ARTICLE IN PRESS

&

Obesity and Coronary Heart Disease:

Epidemiology, Pathology, and
Coronary Artery Imaging
Natraj Katta, MD, Troy Loethen, MD,
Carl J. Lavie, MD, and Martin A. Alpert, MD

ABSTRACT: Overweight and obesity contribute to the

development of cardiovascular disease (CVD) in general
and coronary heart disease (CHD) in particular in part
by their association with traditional and nontraditional
CVD risk factors. Obesity is also considered to be an
independent risk factor for CVD. The metabolic syn-
drome, of which central obesity is an important compo-
nent, is strongly associated with CVD including CHD.
There is abundant epidemiologic evidence of an associa-
tion between both overweight and obesity and CHD. Evi-
dence from postmortem studies and studies involving
coronary artery imaging is less persuasive. Recent stud-
ies suggest the presence of an obesity paradox with
respect to mortality in persons with established CHD.
Physical activity and preserved cardiorespiratory fitness
attenuate the adverse effects of obesity on CVD events.
Information concerning the effect of intentional weight
loss on CVD outcomes in overweight and obese persons
is limited. (Curr Probl Cardiol 2020;00:100655.)

&
I
t has become increasingly apparent during the past half-century
that a relationship exists between overweight (OW)/obesity and
cardiovascular (CV) disease (CVD), particularly coronary heart
disease (CHD).1-20 CHD may be characterized as coronary artery disease
(CAD) and its complications.1-20 OW and obesity are closely associated
with multiple traditional and nontraditional (novel) risk factors for CVD.1-
9,11-20
The metabolic syndrome (MetS) refers to a clustering of risk factors

Curr Probl Cardiol 2020;00:100655

0146-2806/$ see front matter
https://doi.org/10.1016/j.cpcardiol.2020.100655

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for CVD. Patients with the MetS are a particularly high risk for CHD.1-9,11-20
This review discusses the relation of OW and obesity to CVD and CHD
based on epidemiologic and pathologic studies and on studies involving cor-
onary artery imaging. It also provides evidence supporting the existence of
an obesity paradox related to CHD. Finally, it describes the effects of physi-
cal activity, cardiorespiratory fitness (CRF), and intentional weight loss on
CVD and CHD outcomes in patients who are OW or obese.

DEFINITIONS
The World Health Organization and related classifications of body
weight, criteria for central (abdominal, visceral) obesity based on waist
circumference (WC) and waist-hip ratio (WHR), and the most com-
monly-used criteria for the MetS are summarized in Table 1.1,10-12,15-20

OBESITY AND CVD

Risk Factors for CVD

There are a multiple genetic, physiological, and biochemical mechanisms
that facilitate to the development of atherosclerotic vascular disease and by

Table 1. Commonly-used classifications and criteria associated with overweight and obesity

World Health Organization body weight classification*

Underweight <18.5 kg/m2
Normal weight 18.5-24.9 kg/m2
Overweight 25.0-29.9 kg/m2
Class I obesity 30.0-34.9 kg/m2
Class II (severe) obesity 35.0-39.9 kg/m2
Class III (morbid, extreme) obesity 40.0 kg/m2
Class IV (super) obesity 50.0 kg/m2
Commonly-used markers of central obesity
Waist circumference 102 cm in men; 88 cm in women
Waist-hip ratio >1.0 in men; >0.8 in women
Metabolic syndrome (3 of the following 5 required):
Waist circumference 102 cm in men; 88 cm in women
Blood pressure 130/85 mmHg
Serum triglyceride level 150 mg/dL
Serum HDL cholesterol level <40 mg/dL in men; <50 mg/dL
in women
Serum glucose level >110 mg/dL
Table adapted from refs.1,10-12
Abbreviations: kg/m2, kilograms per meter squared; cm, centimeters; mmHg, millimeters of mer-
cury; mg/dL, milligrams/deciliter; HDL, high density lipoprotein.
*Body weight was expressed as body mass index (BMI).

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extension CHD.1-9,11-20 Traditional CVD risk factors associated with OW and

obesity include type 2 diabetes mellitus (DM), hypertension, and various dys-
lipidemias (including elevated serum triglyceride levels, low serum levels of
high-density lipoprotein, and increased serum levels of small dense low-den-
sity lipoprotein and apoprotein B.1-6,11-20 Nontraditional or novel CVD risk
factors associated with OW and obesity include insulin resistance, hyperinsu-
linemia, endothelial dysfunction, various inflammatory markers, and a variety
of pro-thrombotic factors (increased serum fibrinogen levels, von Wil-
lebrand’s factor, plasminogen activating factor-1, clotting factors VII and
VIII).1,11,16-20 Central obesity is key component of the MetS, which itself is
an important risk factor for CVD including CHD.1,15-20 The 27th Bethesda
Conference classified obesity as an independent risk factor for CVD.20

EPIDEMIOLOGIC STUDIES
The relation of obesity to CVD has been the focus of numerous epide-
miologic studies. Most commonly, they have attempted to determine the
relationship of obesity to the risk of CVD or the risk of CHD. Some of
these studies included risk assessment for cerebrovascular disease.

