Overview of Epidemiology and Contribution of Obesity to Cardiovascular Disease

This article provides an overview of the epidemiology of obesity and its contribution to cardiovascular disease. It discusses the limitations of using BMI as a measure of obesity and highlights the importance of adipose tissue quality/function in determining overall health and cardiovascular risks.

Overview of Epidemiology and Contribution of Obesity to
Cardiovascular Disease
Marjorie Bastiena, b, Paul Poiriera, b,⁎, Isabelle Lemieuxa, c, d
, Jean-Pierre Desprésa, c, d
aInstitut Universitaire de Cardiologie et de Pneumologie de Québec, Québec, QC, Canada
bFaculté de Pharmacie, Université Laval, Québec, QC, Canada
cFaculté de Médecine, Université Laval, Québec, QC, Canada
dChaire Internationale sur le Risque Cardiométabolique, Université Laval, Québec, QC, Canada
A R T I C L E I N F O A B S T R A C T
The prevalence of obesity has increased worldwide and is a source of concern since the
negative consequences of obesity start as early as in childhood. The most commonly used
anthropometric tool to assess relative weight and classify obesity is the body mass index
(BMI); BMI alone shows a U- or a J-shaped association with clinical outcomes and mortality.
Such an inverse relationship fuels a controversy in the literature, named the ‘obesity
paradox', which associates better survival and fewer cardiovascular (CV) events in patients
with elevated BMI afflicted with chronic diseases compared to non-obese patients.
However, BMI cannot make the distinction between an elevated body weight due to high
levels of lean vs. fat body mass. Generally, an excess of body fat (BF) is more frequently
associated with metabolic abnormalities than a high level of lean body mass. Another
explanation for the paradox is the absence of control for major individual differences in
regional BF distribution. Adipose tissue is now considered as a key organ regarding the fate
of excess dietary lipids, which may determine whether or not body homeostasis will be
maintained (metabolically healthy obesity) or a state of inflammation/insulin resistance
will be produced, with deleterious CV consequences. Obesity, particularly visceral obesity,
also induces a variety of structural adaptations/alterations in CV structure/function.
Adipose tissue can now be considered as an endocrine organ orchestrating crucial
interactions with vital organs and tissues such as the brain, the liver, the skeletal muscle,
the heart and blood vessels themselves. Thus, the evidence reviewed in this paper suggests
that adipose tissue quality/function is as important, if not more so, than its amount in
determining the overall health and CV risks of overweight/obesity.
© 2014 Elsevier Inc. All rights reserved.
Keywords:
Cardiovascular disease
Obesity
CV risks
Ectopic fat
Epidemiology
The prevalence of obesity has increased dramatically world-
wide over the last decades and has now reached epidemic
proportions. For instance, the global prevalence of obesity has
nearly doubled between 1980 and 2008. According to the
World Health Organization, 35% of adults worldwide aged >20
years were overweight (34% men and 35% women) in 2008
P R O G R E S S I N C A R D I O V A S C U L A R D I S E A S E S 5 6 ( 2 0 1 4 ) 3 6 9 – 3 8 1
Statement of Conflict of Interest: see page 377.
⁎ Address reprint requests to Paul Poirier, Institut universitaire de cardiologie et pneumologie de Québec, 2725 Chemin Ste-Foy, Québec,
Québec, Canada, G1V 4G5.
E-mail address: [e-mail] (P. Poirier).
0033-0620/$ – see front matter © 2014 Elsevier Inc. All rights reserved.
http://dx.doi.org/10.1016/j.pcad.2013.10.016
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including10%menand
14% women being con-
sidered as obese. Prev-
alence is particularly
high in America with
a high proportion of
overweightandobesity
(62% and 26% respec-
tively in both sexes)
while South East Asia
shows the lowest pre-
valence (14% over-
weight in both sexes
and 3% for obesity).1
IntheUnitedStates,
the prevalence of obe-
sity has increased
by 8% between 1976
and 1980,by another
8% between 1988 and
1994 with similar in-
creases between 1988–
1994 and 1999–2000.
