Arrhythmia Risk and Obesity

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ISSN: 1747-0862
Journal of Molecular and Genetic Medicine
The International Open Access
Journal of Molecular and Genetic Medicine
Special Issue Title:
Molecular & Cellular Aspects in Obesity
and Diabetes
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Research Article Open Access
Mozos, J Mol Genet Med 2014, S1
http://dx.doi.org/10.4172/1747-0862.S1-006
Review Article Open Access
Molecular and Genetic Medicine
J Mol Genet Med ISSN: 1747-0862 JMGM, an open access journal Molecular & Cellular Aspects in Obesity and Diabetes
*Corresponding author: Ioana Mozos, M.D., Ph.D., Associate Professor,
Department of Functional Sciences, “Victor Babes” University of Medicine
and Pharmacy, T. Vladimirescu Str. 14, 300173, Timisoara, Romania, Tel:
+40745610004; E-mail: ioanamozos@yahoo.de
Received November 20, 2013; Accepted December 26, 2013; Published January
01, 2014
Citation: Mozos I (2014) Arrhythmia Risk and Obesity. J Mol Genet Med S1: 006.
doi: 10.4172/1747-0862.S1-006
Copyright: © 2014 Mozos I. This is an open-access article distributed under the
terms of the Creative Commons Attribution License, which permits unrestricted
use, distribution, and reproduction in any medium, provided the original author and
source are credited
Arrhythmia Risk and Obesity
Ioana Mozos*
Department of Functional Sciences, “Victor Babes” University of Medicine and Pharmacy, Timisoara, Romania
Keywords: Obesity; Cardiac arrhythmias; Atrial brillation;
Ventricular arrhythmia; QT interval; Late ventricular potentials;
Sudden cardiac death; Electrocardiography; Pathophysiology; Body
mass index; Obstructive sleep apnea; Inammation; Oxidative stress
Introduction
Overweight and obesity are dened, according to the World Health
Organization as abnormal or excessive fat accumulation. A person with
a body mass index (BMI) between 25 and 29,9 kg/m² is considered
overweight, and with a BMI of 30 kg/m² or more obese [1]. Obesity
has reached epidemic proportions, its prevalence continues to increase
worldwide and cardiovascular disease dominates the mortality and
morbidity in obese patients [2,3]. e most rapidly growing segment
of the obese population is the severely obese, with a BMI of 40 kg/m²
or more [4].
Obesity is a cardiovascular risk factor and is signicantly associated
with hypertension, coronary heart disease, cardiac arrhythmias, heart
failure, diabetes mellitus and dyslipidemia [2,5,6]. In obese and
overweight individuals, the cardiac structure and function change
as a consequence of an increased in total plasma and blood volume,
with subsequent increase in le ventricular lling and cardiac
output, causing le ventricular hypertrophy, le atrium and right
ventricular hypertrophy, and the peripheral resistance is decreased
[5,7-9]. Cardiomyopathy of obesity includes increased ventricular
mass and chamber size, hypoplastic coronary arteries and severe
coronary atherosclerosis [10]. e increased abdominal mass impairs
the function of the diaphragm, reducing oxygen supply and enabling
arrhythmia and sudden cardiac death [11]. Hypoxia can cause
pulmonary vasoconstriction, pulmonary hypertension and right heart
failure [11]. Despite higher prevalence of cardiovascular pathology
with excessive fat, a survival advantage has been also described in obese
patients with heart failure, hypertension, myocardial infarction or
peripheral arterial disease: “the obesity paradox” [3,9].
ere are multiple mechanisms linking obesity to cardiovascular
pathology, including the cardiometabolic consequences of obesity,
accelerated atherosclerosis, altered release of adipokines and chemical
mediators, promoting a proinammatory and prothrombotic state,
neurohormonal activation with increased sympathetic tone, endothelial
dysfunction, increased arterial stiness, le ventricular hypertrophy,
hemodynamic alterations, altered cardiomyocyte electrical properties,
obesity-related cardiomyopathy, inltration of fat into the myocardium
and coronary artery calcication [5,6,8,9,12,13].
Obesity increases the risk of arrhythmias. e most commonly noted
arrhythmias include sinus arrhythmia, premature atrial and ventricular
contractions, atrial brillation, ventricular and supraventricular
tachycardia [5]. Cardiac arrhythmias may be precipitated in obese by
several factors, including: hypoxia, hypercapnia, electrolyte imbalances
due to diuretic therapy, coronary heart disease, increased circulating
catecholamines, obstructive sleep apnea, le ventricular hypertrophy,
and fatty inltration of the conduction system [2].
e present review focuses on the mechanisms linking overweight
and obesity with cardiac arrhythmias and provides a brief review of the
latest studies in this area.
Atrial Arrhythmias and Obesity
Premature atrial contractions
Premature atrial contractions (PAC) are independent predictors of
Abstract
Obesity is a known cardiovascular risk factor and it increases the risk of cardiac arrhythmias and sudden cardiac
death. The most commonly reported arrhythmias are atrial brillation and ventricular tachycardia.