Relation of OW and Obesity to CVD and CHD: General

Body Weight Indices
The Framingham Heart Study has proven to be a rich source of data con-
cerning the relation of OW and obesity to CVD risk including CHD risk. The
earliest of these trials was reported by Hubert et al and involved 2252 men
and 2818 women (age range: 28-62 years, follow-up: 26 years).21 Minimum
relative weight was found to be a risk factor for CHD and stroke independent
of risk factors such as age, cholesterol level, systolic blood pressure, left ven-
tricular hypertrophy, and glucose intolerance. In a study of 597 men and 1126
women (age range: 55-65 years, follow-up: 23 years), Harris et al identified a
“U” shaped mortality curve for body mass index (BMI).22 In a trial of 2039
men and 2871 women (age range: 35-70 years, follow-up: 24 years), Kannel
et al noted that the risk of CVD occurred in patients with abdominal and gen-
eral obesity in a linear fashion.23 In an update of this study, Kannel et al
reported that after 26 years of follow-up, each standard deviation of relative
weight gain predicted an increased risk of CHD and stroke of 15% in men and
22% in women.24 In this study, optimal BMI for avoidance of CVD was 22.6
kg/m2 in men and 21.1 kg/m2 in women. Wilson et al showed that OW or obe-
sity determined by BMI in men and women (age range: 35-75 years) followed
for up to 44 years was associated with an increased incidence of CVD.25

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Another large epidemiologic trial, the Nurse’s Health Study, also pro-
vided a wealth of information concerning the relation of body weight to
CVD, particularly CHD. Manson et al studied 115,886 women (age
range: 30-56 years, follow-up: 8 years).26 These investigators noted a
link between obesity and the risk of CHD. A subsequent study showed
that CHD mortality was less than that reported for women in the general
US population.27 In a study by Willett et al of middle-aged women fol-
lowed for 14 years, the highest BMI within the range of weight gains after
18 years of age predicted elevated risk of CHD.28 Rexrode et al studied
44,702 women followed for 12 years.29 This study showed that women
who were nonsmokers and whose BMI was 32 kg/m2 had a relative risk
of CVD mortality of 4.1 compared to women whose BMI was <19 kg/
m2. Cho et al noted that weight gain before the onset of DM was associ-
ated with increased risk of CHD in 5897 women (follow-up: 12 years,
after adjustment for BMI and selected CVD risk factors.30
Baik et al studied 39,756 males (age range: 40-75 years, follow-up: 10
years) as part of the Health Professionals Follow-up Study.31 The risk of
CVD mortality rose progressively with increasing BMI in men <65 years
old. In a previous study these investigators showed that in men 65 years
old no association between BMI and CVD mortality was noted.31
A study by Field et al combined subgroups from the Nurse’s Health
Study and the Health Professionals Follow-up Study.32 The study popula-
tion consisted of 77,690 women and 40,060 men (follow-up: 10 years). In
this study the risk of CHD or stroke rose in patients with increasing sever-
ity of OW or obesity. The first National Health and Nutrition Examina-
tion Survey (NHANES I) Epidemiologic Follow-up Study evaluated the
relation between body weight and risk of CHD in 2 separate reports. In a
study of 1259 women (age range: 65-74 years, follow-up: 14 years), a
BMI 29 kg/m2 was an independent risk factor for CHD.33 In a second
study of 620 men and 960 women (mean age: 77 years, follow-up: 13
years), Harris et al reported that the presence of heavier weight in late
middle age was a risk factor for CHD later in life.34 The presence of
heavier weight during older age served as a risk factor for CHD after
adjusting for weight loss.
Calle et al studied >1,000,000 subjects (follow-up: 14 years).35
Increased BMI, defined as >26.5 kg/m2 in men and >25.0 kg/m2 in
women, predicted CVD in both men and women. In those whose BMI
was >40 kg/m2, respective relative risks for CVD in men and women
were 2.7 and 1.9.
A retrospective study of 866 African-American men and women fol-
lowed for 7 years reported by Adams-Campbell et al assessed the relation

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of BMI to CAD confirmed by invasive coronary angiography.36. In this

study CAD occurred more frequently in subjects who were OW than in
patients with normal weight or in those who were obese.
Zhou et al demonstrated that OW served as an independent predictor of
CHD in 14 target populations comprising 1974 men and women (age
range: 30-59 years, follow-up: 9 years).37
The Manitoba Heart Study comprised 3983 men (mean age at entry:
30.8 years, follow-up: 26 years).38 There were 390 cases of CHD during
follow-up. Elevated BMI was significantly associated with MI, sudden
death, and coronary insufficiency. These findings were not apparent until
year 16 of follow-up. The presence of OW or obesity was found to be the
best predictor of myocardial infarction (MI) after 20 years of observation.
Conversely, in the Pooling Project there was no significant age-adjusted
or age-associated relation between obesity and CHD in male cohorts.5
In a meta-analysis of 8 studies comprising 61,386 adults (follow-up:
>10 years), Kramer et al reported approximately 4000 adverse CVD
events.39 Subjects with obesity, but without the MetS had a 24% higher
risk of CVD events than participants with normal weight without the
MetS. The Copenhagen General Population Study followed 71,527 adults
followed for a mean duration of 3.6 years.40 Adults who were OW or
obese with the MetS manifested increased risk for MI (hazard ratios [HR]
of 1.26, 95% confidence interval [CI]: 1.0-1.6 in patients who were OW
and 1.88, 95% CI: 1.3-2.6 in those who were obese).
Jousilahti et al studied 16,113 Finnish men and women (age range: 30-
59 years, follow-up: 15 years).41 Obesity was found to be an independent
risk factor for CHD mortality among men and contributed somewhat less
to CHD mortality risk in women.
dPITage n the Chicago Western Electric Study 1707 men (age range: 40-55 years),
followed for 22 years.42 After 15 years, all indices of adiposity except for tri-
ceps skinfold thickness were significantly related to CHD mortality.
BMI and fat patterning failed to predict CHD mortality in African-
American women during a follow-up period of 25-28 years in the
Charleston Heart Study.43 In the Adventist Mortality Study of 12,576
women (age range: 30-74 years, follow-up: 26 years), there was a “U”
shaped curve for risk of CHD, hypertensive disease and stroke mortality,
particularly during the fifth to seventh decades of life.44
In a prospective study of 7735 males (age range: 40-59 years, mean
follow-up: 14.8 years), Shaper et al showed that a BMI of 22 kg/m2 was
associated with the lowest risk of CVD mortality.45
The Women’s Health Australia Project included 13,431 women (age
range: from 45 to 49 years) and was designed to assess the relation

