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research-article2014
EUROPEAN
SOCIETY OF
CARDIOLOGY
Review
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
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 proportion of children than ever before are overweight or obese.1
The burden of obesity and its related conditions on healthcare 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 aforementioned risk factors, it could be speculated that obese individuals would have more adverse outcomes compared to
those with normal BMI. However, various prospective
studies have reported a U-shaped relationship between
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: vijay.kunadian@newcastle.ac.uk
Methods
A series of database searches using Medline, EMBASE, and
PubMed were performed using the following key words:
obesity, acute coronary syndrome, coronary revascularization, 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), normal range (18.524.99 kg/m2), overweight (2529.99 kg/
m2), obese class I (3034.99 kg/m2), obese class II (35
39.99 kg/m2), and obese class III (40 kg/m2).10
A study by Timoteo and colleagues12 evaluating inhospital 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 drugeluting stent (DES) implantation demonstrated no significant 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 normalweight, 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 etal.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 MACCEfree 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 cardiovascular outcomes in patients enrolled in a PCI trial comparing 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 cardiac 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 stenting.15 In fact, most of the studies utilized bare metal stents
(BMS). A similar study in the Chinese population16 demonstrated 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 specifically 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
Ghoorah et al.
Table 1. Effect of obesity on cardiovascular outcomes.
Publication
Year
Patient profile
Sample size
Outcomes
Akin
etal.13
2012
Post PCI
5806
Buettner
etal.52
Curtis etal.5
2007
UA/NSTEMI
1676
2005
7767
Gruberg
etal.7
2002
Stable
outpatients
with HF
Known CAD
undergoing PCI
Kosuge
etal.67
Nigam
etal.65
2008
Oreopoulos
etal.9
2008
Poludasu
etal.66
Sarno
etal.15
2009
Post PCI
777
2010
Post PCI
1707
Shechtera
etal.8
2010
ACS
5751
Timoteo
etal.12
2011
Wang
etal.16
2009
2006
Post PCI
9633
3076
894
22 cohort
publications
539
4972
1-year mortality
(%)
3-year mortality
(%)
All-cause mortality
(HR)
In-hospital
mortality (%)
12-month
mortality (%)
In-hospital
mortality rate (%)
6-month mortality
(HR)
Long-term
mortality (HR)
30-day mortality
(OR)
15-year mortality
(OR)
5 year survival
rate (%)
Major adverse
cardiac events at 1
year (%)
30-day mortality
(OR)
1-year mortality
(HR)
In-hospital
mortality (%)
1-year mortality
(%)
Long-term
cardiovascular
thrombotic events
(%)
2530
>30
3.3
2.4
2.4
9.9
7.7
3.6
0.88
0.81
Ref.
1.3
Ref.
0.7
10.6
5.7
4.9
4.4
2.5
1.8
Ref.
0.47 (>25)
0.71
0.63
Ref.
0.66
0.65
84
8.7
90
92
11.3
14.5
Ref.
0.52
0.92
Ref.
0.65
0.91
8.0
4.4
5.9
11.2
5.2
6.9
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 infarction; UA, unstable angina.
mechanisms. Normal vasculature can be disrupted in different ways to produce distinct coronary syndromes.
Acute coronary syndrome (ACS) develops from an occlusion 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 arteries.19 Atherosclerotic plaques contain a lipid pool underneath 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
Ghoorah et al.
CRP and multiple measures of atherosclerosis, including
CAC, aortic wall thickness, and aortic plaque burden, was
weaker in obese individuals compared to nonobese individuals (p<0.05 in nonobese; p>0.1 in obese).36 CRP is therefore a poor predictor of atherosclerosis in obese patients.
This finding has been replicated in stroke patients, where
high levels of CRP (3 mg/l) increased risk of stroke only in
underweight or normal-weight individuals.43 It has been
speculated that the poor predictive accuracy of CRP in obese
subjects may be caused by the close correlation between
CRP and increased adiposity in obesity. In fact, up to onethird of interleukin 6, a powerful CRP inducer, is released
from adipose tissue.44 Thus, in obese patients with high
body adiposity, an increase in CRP levels may lead to an
overestimation of atherosclerotic burden and cardiovascular
risk. With increasing obesity in population, the relationship
between obesity, inflammation and atherosclerosis is crucial
to our understanding and the management of CAD patients;
additional studies are required to help predict cardiovascular
risk in obese individuals.
Discussion
The obesity paradox is a subject of much debate and there
are uncertainties regarding its validity as a true paradox. It
is important to note that even in recent reports from largescale PCI registries, increasing weight did not lead to
adverse outcomes.13 There are a number of possible mechanisms for this effect.
Intensive pharmacotherapy could play a large role in the
potential obesity paradox. Obese patients present younger,
with less high-risk coronary anatomy, and, in some studies,
have been found to be placed on more aggressive pharmacotherapy than normal-weight patients. It has also been
demonstrated that these patients are more likely to reach
targets for secondary prevention. Patients on statins are
more likely to reach their target low-density lipoprotein
cholesterol range if they have a BMI >30 kg/m2.59 In population studies, USA and Canada have the highest levels of
obesity with CAD, yet these patients are also more likely to
meet targets for BP, lipids, and glycaemic control.60
One marker of obesity is visceral abdominal tissue
(VAT) which is linked to low-level inflammation and has
strong risk factor associations with CAD.61 Those with
larger amounts of VAT have been demonstrated to develop
more noncalcified coronary lesions, with greater risk of
progression. But VAT does not predict high levels of calcification within the coronary arteries.62 Adipose tissue is an
endocrine organ and a number of bioactive mediators
released could play a potential role in the development of
obesity-related atherosclerosis and insulin resistance has
been linked to levels of VAT. In addition to endocrine disorders, visceral fat correlates with systolic blood pressure and
reductions in visceral fat has been demonstrated to be
directly associated with reductions in blood pressure.63
As the knowledge of atherosclerosis increases, stratification of patients into high- and low-risk categories is possible. The incidence of STEMI is decreasing, with increases
in the cases of NSTEMI which has been linked to the
decrease in rates of smoking and increases in obesity and
hypertension.64
Although obesity seems to be associated with better outcomes following coronary reperfusion therapy, excess
weight has been shown to accelerate the atherosclerotic process and remains harmful to overall cardiovascular health
especially in adolescents and young men.65 In 1998, the
American Heart Association reclassified obesity as a major,
modifiable risk factor for coronary heart disease.66 National
guidelines strongly recommend weight reduction strategies
in the primary and secondary prevention of CAD.67
Conclusion
Studies based on the WHO definitions of obesity have demonstrated a U-shaped bimodal distribution for mortality
rates after coronary revascularization and BMI. In these
reports, both underweight and extremely obese patients
Ghoorah et al.
(class II or III) have increased mortality, whereas those in
the overweight or obese class I category have lower mortality rates. Various mechanisms have been speculated to
account for this. However, in some other studies, BMI is not
an independent predictor of mortality, and other factors such
as age at presentation and more aggressive treatment regimens have skewed the results to favour an obesity paradox.
More robust studies are needed to analyse this reverse epidemiology phenomenon as the exact mechanism for obesity
paradox is not clear.
Conflict of interest
The authors declare that there is no conflict of interest.
Funding
This work was supported by the National Institute for Health
Research (NIHR) Newcastle Biomedical Research Centre based
at Newcastle-upon-Tyne Hospitals NHS Foundation Trust and
Newcastle University, BH121098.
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