In contrast, data from
the last decade
(1999–2010) suggest that
theprevalenceofobesity
may have plateaued
in the USA.2–4 Accord-
ing to the latest National
Health and Nutrition
Examination Survey
(NHANES), the age-
adjusted obesity pre-
valence was 35.7%
in the United States
in 2010 with no sex
differences. Extreme
obesity has more
than doubled since
1988–1994 NHANES,
shifting from 2.9 to
6.3% in 2010 for grade 3 (severe) obesity while reaching
15.2% for grade 2 obesity (Table 1). 4,5 The age-adjusted
prevalence of overweight and obesity combined (body mass
index; BMI ≥25 kg/m2) was 68.8% in 2010 with a mean BMI of
28.7 kg/m2 in the US population.5 In Canada, the prevalence of
obesity is lower than in the United States reaching 27 and 25%
of Canadian men and women, respectively. It is also relevant
to mention that in Canada, 29% of men and 41% of women
reach cut off values for waist circumference (WC; above 102
cm in men and 88 cm in women) suggesting the presence of
abdominal obesity, with mean WC values of 95.1 cm for men
and 87.3 cm for women.6
Such growing numbers are a source of concern since the
negative consequences of obesity start as early as in
childhood. Some experts predict a decrease life expectancy
at birth in the US during the first half of the 21st century. 7
Each year, 28 million individuals are dying from the
consequences of overweight or obesity worldwide.1 High BMI
is associated with the development of cardiovascular (CV) risk
factors such as hypertension (HTN), dyslipidemia, insulin
resistance, and diabetes mellitus (DM) leading to CV diseases
(CVD), such as coronary heart disease (CHD) and ischemic
stroke.8–10The development of these comorbidities is propor-
tionate to the BMI and obesity is considered as an indepen-
dent risk factor for CVD.11,12Several studies have documented
that a high BMI is significantly associated, in both men and
women, with manifestations of CVD such as angina, myocar-
dial infarction (MI), heart failure (HF) and sudden death.13,14
The higher incidence of CVD events in obese patients seems
to be related to endothelial dysfunction and subclinical
inflammation in addition to the worsening of CVD risk
factors.15 Overall, obesity is associated with an increased
mortality rate,16 but obesity grades must be considered in risk
stratification. In a recent meta-analysis including 2.88 mil-
lions of individuals, all obesity grades combined were
associated with an increase in mortality rate, with a hazard
ratio of 1.18 (95% CI, 1.12–1.25).However, when analyzed
separately, obesity grade 1 (Table 1) was not associated with
an increased mortality risk, with a hazard ratio of 0.97 (95% CI,
0.90–1.04),compared to normal weight. In contrast, severe
obesity (grades 2 and 3) was associated with an increased
mortality risk (hazard ratio of 1.34 – 95% CI, 1.21–1.47).17
Childhood obesity also seems to impact mortality rate in early
adulthood. Increased BMI in children has been positively
associated with the risk of premature death in a population of
American Indians born between 1945 and 1984 and followed
between February 1966 and December 2003.18 According to
the authors, this association could be partly mediated by the
development of glucose intolerance and hypertension, but
not hypercholesterolemia.18 Another study performed in
older children also found a close relationship between BMI
at adolescence and all-cause mortality rate assessed during
adulthood. Indeed, after a follow-up of 31.5 years, it was
reported that a BMI above the 95th percentile assessed during
adolescence predicted increased adult mortality rates in both
men (80% increase) and women (~100% increase) when
compared to those who had a BMI between the 25th and
75th percentiles during their teenage years. Even among
adolescents who had less severe obesity (between the 85th
and 95th percentiles), such moderate obesity was associated
with a 30% increase in all-cause mortality assessed during
adulthood.16 Such an increased mortality rate observed in
adults who were obese at childhood appears to be largely
independent from adult BMI.19
Obesity assessment
The most commonly used anthropometric tool to assess
relative weight and classify obesity is the BMI, which is
expressed as the ratio of total body weight over height
squared (kg/m 2). Individuals with a BMI <18.5 kg/m2 are
considered as being underweight,whereas those with a BMI
between 18.5 and 24.9 kg/m2 are classified as having normal
or acceptable weight. Individuals with a BMI ranging from 25
to 29.9 kg/m 2 are classified as overweight while obesity is
Abbreviations and Acronyms
BF = Body fat
BMI = Body mass index
CHD = Coronary heart disease
CRP = C-reactive protein
CV = Cardiovascular
CVD = Cardiovascular disease
DM = Diabetes mellitus
FFAs = Free fatty acids
HDL = High-density lipoprotein
HF = Heart failure
HTN = Hypertension
Il = Interleukin
LDL = Low-density lipoprotein
LV = Left ventricular
LVH = Left ventricular
hypertrophy
LVM = Left ventricular mass
MI = Myocardial infarction
NHANES = National Health and
Nutrition Examination Survey
NSTEMI = Non-ST segment
elevation myocardial infarction
TGs = Triglycerides
TNF = Tumor necrosis factor
VLDL = Very low-density
lipoprotein
WC = Waist circumference
WHR = Waist-to-hip ratio
370 P R O G R E S S I N C A R D I O V A S C U L A R D I S E A S E S 5 6 ( 2 0 1 4 ) 3 6 9 – 3 8 1

present when BMI reaches ≥30 kg/m2. Beyond that point,
obesity is graded into 3 categories: grade 1 (BMI ranging from
30 to 34.9 kg/m2), grade 2 (BMI ranging from 35.0 to 39.9 kg/
m 2), and grade 3 (BMI ≥40 kg/m2).11 The American Heart
Association has proposed additional obesity subgroups to
take into consideration the rapidly expanding subgroup of
patients with massive obesity and introduced grade 4 obesity
corresponding to a BMI ≥50 kg/m2 and grade 5 as a BMI ≥60 kg/
m 2 20,21 (Table 1). It has also been recently pointed out that
BMI was not very discriminant in order to distinguish lean
from fat body mass particularly among patients with a BMI
≥30 kg/m2.22 Generally, an excess of body fat (BF) is more
frequently associated with metabolic abnormalities than a
high level of lean body mass.10 BMI alone seems to present a
U- or a J-shaped association with clinical outcomes and
mortality. 23 Such an inverse relationship fuels a controversy
in the literature, named the ‘obesity paradox’,which associ-
ates better survival and fewer CVD events in patients with
mildly elevated BMI afflicted with chronic diseases. 22,24,25
Although obesity as defined by the BMI influences CV risk,
one may argue that other adiposity indices should be taken
into consideration by the clinician in the risk stratification of
a given patient (Fig 1). Obesity assessed with the BMI presents
some limitation in the prediction of CV mortality. Among
patients who have CVD, it has been reported that overweight
or mildly obese patients show better outcomes in terms of CV
and total mortality, with a paradoxical association between
BMI and survival. 22 However, reasons for this “obesity
paradox” remain unclear and some of them including the
issue of selection bias are illustrated in Fig 2. Even with a
worse perceived health, poorer adherence to lifestyle behav-
iour, more co-morbidities and risk factors, overweight and
obese cardiac patients appear to nevertheless present a better
prognosis than normal weight individuals.26 One explanation
for this paradox could be found in BF distribution. For
instance, markers of absolute and relative accumulation of
abdominal fat accumulation, such as elevated WC and waist-
to-hip ratio (WHR) have been associated with an increased
risk of MI, HF and total mortality in patients with CVD. 27 In
the Trandolapril Cardiac Evaluation register, increased mor-
tality (23%) was observed among patients with an antecedent
of CVD presenting abdominal obesity. This relationship
remained after exclusion of DM and HTN from the multivar-
iate analyses, underlining the importance of abdominal
obesity as an independent factor of all-cause mortality in
patients with CVD. 28 An increase in both WC and WHR
predicted an increased risk of CVD in men and women; a 1 cm
increase in WC and a 0.01 unit increase in WHR were
respectively associated with a 2% increase and 5% increase
in risk of future CVD events. 29 Of importance, a lower lean
body mass also appeared to partially explain this obesity
paradox,30 underlining the importance of going beyond the
measurement of relative weight in risk assessment (Fig 2).
