Curr Atheroscler Rep (2016) 18:21
DOI 10.1007/s11883-016-0575-4
CORONARY HEART DISEASE (S. VIRANI AND S. NADERI, SECTION EDITORS)
Obesity and Cardiovascular Disease: a Risk Factor
or a Risk Marker?
Taher Mandviwala 1 & Umair Khalid 1 & Anita Deswal 1,2
# Springer Science+Business Media New York (outside the USA) 2016
Abstract In the USA, 69 % of adults are either overweight
or obese and 35 % are obese. Obesity is associated with an
increased incidence of various cardiovascular disorders.
Obesity is a risk marker for cardiovascular disease, in that
it is associated with a much higher prevalence of comor-
bidities such as diabetes, hypertension, and metabolic
syndrome, which then increase the risk for cardiovascular
disease. However, in addition, obesity may also be an in-
dependent risk factor for the development of cardiovascu-
lar disease. Furthermore, although obesity has been shown
to be an independent risk factor for several cardiovascular
diseases, it is often associated with improved survival once
the diagnosis of the cardiovascular disease has been made,
leading to the term “obesity paradox.” Several pathways
linking obesity and cardiovascular disease have been
described. In this review, we attempt to summarize the
complex relationship between obesity and cardiovascular
disorders, in particular coronary atherosclerosis, heart fail-
ure, and atrial fibrillation.
Keywords Obesity . Cardiovascular disease . Hypertension .
Atherosclerosis . Coronary artery disease . Heart failure
This article is part of the Topical Collection on Coronary Heart Disease
* Anita Deswal
adeswal@bcm.edu
1
Baylor College of Medicine, Houston, TX, USA
2
Michael E. DeBakey VA Medical Center, (111B) 2002 Holcombe
Blvd, Houston, TX 77030, USA
Introduction
Over the past two decades, obesity has become a global epi-
demic affecting both pediatric and adult populations. In the
USA, 69 % of adults are either overweight or obese and
35 % are obese [1]. Obesity has been associated with a de-
creased life expectancy as well as with increased morbidity
[2]. The relationship between cardiovascular disease (CV)
and obesity has been widely studied, but a number of questions
still remain. For instance, obesity has been linked to develop-
ment of cardiovascular diseases including atherosclerosis and
symptomatic coronary artery disease (CAD), heart failure
(HF), and atrial fibrillation (Fig. 1). Obesity does increase the
risk of CV disease secondarily through its influence on the
development and severity of comorbidities such as hyperten-
sion, dyslipidemia, and glucose intolerance or diabetes [3].
However, the increase in various CV diseases may also occur
in the absence of other comorbidities and may be due to struc-
tural and functional changes of the myocardium through ex-
cess adipose tissue deposition or through other mechanisms
related to obesity [4]. Furthermore, obesity has been known
to be an independent risk factor for the development of CV
diseases such as HF but has also been shown to be associated
with improved survival once the diagnosis of HF is established
(the so-called “obesity paradox”) [5, 6•, 7]. This obesity para-
dox has also been observed in other CV disease states [8].
In this review, we attempt to emphasize the association of
obesity with CV disease, focusing on whether obesity is an
independent risk factor for the development of CV disease
states such as CAD, HF, and atrial fibrillation. The fact that
obesity is a risk marker, in that it is associated with a much
higher prevalence of comorbidities such as diabetes, hyperten-
sion, and metabolic syndrome, which themselves are risk fac-
tors for the development of CV disease, is well established and
will not be discussed in any detail.
21 Page 2 of 10 Curr Atheroscler Rep (2016) 18:21

Fig. 1 Increased risk of

cardiovascular diseases with 4% increased
increase in body mass index risk of
10 kg increment in
ischemic
(BMI) and body weight. stroke body weight
CAD = coronary artery disease;
HF = heart failure; SBP = systolic
blood pressure; DBP = diastolic
blood pressure 12%
increased
5% and 7%
risk of CAD
1 unit 6% increased
increasedrisk
risk of
of HF in men increment hemorrhagic
& women in BMI stroke
respectively 3 mmHg
higher SBP

2.3 mmHg
4% increased higher DBP
risk of Atrial
Fibrillation

Measures of Obesity initiate disease. Inflammation mediates all stages of athero-

Several measures other than just body weight are used to
measure obesity, including body mass index (BMI), waist
circumference, and waist-to-hip ratio. Body weight indexed
to height to measure the BMI is a commonly used index of
obesity and overweight. An adult is considered normal weight
if the BMI is 18.5 to <25 kg/m2, overweight if the BMI is 25.0
to 29.9 kg/m2, and obese if the BMI is ≥30.0 kg/m2 [9]. Waist
circumference has been shown to be a better index of abdom-
inal obesity than waist-to-hip ratio. It also correlates better
with BMI than waist-to-hip ratio [10]. A recent study showed
overall age-adjusted obesity prevalence to be 35.7 %. There
were, however, race-specific age-adjusted differences noted;
specifically, 36.2 % non-Hispanic white men, 38.8 % non-
Hispanic black men, 32.2 % non-Hispanic white women,
and 58.5 % non-Hispanic black women met the BMI criteria
for obesity [1].
Obesity and Atherosclerotic Disease
The understanding of the pathophysiology of atherosclerosis
and obesity has dramatically changed over the past few de-
cades. Historically, obesity and atherosclerosis were thought
to be simply lipid storage disorders involving triglycerides in
adipose tissue and cholesteryl ester in atheromata. However,
now they are both also viewed as chronic inflammatory dis-
ease states, with activation of both innate and adaptive immu-
nity [11•, 12].
Atherosclerotic disease and obesity share several common
pathophysiological features. First, lipids contribute to both
atherosclerosis and obesity; oxidized low-density lipoprotein
(LDL) and free fatty acids can trigger inflammation and
genesis—from early lesion development to atheroma compli-
cation—and is associated with obesity, insulin resistance, and
type 2 diabetes mellitus. Inflammation may form the major
link between obesity and atherosclerosis: Adipokines released
by adipose tissue induce insulin resistance, endothelial dys-
function, hypercoagulability, and systemic inflammation, all
of which can promote atherosclerosis. The accumulation of
heterogeneous macrophage populations, T cell activation, cell
death, and the effects of numerous cytokines and chemokines
characterize both atherosclerosis and obesity. Inflammatory
biomarkers, such as high-sensitivity C-reactive protein, IL-6,
and IL-18, can predict cardiovascular events, may be used to
guide therapy, and reflect the pathophysiological links be-
tween obesity and its associated metabolic disorders [9].
When evaluated in a clinical trial, a multidisciplinary program,
which aimed to reduce body weight in obese women through
lifestyle changes, was associated with a reduction in markers
of vascular inflammation (CRP, IL-6, and IL-18) and in insu-
lin resistance along with an increase in levels of adiponectin,
an adipocytokine with anti-inflammatory and insulin-
sensitizing properties [13].