The present review focuses on the mechanisms linking overweight and obesity with cardiac arrhythmias and
provides a brief review of the latest studies in this area.
Obesity is one of the very few identied modiable risk factors for the occurrence and progression of atrial
brillation, and the mechanisms linking atrial brillation and obesity include: structural and electrophysiological atrial
remodeling, metabolic factors, sympatho-vagal imbalance, clinical links (obstructive sleep apnea, cardiovascular
comorbidities) and inammation.
The main mechanisms leading to ventricular arrhythmia and sudden cardiac death in obese individuals include
cardiomyopathy, metabolic factors, sympathetic hyperinnervation, obesity-induced electrophysiological remodeling,
coronary heart disease as common comorbidity and radical weight reduction strategies.
Electrocardiographic monitoring, including P wave and QT interval duration, are extremely important in obese
patients. Weight control may be an effective strategy for reducing the burden of cardiac arrhythmias and sudden
cardiac death.

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atrial brillation and stroke, and were associated with several factors,
including age, height, history of cardiovascular disease, natriuretic
peptide levels, but not body mass index [14]. e metabolic syndrome,
a cluster of atherosclerotic risk factors, including central obesity, was
associated with an increased number of extrasystoles, supraventricular
tachyarrhythmias, sinus node arrest and atrial brillation [15-17].
Signicant correlations were found between arrhythmias and the
number of components of the metabolic syndrome, demonstrating a
cause-eect relationship [15].
Sinus arrhythmias
Sinus arrhythmias are frequent in obese patients, especially sinus
bradycardia [18]. Prolonged sinus pauses were revealed by 24-hour
ECG monitoring in a patient with Prader-Willi syndrome, requiring
pacemaker insertion [19]. e Prader-Willi syndrome is a rare genetic
syndrome, resulting from an abnormality in chromosome 15, and is
characterized by severe childhood obesity, short stature, behavioral
disturbances, intellectual disability, and severe hyperphagia [19].
e patients are at increased risk of sudden death, and elevated
inammatory markers, premature atherosclerosis, increased systolic
blood pressure and abnormal microcirculatory responses, could have
an important contribution [19,20].
Atrial brillation
Atrial brillation is the most common sustained arrhythmia in
clinical practice, and is associated with an increased risk of ischemic
stroke, heart failure, systemic embolism, cognitive dysfunction,
dementia, diminished quality of life and exercise capacity, and death
[16,21-27]. e classic risk factors for atrial brillation include
hypertension, valvular disease, cardiomyopathy, male sex, aging, thyroid
disease and diabetes mellitus [22,28,29]. e increasing incidence of
atrial brillation is due to advancing age of the population, a better
survival of individuals with structural heart disease and the current
obesity epidemics [12,25]. Aging increases the risk of developing atrial
brillation through age-dependent structural and electrophysiological
characteristics [22,30]. e majority of patients with atrial brillation
suer from a cardiovascular disorder (substrate related), which may
have an additive eect on the perpetuation of the arrhythmia [22,26],
but there are some patients with “lone” atrial brillation, without
an underlying cardiovascular disorder [28]. Patients with lone atrial
brillation have normal life expectancy, a low risk of stroke, and rarely
progress to persistent or permanent atrial brillation [28].
Several studies demonstrated the link between obesity and atrial
brillation [31,32], but earlier reports did not support this association
[33,34].
Wanahita et al. [31] found a risk of developing atrial brillation up
to 50% in overweight and obese. e mechanisms linking obesity and
atrial brillation are complex, including atrial remodeling, increased
activity in the conduction system of the heart, electrophysiological
remodeling of the le atrium, neurohormonal activation, an
increased sympathetic activity, elevated plasma volume, increasing
le ventricular diastolic lling pressure, metabolic factors (insulin
resistance, dyslipidemia, free fatty acids, reactive oxygen species),
mechanical eects (raised intrathoracic pressures and obstructive sleep
apnea), increased arterial stiness, genetic predisposition and gene-
environment interactions [6,8,16,21,25,27,29,34-37] (Figure 1).
Increased le atrial pressure may increase atrial ectopy, triggering
atrial brillation [36]. Atrial remodeling is characterized by changes in
ion channel function, calcium homeostasis, and atrial structure, such
as cellular hypertrophy, activation of broblasts and subsequent tissue
brosis, enabling the occurrence of “triggers” for atrial brillation and
the formation of a “substrate” for atrial brillation that promotes its
perpetuation [30]. Increased le atrial pressure and volume, shortened
eective refractory period in the le atrium and pulmonary vein may
facilitate atrial brillation in obese patients [38]. Prolonged BMI
– mediated le atrial stretch was associated with the development
of brosis [34]. ere are several clinical links between obesity and
atrial brillation, including hypertension, macro- and microvascular
ischemia, impaired coronary perfusion and obstructive sleep apnea
[27]. A high fat diet, even in the absence of obesity, increases the
sympathetic activity, enabling arrhythmic events [39].
Tsang et al. [34] found obesity as a risk factor for progression of
paroxysmal to permanent atrial fibrillation, depending on the left
atrial size.