Indeed, overweight and obese individuals may show
strikingly different CVD risk factor profiles on the basis of
their BF distribution (Fig 2). Excess abdominal visceral adipose
tissue, irrespective of the BMI, has been associated with a
constellation of diabetogenic and atherogenic abnormalities
such as insulin resistance, increased triglycerides and apoli-
poprotein B levels, low high-density lipoprotein cholesterol
and an increased proportion of small dense low-density
lipoprotein (LDL) and high-density lipoprotein (HDL) particles,
the latter lipid abnormalities being generally described as the
atherogenic dyslipidemia (Fig 3). On the contrary, low levels of
visceral adipose tissue and subcutaneous obesity are associ-
ated with a low risk metabolic risk profile. 31 There is now
Table 1 – Classification of body weight.
Underweight BMI <18.5 kg/m2
Normal or acceptable weight BMI 18.5–24.9 kg/m2
Overweight BMI 25–29.9 kg/m2
Obese BMI ≥30 kg/m2
Grade 1 BMI 30–34.9 kg/m2
Grade 2 BMI 35.0–39.9 kg/m2
Grade 3 BMI ≥40 kg/m2 (severe, extreme,
or morbid obesity)
Grade 4 BMI ≥50 kg/m2
Grade 5 BMI ≥60 kg/m2
Abbreviations: BMI: body mass index.
From Poirier P, Alpert MA, Fleisher LA, Thompson PD, Sugerman HJ,
Burke LE, Marceau P and Franklin BA: Cardiovascular evaluation
and management of severely obese patients undergoing surgery. A
science advisory from the American Heart Association. Circulation
2009;120: 86–95.
INTERMEDIATE
RISK FACTORS
- Blood pressure
- Glucose (diabetes)
- Dyslipidemia
- Insulin resistance
- Inflammation
- Etc.
ANTHROPOMETRIC
ADIPOSITY MARKERS
- BMI
- Waist
- WHR
Cardiovascular(+) (+)
X
events
Fig 1 – Relationships between adiposity indices, intermediate risk factors and cardiovascular events in the general population.
Under this model, most of the association between adiposity indices and cardiovascular disease is explained by altered levels
of intermediate risk factors. However, increased adiposity indices are the main drivers behind the altered levels of
intermediate risk factors. Abbreviations: BMI: Body mass index; WHR: waist-to-hip ratio.
371P R O G R E S S I N C A R D I O V A S C U L A R D I S E A S E S 5 6 ( 2 0 1 4 ) 3 6 9 – 3 8 1

considerable evidence to support the notion that regional fat
accumulation is much more important in CVD risk stratifica-
tion than excess total adiposity per se. On that basis, a simple
anthropometric index of total adiposity such as the BMI
should be refined by measuring additional indices of fat
distribution namely WC, WHR or waist-to height ratio to
discriminate higher-risk individuals. 32,33 Visceral adiposity
can be measured accurately by computed tomography,
magnetic resonance imaging, and with less precision by dual
energy x-ray absorptiometry. Imaging cardiometabolic stud-
ies recently conducted in large cohort studies (Framingham
Heart Study and the Jackson Heart Study) have shown that
excess visceral adiposity accompanied by excess ectopic fat
deposition such as excess heart, liver, and intrathoracic fat
was significantly associated with cardiac and metabolic
abnormalities, and that such relationship was independent
from the amount of total or subcutaneous adipose tissue.34–36
Unfortunately, these imaging techniques are not available for
large scale use to physicians. Since abdominal obesity is of
importance in CVD risk stratification, measuring WC in
addition to the BMI may represent the best alternative
measurement for the health care professional. It is low cost,
easy to perform and shows a reasonable association with
visceral adiposity for a given BMI unit (Fig 2).25,37,38Based on
experts consensus, the World Health Organization has
proposed sex-specific cut-off values associated with in-
creased CVD risk: 94 cm in men and 80 cm in women for
increased risk, and 102 cm in men and 88 cm in women for
substantially increased risk. 39 Many other techniques (air
displacement plethysmography, bioelectrical impedance,
ENTIRE POPULATION OF ASYMPTOMATIC YOUNG ADULTS
Lean Overweight Obese
FOLLOW-UP
(decades)
CVD (-) CVD (+)
Less of:
- Smoking
- Hypertension
- Dyslipidemia
- Diabetes
- Abdominal obesity and metabolic syndrome
- Visceral obesity/ectopic fat
- Physical inactivity
- Poor cardiorespiratory fitness
- Poor nutritional quality
- Etc.