It is important to understand the link between inflammation
and atherosclerosis and how obesity accelerates this process.
Obese individuals have a higher propensity toward inflamma-
tion compared to non-obese individuals. Patients with visceral
obesity have been found to have higher levels of proinflam-
matory adipokines including TNF-alpha, IL-6, MCP-1,
resistin, and leptin [14]. The higher level of inflammation
has been correlated with observations from several large-
scale prospective studies that demonstrated elevated levels
of CRP in obese patients [15]. Elevated CRP levels indepen-
dently predict a higher risk of future myocardial infarction,
Curr Atheroscler Rep (2016) 18:21
peripheral arterial disease, and the risk of developing type II
diabetes mellitus [16–18]. Furthermore, CRP levels correlate
with increased visceral adiposity independent of overall BMI
[19]. This has led to the use of CRP levels in patients with
intermediate risk of coronary artery disease to improve risk
stratification for major adverse cardiovascular events
(MACEs) [20].
As the evidence of atherosclerosis being a chronic inflam-
matory state increased, so did the therapeutic approach to its
treatment. HMG-CoA reductase inhibitors or statins were ini-
tially developed to decrease LDL cholesterol, but many stud-
ies have shown that they also provide an anti-inflammatory
effect including the reduction of CRP levels [21, 22]. Using
this background, the Justification for the Use of Statins in
Primary Prevention: an Intervention Trial Evaluating
Rosuvastatin (JUPITER) trial demonstrated that the number
of cardiovascular events was significantly decreased in
healthy individuals with an LDL cholesterol less than
130 mg/dl but with CRP levels of 2 mg/l or higher, through
the use of 20 mg rosuvastatin daily compared with placebo
[23]. Similarly, salicylates such as aspirin (which of course
also have additional anti-platelet action) have been known to
decrease inflammation and have been used to treat many dif-
ferent conditions ranging from rheumatoid arthritis to primary
prevention of myocardial infarction. Studies, however, have
found that the use of non-acetylated salicylate derivative,
salsalates, which do not increase bleeding times, decreases
inflammation and improves glycemic control in obese indi-
viduals [24–26]. Anti-inflammatory drugs could be beneficial
in improving CV outcomes in obese atherosclerotic patients,
but further long-term studies are necessary.
The relationship between obesity and CAD can be assessed
in two settings. The first is obesity’s role in the pathogenesis of
coronary atherosclerosis and stable ischemic heart disease
and, second, its implications in acute coronary syndromes
(ACSs) and coronary revascularization. It is known that obe-
sity is an independent risk factor for CAD [3], as well as for
ACS when CAD is present [27].
The Pathobiological Determinants of Atherosclerosis in
Youth (PDAY) study allowed a better understanding of the
relationship between obesity and CAD [28]. In this study, the
investigators conducted a post-mortem study on the arteries of
young individuals who had died from accidental causes or
suicides. They concluded that the onset of CAD occurs de-
cades before the actual clinical manifestations. They also de-
termined that higher BMI was associated with more complex
coronary lesions, as shown by an increased number of fatty
streaks, raised lesions, and high-grade complex lesions, when
compared to normal weight individuals. Another study showed
that the complexity of coronary lesions was directly related to
panniculus thickness in all patients with BMI >30 kg/m2 [28].
In addition, obesity likely needs to be long-standing and pres-
ent for at least two decades to become an independent risk
Page 3 of 10 21
factor for clinically significant coronary artery disease, as sug-
gested by several long-term cohort studies [29–31]. One study
showed that a 10-kg increase in body weight was associated
with 12 % increased risk of CAD and 3 mmHg higher systolic
and 2.3 mmHg higher diastolic blood pressure [32].
As detailed earlier, the pathogenesis of CAD in obese indi-
viduals is mediated via adipose tissue, which serves as an ac-
tive paracrine and endocrine organ, and produces a wide array
of adipokines that are directly involved in atherosclerosis [33].
These adipokines interact and influence several other metabol-
ic and immunologic cascades, such as vascular reactivity (e.g.,
leptin, TNF-α, and adiponectin), inflammation (e.g., monocyte
chemotactic protein 1 and IL-8) and coagulation (e.g., plasmin-
ogen activator inhibitor). These pathways often overlap and
activate more bioactive factors, following a positive feedback
course [34–37]. In comparison to normal weight individuals,
circulating platelets in obese counterparts show increased acti-
vation as well as diminished sensitivity to anti-platelet agents
such as aspirin [38, 39]. Despite all this knowledge, the com-
prehensive cellular and molecular pathways linking obesity to
development of CAD and triggering of ACS are not complete-
ly understood. Fat distribution appears to play a key role.
Abdominal obesity is associated with worse outcomes in pa-
tients with known CVD, as demonstrated by data from the
Trandolapril Cardiac Evaluation (TRACE) registry [40].
Moreover, this relationship remained significant after adjust-
ment for comorbidities associated with obesity, such as diabe-
tes and hypertension. In the INTERHEART study, waist-to-hip
ratio, waist circumference, and waist-to-height ratio were all
stronger predictors of myocardial infarction (MI) compared to
BMI alone [41]. This indicates that the “abdominal” compo-
nent of obesity has the most detrimental effects pertaining to
CAD in obese individuals.
Obesity and Acute Cardiovascular Syndromes In a large
study including more than 100,000 patients who presented
with non-ST elevation myocardial infarction (NSTEMI), obe-
sity was found to be the strongest factor linked to NSTEMI
events in younger patients, followed by tobacco use. The
higher the BMI, the lower the mean age at which the patients
presented with NSTEMI [42]. This inverse correlation with
age also holds true for ST elevation myocardial infarction
(STEMI) patients [43]. Based on the available data, obesity
is considered an independent risk factor for STEMI in younger
patients [44, 45]. Moreover, obesity is also linked to develop-
ment of other acute vascular events; for each 1-unit increase in
BMI, there is a 4 % increased risk of ischemic stroke and 6 %
increased risk for hemorrhagic stroke [32, 46].
Obesity and Revascularization for CAD In addition to obe-
sity being a risk factor for the development of ACS, obesity
may also increase the risk of adverse events after treatment for
these conditions. In a follow-up study of patients who
21 Page 4 of 10
received bare metal stents, obesity was found to be an inde-
pendent predictor of increased in-stent restenosis, 1-year tar-
get revascularization, and MACE [47]. The Limus Eluted
from a Durable Versus Erodable Stent Coating (LEADERS)
trial showed that obesity was an independent risk factor for
stent thrombosis [48]. However, a large European cohort of
over 7000 patients did not show any association of BMI and
stent thrombosis or adverse cardiac events [49]. The neutral
effect of obesity in patients with drug eluting stents has been
shown in other studies as well [50, 51]. Based on this data,
whether drug-eluting stents should be given even greater pref-
erence in all obese patients remains debatable. There is also
controversial data regarding obesity and resistance to
thienopyridines, and the clinical relevance of studies linking
obesity with clopidogrel resistance is yet to be confirmed [52].