Watanabe et al. [16] demonstrated an increased risk for the
development of atrial brillation in patients with metabolic syndrome.
Most of the components of the metabolic syndrome were related to
the development of atrial brillation. Inammation, oxidative and
mechanical stress and enlargement of the atrium, loss of muscle mass,
brosis and spatial remodeling of gap junctions have been proposed as
factors linking the components of the metabolic syndrome and atrial
brillation [16,40-42].
Nicolaou et al. [21] reported a greater risk for progression of
atrial brillation in obese elderly women due to the enlarged atrium.
e combination aging-obesity increases sympathetic activity and
angiotensin II production, which increased blood pressure and aects
le atrial remodeling and the onset of atrial brillation, through the
association with le ventricular hypertrophy and subclinical diastolic
dysfunction, which aects the size and function of both atria and
ventricles [21,27,43-45].
Abed and Wittert [35] mentioned atrial electro-structural
dysfunction enabled by obesity-related risk factors, such as
hypertension, vascular disease, obstructive sleep apnea, insulin
resistance and pericardial fat. Atrial brillation risk was associated not
only with pericardial, but also with systemic and regional epicardial
adiposity [27]. e eect of epicardial fat was independent of BMI and
other known risk factors for atrial brillation [46].
Li et al. [26] reported an increased risk of atrial brillation in
patients with myocardial infarction, le ventricular hypertrophy,
obesity and alcohol consumption in a Chinese population, but a lower
prevalence compared to European studies.
Atrial brillation is the most common arrhythmia in women, as
well. Obesity was associated with atrial brillation in postmenopausal
Figure 1: Pathophysiological links between obesity and atrial brillation.

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women [47], among fertile young women [25,29], in pregnant
women with a history of atrial brillation, and in female health care
professionals without cardiovascular history [48]. Karasoy et al. [29]
reported a strong relationship between obesity and new-onset atrial
brillation, especially lone atrial brillation, in young, fertile women.
Hemodynamic changes associated with pregnancy and delivery
and electrophysiological phenomena may play an important role in
developing lone atrial brillation [28,29].
Early life factors may be involved in the pathogenesis of atrial
brillation and obesity among individuals with a low birth weight
[49,50]. A signicant part of the association between birth weight and
atrial brillation is mediated through height and cumulative exposure
to elevated body mass, and lower birth weight protects the atria against
brillation in adults [50]. Genetic or environmental intrauterine factors
may “program” adult body mass, le atrial size and subsequent atrial
brillation risk [50]. Genome studies on patients with atrial brillation
emphasized the importance of genes related to atrial brillation,
especially PITX2, on chromosome 4q25, for the development of the le
atrium, and ZFHX3, in growth regulation of several tissues [50].
Obesity was associated with an increased atrial brillation
risk in community- and population-based cohort studies, and in
cardiothoracic surgery cohorts, independent of type of cardiac surgery
[27,51]. Body mass index was included, as an atrial brillation risk
factor, in multiple risk scores, including the Framingham Heart Study
10-year AF risk calculator [27].
e Atrial brillation Follow-up Investigation of Rhythm
Management Study (AFFIRM) demonstrated better outcomes (lower
all-cause and cardiovascular mortality) in obese patients with atrial
brillation than in lean, concluding that an obesity paradox exists for
outcomes in obese patients with atrial brillation [52].
P wave indices, derived from the surface ECG, include P-wave
duration, morphology and amplitude, may assess atrial electric
function, progressively altered by obesity [27,53]. P wave dispersion,
the dierence between maximum and minimum P wave duration,
an electrocardiographic marker for the prediction of atrial
brillation, was increased in obese women [53]. e most important
electrocardiographic markers of atrial remodeling and prolongation of
atrial conduction time are: an increased maximum P wave duration
in the standard, 12-lead electrocardiogram and long signal-averaged P
wave duration [54].
Adipose tissue itself may be directly involved in the pathogenesis
of cardiovascular disease, considering that obesity has been associated
with generalized enlargement of fat depots, involved in the production
of pro-inammatory cytokines and reactive oxygen species and
uncontrolled release of fatty acids [8,55]. Cardiac adiposity is
characterized by an increase in intramyocardial triglyceride content
and an enlargement of the fat tissue surrounding the heart and vessels,
which can lead to myocardial damage [55]. Fatty acid inltration and
overload promotes fatty acid oxidation, accumulation of triglycerides
and metabolites which can impair calcium signaling, beta-oxydation
and glucose utilization, damage mitochondrial function with increased
production of reactive species, proapoptotic and inammatory
molecules [55]. Fatty inltration or “fatty metamorphosis” can induce
abnormal automaticity from degenerated myocardial cells [56].