FOLLOW-UP
More of:
- Smoking
- Hypertension
- Dyslipidemia
- Diabetes
- Abdominal obesity and metabolic syndrome
- Visceral obesity/ectopic fat
- Physical inactivity
- Poor cardiorespiratory fitness
- Poor nutritional quality
- Etc.
- BMI
- Waist for a given BMI
- Visceral/ectopic fat?
- Cardiorespiratory fitness
- Lean body mass
- Etc.
- BMI
- Waist for a given BMI
- Visceral/ectopic fat?
- Cardiorespiratory fitness
- Lean body mass
- Etc.
NO RECURRENT CVD RECURRENT CVD
Fig 2 – Contribution of the selection bias in the obesity paradox in patients with cardiovascular disease (CVD). Under this
model, patients with CVD* are no longer characterized by the distribution of CVD risk factors/behaviors observed in the entire
population. It is proposed that nonobese individuals who developed CVD in the absence of overall obesity may have been
exquisitely more prone to CVD due to factors other than obesity. This could partly explain why, among individuals with CVD,
obesity is associated with lower mortality. Other important confounding factors for the body mass index (BMI)/obesity paradox
include: lack of control for individual variation in body fat distribution (visceral adiposity/ectopic fat), cardiorespiratory fitness,
muscle mass/cachexia, frailty, physical activity/inactivity level, nutritional quality and intake, markers of adipose tissue
function/quality, underlying diseases, etc.
372 P R O G R E S S I N C A R D I O V A S C U L A R D I S E A S E S 5 6 ( 2 0 1 4 ) 3 6 9 – 3 8 1

skinfold thickness, X-ray absorptiometry, hydrostatic
weighing, etc.) may also be used to assess adiposity and
body composition.39
Obesity and CVD
Obesity has numerous consequences on the CV system.
Chronic accumulation of excess body fat leads to a variety of
metabolic changes, increasing the prevalence of CVD risk
factors but also affecting systems modulating inflammation.40
In addition to its contribution as an independent CVD risk
factor, obesity promotes alterations in other intermediate risk
factors such as dyslipidemia, HTN, glucose intolerance, in-
flammatory state, obstructive sleep apnea/hypoventilation,
and a prothrombotic state, as well as probably many additional
unknown mechanisms. 10 Obesity also induces a variety of
structural adaptations/alterations in CV structure/function.41
Indeed, among the 5,881 participants followed for 14 years in
the Framingham Heart Study, 496 subjects developed HF.
Obese subjects were 2 times more at risk of developing HF
than normal weight individuals. An increased risk of 5% for
men and 7% for women for every unit increase in BMI was
observed after adjustment for established risk factors 42
suggesting a direct link between excess body fat and cardiac
dysfunction (Fig 3).
Epi/pericardial fat:
- Protective until storage
capacity is saturated?
- Renal fat:
- Blood pressure
Pancreas fat:
- Inflammation
- Apoptosis
- -cell function
Muscle fat
Visceral AT
Renal sinus fat
Pancreas fat
Liver fat
Epi/pericardial AT
Perivascular AT
Myocardial fat
Subcutaneous
gluteal-femoral AT
Perivascular AT:
- Local inflammation
- Impaired vascular function
- Vascular remodeling
- infiltrated macrophages
in atherosclerotic lesions
Muscle fat:
- Insulin resistance/inflammation
Subcutaneous AT:
- Neutral "metabolic sink"
Subcutaneous AT
Subcutaneous gluteal-femoral AT:
- Postprandial uptake
of dietary lipids
- "Metabolic sink" protects
against lipid spillover
Liver fat:
- Glucose production
- Insulin degradation
- VLDL production
- Apo B degradation
Visceral AT:
- FFA release
- Inflammatory cytokines
- Adiponectin
- peripheral resistance
- cardiac output
- endothelium-dependent vasodilation
Myocardial fat:
- Impaired myocardial metabolism
- Reduced metabolic flexibility
- Heart failure
- diastolic chamber compliance
- left ventricular (LV) mass
- concentric LV remodelling
- adipositas cordis
Fig 3 – Abnormalities increasing risk of cardiovascular disease among overweight/obese individuals with excess visceral
adipose tissue/ectopic fat. Abbreviations: Apo: apolipoprotein; FFA: free fatty acids; AT: adipose tissue.