Obesity Paradox in Patients with CAD Surprisingly, despite
the observations linking obesity with increased incidence of
acute myocardial infarction (NSTEMI or STEMI), several
large studies have shown obese patients to have better survival
when examining mortality after MI (obesity paradox). Data
from large ACS trials such as the Superior Yield of the New
Strategy of Enoxaparin, Revascularization, and Glycoprotein
IIb/IIIa Inhibitors (SYNERGY) [53] and Metabolic Efficiency
with Ranolazine for Less Ischaemia in NSTE-ACS
(MERLIN)-TIMI 36 [54] have shown an independent inverse
correlation between BMI and overall mortality. A recent meta-
analysis of 10 post–percutaneous coronary intervention (PCI)
and 12 post–coronary artery bypass grafting (CABG) studies
further substantiates the obesity paradox after coronary revas-
cularization. In both post-PCI and post-CABG subgroup of
patients, the 30-day all-cause mortality was lower in obese
patients compared to their normal weight counterparts [55].
The protective effect of obesity, however, seems to decline
when severe or morbid obesity is present (J-shaped relation-
ship), and the lowest mortality may be seen in overweight
patients [56].
Obesity and Heart Failure
Over the last few decades, there have been significant ad-
vancements in available medical and interventional therapies
in cardiology. Despite the use of several mortality-reducing
therapies, the number of cases of incident HF and of acute
decompensated HF hospitalizations has increased [57].
During the same time, incidence of obesity has also been on
the rise. As noted previously, 35 % of the US population is
obese, and approximately 69 % are either overweight or obese
[1]. There exists a well-established link between obesity and
HF; hence, the rising prevalence of both obesity and HF may
make this association an important target for prevention. One
of the first published reports linking obesity and HF in 1956
Curr Atheroscler Rep (2016) 18:21
was a case report of a morbidly obese female who had “heart
failure” from the compressive effects of the physical mass of
the adipose tissue underneath her chest wall [58]. We now
know that obesity has several complex mechanisms by
which it may lead to HF. The term “obesity cardiomyopa-
thy” was first used in 1992, when an analysis of 519 pa-
tients, using right heart catheterization and endomyocardial
biopsy, showed that individuals with higher BMI were
more likely to have dilated cardiomyopathy than their lean
counterparts [59].
Epidemiological Association of Obesity with Heart Failure
Kenchaiah et al. reported the first large epidemiological study
showing obesity to be an independent risk factor for develop-
ment of HF, analyzing 5881 individuals from the Framingham
Heart Study. It was concluded that for each increment of 1 kg/
m2 in BMI, there was an increase in the risk of HF of 7 % for
women and 5 % for men [60]. As compared with subjects with
a normal BMI, obese individuals had a doubling of the risk of
HF. For women, the hazard ratio was 2.17 (95 % confidence
interval (CI), 1.51 to 2.97); for men, the hazard ratio was 1.90
(95 % CI, 1.30 to 2.79). The risk for development of HF was
independent of age, alcohol, and cigarette use and comorbid-
ities including but not limited to diabetes, hypertension, and
history of myocardial infarction. Similarly, an analysis from
the Physician’s Health Study of 21,094 men without known
coronary artery disease showed that compared to normal
weight, overweight and obesity were independently associat-
ed with an increase of HF [61]. Loehr et al. examined the
Atherosclerosis Risk in Communities cohort of over 14,000
individuals and showed obesity to be an independent risk
factor for development of HF, after adjusting the covariates
[62]. Similarly, another large study of over 59,000 individuals
from Finland showed a graded association between BMI and
HF risk, with adjusted hazard ratios of HF for overweight and
obese patients as compared to normal weight of 1.25 (95 %
CI = 1.12–1.39) and 1.99 (95 % CI = 1.74–2.27) in males, and
1.33 (95 % CI = 1.16–1.51) and 2.06 (95 % CI = 1.80–2.37) in
females [63]. In addition to BMI, other anthropometric indices
of obesity including waist circumference, waist-to-hip ratio,
and waist-to-height ratio have also been independently asso-
ciated with incident HF in large, population-based studies;
however, indices such as waist circumference and waist-to-
hip ratio have not been shown to perform better than BMI as
predictors of HF [62, 64].
Protective Effect of Physical Activity It should be noted that
physical activity appears to influence the relationship between
obesity and HF. In the Physicians Health Study, in addition to
increasing BMI, lower level of physical activity was also as-
sociated with an increased risk of HF, with the highest relative
risk of HF seen in obese men who were also physically inac-
tive compared to men who were lean and physically active
Curr Atheroscler Rep (2016) 18:21
[61]. Similarly, in the Finnish cohort discussed above, partic-
ipants demonstrated the protective effect of physical activity at
all levels of obesity, reducing risk of HF in fully adjusted
models by 21–32 % [63].
Mechanisms of Obesity-Associated Heart Failure There
are several possible theories to explain the effect of higher
BMI leading to development of HF (Fig. 2). Obesity can pro-
duce a range of hemodynamic changes that can predispose to
changes in cardiac morphology and ventricular function, in-
cluding left ventricular (LV) dilation, eccentric or concentric
LV hypertrophy, LV systolic and diastolic dysfunction, and
RV dysfunction [65, 66]. Obesity has also been described as
a state of hemodynamic overload associated with increase in
cardiac output and blood pressure [67]. Over a long duration,
this could lead to left ventricular hypertrophy, depressed
systolic function, and impaired relaxation [68, 69]. While
these changes occur in all classes of obesity, they are most
pronounced in the severely obese and could potentially
lead to HF in such individuals. Another mechanism in-
volves a direct effect of excess body fat on the myocardium
causing cardiac adaptation and remodeling, which has of-
ten been termed obesity cardiomyopathy [70, 71].
Although the concept of a cardiomyopathy related to obe-
sity has previously been described, severe left ventricular
systolic dysfunction occurs uncommonly due to obesity
alone and its presence should trigger an investigation for
other contributory factors, before attributing it to obesity
alone. On the other hand, HF with preserved left
Fat
Metabolic
Neurohormonal
Leptin, resistin
Adiponectin deficiency
Inflammtory cytokines
Sympathetic tone
OBESITY
Hemodynamic
SVR LV hypertrophy
Blood volume LV dilatation
CO
Associated
comorbidities
Hypertension
Diabetes
CAD/MI
Sleep disordered
breathing, hypoxia
Fig. 2 Interplay of various mechanisms in obese individuals that may
lead to the development of heart failure. SVR = systemic vascular
resistance; CO = cardiac output; CAD = coronary artery disease;
Page 5 of 10 21
ventricular ejection fraction (HFpEF) is seen much more
frequently in obese patients [72, 73].
