Obesity & Cardiovascular Outcomes: A Review

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European Heart Journal: Acute Cardiovascular
http://acc.sagepub.com/content/early/2014/02/13/2048872614523349
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DOI: 10.1177/2048872614523349
published online 13 February 2014European Heart Journal: Acute Cardiovascular Care
Kuldeepa Ghoorah, Peter Campbell, Alexandra Kent, Annette Maznyczka and Vijay Kunadian
Obesity and cardiovascular outcomes: a review
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EUROPEAN
SOCIETY OF
CARDIOLOGY
®
Introduction
Obesity and its associated conditions are fast becoming a
burden in modern health care. In 2010, more than a quarter
of the English male population was classified as obese,
with a body mass index (BMI) >30 kg/m2. A larger propor-
tion of children than ever before are overweight or obese.1
The burden of obesity and its related conditions on health-
care provision will only increase in the coming decades.
There is a strong correlation between obesity and a number
of risk factors for coronary artery disease (CAD) including
hypertension, dyslipidaemia and insulin resistance.2 In
2008, CAD caused in excess of 88,000 deaths and over
80,000 percutaneous coronary interventions (PCI) are now
carried out in the UK every year, a 300% increase in a
decade.3
Given the association of obesity with the aforemen-
tioned risk factors, it could be speculated that obese indi-
viduals would have more adverse outcomes compared to
those with normal BMI. However, various prospective
studies have reported a U-shaped relationship between
obesity and mortality from various diseases, including
myocardial infarction (MI) and heart failure, suggesting
that patients with higher BMI have similar or lower short-
and long-term mortality rates.4–8 A recent meta-analysis
demonstrated that those patients who are classed as over-
weight or obese have lower mortality rates post PCI follow-
ing MI (both ST-elevation myocardial infarction (STEMI)
and non-ST-elevation myocardial infarction (NSTEMI)).9
This phenomenon has been termed the ‘obesity paradox’ or
‘reverse epidemiology’. However, there is still much
Obesity and cardiovascular
outcomes: a review
Kuldeepa Ghoorah2, Peter Campbell1, Alexandra Kent2, Annette
Maznyczka2, and Vijay Kunadian1,2
Abstract
The prevalence of obesity is increasing at an epidemic rate globally with more than 1 billion adults overweight and at
least 300 million of them clinically obese. This is expected to rise further in the next 20 to 30 years. Obesity is known to
be an independent risk factor for serious health conditions, including hypertension, type 2 diabetes, and cardiovascular
diseases. Given the association of obesity with cardiovascular disease, it could be speculated that obese individuals would
have adverse outcomes after a cardiovascular event compared to those with normal body mass index (BMI). However,
various studies have reported a paradoxical U-shaped relationship between obesity and mortality from various diseases,
including myocardial infarction and heart failure, suggesting that patients with higher BMI have similar or lower short- and
long-term mortality rates. This phenomenon has been termed the ‘obesity paradox’ or ‘reverse epidemiology’. The goal
of this review is to evaluate the potential mechanisms behind the obesity paradox and its implications.
Keywords
Body mass index, coronary revascularization, myocardial infarction, obesity, obesity paradox, overweight, percutaneous
coronary intervention, reverse epidemiology
Received: 19 November 2013; Accepted: 8 January 2014
1Newcastle University, Newcastle, UK.
2 Newcastle Upon Tyne Hospitals NHS Foundation Trust, Newcastle,
UK.
Corresponding author:
Vijay Kunadian, Institute of Cellular Medicine, Faculty of Medical
Sciences, Newcastle University, Floor 3 William Leech Building,
Newcastle upon Tyne, NE2 4HH, UK.
Email: [email protected]
523349ACC0010.1177/2048872614523349European Heart Journal: Acute Cardiovascular CareGhoorah et al.
research-article2014
Review
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2 European Heart Journal: Acute Cardiovascular Care
disagreement about the nature of the obesity paradox,
whether it exists, and if it does by what mechanism is this
beneficial effect manifested.
The goal of this review is to evaluate the potential mech-
anisms behind the obesity paradox, and its implications in
the management of patients with CAD and undergoing PCI.
Methods
A series of database searches using Medline, EMBASE, and
PubMed were performed using the following key words:
obesity, acute coronary syndrome, coronary revasculariza-
tion, myocardial infarction, obesity paradox, body mass
index, percutaneous coronary intervention, atherosclerosis,
reverse epidemiology.