Several biomarkers have been identied as a link between obesity
and atrial brillation, including inammatory markers, adipocytokines,
pericardial and epicardial fat, and atrial tissue [27,57,58]. Obesity is an
established inammatory condition [59], and adipocytes enable local
inammation through adipocytokines and proinammatory cytokines
[60]. Inammation, measured by plasma levels of high sensitivity
C reactive protein, brinogen and soluble intracellular adhesion
molecule-1, was signicantly associated with the risk of incident atrial
brillation in healthy, middle-aged women, free of cardiovascular
disease [58]. Various other inammatory markers have been associated
with atrial brillation, including tumor necrosis factor alpha, interleukin
2, 6 and 8 [24]. Inammatory inltrates, myocyte necrosis, and brosis
have been found in atrial biopsies of patients with atrial brillation
[61,62]. Chronic inammation may induce electrophysiological and
structural changes in the atrial myocardium predisposing patients with
triggering atrial foci to atrial brillation [63]. Proposed mechanisms
linking inammation and atrial brillation include endothelial
dysfunction, production of tissue factor from monocytes, increased
platelet activation, and increased expression of brinogen [24]. It is
still not clear if inammatory markers elevation is a consequence or a
cause of atrial brillation [23,58]. Probably preexisting inammation
initiates the arrhythmia that subsequently propagates an inammatory
response, enabling persistence of atrial brillation [23]. C-reactive
protein has been shown to decrease cardiac contractility [64]. On the
other hand, it was suggested that inammation is not a major mediator
of the atrial brillation risk associated with obesity [48].
Adiponectin is one of the adipocytokines secreted by the adipose
tissue, both a biomarker and a possibly mediator of cardiovascular
disease, with antiatherogenic, antidiabetic and antiinammatory
properties, able to inuence the extent of atrial and le ventricular
remodeling, which can increase cardiac contractility and action potential
duration by inhibiting delayed rectier potassium currents [59,60,65].
Higher adiponectin levels were detected in patients with chronic atrial
brillation than in paroxysmal atrial brillation, correlated with a
collagen type I degradation marker, demonstrating that adiponectin
is a useful marker of atrial remodeling [65]. Activation of broblasts
and subsequent brosis contribute to atrial structural remodeling and
heterogeneity of the cardiac conduction tissue [56,60,65].
Epicardial fat tissue modulates atrial electrophysiological
and contractive properties, through inammatory cytokines,
adipocytokines and adipocyte-cardiomyocyte interactions, and heart
failure epicardial fat has a greater arrhythmogenic eect on the le
atrium, prolonging action potential duration [66]. Epicardial adipose
tissue was also suggested to be involved in the maintenance of atrial
brillation [67]. e right atrium is more resistant to hypoxia/
reoxygenation than the le atrium, due to higher heat shock proteins
[68]. Several experiments showed that epicardial adipocytes modulate
atrial cardiac ionic currents with decrease of delayed rectier inward
and outward currents and increase of late sodium currents and L-type
calcium currents [69].
Future research should focus on the relation between atrial
brillation and adiposity phenotypes, gene-environment interactions,
obesity years, childhood obesity, increased risk due to comorbidities,
weight loss, atrial remodeling and reverse remodeling, mechanisms
of resolution of atrial brillation and new biomarkers [23,27].
Electrocardiographic monitoring is extremely important in obese
patients, considering that a substantial proportion of atrial brillation
episodes are asymptomatic.
Ventricular Arrhythmias and Obesity
Patients with morbid obesity have high rates of sudden cardiac
death (SCD), before the development of heart disease [70-72]. SCD
is more common in obese persons than in lean individuals, although

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progression to heart failure may be the most common cause of death
in patients with obesity-associated cardiomyopathy [6,12,13]. Obesity
was an important comorbidity in SCD patients with structurally normal
hearts [73]. e main mechanisms leading to arrhythmia and SCD in
obese include cardiomyopathy, with myocyte hypertrophy, abnormal
cardiomyocyte lipid deposits, lipotoxicity of the myocardium induced
by free fatty acids, cardiac brosis and mononuclear cell inltration,
and obesity-induced electrophysiological remodeling, myocardial
infarction, le ventricular hypertrophy, impaired connexins,
sympathetic hyperinnervation and parasympathetic withdrawal [13,72-
77] (Figure 2). Fatty inltration separates the myocardial bundles and
disrupts their parallel orientation, impairing ventricular activation and
resulting in heterogeneous repolarization [72].
Obesity is a known risk factor for coronary heart disease and
myocardial infarction, due to the association with other cardiovascular
risk factors [78-80]. Ischemia/reperfusion injury enabled scar
expansion and inadequate brosis in obese rats and mice [74-76].
Feeding rats a high calorie diet resulted not only in increased body
weight, visceral fat content, plasma insulin, nonesteried free fatty
acids and triglycerides, but also in cardiac hypertrophy [75]. Myocyte
hypertrophy may lead to le ventricular hypertrophy in “healthy”
obese rats aer high-fat diet [7]. e fatty acid milieu causes structural
and functional changes in the heart of obese [7].
Hearts of female rats fed a high-fat diet were associated with
arrhythmias and an impaired reparative brotic response following
an ischemic insult, due to sympathetic hyperinnervation and impaired
gap junction proteins, despite a nonsignicant increase in body weight,
a normal plasma lipid prole [76].