Although the relationship between obesity and incident HF
may be related to hemodynamic and anatomic cardiac changes
related to excess body mass, evidence suggests that the rela-
tionship is also mediated by obesity-related metabolic, inflam-
matory, and neurohormonal changes. Obesity and insulin re-
sistance are highly correlated, which may in part potentiate the
link between obesity and HF. In the Uppsala study, insulin
sensitivity but not anthropometric indices of obesity was in-
dependently predictive of HF risk when both were evaluated
together in a fully adjusted model [74]. Abnormalities in the
adipokine pathway, as well as other inflammatory cytokines
seen in obese individuals, may contribute to the pathophysi-
ology of HF [70, 75]. The adipokine resistin, expressed by
adipocytes and associated with insulin resistance and inflam-
mation, was associated with the risk of developing HF inde-
pendent of coronary heart disease and other risk factors in a
Framingham offspring analysis [76]. Of note, leptin has been
studied in great detail. Produced by adipocytes, its levels have
been found to directly correlate with BMI and waist circum-
ference. Higher levels have been associated with an increased
risk for incident HF in patients without pre-existing coronary
artery disease, although this association was absent in patients
with pre-existing CAD [75]. The role of inflammation is also
supported by an analysis from the Multi-Ethnic Study of
Atherosclerosis (MESA). Although the risk of HF was 83 %
higher in obese compared to that in non-obese subjects after
adjustment for traditional risk factors, the relationship be-
tween obesity and incident HF was no longer significant after
Cardiac steatosis:
lipotoxicity
Insulin resistance
Systolic
and HEART
diastolic FAILURE
dysfunction
Pulmonary
arterial
hypertension:
RVH & dilation
MI = myocardial infarction; RVH = right ventricular hypertrophy;
LV = left ventricular
21 Page 6 of 10
adjustment for the inflammatory biomarkers, IL-6 or C-
reactive protein [77]. Finally, as is well known, obesity is
associated with the other comorbid risk factors that contribute
to incident HF, such as DM, HTN, and CAD [68].
Obesity Paradox in HF Several studies have shown that
despite being an independent risk factor for the development
of HF, obesity is associated with lower mortality in patients
with established HF, the “obesity paradox in HF” [5, 6•, 78].
Several hypotheses have been suggested to explain this appar-
ent paradox [6•, 79]. Severe HF due to its catabolic effect may
be associated with weight loss, known as “cardiac cachexia,”
and was initially thought to be the explanation for better sur-
vival in overweight or obese HF patients. Although the
obesity paradox in established HF has been demonstrated in
several studies, a more recent study found that that even over-
weight and obesity prior to incident HF (i.e., pre-morbid or
pre-HF higher body mass index) are associated with improved
survival compared to normal weight up to 10 years after de-
velopment of HF, suggesting that weight loss due to advanced
HF may not completely explain the protective effect of higher
body mass index (BMI) in HF patients [80•].
Several neuro-humoral pathways have also been postulated
to explain the obesity paradox in HF. In obese patients, high
levels of serum lipoproteins may neutralize bacterial toxins or
circulating cytokines, such as TNF-α [81]. Obese patients also
have decreased adiponectin levels and low catecholamine re-
sponse, both of which may be associated with improved HF
survival [79]. Levels of circulating stem cells are also
increased in obese patients, which may lead to improved out-
comes [82]. Furthermore, obese patients are likely to be diag-
nosed early with HF due to the symptoms produced by excess
body weight, such as dyspnea and edema. This may lead to an
Genetics
Comorbidities
CAD (DM, HTN,
OSA etc)
Obesity
Ventricular Inflammation
remodeling
Fig. 3 Interplay of various mechanisms in obese individuals that may lead to the development of atrial fibrillation. CAD = coronary artery disease;
DM = diabetes mellitus; OSA = obstructive sleep apnea; HTN = hypertension
Curr Atheroscler Rep (2016) 18:21
apparently improved life span, i.e., lead time bias [80•]. Obese
patients have multiple comorbidities, such as diabetes mellitus
and hypertension, and hence represent a high-risk screening
population. Moreover, given higher blood pressures in the
overweight and obese population groups, greater up-titration
of disease modifying therapies could be possible. All these
hypotheses could explain the reasons behind the observed
obesity paradox in HF. Interestingly, a recent study found that
the obesity paradox was not seen in overweight male patients
after adjustment for confounding variables but remained in
overweight female patients [83]. The protective effect in fe-
male patients could be partially explained by recent research
which suggests that female hearts have greater myocardial
fatty acid uptake and lesser myocardial glucose utilization in
advanced HF [83]. Future studies are needed to further under-
stand the pathways involved.
Currently, the most recent HF guidelines by the American
College of Cardiology/American Heart Association do not
specifically recommend weight reduction in obese patients
with HF [84]. Large, prospective, randomized control trials
with long follow-up would be able to definitively answer the
effectiveness of intentional weight loss interventions in obese
HF patients. Nevertheless, based on the data available, obese
HF patients appear to benefit from exercise interventions.
Atrial Fibrillation
Atrial fibrillation (AF) is one of the most common arrhythmias
worldwide and is more commonly observed in obese individ-
uals [85]. A report from the Framingham study showed that
after adjustment for CV disease risk factors, and the occur-
rence of interim myocardial infarction or HF, every 1-unit
Atrial
Atrial enlargement,
fibrosis & remodeling
Fibrillation
Curr Atheroscler Rep (2016) 18:21
increment in BMI was independently associated with a 4 %
increase in risk of AF in both men and women [85] (Fig. 1).
When examined by BMI categories of obesity, the investiga-
tors found that compared to normal weight individuals, obese
individuals had a 50 % increased risk of AF. The Danish Diet,
Cancer, and Health Cohort Study also demonstrated a higher
risk of AF associated with increased anthropometric measure-
ments such as height, weight, BMI, hip circumference, and
waist circumference, as well as with increased bioimpedance-
derived measures of body fat mass, body fat percentage, and
lean body mass [86].
Mechanisms for Atrial Fibrillation with Obesity The
Framingham study demonstrated that the excess risk of AF
associated with obesity appeared to be mediated by left atrial
dilatation. [87]. The investigators observed a graded increase
in left atrial size as BMI category increased from normal to
overweight to obese, consistent with previous observations of
obesity as a major risk factor for the development of left atrial
enlargement [88, 89]. After adjusting for left atrial diameter,
obesity was no longer associated with an increased risk for the
development of AF, whereas left atrial diameter remained
strongly associated with risk of AF. Left atrial dilation/
remodeling which is an established mechanistically important
factor in the pathogenesis of AF is likely multifactorial in
obesity and occurs as a result of increased central blood vol-
ume, and secondary to elevated left ventricular diastolic pres-
sures both due to obesity-driven load with increase in left
ventricular mass and HF, as well as secondary to obesity-
associated hypertension, diabetes, and obstructive sleep apnea
(Fig. 3) [90•].