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between BMI and CVD risk.46 In this study Brown et al demonstrated

that a BMI of 19-24 kg/m2 was the optimal BMI for minimizing CVD
risk. In a retrospective analysis of data that were obtained prospectively,
Benedetto et al assessed the relation of BMI categories to early and late
mortality after first time isolated coronary artery bypass grafting
(CABG).47 The study population consisted of 3269 subjects with normal
weight, 6660 subjects who were OW, 3821 subjects who were obese, and
211 subjects who were morbidly obese. Propensity scoring was used to
adjust for potential confounding factors. Early mortality was not affected
by the presence of OW, obesity or morbid obesity regardless of the
patient’s risk profile. OW was not protective against late death compared
to normal weight subjects. The obese state was associated with a higher
risk for late death (HR: 1.22, 95% CI: 1.07-2.66, P< 0.006) and a trend
toward late mortality in those with morbid obesity (HR: 1.36, 95% CI:
0.24-2.49).

Relation of Fat Distribution to CVD and CHD Risk

Epidemiologic studies strongly suggest that the presence of central
obesity is superior to general indices of body weight (BMI, relative
weight) as a predictor of CVD and CHD morbidity and mortality.
In a study of 27,098 adults from 52 countries Yusuf et al showed that
BMI was minimally associated with MI after adjustment for other CVD
risk factors (odds ratio [OR] of 1.12, 95% CI: 1.03-1.22).48 In contrast,
the ORs for WHR as a predictor of MI were substantially higher (1.90 in
the fourth and 2.52 in the fifth quintile). In the INTERHEART Study,
WHR was the strongest predictor of MI.49 In this study, other measures
of abdominal obesity were also stronger predictors of MI than was BMI.
A review of relevant studies by Rao et al demonstrated that high BMI
and high WHR were independent risk factors for CHD mortality.50
Hamer et al combined data from the Health Study of England with data
from the Scottish Health Survey (22,308 subjects, mean age: 54 years).51
Patients who were obese with lower metabolic risk (WC <102 cm for
men and <88 cm for women, normotensive, no DM, normal C-reactive
protein (CRP), normal high-density lipoprotein cholesterol) had no
increase in CVD risk compared to healthy nonobese individuals.
In a case control study of men and women <70 years old (216 cases,
261 controls), increased mid-thigh girth and subcutaneous fat mass
appeared to have a protective effect against CHD.52
Rexrode et al showed that WHR and WC were independently associ-
ated with CHD risk in 44,702 women in the Nurse’s Health Study.53

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Coutinho et al studied 15,547 subjects with CAD to determine the rela-

tive associations of BMI and WHR to 5-year survival.54 The study popu-
lation consisted of 55% men (mean age: 66 years). A total of 4699 deaths
occurred over a median follow-up period of 4.7 years. Those with a nor-
mal BMI, but with a high WHR had a higher mortality rate than those
with a normal BMI and a normal WHR (HR: 1.10, 95% CI: 1.05-1.17),
those who were OW with a normal WHR (HR: 1.20, 95% CI: 1.09-1.31),
and those who were obese with a high WHR (HR: 1.27, 05% CI: 1.18-
1.39). The p values for all comparisons were <0.0001.
Sharma et al studied 7057 patients >65 years old with known CAD
who were at normal weight, but had central obesity (those with a high
WHR or high WC).55 The mean follow-up time was 7.1 years. The high-
est mortality risk occurred in those with a normal BMI and central obesity
(HR: 1.29, 95% CI: 1.14-1.46 for high WHR and HR: 1.29, 95% CI: 1.12-
1.50 for high WC). High WHR was predictive of mortality overall (HR:
2.14, 95% CI: 1.93-2.38), but high WC overall was not predictive of mor-
tality. High WHR predicted mortality in both men and women, whereas
WC predicted mortality only in men (HR: 1.12, 95% CI: 1.01-1.24).
A study by Zhang et al demonstrated that the relative risk of CVD mor-
tality rose progressively with increasing quintiles of WC (1.00, 1.04,
1.04, 1.28, and 1.99) after adjustment for BMI and selected risk factors
for CVD.56
The previously-cited study by Baik et al noted that WHR predicted CVD
mortality in men 65 years of age.31 In the same group of patients, Rimm et
al reported that in those 21 years of age, BMI, WHR, and weight gain
were associated with increased risk of CAD.57 In patients 65 years of age or
older, WHR was superior to BMI in predicting CAD risk.
In a Brazilian study of 2396 patients reported by Fontela et al, conicity
index, BMI, and WC were assessed to determine their relation to CAD
mortality.58 None of these anthropomorphic measurements proved to be
independent predictors of CAD mortality.
The Paris Prospective Study consisted of 6718 men (age range: 42-
53 years, average follow-up: 6.6 years).59 Thirteen upper and lower body
skinfold thicknesses were measured. Higher ratios of truncal to mid-thigh
skinfold thickness were most predictive of CHD, even after adjusting for
blood pressure, cholesterol, and DM.
In the Study of Men Born in 1913, 792 were evaluated at 54 years
age.60 Follow-up occurred 13 years later. BMI and skinfold thickness
measurements were obtained as was WC. None of these measurements
were significantly associated with ischemic heart disease, stroke, and all-
cause mortality. In contrast, WHR was significantly associated with

