyde, NF-κB, TGF-β, and TNF-α. However, several
sinoatrial node of streptozotocin-induced diabetic rats failed studies in humans have shown little or no cardiovascular benefits
to see differences in connexin 40 expression but identified from antioxidant supplementation demonstrating the need for
increased transcript expression for connexin 45 among changes better understanding of the mechanisms that oxidative stress
in numerous other ion channels including transient receptor contributes to atrial fibrillation in the context of diabetes (Sesso
potential channel (TRPC) 1, TRPC6, voltage gated calcium et al., 2008; Violi et al., 2014).

There has been limited investigation into the mechanisms (Gaudino et al., 2003) and increased occurrence during
linking oxidative stress, diabetes and arrhythmias. One of myocarditis (Spodick, 1976). In human patients, C-reactive
the most extensively studied mechanisms is Ca2+ /calmodulin- protein (Aviles et al., 2003) has been associated with incidence of
dependent protein kinase II (CaMKII). CaMKII is a serine- atrial fibrillation and was able to predict future development and
threonine kinase that has emerged as an important nodal point to polymorphisms in the interleukin-1 family affect risk for atrial
allow cardiomyocytes to respond to perturbances in calcium and fibrillation (Cauci et al., 2010; Gungor et al., 2013). Inflammation
reactive oxygen species through the activation of a diverse group has also been suggested as an underlying pathogenic mediator
of downstream targets to regulate membrane excitability and for diabetes. Since it was identified that TNF-α secretion by
calcium cycling (Voigt et al., 2012; Mesubi and Anderson, 2016). adipocytes played a role in the body’s update of glucose and
CaMKII is increased in atria of atrial fibrillation patients and in response to insulin which contributes to the development of
mouse models of susceptible to atrial fibrillation (Purohit et al., diabetes (Hotamisligil et al., 1993), extensive research has been
2013). CaMKII has been shown to influence calcium dynamics done looking at the role of inflammation in diabetes (Wellen and
through several different mechanisms in the diabetic heart. In Hotamisligil, 2005; Calle and Fernandez, 2012).
obese Zucker rats and high-fat-fed rodents, there is increased The connection between inflammation, arrhythmias and
muscle mitochondrial content and CaMKII activation (Jain et al., diabetes is not currently well characterized and an ongoing area
2014). Increases in mitochondrial reactive oxygen species and of research however, hypoglycemia, which has been suggested to
S-nitrosylation of the ryanodine receptor lead to increased SR trigger atrial fibrillation (Odeh et al., 1990; Celebi et al., 2011;
calcium leak and activation of CAMKII. CaMKII may also Ko et al., 2018), increases markers of inflammation (Investigators
contribute to connexin alterations and electrical conduction et al., 2013). In a recent study, toll-like receptor (TLR) 2 knockout
changes observed in diabetes (Zhong et al., 2017). In ApoE mice have decreased incidence of arrhythmias compared to
knockout mice fed a high fat diet, downregulation of the ion wild-type mice in a streptozotcin model of diabetes mellitus
channels, connexin-43 upregulation and ventricular remodeling (Monnerat et al., 2016). This is thought to occur through
could be prevented by administration of a CaMKII antagonist. IL-1β production by macrophages since macrophages from TLR2
Post-translational modifications of CamKII may contribute to knockout animals had lower levels of MCHIIhigh macrophages