Interestingly, genetic studies have suggested a link between
non-valvular AF and obesity. Specifically, polymorphisms of
TaqIB cholesteryl transfer protein gene and 1444 C/T of CRP
gene have been shown to be associated with an increased
susceptibility in obese males [91]. Additionally, a G protein-
coupled potassium channel known as GIRK4 (G protein-
coupled inward rectifier K channel), which is found prevalent-
ly in the heart, has been shown to be abnormally expressed in
obese individuals with AF [92].
Several recent studies have described the relationship be-
tween thickness of epicardial adipose tissue (EAT) and AF
burden [91]. A significant correlation exists between EAT
and BMI, waist circumference, or visceral adipose tissue
[93]. The Framingham study reported that pericardial fat vol-
ume predicted AF, independently of other measures of adipos-
ity, including BMI [94]. Furthermore, studies indicate that
pericardial fat is associated with the increased prevalence
and severity of AF, independent of traditional risk factors,
including left atrial dilation [95], suggesting that EAT volume
may have prognostic significance besides traditional measures
of obesity [96, 97]. It has been speculated that the direct im-
pact of obesity on atrial substrate may be mediated via EAT
Page 7 of 10 21
[96]. As detailed before, adipose tissue produces a variety of
bioactive molecules, such as inflammatory mediators and
adipocytokines that have been shown to mediate the effect
of visceral fat on other tissues. Among others, EAT also se-
cretes activin A and matrix metalloproteinases (MMPs),
which may mediate the fibrotic effect of EAT on the atrial wall
[98]. Inflammatory markers such as CRP, TNF-α, IL-2, IL-6,
IL-8, and monocyte chemoattractant protein (MCP)-1 have
been associated with AF [99] and are produced and secreted
by EAT, specifically in the setting of obesity, diabetes, and
ischemic cardiomyopathy. There is also increasing evidence
that implicates inflammation in AF development and perpet-
uation. In addition, EAT accumulation is associated with fatty
infiltration from the epicardial layer, which advances deep into
the myocardium, contributing to myocardial functional disor-
ganization and the formation of local arrhythmogenic
substrate [100]. EAT may also affect the atrial cellular com-
ponents by providing a source for precursor cells that can
differentiate into myofibroblasts and thus contribute to atrial
remodeling, a substrate for AF [101].
Furthermore, patients with lower BMI and a single episode
of new-onset AF have a lower risk of progressing to perma-
nent AF compared to obese individuals [98]. Interestingly, a
recent trial in Australia comparing the Long-Term Effect of
Goal Directed Weight Management in an Atrial fibrillation
Cohort (LEGACY) found that long-term weight loss is asso-
ciated with a significant decrease in the incidence of recurrent
AF [102]. In LEGACY, the individuals with ≥10 % weight
loss resulted in a sixfold greater probability of AF-free surviv-
al [102]. The risk of developing hypertension, diabetes, met-
abolic syndrome, coronary artery disease, and sleep apnea is
expectedly significantly higher in obese individuals.
Therefore, the risk of AF is also increased in obese patients
through the various mechanisms that contribute to the devel-
opment of AF in patients with these comorbidities [90•].
Conclusion and Future Directions
In summary, we have discussed the evidence that supports
obesity as both an independent risk factor and a risk marker
for the development of asymptomatic and symptomatic coro-
nary artery disease, heart failure, and atrial fibrillation. Future
studies exploring the role of weight loss as a positive disease
modifier in these conditions are urgently needed.
Compliance with Ethical Standards
Conflict of Interest Taher Mandviwala and Umair Khalid declare that
they have no conflict of interest.
Anita Deswal declares research support from Novartis as site-PI of
multicenter clinical trial, and grant support from the NIH as site-PI for
clinical trials.
21 Page 8 of 10
Human and Animal Rights and Informed Consent This article does
not contain any studies with human or animal subjects performed by any
of the authors.
References
Papers of particular interest, published recently, have been
highlighted as:
• Of importance
1. Flegal K, Carroll M, Kit B, Ogden C. Prevalence of obesity and
trends in the distribution of body mass index among US adults,
1999–2010. JAMA. 2012;307:491–7.
2. Fontaine K, Redden D, Wang C, Westfall A, Allison D. Years of
life lost due to obesity. JAMA. 2003;289:187–93.
3. Poirier P, Giles T, Bray G, et al. Obesity and cardiovascular dis-
ease: pathophysiology, evaluation, and effect of weight loss.
Circulation. 2006;113:898–918.
4. Poirier P, Martin J, Marceau P, Biron S, Marceau S. Impact of
bariatric surgery on cardiac structure, function and clinical mani-
festations in morbid obesity. Expert Rev Cardiovasc Ther. 2004;2:
193–201.
5. Horwich TB, Fonarow GC, Hamilton M, MacLellan W, Woo M,
Tillisch J. The relationship between obesity and mortality in pa-
tients with heart failure. J Am Coll Cardiol. 2001;38:789–95.
6.• Lavie CJ, Alpert MA, Arena R, Mehra MR, Milani RV, Ventura
HO. Impact of obesity and the obesity paradox on prevalence and
prognosis in heart failure. JACC Heart Fail. 2013;1(2):93–102.
Lavie et al. review the data on obesity and cardiopulmonary
fitness in heart failure patients. The article also includes infor-
mative data on obesity and its impact on treatments such as
heart transplantation and LV assist devices.
7. Shah R, Gayat E, Januzzi Jr JL, et al. Mebazaa A Body mass index
and mortality in acutely decompensated heart failure across the
world: a global obesity paradox. J Am Coll Cardiol. 2014;63:
778–85.
8. Akin I, Nienaber C. “Obesity paradox” in coronary artery disease.
World J Cardiol. 2015;7(10):603–8.
9. Clinical Guidelines on the Identification, Evaluation, and
Treatment of Overweight and Obesity in Adults: The Evidence
Report: National Institutes of Health. Obes Res. 1998;2:51S–
209S.
10. Kurpad SS, Tandon H, Srinivasan K. Waist circumference corre-
lates better with body mass index than waist-to-hip ratio in Asian
Indians. Natl Med J India. 2003;16(4):189–92.
11.• Rocha V, Libby P. Obesity, inflammation, and atherosclerosis. Nat
Rev Cardiol. 2009;6:399–409. Rocha et al. review in detail the
interplay between obesity and inflammation leading to the de-
velopment of atherosclerosis.