373P R O G R E S S I N C A R D I O V A S C U L A R D I S E A S E S 5 6 ( 2 0 1 4 ) 3 6 9 – 3 8 1

Cardiac adaptations to obesity
Chronic excessive accumulation of body fat causes adapta-
tions of the CV system aiming at maintaining whole body
homeostasis. Increased cardiac output and a decrease in
peripheral resistance are of importance in this adaptative
state. Stroke volume, the major determinant in the increased
cardiac output in the obese patient, increases due to the
augmentation of circulating blood volume. 43,44 Expanded
blood volume contributes to increase heart preload shifting
the Franck-Starling curves to the left. Over the long term, such
an increase in cardiac burden induces ventricular remodelling
with enlargement of the cardiac cavities and increased wall
tension which may eventually lead to left ventricular (LV)
hypertrophy (LVH).45,46 Ventricle thickening is accompanied
by a decrease in diastolic chamber compliance, eventually
resulting in an increase in LV filling pressure leading to LV
diastolic dysfunction which may be normalized with weight
loss 47 or aerobic exercise training.48 Early in the development
of the disease, LVH adapts to LV chamber enlargement and
systolic function is preserved. However, when LVH is getting
more important than LV dilatation, impairment in systolic
function will eventually be observed.11 In addition to LVH,
muscular degeneration, increased total blood volume, dia-
stolic and systolic dysfunctions are the main precursors of HF
in obesity. In addition, several co-morbidities associated with
obesity may exacerbate or predispose obese patients to HF,
such as HTN, sleep apnea and DM. 11 For instance, severe
obesity has been known for more than 25 years to be a strong
and independent predictor of increased LV mass (LVM), LV
wall thickness, LV internal dimension, poorer LV systolic
function and greater diastolic dysfunction, 49,50 and those
cardiac adaptations to obesity are also modulated by the
duration of the obesity.50 The process behind LV remodelling
is still not completely understood. Recently, Neeland and
colleagues51 performed a large clinical prospective study to
investigate the impact of body composition on LV function
assessed by magnetic resonance imaging. In a multi-ethnic
cohort of 2710 participants presenting normal weight (24%),
overweight (32%) and obesity (44%), obesity, as expected, was
associated with higher LVM, end-diastolic volumes, wall
thickness and concentricity. However, these alterations in
CV structure/function were dependent upon individual dif-
ferences in BF distribution. Excess visceral adiposity was
independently associated with the concentric LV remodelling
(including increased LV wall thickness, increased LV mass/
volume ratio – 3D measure of concentric geometry of the left
ventricle and smaller LV end-diastolic volume) in addition
with lower cardiac output and increased peripheral resistance
(Fig 3). In contrast, gluteal-femoral adiposity was associated
with eccentric LV remodelling (increased LV end-diastolic
volume with reduced LVM, concentricity and wall thickness),
a higher cardiac output and lower systemic vascular
resistance.51 These results are in accordance with another
study performed in an obese cohort of 5,098 participants
(Multi-Ethnic Study of Atherosclerosis), where higher LVM-to-
volume ratio was linearly correlated with adiposity measure-
ments such as the WHR, WC, and estimated fat mass. 52 It
should be emphasized that changes in cardiac structure
associated with obesity are not only observed in the adult
population. It is also not uncommon to observe cardiac
changes in the youth. Alterations may even be present early
in life; obese children as young as 2 years old might present
larger LV cavity compared to normal weight children. 53
Clinical studies have reported greater epicardial fat, left atrial
and LV enlargement in obese children compared to lean
controls. However, the impact of such early cardiac changes
on later clinical outcomes in adulthood such as incident HF is
still lacking in the literature.54
In the heart itself, many additional alterations are ob-
served along with increased adiposity. In healthy individuals,
epicardial fat depot is distributed on the heart surface, close
to the coronary arteries. With obesity, outside of the
intracellular accumulation of fat, a higher amount of extra-
cellular fat deposition builds up in the epicardium. The
proximity of epicardial fat and coronary arteries might be
associated with the atherosclerosis burden.55,56Also, epicar-
dial fat deposition is correlated with the amount of visceral
fat.57 The potential link between fat accumulation on the
heart surface and risk of CVD is far from being fully
understood. However, epicardial fat seems to produce poten-
tial pro-inflammatory adipo(cyto)kines and macrophage sig-
nals that may be involved in the development of CHD. 55 For
instance, in visceral obesity, epicardial fat could influence
blood vessels by its action as a paracrine organ while
secreting locally pro-atherosclerotic molecules (such as inter-
leukin or Il-1β, Il-6 or tumor necrotic factor-α) and less
adiponectin compared to subcutaneous fat.58 Fat infiltration
within the heart may cause direct damage that may lead to
HF.59,60 In fact, myocytes degeneration may be caused by a
progressive accumulation of fat between muscle fibers (Fig 3).
Secondary to this infiltration, a restrictive cardiomyopathy
may develop impairing heart contraction. In this context, fat
accumulation produces small irregular aggregates or bands of
adipose tissue that might range between the myocardial cells.
This phenomenon may contribute to muscular cell atrophy as
a result of the increased pressure produced by these fat
depots creating cardiac dysfunction. 61 This myocardium
degeneration is also known as adipositas cordis (Fig 3).9
Contribution of obesity to CVD
Atherosclerosis is a degenerative process starting early in life
and progressing throughout lifetime. Progression of atheroscle-
rosis is related to age, but many chronic inflammatory
conditions such as obesity and diabetes may exacerbate its
development.62 The relationship between obesity and develop-
ment of CVD is now overwhelmingly clear. As discussed earlier,
large prospective studies such as the Framingham Heart Study,
the Manitoba Study, and the Harvard School of Public Health
Nurses Study and many others have documented obesity as an
independent predictor of CVD.13,14,63
In a recent large study, the
potential relationship between BMI categories and the incidence
of non ST-segment elevation MI (NSTEMI) were assessed
retrospectively. The study included a cohort of 111,847 patients
with unstable angina and NSTEMI. Obesity was the strongest
factor associated with NSTEMI at younger age followed by
tobacco use. Respectively,for all BMI categories (overweight,
374 P R O G R E S S I N C A R D I O V A S C U L A R D I S E A S E S 5 6 ( 2 0 1 4 ) 3 6 9 – 3 8 1

obese class 1, 2 and 3), the mean age incidence for NSTEMI
occurrence was 3.5, 6.8, 9.4, and 12.0 years earlier compared to
normal weight individuals.58 In the future, experts predicted
that the current growth rate of obesity (an estimated 7%
increase in men and 10% increase in women in 2020) will lead
to an increase in the number of CVD events of ~14% in 2035.64
This is not surprising since in studies involving young patients