its role in diabetes-induced arrhythmias. Animal studies show and NLRP3 inflammasome. IL-1β was decreased in the hearts
that mitochondria isolated from streptazocin treated rat hearts of TLR2 knockout animals and IL-1β could decreased potassium
have increased total O-linked N-acetylglucosamine (O-GlcNAc) current and increase calcium sparks in isolated cardiomyocytes.
and O-GlcNAc transferase levels, with O-GlcNAc transferase Furthermore, inhibition of the NLRP3 inflammasome or IL-1β
being localized in the mitochondrial matrix as opposed to reversed diabetes-induced arrhythmias.
an inner membrane localization in control rats (Banerjee
et al., 2015). Mislocalization of O-GlcNAc transferase results
in decreased interactions with complex IV of the electron THE IMPACT OF DIABETES THERAPIES
transport chain, resulting in impairments of its activity. Acute ON ARRHYTHMIAS
hyperglycemia in cardiomyocytes has been shown to result
in covalent and persisting modifications of Ca2+ /calmodulin- Current type 2 diabetes therapies aim to treat hyperglycemia to
dependent protein kinase II (CaMKII) by O-GlcNAc, which can reduce and maintain glucose concentration to normal levels in
also be observed in the heart and brain of diabetic humans and an effort to prevent the development of complications (Kahn
rats (Erickson et al., 2013). O-GlcNAc modification of CaMKII et al., 2014). Since the process through which diabetes causes
leads to increased activation of spontaneous sarcoplasmic arrhythmias is not currently know, the impact of current
reticulum Ca2+ release resulting in arrhythmias (Erickson et al., therapies is just beginning to be understood. Studies suggest that
2013). In diabetic humans and mouse models of diabetes, there merely controlling glucose levels is not beneficial (Group et al.,
are increased levels of oxidized CaMKII (Luo et al., 2013). 2008; Duckworth et al., 2009) and potentially detrimental (Action
Oxidized CaMKII has been linked with ventricular arrhythmia to Control Cardiovascular Risk in Diabetes Study et al., 2008)
(Wang et al., 2018) and atrial fibrillation (Purohit et al., 2013) in controlling cardiovascular complications. This lack of benefit
however, how oxidized CaMKII contributes to atrial fibrillation from intense glycemic control includes the rate impact the rate of
with diabetes is not currently defined. In addition to changes new-onset atrial fibrillation (Fatemi et al., 2014). However, poorly
in CaMKII, abnormal calcium handling has been observed in controlled diabetes has also been linked to increased incidence of
diabetic hearts however, how this relates to arrhythmogenesis has atrial fibrillation showing that the role of glycemic control is not
no yet been investigated (Belke and Dillmann, 2004; Lacombe fully understood at this time (Huxley et al., 2012).
et al., 2007). Metformin is currently the most widely used medication
to treat type 2 diabetes and acts to suppress gluconeogenesis
thus lowering glucose levels. Metformin has been associated
ROLE OF INFLAMMATION with decreased atrial fibrillation risk compared with diabetic
patients not taking medication (Chang et al., 2014). In vitro
Inflammation has been identified as a risk factor for cardiac studies using an atrial cell line demonstrated that metformin
arrhythmias due to the increased frequency of incidence decreased reactive oxygen species in response to pacing and
following cardiac surgery (Bruins et al., 1997), genetic studies prevented cardiomyocyte remodeling (Chang et al., 2014). In