12. Ross R. Atherosclerosis–an inflammatory disease. N Engl J Med.
1999;340(2):115–26.
13. Esposito K, Pontillo A, Di Palo C, et al. Effect of weight loss and
lifestyle changes on vascular inflammatory markers in obese
women: a randomized trial. JAMA. 2003;289:1799–804.
14. Shoelson SE, Herrero L, Naaz A. Obesity, inflammation, and in-
sulin resistance. Gastroenterology. 2007;132:2169–80.
15. Ridker P. C-reactive protein and the prediction of cardiovas-
cular events among those at intermediate risk: moving an in-
flammatory hypothesis toward consensus. J Am Coll Cardiol.
2007;49:2129–38.
Curr Atheroscler Rep (2016) 18:21
16. Everett B, Kurth T, Buring J, Ridker P. The relative strength of C-
reactive protein and lipid levels as determinants of ischemic stroke
compared with coronary heart disease in women. J Am Coll
Cardiol. 2006;48:2235–42.
17. Ridker P, Stampfer M, Rifai N. Novel risk factors for systemic
atherosclerosis: a comparison of C-reactive protein, fibrinogen,
homocysteine, lipoprotein(a), and standard cholesterol screening
as predictors of peripheral arterial disease. JAMA. 2001;285(19):
2481–5.
18. Pradhan A, Manson J, Rifai N, Buring J, Ridker P. C-reactive
protein, interleukin 6, and risk of developing type 2 diabetes
mellitus. JAMA. 2001;286:327–34.
19. Visser M, Bouter L, McQuillan G, Wener M, Harris T. Elevated C-
reactive protein levels in overweight and obese adults. JAMA.
1999;282:2131–5.
20. Pearson T, Mensah G, Alexander R, et al. Markers of inflamma-
tion and cardiovascular disease: application to clinical and public
health practice: a statement for healthcare professionals from the
Centers for Disease Control and Prevention and the American
Heart Association. Circulation. 2003;107:499–511.
21. Ridker P, Rifai N, Pfeffer M, et al. Inflammation, pravastatin, and
the risk of coronary events after myocardial infarction in patients
with average cholesterol levels. Cholesterol and recurrent events
(CAre) investigators. Circulation. 1998;98:839–44.
22. Ridker P, Rifai N, Clearfield M, et al. Measurement of C-reactive
protein for the targeting of statin therapy in the primary prevention
of acute coronary events. N Engl J Med. 2001;344:1959–65.
23. Ridker P, Danielson E, Fonseca F, et al. Rosuvastatin to prevent
vascular events in men and women with elevated C-reactive pro-
tein. N Engl J Med. 2008;359:2195–207.
24. Yuan M, Konstantopoulos N, Lee J, et al. Reversal of obesity and
diet-induced insulin resistance with salicylates or targeted disrup-
tion of ikkbeta. Science. 2001;293:1673–7.
25. Fleischman A, Shoelson S, Bernier R, Goldfine A. Salsalate im-
proves glycemia and inflammatory parameters in obese young
adults. Diabetes Care. 2008;31:289–94.
26. Koska J, Ortega E, Bunt J, et al. The effect of salsalate on insulin
action and glucose tolerance in obese non-diabetic patients: results
of a randomised double-blind placebo-controlled study.
Diabetologia. 2009;52:385–93.
27. Wolk R, Berger P, Lennon J, Brilakis E, Somers V. Body mass
index: a risk factor for unstable angina and myocardial infarction
in patients with angiographically confirmed coronary artery dis-
ease. Circulation. 2003;108:2206–11.
28. McGill H, McMahan C, Herderick E, et al. Obesity accelerates the
progression of coronary atherosclerosis in young men.
Circulation. 2002;105:2712–8.
29. Rabkin S, Mathewson F, Hsu P. Relation of body weight to devel-
opment of ischemic heart disease in a cohort of young North
American men after a 26 year observation period: the Manitoba
Study. Am J Cardiol. 1977;39:452–8.
30. Manson J, Colditz G, Stampfer M, et al. A prospective study of
obesity and risk of coronary heart disease in women. N Engl J
Med. 1990;322:882–9.
31. Wilson P, D’Agostino R, Sullivan L, Parise H, Kannel W.
Overweight and obesity as determinants of cardiovascular risk:
the Framingham experience. Arch Intern Med. 2002;16:1867–72.
32. Din-Dzietham R, Liu Y, Bielo M, Shamsa F. High blood pressure
trends in children and adolescents in national surveys, 1963 to
2002. Circulation. 2007;116(13):1488–96.
33. Lau D, Dhillon B, Yan H, Szmitko P, Verma S. Adipokines: mo-
lecular links between obesity and atheroslcerosis. Am J Physiol
Heart Circ Physiol. 2005;288:2031–41.
34. Juge-Aubry C, Henrichot E, Meier C. Adipose tissue: a regulator
of inflammation. Best Pract Res Clin Endocrinol Metab. 2005;19:
547–66.
Curr Atheroscler Rep (2016) 18:21
35. Knudson J, Dincer U, Zhang C, et al. Leptin receptors are
expressed in coronary arteries and hyperleptinemia causes signif-
icant coronary endothelial dysfunction. Am J Physiol Heart Circ
Physiol. 2005;289:48–56.
36. Trayhurn P, Wood I. Signaling role of adipose tissue:
adipokines and inflammation in obesity. Biochem Soc Trans.
2005;33:1078–81.
37. Payne G, Kohr M, Tune J. Epicardial perivascular adipose tissue
as a therapeutic target in obesity-related coronary artery disease.
Br J Pharmacol. 2012;165(3):659–69.
38. Anfossi G, Russo I, Trovati M. Platelet dysfunction in central
obesity. Nutr Metab Cardiovasc Dis. 2009;19:440–9.
39. Salama M, Morad A, Saleh M, Sabri N, Zaki M, ElSafady L.
Resistance to low-dose aspirin therapy among patients with acute
coronary syndrome in relation to associated risk factors. J Clin
Pharm Ther. 2012;37:630–6.
40. Kragelund C, Hassager C, Hildebrandt P, Torp-Pedersen C, Kober
L. Impact of obesity on long-term prognosis following acute myo-
cardial infarction. Int J Cardiol. 2005;98:123–31.
41. Yusuf S, Hawken S, Ounpuu S, et al. Effect of potentially modi-
fiable risk factors associated with myocardial infarction in 52
countries (the INTERHEART study): case–control study. Lancet.
2004;364:937–52.
42. Madala M, Franklin B, Chen A, et al. Obesity and age of first non-
ST-segment elevation myocardial infarction. J Am Coll Cardiol.
2008;52:979–85.