Definition of obesity
The World Health Organization (WHO) classifies obesity
based on BMI as follows: underweight (<18.5 kg/m2), nor-
mal range (18.5–24.99 kg/m2), overweight (25–29.99 kg/
m2), obese class I (30–34.99 kg/m2), obese class II (35–
39.99 kg/m2), and obese class III (≥40 kg/m2).10
The obesity paradox
The obesity paradox was first observed in 1996 in a study
involving 3571 consecutive patients with CAD undergoing
PCI.11 Overweight and obese patients had lower in-hospital
mortality rates compared to normal-weight patients (mor-
tality rates: 2.8% for BMI ≤25 kg/m2, 3.7% for BMI >35
kg/m2, and 0.9% for BMI 26–34 kg/m2; p<0.001).11 Since
then, several contemporary studies have been carried out to
shed more light on this phenomenon. The results of these
studies are summarized in Table 1.
In a robust 5-year study by Gruberg and colleagues,7
involving 9633 consecutive patients undergoing PCI, the
rate of major in-hospital complications, including cardiac
mortality, was significantly lower in overweight (0.7%) or
obese patients (0.4%) compared to their normal-weight
(1.0%) counterparts (p=0.001). In addition, the overweight
or obese patients had nearly one-half the in-hospital and
1-year mortality rates post PCI compared with normal-
weight patients (1 year all-cause mortality rates: normal
BMI cohort 10.6%, overweight cohort 5.7%, and obese
cohort 4.9%; p<0.0001).7 More recently, Dhoot et al.6
investigated the effect of morbid obesity (BMI ≥40 kg/m2)
on in-hospital mortality and outcomes post revasculariza-
tion in 413,673 patients presenting with STEMI and
NSTEMI. The study demonstrated that morbidly obese
patients had an unadjusted mortality rate of 3.5 vs. 5.5%
(p<0.0001) in those patients who were not classed as obese.
After adjustment, patients with morbid obesity were still
found to have lower odds of in-hospital mortality, com-
pared to those who were not classed as morbidly obese.6
A study by Timoteo and colleagues12 evaluating in-
hospital and long-term mortality in 539 consecutive patients
undergoing primary PCI for STEMI demonstrated that, in
fact, overweight patients have a better prognosis compared
with patients in the normal-weight and obese groups.
In-hospital mortality was 8.0% for patients with normal
BMI, 4.4% for overweight patients and 5.9% for obese
patients (p=0.296). At 30 days, mortality rate was 9.6, 5.2,
and 6.9% (p=0.212), and at 1-year follow up, 11.2, 5.2, and
6.9% (p=0.064), respectively.12
A multicentre German Drug-Eluting Stent (DES.DE)
registry13 comparing in-hospital and 1-year outcomes
among unselected patients undergoing PCI with drug-
eluting stent (DES) implantation demonstrated no signifi-
cant difference in major adverse cardiovascular or
cerebrovascular events (MACCE; the composite of death,
MI, and stroke) or target vessel revascularization (TVR)
outcomes based on BMI. Rates of MACCE in normal-
weight, overweight, and obese patients were 7.1, 5.6, and
5.5% (p=0.09) and rates of TVR in survivors were 10.9,
11.7, and 11.6% (p=0.56), respectively.13 In a Japanese
study, Ikeda et al.14 followed 121 patients for 8 years after
they underwent PCI for MI of the left anterior descending
artery for MACCE (all causes of death, stroke, target lesion
revascularization, TVR, nonfatal MI, and hospitalization).
Those with BMI >25 kg/m2 had on average longer MACCE-
free survival than those with BMI <25 kg/m2. Further analysis
demonstrated that a higher BMI with lower insulin resistance
was the best indicator of MACCE-free survival.14
Sarno and colleagues15 assessed the effect of BMI on car-
diovascular outcomes in patients enrolled in a PCI trial com-
paring a sirolimus-eluting stent with a durable polymer to a
biolimus-eluting stent with a biodegradable polymer. In this
study, at follow up after 1 year, the cumulative rate of car-
diac death, MI, and TVR was significantly higher in the
obese group (8.7% in normal-weight, 11.3% in overweight,
and 14.5% in obese patients). BMI was also found to be an
independent predictor of stent thrombosis. Interestingly, in
this study, all patients received DES, compared to other
studies confirming the obesity paradox where the patient
cohort were described to have PCI. It was not specified
whether PCI involved balloon angioplasty or a type of stent-
ing.15 In fact, most of the studies utilized bare metal stents
(BMS). A similar study in the Chinese population16 demon-
strated that long-term cardiovascular thrombotic events
were significantly higher in the obese group (5.9 vs. 3.2% in
normal-weight and 3.8% in overweight patients; p=0.001).