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ischemic heart disease and stroke (P= 0.04). Adjustment for traditional
CVD risk factors attenuated this association.
Prineas et al assessed the relation between WHR and 4-year risk of
fatal CAD in 32,858 women (age range: 55-69 years).61 In the highest ter-
cile of WHR compared to the lowest tercile of WHR, the relative risk of
death from CAD was 3.3 (95% CI: 2.0-5.6). There was a trend towards
an increased relative risk when the middle tercile was compared with the
lowest tercile. High WHR was, for the most part, an independent risk fac-
tor for CAD-related death, although multiple other CVD risk factors were
also considered to be important predictors of this endpoint on multivari-
ate analysis.
In a study reported by Jonsson et al, 22,025 Swedish men (age range:
27-61 years) were followed for 23 years.62 The cumulative mortality rate
was 20% (13% for CHD events). The relative risk for CHD events in
patients who were OW was 1.26 (95% CI: 1.12-1.37) and was 1.76 (95%
CI: 1.49-2.68) in patients who were obese. CHD events and CHD itself
were thought to be closely-related to CVD risk factors.
A study of 105,062 US male veterans followed for 23 years reported
by Terry et al, the relative risk of ischemic heart disease death per stan-
dard deviation of WHR ranged from 1.11 to 1.17 (higher in younger sub-
jects).63 BMI was not a significant risk predictor for younger subjects, but
became a significant risk predictor among veterans 21-30 years of age.
Bengtsson et al reported the results of a study of 1462 randomly selected
Swedish women (age range: 38-60 years) who were followed for total mor-
tality over 20 years.64 WHR was an independent predictor of total mortality
and death from MI (relative risk: 1.67, 95% CI: 1.18-2.36).
Lakka et al studied 1346 Finnish men (age range: 42-60 years) with no
evidence of CVD at entry.65 The average follow-up period was 10.6 years,
during which time 123 acute CHD events occurred. After adjustment for
confounding variables, WHR (P< 0.009), WC (P < 0.010), and BMI (P
< 0.013) cumulatively were associated with a nearly 3-fold risk of CHD
events. WHR provided additional value beyond BMI, but the converse
was not true. Patients with abdominal obesity combined with cigarette
smoking and poor cardiorespiratory fitness respectively were shown to
have 5.5 and 5.1 times the risk of CHD events.
In a study of 9206 Australian adults (age range: 20-69 years) after
adjustment for multiple CVD risk factors, WHR was a dominant and
independent predictor of CVD and CHD mortality.66 WHR was a better
predictor than WC and WC was a better predictor than BMI.
Lapidus et al studied 1462 Swedish women (age range: 38-60 years) to
assess the relation of the distribution of adipose tissue to the risk of CVD

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and death.67 On multivariate analysis, WHR and WC were associated

with 12-year incidence of MI independent of age, BMI, cigarette smok-
ing, dyslipidemias and, and systolic blood pressure.
In a substudy of the Honolulu Heart Study, Curb et al reported that in
Japanese-American men, BMI, subscapular skinfold thicknesses central-
ity index predicted CHD after adjustment for selected CVD risk factors.68
A study of 2512 men (follow-up: 14 years) by Yarnell et al demon-
strated that subscapular skinfold thickness significantly predicted ische-
mic heart disease after adjustment for age, smoking, and social status.69
Other skinfold thickness measurements contributed marginally to ische-
mic heart disease prediction relative to BMI.

PATHOLOGY
Studies derived from postmortem evaluation have shown mixed results
concerning to the relationship between OW/obesity and CHD. The Interna-
tional Atherosclerosis Project (1960-1964).70 This study contained autopsy
data on 350 persons from 6 geographic regions. The study showed that among
those who died accidentally there was no relation between any of the weight
indices used and the extent of atheromata. In a World Health Organization
Study conducted in Europe and reported by Sternby, there was no significant
difference in the prevalence of coronary stenosis or the extent of atherosclero-
sis between normotensive, nondiabetic patients who were obese and subjects
at normal weight.71 In this study, subjects with wasting diseases were
excluded. Giertson et al reported no significant difference in the extent of coro-
nary atherosclerosis between 408 patients who were underweight and those
who were OW (age range: 15-89 years).72 A retrospective autopsy study
reported by Ackerman et al showed that the degree of coronary atherosclerosis
was similar in persons who were OW and persons with average weight.73
Yater et al found no significant difference in body weight between 237
men who died of CHD and 297 men who suffered accidental death.74
Lee and Thomas reported no significant difference in body weight
between 450 persons (age range: 30-60 years) who succumbed to acute
MI and persons with average body weight in the general population
matched who were for age and sex.75
Several studies have described a relation between abdominal panniculus
thickness and coronary atherosclerosis. Wilens et al described postmortem
findings in 1260 cases. Advanced coronary atherosclerosis occurred twice as
often in those with an abdominal panniculus >3 cm as in persons with poor
nutritional status.76 The Pathobiological Determinants of Atherosclerosis in
Youth (PDAY) Study comprised 3000 males and females (age range: 15-34