who died from non-cardiac causes, obesity was one of the major
predictors of extended fatty streaks and advanced lesions
(fibrous plaques and plaques with calcification or ulceration)
in the right coronary artery and in the abdominal aorta.65–68In
young adults, obesity through lifetime is positively related to
atherosclerosis development as measured by carotid intimal-
medial thickness. This finding supports the notion of a potential
cumulative cardiovascular effect of childhood obesity on adult
CV outcomes.69 From a pathophysiological point of view, young
individuals with visceral obesity seem to have more infiltrated
macrophages (macrophages/mm2) in their atherosclerotic
lesions.70 It was reported that young obese individuals are
more subject to endothelial dysfunction. For instance, obesity,
particularly abdominal obesity, has been associated with
decreased endothelial dependent vasodilation even in the
absence of established CVD risk factors. 71,72 Endothelium-
dependent vasodilation is considered as an early marker of
atherosclerosis development, probably via its relationship with
nitric oxide.73 Outside endothelial dysfunction, the early devel-
opment of atherosclerosis in obesity is also probably related to
the resistance of blood vessels and their inflammation.9,74
Thus, common pathophysiological pathways relate obesity
and processes leading to accelerated atherosclerosis; both
involving inflammation and alterations in lipid metabolism
(Fig 3).The pathophysiology of obesity,in contrast to athero-
sclerosis, involves free fatty acids (FFAs) and triglycerides, rather
than LDL cholesterol. In obesity, chronic caloric excess induces
the accumulation of dietary fatty acids in the adipose tissue until
its storage capacity becomes saturated, leading to a spillover of
lipids which are then stored in normally lean tissues such as the
liver, muscles and in the intra-abdominal or visceral adipose
depots. Such saturation in the storage capacity of lipids in
subcutaneous adipose tissue and the resulting ectopic fat
deposition induce a combined state of inflammation and insulin
resistance.75 In addition, adipo(cyto)kines secreted by adipose
tissue are also involved in modulating processes promoting
atherosclerosis such as endothelial vasomotor dysfunction,
hypercoagulability and dyslipidemia.76 Levels of many inflam-
matory mediators are altered in obesity. First, circulating C-
reactive protein (CRP) and tumor necrosis factor (TNF) (produc-
tion by adipose tissue) levels are increased, but other mediators
(such as Il- 6 and 1β, and monocyte chemo-attractant protein 1)
and hormones (such as adiponectin and leptin) are also known
to potentially contribute to the inflammatory profile observed in
obesity, particularly of abdominal obesity.75,77 Regarding the
inflammatory process itself, monocytes and macrophages
involved in the evolution of the atheroma differ between lean
and obese individuals. Obesity leads to a shift in “alternatively”
activated macrophages (recognized for their protective function
in metabolic homeostasis) to “classically” activated macro-
phages (characterized by the production of pro-inflammatory
factors such as Il-6 and nitric oxide synthase 2), a pro-
inflammatory state that contributes to insulin resistance.78,79
White adipose tissue itself also seems to be of importance in the
inflammatory state of obesity. Excessive adipose tissue growth,
as seen in obesity, requires increased blood supply and total
adipose tissue blood flow is globally increased. However,
perfusion per unit of adipose tissue decreases with increased
adiposity. The difference in perfusion may represent a 35%
reduction in relative perfusion when an obese individual is
compared to a nonobese control. 80 This miss-match in the
perfusion leads to a relative diminution of oxygen supply to
adipocytes, which contributes to cellular hypoxia, organ stress
and dysfunction, pro-inflammatory responses and metabolic
disease.81,82 In addition, under such state of hypoxia, cells
secrete macrophages-attractive chemokines,which may lead
to secretion of various pro-inflammatory factors, also called
adipo(cyto)kines.83,84On the other hand, in association with the
lower blood supply or the chronic state of inflammation, multi-
nucleates giant cells (fusion of many macrophages) are found in
the expanded white adipose tissue of obese individuals.85During
their action of phagocytosis,these cells acutely secrete pro-
inflammatory cytokines (Il-1α, TNF-α).86 Activation of these
giant macrophages is related to necrotic-like adipocyte death
found in a higher proportion in obese individuals than in
nonobese individuals.87
Abdominal obesity
In a state of a positive energy balance, excess FFAs should be
preferentially stored in adipose tissue. Adipocytes expand in
order to store energy and as the demand for lipid storage
increases, pre-adipocytes located in the adipose tissue differ-
entiate to become mature and participate to fat storage. When
the adipose tissue has reached its maximal expansion capacity,
a “spill over” of lipids from adipocytes occurs, resulting in an
increase of circulating FFAs. Lipids then start to accumulate in
ectopic sites (visceral adipose tissue, intrahepatic, intramuscu-
lar, renal sinus, pericardial, myocardial and perivascular fat,
etc.), a phenomenon leading to lipotoxicity.88 In addition to its
role as the main energy reserve of the body, adipose tissue is
now considered as a key organ regarding its ability to control
overall energy flux and partitioning in the body, as the fate of
excess dietary lipids (storage in subcutaneous adipose tissue vs.
accumulation in lean tissues) may determine whether or not
body homeostasis will be maintained (metabolically healthy
obesity) or a state of inflammation/insulin resistance will be
produced, with deleterious consequences on the vascular wall
and the myocardium.40 Adipose tissue can be categorized as an
endocrine organ orchestrating crucial interactions with vital
organs and tissues such as the brain, the liver, the skeletal
muscle, the heart and blood vessels themselves. As mentioned
earlier, depending on their location, fat depots present distinct
metabolic properties, different states of inflammation or
adipo(cyto)kines excretion,leading to major individual differ-
ences regarding the impact of obesity on cardiometabolic risk
(from protective to neutral to increased risk) (Fig 3).40,89 A
important distinction should therefore be made between the
various adipose depots;the non-ectopic fat (or subcutaneous
fat) appears to be less metabolically deleterious, its primary role
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being energy storage, whereas excess ectopic fat defined as an
excess lipid accumulation in the visceral adipose depots and in
normally lean tissues (intrahepatic, intramuscular, renal sinus,
pericardial, myocardial and perivascular fat) is clearly a health
hazard.32,82The first hypothesis explaining the close relation-
ship between visceral obesity and metabolic complications
involves the old «portal free fatty acid» theory.90 Related to its
close proximity to the liver and drained by the portal
circulation, excess visceral adipose tissue could alter lipopro-
tein metabolism mainly by inducing an overproduction of large
triglyceride (TGs)-rich very low density lipoproteins (VLDLs).