The incidence of stent thrombosis increased with increasing
BMI (0.9, 1.0, and 1.9% in normal, overweight, and obese
patients, respectively; p=0.029); again, DES were specifi-
cally used in all patients.16 DES were primarily developed to
reduce the incidence of restenosis, the major disadvantage
of BMS. Clinical trials have confirmed a reduction of 50–
70% in target lesion revascularization by DES compared to
BMS. However, DES requires a longer period of dual
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Ghoorah et al. 3
antiplatelet therapy to prevent stent thrombosis.17 In both
studies described above, all patients received the same dose
of clopidogrel, regardless of their weight.16,17 Antiplatelet
therapy might not have provided effective platelet inhibition
in patients with higher BMI, therefore leading to a greater
occurrence of stent thrombosis.
Obesity and atherosclerosis
Atherosclerosis, the process by which CAD develops is
an active process involving many complex biological
mechanisms. Normal vasculature can be disrupted in dif-
ferent ways to produce distinct coronary syndromes.
Acute coronary syndrome (ACS) develops from an occlu-
sion usually resulting from plaque rupture and thrombus
formation.18 Stable angina often occurs from stable
highly fibrous plaques, and these plaques are less prone
to rupture and thrombosis and cause stenosis of the arter-
ies.19 Atherosclerotic plaques contain a lipid pool under-
neath a fibrous cap. The thickness of this cap has been
linked to the likelihood of plaque rupture.20 Thick fibrous
caps are less prone to rupture and can lie dormant for
Table 1. Effect of obesity on cardiovascular outcomes.
Publication Year Patient profile Sample size Outcomes Outcomes according to body mass
index (kg/m2)
18.5–25 25–30 >30
Akin etal.13 2012 Post PCI 5806 1-year mortality
(%)
3.3 2.4 2.4
Buettner
etal.52
2007 UA/NSTEMI 1676 3-year mortality
(%)
9.9 7.7 3.6
Curtis etal.52005 Stable
outpatients
with HF
7767 All-cause mortality
(HR)
Ref. 0.88 0.81
Gruberg
etal.7
2002 Known CAD
undergoing PCI
9633 In-hospital
mortality (%)
1.3 Ref. 0.7
12-month
mortality (%)
10.6 5.7 4.9
Kosuge
etal.67
2008 Post PCI for
STEMI
3076 In-hospital
mortality rate (%)
4.4 2.5 1.8
Nigam
etal.65
2006 Acute MI 894 6-month mortality
(HR)
Ref. 0.47 (>25)
Long-term
mortality (HR)
Similar across all groups
Oreopoulos
etal.9
2008 Post PCI 22 cohort
publications
30-day mortality
(OR)
Ref. 0.71 0.63
1–5-year mortality
(OR)
Ref. 0.66 0.65
Poludasu
etal.66
2009 Post PCI 777 5 year survival
rate (%)
84 90 92
Sarno
etal.15
2010 Post PCI 1707 Major adverse
cardiac events at 1
year (%)
8.7 11.3 14.5
Shechtera
etal.8
2010 ACS 5751 30-day mortality
(OR)
Ref. 0.52 0.92
1-year mortality
(HR)
Ref. 0.65 0.91
Timoteo
etal.12
2011 Post PCI for
STEMI
539 In-hospital
mortality (%)
8.0 4.4 5.9
1-year mortality
(%)
11.2 5.2 6.9
Wang
etal.16
2009 Post PCI 4972 Long-term
cardiovascular
thrombotic events
(%)
3.2 3.8 5.9
ACS, acute coronary syndrome; BMI, body mass index; CAD, coronary artery disease; HF, heart failure; HR, hazard ratio; MI, myocardial infarction;
NSTEMI, non-ST-elevation myocardial infarction; OR, odds ratio; PCI, percutaneous coronary intervention; STEMI, ST-elevation myocardial infarc-
tion; UA, unstable angina.
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4 European Heart Journal: Acute Cardiovascular Care
many years. The architecture of individual plaques is not
fixed and some lesions can contain a mix of both thick
and thin sections of fibrous cap. Thin fibrous caps with a
large lipid pool have been demonstrated to cause more
thrombus formation and resulting ACS.21
Obese patients undergoing coronary angiography tend to
have a number of distinct differences on presentation compared
to healthy-weight individuals. Obese patients tend to be
younger and are more likely to have diabetes and hyperten-
sion.13,22–25 A study of 928 patients who underwent coronary
angiography22 were categorized as having high-risk coronary
anatomy (HRCA) if their left main coronary artery had >50%
stenosis or they had significant three vessel coronary disease
(>70% narrowing). Demographic data from the study showed
that obese patients were younger (61.4±10.7 vs. 65.3±11.4 years;
p<0.0001) and had higher prevalence of hyperlipidaemia
hypertension, and diabetes mellitus. Obese patients however,
had a lower incidence of HRCA compared to nonobese patients
(23 vs. 37%, respectively; p=0.0002). Multivariate regression
analysis showed that advancing age (p<0.0001) was an inde-
pendent predictor of HRCA. Long-term (30–36 months) mor-
tality did not differ significantly between obese (6.9%) and
nonobese (8.2%) patients but was significantly higher in
patients with HRCA (12.4%) than in those without HRCA
(5.6%; p=0.0003).22 These results suggest that obese patients
had lower long-term mortality as they had a lower prevalence
of HRCA and because they were younger and were likely to be
referred for angiography and/or coronary revascularization ear-
lier, a potential explanation for the obesity paradox.