diabetic Goto-Kakizaki rats, metformin treatment decreased in drug resistant patients. Catheter ablation has been shown
cardiac fibrosis and arrhythmias (Fu et al., 2018). Alterations in in a large study composed of 1,464 patients to have the same
small conductance calcium-activated potassium channels were efficacy and safety in diabetes patients as the general population
observed in the atria of these animals, which was corrected with (Anselmino et al., 2015). However, due to the presence of other
metformin treatment, suggesting that metformin may restore atrial fibrillation recurrence predictors such as alterations in the
the atrial electrophysiology. Metformin has also been shown electrical and anatomical composition of the atrial myocytes,
to prevent high glucose induction of apoptosis, autophagy metabolic alterations and other comorbidities (D’Ascenzo et al.,
and connexin-43 downregulation in H9C2 cells, a ventricular 2013), the need to redo ablation is more common (Chao et al.,
myoblast cell line (Wang et al., 2017). However, there have been 2010; Anselmino et al., 2015). However, smaller studies have
reported incidences of onset of atrial fibrillation with metformin shown that while ablation is equally effective in diabetic patients,
use in diabetic patients (Boolani et al., 2011), which may be there are increased numbers of thrombotic or hemorrhagic
attributed to lactic acidosis, which occurs rarely with metformin complications (Tang et al., 2006).
treatment (Salpeter et al., 2010). Thromboprophylaxis therapies are also commonly used in
Thiazolinediones are peroxisome proliferator-activated patients with atrial fibrillation to decrease risk of stroke and
receptor-γ agonists, which decrease glucose levels by increasing other complications. A number of clinical trials investigating
storage of fatty acids in adipocytes, also decrease incidences the effectiveness of various theromboprophylaxis therapies have
of atrial fibrillation onset, which might also be influenced by included diabetic subpopulations. In the Rivaroxaban Once Daily
their anti-inflammatory actions (Chao et al., 2012; Pallisgaard Oral Direct Factor Xa Inhibition Compared with Vitamin K
et al., 2017; Zhang Z. et al., 2017). However, other studies have Antagonism for Prevention of Stroke and Embolism Trial in
shown in patients with coronary disease, thiazolinediones have Atrial Fibrillation (ROCKET-AF) trial, 40% of the patients had
no improvements in atrial fibrillation compared with other diabetes (Patel et al., 2011). The Randomized Evaluation of
diabetes treatments including metformin, insulin, sulfonylurea Long-Term Anticoagulation Therapy (RE-LY) trial comparing
or meglitinides, suggesting that the anti-inflammatory effects warfarin and high dose dibagatran was composed of about
of thiazolinediones does not further improve anti-arrhythmia 23% diabetic patients (Connolly et al., 2009). The Effective
effects of controlling glucose levels (Pallisgaard et al., 2018). Anticoagulation with Factor Xa Next Generation in Atrial
Dipeptidyl peptidase-4 (DPP-4) inhibitors, such as alogliptin, Fibrillation-Thrombolysis in Myocardial Infarction (ENGAGE
which increases incretin levels to inhibit glucagon release AF-TIMI) trial had ∼36% diabetic participants (Giugliano et al.,
leading to increased insulin secretion are also a common 2013). No differences were observed between diabetic and
treatment for type 2 diabetes. In an alloxan-induced rabbit non-diabetic patients in any of these studies. The Apixaban
model of diabetes mellitus, diabetic rabbits had increased for Reduction in Stroke and Other Thromoembolic Events
left ventricular hypertrophy and left atrial dilation (Zhang in Atrial Fibrillation (ARISTOTLE) trail, composed of ∼25%
X. et al., 2017). Diabetic hearts had a higher level of atrial diabetic patients, found no difference in the primary outcome of
fibrillation inducibility and treatment with alogliptin prevented decreased stroke and thromboembolic events between diabetic
morphological changes and increased propensity for atrial and non-diabetic patients (Granger et al., 2011). However,
fibrillation. Additionally reactive oxygen species, mitochondrial diabetic patients had an increased risk of bleeding compared with
membrane depolariazation and mitochondrial biogenesis were non-diabetic participants. Taken together, these studies suggest
improved with alogliptin. In a Taiwanese population, DPP-4 that anti-arrhythmic and anti-thromboprophylaxis therapies are
inhibitors, in conjunction with metformin, decreased the onset effective in diabetic patients with few adverse effects.
of atrial fibrillation compared to diabetics taking metformin The renin-angiotensin system is involved in the genesis of
and other second-line therapies (Chang et al., 2017). Other arrhythmias through its impact on structural and electrical
standard diabetes therapies may also have beneficial effects on remodeling (Iravanian and Dudley, 2008). Therapies targeting
cardiac arrhythmias. Retrospective studies suggest that there this pathway including angiotensin-converting enzyme (ACE)
may be differences in sudden cardiac arrest and ventricular inhibitors and angiotensin-II receptor blockers (ARB) have been
arrhythmias between types of sulonylurea medications, where hypothesized to be beneficial in preventing atrial fibrillation
glyburide was found to have lower risk for sudden cardiac arrest occurrence and are currently the focus of numerous studies
and ventricular arrhythmias compared with glipizide (Leonard (Iravanian and Dudley, 2008). Activation of the renin-
et al., 2018). angiotensin system is often associated with diabetes where
it is thought to impact the initiation and progression of the
disease (Giacchetti et al., 2005). While there have not been
ARRHYTHMIA THERAPIES IN DIABETIC direct studies linking the renin-angiotensin system and diabetes-
PATIENTS induced arrhythmias, it is likely that they are intertwined since
the renin-angiotensin system impacts nearly all contributing
Pharmacological therapies for arrhythmia include agents that factors including cardiac remodeling, electrical remodeling
control rate and rhythm. Currently, there has been no research and inflammation (Iravanian and Dudley, 2008). Inhibitors
examining the efficacy of anti-arrhythmic medications in patients of the renin-angiotensin system have been shown to reduce
with diabetes (Dobbin et al., 2018). Surgically, catheter ablation cardiovascular events, decrease diabetic complications and
is an established therapeutic option for heart rhythm control can reduce incidence of new onset diabetes (Hansson et al.,