43. Das S, Alexander K, Chen A, et al. Impact of body weight and
extreme obesity on the presentation, treatment, and in-hospital
outcomes of 50,149 patients with ST-Segment elevation myocar-
dial infarction results from the NCDR (National Cardiovascular
Data). J Am Coll Cardiol. 2011;58(25):2642–50.
44. Bajaj S, Shamoon F, Gupta N, et al. Acute ST-segment elevation
myocardial infarction in young adults: who is at risk? Coron
Artery Dis. 2011;22:238–44.
45. Jamil G, Jamil M, Alkhazraji H, et al. Risk factor assessment of
young patients with acute myocardial infarction. Am J Cardiovasc
Dis. 2013;3:170–4.
46. Lavie C, Milani R, Ventura H. Obesity and cardiovascular disease:
risk factor, paradox and impact of weight loss. J Am Coll Cardiol.
2009;53(21):1925–32.
47. Nikolsky E, Kosinski E, Mishkel GJ, et al. Impact of obesity on
revascularization and restenosis rates after bare-metal and drug-
eluting stent implantation (from the TAXUS-IV trial). Am J
Cardiol. 2005;95:709–15.
48. Sarno G, Garg S, Onuma Y, et al. The impact of body mass index
on the one year outcomes of patients treated by percutaneous
coronary intervention with biolimus- and sirolimus-eluting stents
(from the LEADERS Trial). Am J Cardiol. 2010;105:475–9.
49. Sarno G, Raber L, Onuma Y, et al. Impact of body mass index on
the five-year outcome of patients having percutaneous coronary
interventions with drug-eluting stents. Am J Cardiol. 2011;108:
195–201.
50. Akin I, Tolg R, Hochadel M, et al. No evidence of “obesity para-
dox” after treatment with drug-eluting stents in a routine clinical
practice: results from the prospective multicenter German
DES.DE (German Drug-Eluting Stent) Registry. JACC
Cardivasc Interv. 2012;5(2):162–9.
51. Wang Z, Zhou Y, Zhao Y, et al. Effect of obesity on repeat
revascularization in patients undergoing percutaneous coro-
nary intervention with drug-eluting stents. Obesity (Silver
Spring). 2012;20:141–6.
52. Feher G, Koltai K, Alkonyi B, et al. Clopidogrel resistance: role of
body mass and concomitant medications. Int J Cardiol. 2007;120:
188–92.
Page 9 of 10 21
53. Mahaffey K, Tonev S, Spinler S, et al. Obesity in patients with
non-ST-segment elevation acute coronary syndromes: results from
the SYNERGY trial. Int J Cardiol. 2010;139:123–33.
54. Kadakia M, Fox C, Scirica B, Murphy S, Bonaca M, Morrow D.
Central obesity and cardiovascular outcomes in patients with acute
coronary syndrome: observations from the MERLIN-TIMI 36 tri-
al. Heart. 2011;97:1782–7.
55. Oreopoulos A, Padwal R, Norris C, Mullen J, Pretorius V,
Kalantar-Zadeh K. Effect of obesity on short- and long-term mor-
tality postcoronary revascularization: a meta-analysis. Obesity
(Silver Spring). 2008;16:442–50.
56. Li Y, Lin G, Lin C, Wang J, Han C. Relation of body mass index to
mortality among patients with percutaneous coronary intervention
longer than 5 years follow-up: a meta-analysis. Int J Cardiol.
2013;168:4315–8.
57. Bui A, Horwich T, Fonarow G. Epidemiology and risk profile of
heart failure. Nat Rev Cardiol. 2011;8(1):30–41.
58. Counihan T. Heart failure due to extreme obesity. Br Heart J.
1956;18(3):425–6.
59. Kasper EK, Hruban RH, Baughman KL. Cardiomyopathy of obe-
sity: a clinicopathologic evaluation of 43 obese patients with heart
failure. Am J Cardiol. 1992;70(9):921–4.
60. Kenchaiah S, Evans J, Levy D, et al. Obesity and the risk of heart
failure. N Engl J Med. 2002;347:305–13.
61. Kenchaiah S, Sesso H, Gaziano J. Body mass index and vigorous
physical activity and the risk of heart failure among men.
Circulation. 2009;119(1):44–52.
62. Loehr L, Rosamond W, Poole C, et al. Association of multiple
anthropometrics of overweight and obesity with incident heart
failure: the Atherosclerosis Risk in Communities study. Circ
Heart Fail. 2009;2(1):18–24.
63. Hu G, Jousilahti P, Antikainen R, Katzmarzyk PT, Tuomilehto J.
Joint effects of physical activity, body mass index, waist circum-
ference, and waist-to-hip ratio on the risk of heart failure.
Circulation. 2010;121(2):237–44.
64. Hu G, Jousilahti P, Antikainen R, Katzmarzyk P, Tuomilehto J.
Joint effects of physical activity, body mass index, waist circum-
ference, and waist-to-hip ratio on the risk of heart failure.
Circulation. 2010;121:237–44.
65. Pascual M, Pascual D, Soria F, et al. Effects of isolated obesity on
systolic and diastolic left ventricular function. Heart. 2003;89(10):
1152–6.
66. Alpert M, Alexander J. Obesity and ventricular function in man:
systolic function. In: Alpert MA, Alexander JK, editors. The heart
and lung in obesity. Armonk, New York: Futura Publishing
Company; 1998. p. 77–94.
67. Alexander J, Dennis E, Smith W, Amad K, Duncan W, Austin R.
Blood volume, cardiac output, and distribution of systemic blood
flow in extreme obesity. Cardiovasc Res Cent Bull. 1962;1:39–44.
68. Alpert M, Lambert C, Panayiotou H, et al. Relation of duration of
morbid obesity to left ventricular mass, systolic function, and di-
astolic filling, and effect of weight loss. Am J Cardiol. 1995;76:
1194–7.
69. Nakajima T, Fujioka S, Tokunaga K, Hirobe K, Matsuzawa Y,
Tarui S. Noninvasive study of left ventricular performance in
obese patients: influence of duration of obesity. Circulation.
1985;71:481–6.
70. McGavock J, Victor R, Unger R, Szczepaniak L. Adiposity of the
heart, revisited. Ann Intern Med. 2006;144:517–24.
71. Poirier P, Giles T, Bray G, et al. Obesity and cardiovascular dis-
ease: pathophysiology, evaluation, and effect of weight loss.
Arterioscler Thromb Vasc Biol. 2006;26:968–76.
72. Kapoor J, Heidenreich P. Obesity and survival in patients with
heart failure and preserved systolic function: a U-shaped relation-
ship. Am Heart J. 2010;159:75–80.