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years), In this study McGill et al described fatty streaks in the right and left
anterior descending coronary arteries in adolescents and young men with an
increased BMI.77 Fatty streaks in the right coronary artery were greater in the
right coronary artery in young men with a thick abdominal panniculus. There
was a trend toward greater fatty streaks in the right coronary artery young
women with a thick abdominal panniculus. There was no association between
BMI and coronary atherosclerosis in young women. Previously, McGill et al
studied 1532 autopsied young persons who died of causes other than CHD.
In males, the percentages of fatty streaks and raised right coronary lesions
were 2-4 times higher in subjects whose abdominal panniculus thickness was
>17 mm compared to males whose abdominal panniculus  17 mm.78
Strong et al reported the results of a study of 1108 males (age range:
13-34 years) who succumbed to diseases other than CHD.79 A positive
correlation was noted between body weight-height indices and raised cor-
onary lesions in white Americans, but not in African-Americans. How-
ever, the differences in panniculus thickness between groups were small.
Patel et al reported findings from 672 autopsy cases of men (age range:
25-64 years), 70% of whom suffered accidental death.80. There was a
weak correlation between abdominal panniculus thickness and raised cor-
onary artery lesions in white men, but not in African-American men.
In a retrospective analysis of medical records of all nonelderly resi-
dents of Olmstead County, MN between 1981 and 2009 who died from
non-natural causes and who had CAD at autopsy (n = 545), Smith et al
noted a nonlinear decline in CAD that was associated with a decrease in
hypertension.81 Trends identifying increasing obesity and DM were
thought to contribute to the end of the decline in CAD.
In a postmortem evaluation of 110 subjects in which biopsies of subcuta-
neous fat were acquired Bjurulf et al showed that the severity of coronary
atherosclerosis correlated with the size, but not the number of fat cells.82.
Autopsy findings in a study of 37 Japanese-American men showed a
positive correlation between CHD severity and relative weight >116%.83
Wilkens et al reported greater severity of CHD on autopsy and a higher
incidence of catastrophic CHD events in normotensive men who were
obese, but not in women.84

INVASIVE ANGIOGRAPHIC AND COMPUTED

TOMOGRAPHIC IMAGING
Coronary anatomy has been studied using invasive coronary angiogra-
phy, computed tomographic coronary angiography and by assessment of
coronary artery calcium using computed tomography.

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Invasive Coronary Angiographic Studies

The Honolulu Heart Program was a study of 357 men drawn from a
cohort of 7591 men without established CHD at entry.85 Invasive coro-
nary angiography was performed on entry and was repeated during a fol-
low-up period of 20 years. Thirty-five men with <50% stenosis
represented controls. There was no significant difference in BMI between
controls and subjects with greater degrees of coronary stenosis.
Cramer et al 262 patients with established CHD based on invasive cor-
onary angiography on entry followed by repeat invasive coronary angiog-
raphy 2-182 months after the initial angiogram.86 No significant
difference in the progression of coronary lesions between those with a rel-
ative weight greater than 120% and those with lower relative weights.
Stalls et al consulted an invasive coronary angiographic database of
33,119 patients. They reported that although black subjects had higher
frequencies of CVD risk factors and were more commonly morbidly
obese, they were significantly less likely to have significant coronary
artery stenosis on angiography.87
These cross-sectional invasive coronary angiographic studies and others
assessing coronary artery stenosis in patients who were OW or obesity
showed little or no relation between BMI and severity of CAD.88-96
Farhang et al studied 414 patients with suspected CAD who underwent
invasive coronary angiography (mean age: 61.2 years, 60.4% male).97
Severity of CAD was assessed using the Synergy between Percutaneous
Intervention with Taxus and Cardiac Surgery (SYNTAX) and Duke scor-
ing systems. There was a negative correlation between BMI and both
SYNTAX score and Duke score (P = 0.001 for both). There was a posi-
tive correlation between WHR and severity of CAD using the Duke score
(P = 0.03).
To assess the influence of BMI on extent of coronary atherosclerosis in
patients at risk for CAD based on CVD risk factors, Rossi et al studied
1299 consecutive patients (69.7% male) who underwent invasive coro-
nary angiography.90 The study population consisted of patients with nor-
mal weight (36.5%) patients who were OW (43.6%) OW, and patients
who were obese (19.6%). During a mean follow-up period of 40 months,
the patients who were OW or obese had a higher incidence of CHD
events than normal weight patients (62.7% in patients who were OW,
74.9%, in patients who were obese and 53.2% in patients with normal
weight, (P < 0.05).
In a study by Alkawam et al 7567 patients were hospitalized for chest
pain and underwent invasive coronary angiography.98 The study included