The expanded visceral adipose depot also contributes to an
increased delivery of non-esterified FFAs and cytokines to the
liver. This theory must be considered with some caution as the
majority of FFAs (80%) found in the portal circulation appear to
originate from the lipolytic activity of systemic adipose tissue.
Thus, although there is a clear relationship between excess
visceral adiposity and the flux of non-esterified FFAs to the
liver, the precise role of this phenomenon to the disturbed
hepatic metabolism remains debated. However, FFAs issued
from the visceral adipose tissue are transformed into VLDLs
enriched with TGs which leads to the formation of TG-rich LDL
particles, which, through the action of the enzymes hepatic
lipase and cholesteryl ester transfer protein, become
remodelled into small and dense LDL particles which are
believed to promote atherosclerosis.91–93For instance, smaller
and denser LDL particles appear to be particularly atherogenic;
they can penetrate easily within the vascular wall and are
susceptible to oxidation.94A high proportion of small and dense
LDL has been associated with an increased risk of CHD. In a
study performed by Lamarche and colleagues, one third of
patients with CHD had normal LDL concentrations, but showed
an increased proportion of dense LDL.95 Apolipoprotein B is of
particular importance to determine the risk associated with the
small LDL phenotype.96,97It is now well-known that an excess
of visceral adipose tissue in obese and non-obese patients is
clearly associated with cardiometabolic abnormalities such as
insulin resistance, hyperinsulinemia, glucose intolerance, type
2 DM, an atherogenic dyslipidemia (high TGs, apolipoprotein B,
small and dense LDL, low HDL), inflammation, altered cytokine
profile, impaired fibrinolysis and increased risk of thrombosis,
as well as endothelial dysfunction (Fig 2).96,98,99
High-density lipoproteins
High-density lipoproteins (HDL) have a protective role on the
vascular wall. There is a well-established negative correlation
between HDL-cholesterol concentrations, apolipoprotein A1
levels (a significant protein contained in HDL) and CVD
incidence.100 Although the protective effects of HDL on CV
health were initially believed to be related to their ability to
promote reverse cholesterol transport,101 it is now well
documented that this lipoprotein class also has numerous
additional properties which may be beneficial such as anti-
inflammatory, antioxidant, and antithrombotic properties.102
In the viscerally obese individual, HDL levels are decreased by
the successive actions of cholesteryl ester transfer protein and
hepatic lipase. As a consequence, HDL particles also become
smaller and denser which can also affect their catabolism and
their potentially protective properties.100Also, it is possible that
visceral obesity may be associated with compositional changes
in HDL particles, making them less efficient regarding their
protective action on cholesterol efflux.103 Dysfunctional HDL
particles may also become pro-inflammatory instead of anti-
inflammatory; they may display reduced antioxidant and anti-
inflammatory properties which could contribute to diminish
their ability to prevent LDL oxidation,thereby contributing to
atherosclerosis.104 It is well known that low levels of HDL are
associated with an increased risk of developing CVD, 105 but
high levels of HDL may not always be protective, since in a
context of chronic inflammation, HDL may be less
functional.106 Level of physical activity also has an influence
on HDL quality. For instance obese exercise-trained individuals
have been shown to be characterized by improved HDL redox
activity compared to sedentary untrained individuals while
presenting HDL functional proprieties which were similar to
lean active individuals.107
Adipo(cyto)kines and CVD
There is now overwhelming evidence that adipose tissue is a
key organ in the production and in the regulation of endocrine
and paracrine hormones modulating inflammation and other
important metabolic processes. Cytokines produced by adipose
tissue (or adipokines) have been classified in two main
categories: 1) “healthy” adipokines (adiponectin and omentin)
and 2) “unhealthy” adipokines (TNF-α, Il-6, plasminogen
activator inhibitor-1, adipocyte fatty acid-binding protein,
lipocalin-2, chemerin, leptin, visfatin, vaspin, resistin), which
are upregulated in obesity.82 Adiponectin and omentin appear
to play important roles in regulating endothelial function. The
first suppresses TNF-α secretion, attenuates production of
reactive oxygen species induced by high glucose, oxidized LDL
and palmitate, stimulates endothelial cell migration and pre-
vents cell apoptosis.108On the other hand, omentin appears to
promote nitric oxide production.109 Levels of plasma
adiponectin are decreased in obesity.110
In 1994, the first protein selectively derived from adipocytes,
leptin, was discovered.111 The primary role initially attributed
to this protein was to control appetite by a central action
inhibiting food consumption. More recently, it has become
evident that leptin has numerous important biological func-
tions and that some of them may have an impact on the CV
system.100 In 2006, leptin was found to be a regulator of non-
esterified FFAs oxidation by peripheral tissues.112 By its action
on non-esterified FFAs oxidation, leptin was shown to prevent
the accumulation of deleterious ectopic fat in peripheral organs
i.e. heart, skeletal muscles, kidney, and pancreas. Fat accumu-
lation in target organs may produce irreversible damages by the
accumulation of ceramides (cytotoxic lipids), which may,
through increased nitric oxide formation, cause apoptosis of
lipid-laden cells (such as beta-cells and cardiomyocytes). 113
Leptin was also suggested to have a potential role in inflam-
mation according to the fact that leukocyte receptors were
found on the protein, although the relationship between
leptinemia and CVD remains debated.114,115It is now consid-
ered that adipo(cyto)kines secreted by adipose tissue activate
several pathways, some having protective roles whereas others