21 Page 10 of 10
73. Ather S, Chan W, Bozkurt B, et al. Impact of noncardiac comor-
bidities on morbidity and mortality in a predominantly male pop-
ulation with heart failure and preserved versus reduced ejection
fraction. J Am Coll Cardiol. 2012;59(11):998–1005.
74. Ingelsson E, Sundstrom J, Arnlöv J, Zethelius B, Lind L. Insulin
resistance and risk of congestive heart failure. JAMA.
2005;294(3):334–41.
75. Wannamethee S, Shaper A, Whincup P, Lennon L, Sattar N.
Obesity and risk of incident heart failure in older men with and
without pre-existing coronary heart disease: does leptin have a
role? J Am Coll Cardiol. 2011;58:1870–7.
76. Frankel D, Vasan R, D’Agostino R, et al. Resistin, adiponectin,
and risk of heart failure the Framingham offspring study. J Am
Coll Cardiol. 2009;53(9):754–62.
77. Bahrami H, Bluemke D, Kronmal R, et al. Novel metabolic risk
factors for incident heart failure and their relationship with obesity:
the MESA (Multi-Ethnic Study of Atherosclerosis) study. J Am
Coll Cardiol. 2008;51(18):1775–83.
78. Bozkurt B, Deswal A. Obesity as a prognostic factor in chronic
symptomatic heart failure. Am Heart J. 2005;150(6):1233–9.
79. Kistorp C, Faber J, Galatius S, et al. Plasma adiponectin, body
mass index, and mortality in patients with chronic heart failure.
Circulation. 2005;112:1756–62.
80.• Khalid U, Ather S, Bavishi C, et al. Pre-morbid body mass index
and mortality after incident heart failure: the ARIC Study. J Am
Coll Cardiol. 2014;64(25):2743–9. This is the first study that
describes the obesity paradox in heart failure, based on pre-
heart failure (i.e. premorbid) BMI. The authors found that
obesity and underweight compared to normal weight prior
to the development of heart failure was associated with im-
proved survival after the development of heart failure.
81. Lavie C, Ventura H. Weighing in on obesity and the obesity par-
adox in heart failure. J Card Fail. 2011;17:381–3.
82. Blogowski W, Serwin K, Budkowska M, et al. Clinical analysis of
systemic and adipose tissue levels of selected hormones/
adipokines and stromal-derived factor-1. J Biol Regul Homeost
Agents. 2012;26:607–15.
83. Vest A, Wu Y, Hachamovitch R, Young J, Cho L. The heart failure
overweight/obesity survival paradox: the missing sex link. J Am
Coll Cardiol HF. 2015;3:917–26.
84. Yancy C, Jessup M, Bozkurt B, et al. 2013 ACCF/AHA guideline
for the management of heart failure: a report of the American
College of Cardiology Foundation/American Heart Association
Task Force on Practice Guidelines. J Am Coll Cardiol. 2013;62:
147–239.
85. Wang T, Parise H, Levy D, et al. Obesity and the risk of new-onset
atrial fibrillation. JAMA. 2004;292:2471–7.
86. Frost L, Benjamin E, Fenger-Grøn M, Pedersen A. Tjønneland A,
Overvad K. Body fat, body fat distribution, lean body mass, and
atrial fibrillation and flutter. A Danish cohort study. Obesity
(Silver Spring). 2014;22:1546–52.
Curr Atheroscler Rep (2016) 18:21
87. Wanahita N, Messerli F, Bangalore S, Gami A, Somers V,
Steinberg J. Atrial fibrillation and obesity: results of a meta-anal-
ysis. Am Heart J. 2008;155:310–5.
88. Iacobellis G, Ribaudo M, Leto G, et al. Influence of excess fat on
cardiac morphology and function: study in uncomplicated obesity.
Obes Res. 2002;10:767–73.
89. Gottdiener J, Reda D, Williams D, Materson B. Left atrial size in
hypertensive men: influence of obesity, race and age. J Am Coll
Cardiol. 1997;29:651–8.
90.• Goudis C, Korantzopoulos P, Ntalas I, Kallergis E, Ketikoglou D.
Obesity and atrial fibrillation: a comprehensive review of the path-
ophysiological mechanisms and links. J Cardiol. 2015;66(5):361–
9. Goudis et al. review the most recent clinical and experimen-
tal studies linking obesity to atrial fibrillation.
91. Yang W, Xu L, Zhang H. Association of CETP and CRP gene
polymorphisms with non-valvular atrial fibrillation in Chinese
Han population. Zhonghua Yi Xue Yi Chuan Xue Za Zhi.
2008;25:225–229.
92. Kang Y, Hu Y, Li N. Advances in research on G protein-coupled
inward rectifier K(+) channel gene. Zhongguo Yi Xue Ke Xue
Yuan Xue Bao. 2012;34:426–430.
93. Rabkin S. The relationship between epicardial fat and indices of
obesity and the metabolic syndrome: a systematic review and me-
ta-analysis. Metab Syndr Relat Disord. 2014;12:31–42.
94. Thanassoulis G, Massaro J, O’Donnell CJ, et al. Pericardial fat is
associated with prevalent atrial fibrillation: the Framingham Heart
Study. Circ Arrhythm E. 2010;3(4):345–50.
95. Al Chekakie M, Welles C, Metoyer R, et al. Pericardial fat is
independently associated with human atrial fibrillation. J Am
Coll Cardiol. 2010;56:784–8.
96. Wong C, Abed H, Molaee P, et al. Pericardial fat is associated with
atrial fibrillation severity and ablation outcome. J Am Coll
Cardiol. 2011;57(17):1745–51.
97. Shin S, Yong H, Lim H, et al. Total and interatrial epicardial
adipose tissues are independently associated with left atrial remod-
eling in patients with atrial fibrillation. J Cardiovasc
Electrophysiol. 2011;22(6):647–55.
98. Hatem S, Sanders P. Epicardial adipose tissue and atrial fibrilla-
tion. Cardiovasc Res. 2014;102:205–13.
99. Guo Y, Lip G, Apostolakis S. Inflammation in atrial fibrillation. J
Am Coll Cardiol. 2012;60:2263–70.
100. Mahajan R, Brooks A, Shipp N. Epicardial fat infiltration of atrial
musculature creates the substrate for atrial fibrillation in obesity.
Heart Rhythm. 2012;9:124.
101. Zuk P, Zhu M, Ashjian P, et al. Human adipose tissue is a source of
multipotent stem cells. Mol Biol Cell. 2002;13:4279–95.
102. Pathak R, Middeldorp M, Meredith M, Mehta A, MActSt,
Mahajan R, Wong C, Twomey D, Elliott A, Kalman J,
Abhayaratna W, Lau D, Sanders P. Long-Term Effect of Goal-
Directed Weight Management in an Atrial Fibrillation Cohort. J
Am Coll Cardiol. 2015;65:2159–2169