Increased intracellular lipid content can impair repolarization due
to a decrease in potassium channel protein levels, causing ventricular
tachycardia and sudden cardiac death [13]. Adipocytokines from
epicardial fat signicantly decrease delayed rectier outward currents in
cardiomyocytes, prolonging action potential duration and facilitating
triggered activity with early aer depolarizations [81].
Obese patients have an increased frequency of premature
ventricular contractions compared to healthy controls, unrelated to
hypertension or concentric ventricular hypertrophy [13,82].
Besides changes in P wave and PR interval, several other
electrocardiographic changes may occur in obese individuals,
including an increased heart rate, prolonged QT interval and QRS
complex duration, increased QT dispersion, modied QRS voltage,
STT abnormalities, multiple electrocardiographic criteria for le
ventricular hypertrophy, attening of the T waves and leward shis
of the P wave, QRS and T wave axes [4,18,83-85]. Many of these ECG
abnormalities are reversible with substantial weight loss [84].
Obese individuals have a faster heart rate and reduced heart rate
variability due to abnormalities in sympatho-vagal balance, factors
associated with an increased risk of myocardial infarction and sudden
cardiac death [3,12].
erapy of ventricular arrhythmias in obese patients includes
ICD and pacemaker implantation, chronic optimal medical therapy,
programmed weight reduction [85]. Food-, plant- and drug-based
therapies for weight loss have, lately, gained great attention [86].
Several ventricular arrhythmias and SCD were reported due to weight
loss pills in young women [86-88]. Sibutramine, an oral anorexiant,
prolongs the QT interval and causes a reversible cardiomyopathy,
ventricular brillation and cardiac arrest, and was withdrawn from
the market worldwide [89,90]. Potassium loss due to diuretics can
prolong the QT interval and cause serious arrhythmias [90]. Clinicians
prescribing weight loss pills should consider the cardiovascular prole
and monitor their patients for ECG abnormalities.
e QT Interval and QT Dispersion in Obese
Weight gain delays cardiac repolarization, and several studies
reported prolonged QT intervals in obese patients, including persons
with uncomplicated obesity and abdominal fat deposition [13,52,91-
96]. Other studies, conducted in patients with uncomplicated obesity,
reported no eect of weight gain on cardiac repolarization [97].
e dierences between the outcomes of the studies may be due to
heterogeneity of study populations, dierent QT interval measurement
techniques and measurement errors [52].
Prolonged heart rate corrected QT interval (QTc) correlated with
body mass index, waist circumference, waist-to-hip ratio, and obese
patients with glucose intolerance and hyperinsulinemia are more likely
to have a prolonged QT interval [93,94,96,98]. e correlation between
QTc and waist circumference was stronger than the one between
QTc and body mass index, indicating that abdominal obesity is a
more important predictor of cardiac risk than BMI in obese patients
[96]. e prolonged QT interval was associated with an increased
sympathetic and decreased parasympathetic tone in obese patients
[6]. Insulin resistance and decreased serum HDL cholesterol were
risk factors for QTc prolongation in obese children [99]. Patients
with uncomplicated metabolic syndrome had a greater dispersion of
ventricular repolarization time and increased maximal and minimal
QTc [100].
e QTc interval correlated with free fatty acid level in normal
subjects and obese women, and fatty inltration can increase
dispersions of action potential duration, increasing the possibility
of reentry circuits [81,93,101]. Corbi et al. [93] found a signicant
relationship between QTc intervals, waist-to-hip ratio, plasma free
fatty acids, epinephrine and norepinephrine concentrations, suggesting
autonomic nervous system dysfunction as a possible mechanism of
the prolonged QTc intervals in visceral obesity. Elevated plasma free
fatty acid level has a stimulatory eect on the sympathetic nervous
system [102]. QT dispersion in nonapneic simple snoring, overweight
adults was signicantly increased [95]. An increased QT dispersion in
obese women was associated with le ventricular hypertrophy and late
ventricular potentials [103].
QT interval prolongation in obese patients is related to the
functional and structural changes in the heart, metabolic factors
Figure 2: Pathophysiological links between obesity and sudden cardiac death.

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including hyperinsulinemia, glucose intolerance, free fatty acids,
decreased HDL cholesterol, autonomic dysfunction, fatty inltration
and comorbidities [52,93,99,101].
Body mass index did not aect overall QT duration, but QT
dispersion was signicantly higher in normal-weight coronary patients
than in obese [98]. On the other hand, intraventricular conduction was
aected in obese patients with an old myocardial infarction [11].
Reduction of body weight in obese women resulted in signicant
shortening of the QTc interval and QT dispersion, correlated with
reduction in plasma free fatty acid concentration [93] and regression
of le ventricular hypertrophy [104]. Shortening of the QT interval
and cardiac parasympathetic activity increase, may reduce the risk of
potentially fatal arrhythmias and sudden death [93]. Sleeve gastrectomy
in morbidly obese patients was associated with QT interval shortening
3 months aer surgery [105].