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414 patients who were obese (BMI 30 kg/m2, 80% of whom had CAD.
These patients displayed CAD at a younger age than patients who were
not obese (57 years vs 63 years). Of the 332 patients with obesity and
CAD 55.4% had obstructive CAD. Traditional CVD risk factors such as
male gender and cigarette smoking favored obstructive CAD, whereas
dyslipidemia favored nonobstructive CAD.
Cepeda-Valery reported the results of an invasive coronary angio-
graphic study of 95 patients with acute MI assessing the relation of obe-
sity to SYNTAX score and CAD severity.99 On univariate analysis
obesity was associated with a lower SYNTAX score (P = 0.009), fewer
lesions >50% (P = 0.03), and less proximal left anterior descending coro-
nary stenosis (P = 0.02), whereas age, cigarette smoking, and DM were
significant predictors of more severe CAD. On multivariate analysis obe-
sity remained a significant predictor of less severe CAD including lower
SYNTAX score (P = 0.04), fewer coronary stenotic lesions >50%
(P = 0.007), and a lower likelihood of proximal left anterior descending
coronary stenosis (P = 0.03). Age, cigarette smoking, and DM remained
significant predictors of severe CAD.

Computed Tomographic Coronary Artery Imaging Studies

Multiple studies employing computed tomography of the coronary arter-
ies have evaluated the relation of obesity to CAD and CAC. Labounty et al
studied 13,874 patients who were suspected of having CAD and who under-
went computed tomographic coronary angiography.100 Subjects with an
increased BMI had a greater prevalence, extent and severity of CAD that
could not be attributed entirely to CVD risk factors. In this study an indepen-
dent association existed between BMI and risk of MI.
In the Muscatine Heart Study consisting of 384 males and females
(15 years old at entry, follow-up: 15 years), obesity (assessed by BMI
and triceps skinfold thickness) was strongly associated with coronary
artery calcification (CAC) detected by computed tomography.101
In the Dallas Heart Study See et al reported that WHR was the only
anthropomorphic measure of obesity associated with CAC on computed
tomography (OR: 1.91).102
Several studies have utilized the Agaston score derived from cardiac
computed tomography to quantify CAC. In a retrospective study of 6661
patients (mean age: 57.1 years), Aljizeeri et al evaluated the association
of CAC (Agaston score) and indices of body weight including BMI and
% body fat.103 The study included patients who were underweight
(0.1%), patients with normal weight (21.3%), patients who were OW

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(39.1%), and patients who were obese (39.4%). An independent associa-

tion existed between the presence of CAC and BMI (5 kg/m2 increments,
OR: 1.05, 95% CI: 1.00-1.11, P= 0.038) and % body fat (OR: 2.38, 95%
CI: 1.05-5.41, P = 0.038). BMI categories and body surface area failed to
independently predicted CAC score. Percent body fat predicted CAC
score in men, but not in women.
In the Coronary Artery Risk Development in Young Adults (CARDIA)
study included 3275 healthy persons who were not initially obese (age range:
18-30 years, follow-up up to 25 years).104 Assessment for associated risk fac-
tors and CAD occurred every 2-5 years. During the follow-up period, 40% of
participants developed obesity that was either generalized or abdominal.
CAC developed at a rate of 16 per 1000 patient years in patients who were
obese for >20 years compared to 11 per 1000 patient years in those who
remained nonobese. Ten-year progression of CAC (Agaston score) was seen
in 25.2% of those with generalized obesity and in 27.2 % of those with
abdominal obesity >20 years. Respective rates of progression in patients
who were not obese were 20.2% and 19.5%.
Yoon et al retrospectively studied 1218 subjects who were obese, but met-
abolically healthy to determine the risk of development of the MetS and pro-
gression of CAC score during a median follow-up period of 45 months.105
Obesity was defined as a BMI 25 kg/m2. Patients who were obese, but met-
abolically healthy was were classified as class I if there was obesity and one
other component of the MetS and class II if there was obesity and no other
components of the MetS. CAC at baseline was 0 units for all patients. Meta-
bolically healthy patients without obesity served as the reference group. Dur-
ing the follow-up period, 32.2 % of class I and 10.2% of class II
metabolically healthy subjects who were obese developed the MetS (HR:
2.174, 95% CI: 1.513-3.127 for class I and HR: 1.166, 95% CI: 0.434-3.129
for class II patients). Class I patients developed a significant increase in
Agaston score (HR: 1.653, 95% CI: 1.144-2.390), whereas class II patients
experienced no significant change in Agaston score. In class I patients who
maintained metabolic health during follow-up, no significant change in
Agaston score was noted.
Chang et al studied 14,828 metabolically healthy adults (no evidence of
CVD, MetS absent, homeostatic model assessment normal).106 The study
population consisted of normal individuals and subjects who were metaboli-
cally healthy and obese. CAC scores were obtained on all patients. Patients
who were metabolically healthy but obese had a higher prevalence of CAC
than normal weight subjects. Multivariable analysis showed the CAC ratio
of metabolically healthy patients with obesity compared to normal weight
subjects (risk ratio: 2, 95% CI: 1.48-3.43) Additional adjustment for

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metabolic risk factors weakened this association to the point where CAC
score was no longer significantly different between the 2 groups. Thus, the
prevalence of CAC is higher in metabolically healthy subjects with obesity,
but this appears to be mediated by metabolic risk factors below levels tradi-
tionally considered to be abnormal.