1999; Heart Outcomes Prevention Evaluation Study, 2000; tissues potentiates disease progression through changes in the
Brenner et al., 2001; Dahlof, 2002; Bangalore et al., 2011). heart’s energy needs, the production of paracrine signaling
This has been confirmed in a large clinical trial investigating factors and alterations in receptors that influence ion channel
the effects of the ARB valsartan on diabetes development in activity in the heart. Alterations in the architecture of the
patients with impaired glucose tolerance where valsartan was heart including fibrosis, fat deposition and hypertrophy change
found to reduce incidence of diabetes but did not reduce the the electrical conduction of the heart and disrupt the pattern
rate of cardiovascular events (Group et al., 2010). However, of the electrical signal. They are also an important source
in patients with impaired fasting glucose or impaired glucose of paracrine factors that enhance disease progression. Taken
tolerance, the ACE inhibitor Ramipril was not able to reduce together, these alterations within the heart change the electrical
new incidence of diabetes in patients with impaired fasting conduction by regulating ion channels and gap junctions between
glucose but did promote normoglycemia (Investigators et al., cardiomyocytes changing the electrical signaling. While anti-
2006). While renin-angiotensin system targeted therapies show arrhythmic therapies appear to be effective in diabetic patients,
promise in reducing incidence of cardiac arrhythmias and the effectiveness of diabetes therapeutics on prevention of cardiac
diabetes, additional research is necessary to further understand arrhythmias is unclear. Due to the complex nature of diabetes and
the mechanisms involved and confirm studies performed in cardiac arrhythmias, further experimental and clinical research
small patient populations. is necessary to fully elucidate the relationship between diabetes
and arrhythmias in the hope of developing improved therapeutic
CONCLUSIONS strategies in the future.
The impact of diabetes on the electrical conduction of the AUTHOR CONTRIBUTIONS

heart and development of cardiac arrhythmias is becoming
increasingly apparent. Due to the complex, multifactorial nature The author confirms being the sole contributor of this work and
of diabetes, the relationship between diabetes and cardiac has approved it for publication.
arrhythmias is not yet fully understood however, correlations
between increased blood glucose levels, glucose fluctuation and ACKNOWLEDGMENTS
hypoglycemia, and arrhythmias have been observed and are a
likely initiator of the disease. Autonomic dysfunction, which This work was supported by an American Heart Association
is known to contribute to diabetic complications in other Scientific Development Grant 17SDG33400114 (LG).
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published: 26 November 2018

Diabetes and Arrhythmias:

The prevalence of diabetes is rapidly increasing and closely associated with

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Study Location Duration Population characteristics Findings

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diabetic rat model, diabetic rats had increased heterogeneity of

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The impact of diabetes on the electrical conduction of the AUTHOR CONTRIBUTIONS

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