QT prolongation, cardiac arrhythmias and sudden deaths have been
reported among dieters using very low energy diets, recommending
regular inpatient electrocardiographic monitoring for obese patients
on therapeutic starvation [106].
Late Ventricular Potentials in Obese
Late ventricular potentials are high frequency, low amplitude
signals, appearing in the terminal part of the QRS complex, obtained
using signal averaged ECG [77]. According to an international
convention, late ventricular potentials are present, if 2 of the following
criteria are positive: SAECG-QRS duration >120 ms, low amplitude
signal: LAS40 (duration of the terminal part of the QRS complex with
an amplitude below 40 μV>38 ms, and the root mean square signal
amplitude of the last 40 ms of the signal <20 μV (RMS40) [107].
Several studies reported late ventricular potentials in obese
patients [72,92,108]. e presence of late ventricular potentials in
obese individuals could be secondary to changes in obesity-associated
cardiomyopathy, including brosis, fat and mononuclear cell
inltration and myocyte hypertrophy [12,109].
Late ventricular potentials are aected by body size and le
ventricular mass [108]. Masui et al. [108] reported no correlation
between QRS duration and root mean square voltage with body
weight and body mass index, sum of skin folds or le ventricular mass.
Positive linear correlations were found between low amplitude signals
and weight, body mass index, sum of skin folds [108]. Subadipose
tissue may prolong low amplitude signals by attenuation of the QRS
complex, suggesting that low amplitude signals are inappropriate for
the denition of positive late ventricular potentials in obese persons
[108].
Lalani et al. [72] considered pericardial adipose tissue, brosis and
myocyte hypertrophy to be related with the increased frequency of late
ventricular potentials in obese individuals, and body mass index as an
independent predictor of abnormal signal averaged ECG results.
Body mass index correlated with SAECG-QRS duration and LAS40
in patients with an old myocardial infarction, suggesting a body mass
index dependent sudden cardiac death risk [110].
Cardiac Conduction System Involvement in Obese
Frank et al reported unfrequent conduction abnormalities in obese
patients [18]. Involvement of the conduction system in sudden death
of obese young people has been explored by Bharati et al, reporting
an hypertrophied and enlarged heart, focal mononuclear cells in and
around the sinoatrial node, marked fat throughout the conduction
system, brosis of the atrioventricular bundle and le bundle branch,
a brous atrioventricular node and focal brosis of the ventricular
septum [111]. e mild to moderately obese patients demonstrated a
higher degree of brosis compared to the markedly obese, showing a
higher amount of fat [111].
Obstructive Sleep Apnea and Arrhythmias in Obese
Patients
Obstructive sleep apnea (OSA) is dened by recurrent episodes of
upper airway collapse during sleep, impairing ventilation and resulting
in subsequent hypoxia, hypercapnia, sleep arousals and loud snoring
[53,112]. Overnight polysomnography is the gold standard test to
diagnose and stratify sleep apnea, but patients may be screened for OSA
with a simple tool, as well, such as Berlin questionnaire [113]. Central
obesity is a common nding and major risk factor for obstructive sleep
apnea and increased adipose tissue predisposes to airway narrowing
[6,112]. e major risk factors for OSA are, besides obesity, age, male
gender and alterations in craniofacial structure [114].
OSA is a risk factor for excessive daytime sleepiness, road
trac accidents, cardiovascular morbidity (hypertension, stroke,
metabolic syndrome) and mortality [112]. Both tachyarrhythmia and
bradyarrhythmia are possible causes of cardiovascular morbidity in
patients with OSA [114]. OSA is also independently associated with
type 2 diabetes mellitus, insulin resistance, diabetic microvascular
complications, dyslipidemia and bronchial asthma [115].
Increased mortality in patients with OSA, particularly at night,
emphasizes the importance of identifying the mechanisms of
myocardial electrical instability [115]. e main mechanisms linking
OSA with cardiac arrhythmias are: increased intrathoracic pressure,
autonomic imbalance (repetitive oscillations between sympathetic
and parasympathetic predominance), systemic and pulmonary
hypertension, structural and electrical atrial and ventricular remodeling,
inammation, diastolic dysfunction, endothelial dysfunction,
atherogenesis and myocardial ischemia, night-time hypoxemia
and acidosis [22,27,28,53,114-117]. Repetitive inspiration against
collapsed upper airways generates important shis in intrathoracic
pressure, transmitted to the atria and contributing to atrial remodeling
(enlargement and brosis) [53]. Hypoxemia may cause pulmonary
vasoconstriction and pulmonary hypertension and stimulates the
sympathetic nervous system via reex mechanisms [28,118]. e
combination of repetitive uctuations in heart rate, blood pressure
and intrathoracic pressure during sleep with increased sympathetic
tone, leads to increased le and right ventricular wall stress, le and
right ventricular hypertrophy and systolic and diastolic heart failure
[118]. Several observations point toward a long-lasting sympathetic
hyperactivity, aected by comorbidities [119].