THE OBESITY PARADOX AND CHD

There is ample evidence to support the presence of an obesity paradox
with regard to total and CHD mortality once CHD is confirmed.107-131
Wang et al performed a systematic review and meta-analysis on
1,300,794 patients with data culled from 89 studies to assess the associa-
tion of BMI to risk of mortality and CV events in patients with CAD dur-
ing a mean follow-up of 3.2 years.108 Compared to normal weight
patients, underweight status was associated with a significantly higher
risk of short-term mortality (relative risk: 2.24, 95% CI: 1.85-2.72) and
long-term mortality (relative risk: 1.70, 95% CI: 1.56-1.86). OW was
associated with significantly lower short-term mortality risk (relative
risk: 0.69, 95% CI: 0.64-0.75) and long-term mortality risk (relative risk:
0.79, 95% CI: 0.74-0.82). Similarly, obesity was associated with signifi-
cantly lower short-term mortality risk (relative risk: 0.68, 95% CI: 0.61-
0.75) and long-term mortality risk (relative risk: 0.79, 95%CI: 0.73-
0.85). Long-term benefit of obesity abated after 5 years of follow-up.
Patients with class II and class III obesity demonstrated lower short-term
mortality risk (relative risk: 0.76, 95% CI: 0.62-0.91), but higher mortal-
ity risk after 5 years of follow-up (relative risk: 1.25, 95% CI: 1.14-1.38)
compared to normal weight patients. Meta-regression analysis showed
attenuation of the inverse risk of obesity on mortality over longer follow-
up. Romero-Corral et al performed a systematic review and meta-analysis
of 40 studies comprising > 250,000 patients with documented CAD.109
The referent group in this study consisted of subjects whose BMI ranged
from 19.0 to 24.9 kg/m2 (normal weight). Total mortality was signifi-
cantly lower in patients who were OW than in those with class I obesity.
Patients who were underweight (<19.0 kg/m2 manifested the highest risk
for total mortality among the weight groups studied including those with
normal weight. It is of interest that the relative risk for total mortality in
patients whose BMI was 35 kg/m2 was not significantly different than
that of the referent group. Similar findings were observed in subgroups
receiving percutaneous coronary revascularization following acute MI. In
the CABG subgroup the relative risks for total mortality in patients who
were OW and in those with class I obesity were similar to that of the

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referent group, as were the relative risks for total mortality for patients
whose BMI was 35 kg/m2 and in those who were underweight. These
investigators also assessed the relation of CV mortality to BMI classifica-
tion. Relative risk of CV mortality was somewhat lower in those who
were OW and in those with class I obesity. However relative risks for CV
mortality were higher than that of the referent group in patients who were
underweight and in those whose BMI was 35 kg/m2.
Das et al reported the results of a study of 50,000 patients with acute
ST segment elevation MI.110 Subjects whose BMI ranged from 30 to 35
kg/m2 had the lowest mortality risk among the groups studied.
In a study by Kragelund et al, in-hospital adjusted mortality among
patients with ST segment or non-ST segment elevation MI was lower in
patients whose BMI was 40 kg/m2 than it was in subjects whose BMI
was < 40 kg/m2.111
The TARGET trial comprised 4800 patients with CAD who received a
bare metal stent and were treated with abciximab or tirofiban.112 No sig-
nificant difference in death or MI at 30 days or 180 days was noted
between those with and without obesity. In this study target vessel revas-
cularization at 6 months was more common in patients <65 years old
with obesity than in any of the other study subgroups.
Multiple studies have reported greater use of percutaneous coronary inter-
ventions in patients who were obese than in those who were not obese.113-121
In contrast to most studies, Akin et al did not report better outcomes in
patients with obesity following percutaneous coronary intervention in a
German registry.122
Studies assessing the effects of obesity on mortality and other out-
comes in patients undergoing CABG have produced variable results. A
study of 6068 patients undergoing CABG reported by Habib et al demon-
strated that 12-year mortality was similar between normal weight subjects
and those whose BMI values ranged from 32 to 36 kg/m2, but was signifi-
cantly greater in those whose BMI was  36 kg/m2.123 Terada et al
reported lower short-term mortality in patients who were OW receiving
CABG compared to patients in other body weight categories.124 In a
study of 4713 patients who were obese, 243 patients who were morbidly
obese, and 1014 patients with normal weight who underwent isolated
CABG, Kuduvalli et al reported no significant differences in the inci-
dence of mortality, MI, stroke, re-exploration of the thorax, or renal fail-
ure during short-term follow-up among the 3 study groups.125 In a study
of 31,021 patients with CHD (follow-up: 46 months) Oreopoulos et al
reported that medically-treated patients who were OW or had class I obe-
sity who had significantly lower mortality risk than subjects who were

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underweight or those who were at normal weight.126 In patients undergo-

ing CABG, subjects with a BMI of 35-39.9 kg/m2 had the lowest mortal-
ity rates among the weight groups studied. Other studies have reported
similar findings.47,127-129 In most of these studies, patients with class I
and class II obesity were more commonly re-vascularized than other BMI
subgroups.
DeSchutter et al studied 519 patients with CHD before and after car-
diac rehabilitation (follow-up >3 years).130 All-cause mortality was high-
est in the subgroup with the highest CRP level and lower BMI. Higher
BMI was associated with lower mortality in the entire study population
and was associated with a trend toward lower mortality in the higher and
lower CRP subgroups. High body fat was associated with lower mortality
in the higher CRP subgroup, but not in the lower CRP subgroup.
The bulk of evidence suggests that in patients with CHD who are OW
and in those with class I obesity, mortality rates are similar to or lower
than mortality rates of normal weight individuals regardless of the clini-
cal presentation.107-131 Persons who are underweight have consistently
been shown to have the highest risk for mortality. Variability exists
regarding mortality among those who are more severely obese.