A similar study by Niraj et al.24 reported a negative cor-
relation between BMI and age (R=−0.15; p<0.001) and
between BMI and Duke Jeopardy score, a prognostic tool
predicting 1-year mortality in CAD (r=−0.07; p<0.05),
thereby confirming that obese patients present younger and
have a lower prevalence of high-risk CAD. However, after
adjusting for comorbidities, BMI was not found to be an
independent predictor of the severity of coronary lesions.24
In obese patients with less stenotic disease, intensive
pharmacotherapy could have enhanced benefits over a
patient with widespread stenotic disease. When comparing
the effect of statin therapy based on BMI, Nicholls et al.25
demonstrated that intensive statin treatment led to greater
impacts on atherosclerotic burden in patients with higher
BMI. Obese patients who had intensive lipid-lowering ther-
apy were reported to have a significant reduction on plaque
progression rates compared to moderate lipid-lowering
therapy (median progression rate –1.88 vs. +6.5% with the
moderate lipid-lowering strategy; p=0.01).25 These results
highlight the potential antiatherosclerotic benefits of lipid
lowering drugs in obese patients.
Obesity and coronary calcium
Coronary artery calcification (CAC) score can be used as a
marker of atherosclerotic disease.26 CAC is an active process
similar to bone formation with similar transcription factors,
cytokines and cell types.27,28 Noncalcified plaques have been
demonstrated to be less stable and more prone to rupture and
erosion.29 A study of 112 ACS and stable CAD patients dem-
onstrated that ACS patients were more likely to have a higher
number of noncalcified plaques (4.6±3.5 vs. 1.3±1.9; p<0.05)
and the plaques were more likely to have a large necrotic
core (0.58±0.73 vs. 0.22±0.43 mm2).30 While stable angina
patients had higher frequencies of extensive calcification,
acute MI patients displayed spottier calcification, which is a
large number of small deposits of calcium.31 The average
number of calcium deposits within an arc of <90 degrees per
patient in acute MI was 1.4±1.3, compared to 0.5±0.8 in sta-
ble angina (p<0.0005).31 It has been demonstrated that there
is an inverse relationship between bone mineral density and
coronary calcification, where there is greater bone mineral
density, there is less coronary calcification.28,32
BMI plays a role in the level of bone mineral density and
it is proposed that the physiological strain of a greater body
mass translates to denser bones. In patients aged 60 and
over, BMI and bone mineral density demonstrate a linear
relationship, with bone mineral density increasing with
increasing weight. Kovacic and colleagues33 prospectively
collected data on 9993 patients undergoing PCI, analysing
coronary calcium and BMI. BMI was found to be an inde-
pendent negative predictor of lesion calcification (odds
ratio, OR, 0.957, 95% CI 0.945–0.970; p<0.0001). Positive
indicators included age, hypertension, peripheral vascular
disease and diabetes.33 Given the above findings that obese
patients have potentially lower levels of CAC, it could be
speculated that this is a potential mechanism explaining the
obesity paradox.
Obesity and inflammation
Low level inflammation is linked to the process of athero-
sclerosis.34 In healthy-weight populations, levels of
C-reactive protein (CRP) correlate to CAC.35 However, in
the obese population this correlation attenuates to insignifi-
cance and high levels of CRP do not indicate high levels of
CAC.36 Inflammation and the concurrent vascular endothe-
lial damage play an important role in the pathogenesis of
CAD. Large-scale trials and meta-analyses have demon-
strated that CRP and fibrinogen are predictors of CAD.37,38
BMI and CRP correlate strongly, with increasing BMI lead-
ing to higher levels of CRP in both genders, with a particu-
larly strong relationship in women.39 CRP is synthesized in
the liver in response to the cytokine interleukin 6, which is
produced in response to inflammation and by adipose cells
directly, explaining the relationship between obesity and
CRP.40–42
Gupta and colleagues36 studied patients aged 30–65 years
from the Dallas Heart Study to determine whether BMI had
any effect on the relationship between CRP and atheroscle-
rosis. Their study demonstrated that the association between
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