All kinds of arrhythmias have been observed in patients with OSA,
ranging from asymptomatic sinus bradycardia to fatal ventricular
arrhythmias and asystole [112,114]. A paroxysm of atrial brillation
may lead to central sleep apnea, due to an acute decrease in le
ventricular lling, with an increase in pulmonary wedge pressure and
consequent stimulation of pulmonary vagal receptors [28]. Both OSA
and central sleep apnea modulate the autonomic nervous system at
night through central respiratory-cardiac coupling in the brainstem,
chemoreexes, baroreexes, and reexes related to lung ination
and arousals [120]. e repetitive oscillations between sympathetic
and parasympathetic predominance enable the development of
cardiac arrhythmias: bradyarrhythmias when parasympathetic

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J Mol Genet Med ISSN: 1747-0862 JMGM, an open access journal Molecular & Cellular Aspects in Obesity and Diabetes
tone predominates, and atrial and ventricular arrhythmias when
sympathetic tone predominates [118].
Studies on the prevalence of bradyarrhythmias in patients with
OSA have yielded conicting results [118]. Many studies reported
sleep-related bradyarrhythmias or asystole in patients with OSA, not
related to a diseased sinus node or atrio-ventricular conduction system
[112,121]. Uninhibited paroxysmal parasympathetic discharges lead to
marked paroxysmal bradycardia [113]. Bradyarrhythmias during sleep
are associated with OSA severity, and concomitant chronic obstructive
pulmonary disease or beta 2-therapy may play a role in development
of tachyarrhythmias [117]. Other studies reported no increase in
bradyarrhythmias rates [122,123].
Atrial remodeling related to OSA may cause atrial arrhythmias,
including interatrial block, atrial brillation and utter. It has been
reported that OSA may increase le atrial size independently of obesity,
hypertension and diastolic dysfunction [118]. OSA was found as an
independent risk factor for atrial brillation [113]. e association
between atrial brillation prevalence and OSA is related to the severity
of hypoxemia [124], chronically increased sympathetic activity due to
hypoxemia and hypercapnia, surges in adrenergic and vagal tone, atrial
remodeling, and a higher prevalence of traditional risk factors [113,118].
Nocturnal hypoxemia may cause mitochondrial dysfunction, resulting
in repetitive oxidative stress and increased production of inammatory
cytokines, leading to endothelial dysfunction, insulin resistance,
hypercoagulability and adverse myocardial remodeling [113]. e
increased sympathetic tone and intrathoracic pressure may lower atrial
eective refractory period due to activation of acetylcholine-dependent
potassium channels, enabling pulmonary vein discharges and atrial
dilation [113]. e high prevalence of atrial brillation explains the
increased risk of stroke and heart failure in patients with OSA [112].
OSA not only promotes initiation of atrial brillation, but also
may contribute to its progression, and makes management of atrial
brillation more dicult [113,125]. OSA was associated with higher
rates of early and overall recurrence aer catheter ablation of atrial
brillation and it predicts atrial brillation recurrence aer pulmonary
vein isolation [113,125-127]. A signicantly higher incidence of atrial
brillation recurrences following cardioversion and ablation was found
in patients with untreated compared to treated OSA, suggesting that
OSA may trigger atrial brillation [128]. Serum markers of oxidative
stress and free radical production predict atrial brillation recurrences
aer atrial brillation ablation [113]. It is important for physicians to
monitor atrial brillation patients for OSA and monitor those with
OSA for atrial brillation [125].
A signicant association between OSA and ventricular arrhythmias
has been also demonstrated, due to myocardial ischemia, the
procoagulant, proinammatory and heightened adrenergic state, heart
remodeling, systolic and diastolic heart failure, arterial desaturation
and arousal [118,129]. Ventricular ectopy and nonsustained ventricular
tachycardia were recorded during sleep, but the prognosis of
nonsustained ventricular tachycardia is debatable in the absence
of heart disease [130]. A high prevalence of OSA was also found in
implantable cardioverter-debrillator recipients [53]. Namtvedt et
al. [117] reported an increased prevalence of ventricular premature
complexes in middle-aged patients with mild or moderate OSA. A high
prevalence of sleep-disordered breathing (60%) was found in patients
with ventricular arrhythmias and normal le ventricular function,
demonstrating a strong association in patients without heart failure
[129]. Repetitive intermittent hypoxemia and hypercapnia due to
OSA, act through chemoreceptors, increase sympathetic activity and
induce ventricular arrhythmias [129]. Only few studies investigated the
association between OSA and sudden cardiac death. Habitual snorers
and patients with OSA had a higher risk of sudden cardiac death in the
early morning [131,132].
Obstructive sleep apnea is increasing in the pediatric population,
as well, and is more common among overweight and obese boys [114].
QT dispersion was signicantly increased only in obese children
with OSA [114]. QT dispersion increases also in adult patients with
moderate-to-severe OSA, and a positive correlation was found between
QT dispersion and the severity of OSA [133].
Patients who presented advanced atrioventricular block had more
severe OSA than those without arrhythmias [134].