RELATION OF PHYSICAL ACTIVITY AND CRF TO CVD

AND CHD IN PATIENTS WHO ARE OW OR OBESE
Substantial evidence confirms the important impact of physical activity
and CRF on the overall incidence of CVD and on all-cause and CVD
mortality in patients who are OW or obese.132-138 Recent studies suggest
that CRF may be more important than BMI for predicting prognosis; that
is, that patients who are OW or obese with preserved CRF may have a
better prognosis than do lean subjects with low CRF.132-138
McAuley et al studied 9563 men with CHD (mean follow-up: 33.4 years)
matched for age and gender.136 Subjects in the lowest tercile for CRF were
classified as unfit, whereas those in higher terciles were classified as fit. Dur-
ing follow-up, fit patients had a good prognosis with respect to all-cause and
CVD mortality regardless of BMI, WC or percent body fat. In the unfit group
patients with the lowest BMI, WC and percent body fat had a worse progno-
sis than those with a greater degree of adiposity.
In a recent study from Norway, 6493 participants with CHD were fol-
lowed for a median of 12.5 years to assess the impact of physical activity
and BMI on all-cause and CVD mortality.137 Patients who were OW or
obese had lower all-cause and CVD mortality than did lower weight sub-
jects indicating an obesity paradox. However, this was observed only in

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patients who did not meet international physical activity guidelines. Thus,
in this study physical activity was more important than BMI in predicting
prognosis. In a follow-up study from the same cohort, 3307 patients with
CHD were followed for a mean of 15.7 years.138 Changes in BMI and
physical activity were assessed to determine their effect on all-cause and
CVD mortality. Weight loss produced no significant reduction in all-
cause or CVD mortality. In fact, there was a reduction in mortality in
patients with weight gain whose BMI was normal at baseline. Sustained
or increased physical activity over time was associated with decreased
all-cause and CVD mortality.
In aggregate, these studies suggest that physical activity and preserved
CRF are able to attenuate the adverse effects of OW and obesity on all-
cause and CVD mortality.

EFFECTS OF WEIGHT LOSS

Intentional weight loss can favorably modify many of the traditional
CVD risk factors related to OW and obesity including hypertension, ath-
erogenic dyslipidemia and type 2 DM.1-9,11,139 Weight loss also reduces
insulin resistance and inflammation, improves endothelial function, and
decreases the incidence of the MetS.1,11,15-19
The Asia Pacific Cohort Collaboration investigators studied 33 cohorts
comprising 310,000 patients. They reported that each 2 kg/m2 decrease in
BMI was associated with a 14% decrease in the risk of CHD. In the Aus-
tralia/New Zealand cohort, the decrease in CHD risk was 10%.140
Pack et al performed a systematic review and meta-analysis of 35,335
patients to determine the importance of weight loss in patients with
CAD.141 The endpoint of the study was a composite of all-cause mortal-
ity, CVD mortality, and major adverse cardiac events. The study group
was 72% male and had an average age of 64 years. The average BMI was
30 kg/m2 and the average follow-up period was 3.2 years. Overall, the
study group demonstrated a greater risk of the composite endpoint with
lack of weight loss (relative risk: 1.30, 95% CI: 1.00-1.69, P = 0.05).
However, intentional weight loss was associated with improved outcomes
(relative risk: 0.67, 95%CI: 0.56-0.80, P < 0.001), whereas observational
weight loss was associated with worse outcomes (relative risk: 1.62, 95%
CI: 1.06-2.08, P < 0.001). Although data are limited concerning the
effect of intentional weight loss on CVD outcomes these studies suggest
that intentional weight loss may improve prognosis in patients with CVD
in patients who are OW or obese. However, it is clear further investiga-
tions are required to verify the findings in these studies.

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CONCLUSIONS
OW and obesity are closely linked to both traditional and novel risk
factors for CVD Central obesity is an important component of the MetS.
Epidemiologic studies suggest an association between OW/obesity and
CVD including CHD and its complications. This is particularly true of
patients with central obesity. The evidence is less robust in studies
derived from autopsy and coronary angiographic data. Obesity is classi-
fied as an independent risk factor of CVD. There is substantial evidence
to support the existence of an obesity paradox with respect to total and
CVD mortality. Low CRF facilitates the development all-cause and CVD
mortality in patients with CHD who are OW or obese. Preserved CRF
and physical activity attenuates the adverse effects of OW and obesity on
all-cause and CVD mortality. Although intentional weight loss can favor-
ably modify many CVD risk factors, evidence of an association between
weight reduction and improvement in CVD outcomes remains sparse.

Authors’ contributions
Natraj Katta, MD: conceptualization, data collection, writing of orig-
inal draft, review and editing; Troy Loethen, MD: data collection, writ-
ing original draft, review and editing; Carl J. Lavie, MD:
conceptualization, data collection, writing original draft, review and edit-
ing; Martin A. Alpert, MD: supervisor, conceptualization, data collec-
tion, writing first draft, review and editing.

Funding
None.

Conflicts of interest
None of the authors reports actual or potential conflicts of or compet-
ing interests related to contents of this manuscript.

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