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can act in opposite directions. Some of these adipokines
probably play an important role in atherosclerosis development
and progression to CV outcomes. Adiponectin clearly exhibits
anti-inflammatory, anti-atherosclerotic and potentially
cardioprotective properties (including anti-apoptotic and anti-
oxidant effects).116 More precisely, adiponectin inhibits the
expression of TNF-α-induced endothelial adhesion molecules,
inhibits macrophage-to-foam cell transformation, suppresses
TNF-α expression in macrophages and adipose tissue, reduces
intracellular cholesteryl ester content in macrophages and
inhibits smooth muscle cell proliferation. 108,116Some clinical
trials have shown that high levels of adiponectin are associated
with lower risk of CVD 117 and may be associated with lower
atherosclerosis plaque development in men118 although such
relationship remains debated as well. In addition, adiponectin
may have a beneficial impact on the myocardium itself. For
instance, by its action in promoting cell survival and inhibiting
cell death, adiponectin may have a direct effect on
cardiomyocytes acting as a “heart protector”.119 In contrast, in
chronic HF, adiponectin levels are increased and such in-
creased levels are associated with a worsened prognosis. 120
Some authors have attempted to explain this paradox by a
certain “adiponectin resistance” that may be found among
patients with massive heart injuries. Under this model, higher
levels of adiponectin may represent a counter-regulatory
response necessary to promote anti-inflammatory and anti-
oxidative processes to compensate for heart degeneration.82,121
Along the same line, omentin may also provide protective
effects on the CV system by its vasodilation effect on vessels, its
anti-inflammatory action (attenuation of CRP) and its action to
prevent arterial calcification.122 Although the above evidence
supports the relevance of increasing adiponectin levels thera-
peutically, whether or not pharmacotherapies substantially
increasing circulating adiponectin levels translate into benefits
in terms of cardiovascular outcomes is not established and very
controversial.123–125Indeed, studies with glitazones, a class of
drugs producing robust and consistent increases in circulating
adiponectin levels have all failed to show clear CV
benefits.123–125Thus, which features of subcutaneous adipose
tissue “endocrine” secretions could be eventually targeted in
abdominal obesity to reduce CVD risk remains unknown.
However, as regular physical activity/exercise has been shown
to be beneficial in terms of protection against CVD and as
regular exercise has also been shown to mobilize ectopic fat
and visceral adipose tissue, reducing sedentary time in the
viscerally obese patients and regular endurance exercise
training appears to represent important components of a
lifestyle modification program to reduce CVD risk in patients
with abdominal obesity.32
Conclusions
Basic, clinical and population studies have provided robust
evidence supporting the notion that obesity is associated with
numerous alterations increasing the risk of CVD (Figs 1, 2). The
pathophysiological processes linking obesity to atherosclerosis
and CVD clearly involve a chronic inflammatory state. This
inflammatory profile is usually the result of combined factors,
such as visceral obesity and excess ectopic fat, insulin
resistance, an atherogenic dyslipidemia and HTN. Such con-
stellation of additional metabolic abnormalities found in
patients with “at risk obesity” has often contributed to confuse
the issue of obesity as a CVD risk factor in contrast to the
“obesity paradox” (Fig 3). There is no doubt that obesity is
associated with changes in CV structure and function. Howev-
er, before weight loss interventions can be recommended,
patients must be assessed for their adiposity-related risk.
Unfortunately, healthcare providers and systems have not
done a proper job of assessing excess adiposity even in its
simplest form, such as measuring BMI.25 As an initial step, we
need to emphasize further the importance of assessing
adiposity in clinical practice. Although it can be argued that
preventive approaches should focus on the entire population,
the identification of “at risk” overweight/obese individuals in
clinical practice nevertheless requires simple tools and strate-
gies to better assess and manage these patients. We must
therefore identify those individuals at highest risk of
comorbidities in order to optimally use our limited health care
resources. Under these considerations, the identification of
individuals with excess visceral/ectopic fat is key so that these
high risk patients could benefit from the support of health care
professionals in their attempt to reshape their nutritional and
lifestyle habits. In this regard, we know from decades of short
term weight loss studies that although achieving weight loss is
feasible over the short term, long term maintenance of a
reduced body weight is a daunting task due to the fact that
patients live in an obesogenic environment and do not have
access to the long term support which has been found to be
required to achieve long term success. Furthermore, the
remarkable recent findings of the one study126and the failure
of another 127,128to permanently reduce body weight despite
expensive resources and support suggest that we may have
focussed too much on weight loss rather than on key upstream
behaviors such as nutritional quality and inactivity/sedentary
behavior/exercise. In addition, too many weight loss trials have
been conducted in fairly low risk population of largely obese
women participants with no cardiovascular outcomes. Maybe
the time has come to consider a new paradigm where we use
simple tools to redefine higher risk overweight/obesity (such as
WC, TGs, nutritional quality and inactivity/activity level)32 and
new therapeutic objectives: improving nutritional quality,
reducing sedentary behaviors and increasing physical activity).
Such a new model can be experimentally tested.
Statement of Conflict of Interest
All authors declare that there are no conflicts of interest.
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