OSA is a common but underestimated disorder, linked to
cardiovascular morbidity and mortality. Unfortunately, OSA is largely
undiagnosed, due to the insucient awareness of the disorder among
physicians and there should be heightened suspicion of OSA in patients
with atrial brillation [112,113]. e deleterious cardiovascular eects
of OSA may be reversible with early therapy [114], and patients could
benet of weight normalization, ECG monitoring, continuous positive
airway pressure ventilation (CPAP) and avoidance of factors known
to increase upper airway obstruction, such as alcohol consumption
(alcohol reduces the muscle tone of the upper airways and prologs
apnea) and use of sedatives [112,117]. CPAP may improve oxidative
stress and reduce the structural and electrical remodeling of the atria
due to OSA, resulting in a lower atrial brillation recurrence rate
[113,127]. On the other hand, CPAP reduces preload, which may
further compromise diastolic lling of the ventricles, already impaired
to the loss of atrial pump in atrial brillation [113]. More attention
should be given to patients with more severe OSA or concomitant
comorbidities [117].
Oxidative Stress and Arrhythmogenesis
Obese subjects exhibit increased systemic oxidative stress, enhanced
by abdominal adiposity and associated with adiponectin deciency
[135]. Recent clinical and experimental evidence demonstrated the
involvement of oxidative stress in cardiac electrical and structural
remodeling [23,136,137]. Reactive oxygen species may impair Na,
K and Ca channels, Na-Ca exchanger activity, may be implicated in
gap junction remodeling, decrease the action potential amplitude and
duration, and increase the incidence of cardiac arrhythmias in animal
models [136-140].
Oxidative stress results in decreased hERG protein levels,
accelerated activation and deactivation of hERG, and increase in current
amplitude of hERG and hKv1.5, allowing a greater amount of K ions
to ow through these channels in the phase 3 of the action potential,
downregulation of Ito (responsible for the rapid repolarization phase),
and increases the channel opening probability of Ik1 (inward rectifying
channel) [136,137].
An abundance of oxidative markers was found in atrial tissues from
patients with persistent atrial brillation, although plasma markers of
oxidative stress did not correlate with developing atrial brillation [23].
Not only L-type calcium channels and sodium channels are sensitive
to the redox state, but also cardiac creatine kinase, explaining the link
between inammation and the structural remodeling of the atrium [23].
General and mitochondrial anti-oxidants may be promising
therapeutic strategies of arrhythmias in obese patients [137].

Citation: Mozos I (2014) Arrhythmia Risk and Obesity. J Mol Genet Med S1: 006. doi: 10.4172/1747-0862.S1-006
Page 7 of 10
J Mol Genet Med ISSN: 1747-0862 JMGM, an open access journal Molecular & Cellular Aspects in Obesity and Diabetes
Conclusions
e present review illustrates the signicant association of excess
body weight with an increased arrhythmia risk, and the mechanisms
explaining the high prevalence of atrial and ventricular arrhythmias in
overweight and obese patients, with implications for prevention and
therapy of atrial brillation and sudden cardiac death. Atrial brillation
is very common in obese patients with cardiovascular disorders. Obesity
impairs ventricular depolarization and repolarization, prolongs the QT
interval and is frequently associated with ventricular arrhythmias, even
before the development of heart disease.
Obstructive sleep apnea is common in obese patients and it is
linked to atrial and ventricular arrhythmias due to structural and
electrical cardiac remodeling, an increased sympathetic tone, systemic
and pulmonary hypertension, intermittent hypoxia and inammation,
activation of humoral, metabolic and thrombotic factors.
Obesity is one of the very few identied modiable risk factors
for arrhythmias, and the development of a risk score, incorporating
clinical, biochemical, ECG and genetic obesity markers would be useful
in assessing arrhythmia risk. Considering the multiple factors linking
obesity and cardiac arrhythmias, may provide a more comprehensive
picture of arrhythmia risk, enabling preventive and therapeutic
measures. Future research should focus on the genetic component
enabling the association obesity-cardiac arrhythmias, changes in the
molecular components of the ion channels and repolarization reserve,
nontraditional obesity biomarkers predicting arrhythmia risk, without
neglecting the use of other known ECG markers.
Weight control may be a reasonable strategy for reducing the
burden of cardiac arrhythmia, but electrocardiographic monitoring is
recommended for obese patients during weight reduction programs.
Prevention and treatment of obesity and detection and control of
obstructive sleep apnea could represent cornerstones for the prevention
of cardiac arrhythmias. Standard 12-lead ECG can play an important
role in obese patients in predicting atrial brillation (P wave duration
and dispersion) and ventricular arrhythmia risk (QT interval duration
and dispersion). ECG is the gold standard for diagnosis of arrhythmias,
considering that most of the patients are asymptomatic.
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Citation: Mozos I (2014) Arrhythmia Risk and Obesity. J Mol Genet Med S1:
006. doi: 10.4172/1747-0862.S1-006
This article was originally published in a special issue, Molecular & Cellular
Aspects in Obesity & Diabetes handled by Editor(s). Dr. Masayoshi
Yamaguchi, Emory University School of Medicine, USA
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