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European Heart Journal Acute Cardiovascular Care Volume issue 2014 [doi 10.1177 2048872614523349] Ghoorah, K.; Campbell, P.; Kent, A.; Maznyczka, A.; Kunadian, V. -- Obesity and cardiovascular outco (1)

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European Heart Journal: Acute Cardiovascular
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Obesity and cardiovascular outcomes: a review
Kuldeepa Ghoorah, Peter Campbell, Alexandra Kent, Annette Maznyczka and Vijay Kunadian
European Heart Journal: Acute Cardiovascular Care published online 13 February 2014
DOI: 10.1177/2048872614523349
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ACC0010.1177/2048872614523349European Heart Journal: Acute Cardiovascular CareGhoorah et al.
EUROPEAN
SOCIETY OF
CARDIOLOGY ®
Review
European Heart Journal: Acute Cardiovascular Care
1­–9
© The European Society of Cardiology 2014
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DOI: 10.1177/2048872614523349
acc.sagepub.com
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
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
obesity and mortality from various diseases, including
myocardial infarction (MI) and heart failure, suggesting
that patients with higher BMI have similar or lower shortand long-term mortality rates.4–8 A recent meta-analysis
demonstrated that those patients who are classed as overweight or obese have lower mortality rates post PCI following 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
1Newcastle
2Newcastle
University, Newcastle, UK.
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]
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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 mechanisms 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 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 (18.5–24.99 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 (mortality 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 normalweight 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 revascularization 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, compared to those who were not classed as morbidly obese.6
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 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 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
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Ghoorah et al.
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
Akin et
al.13
2012
Post PCI
5806
Buettner
et al.52
Curtis et al.5
2007
UA/NSTEMI
1676
2005
7767
Gruberg
et al.7
2002
Stable
outpatients
with HF
Known CAD
undergoing PCI
Kosuge
et al.67
Nigam
et al.65
Oreopoulos
et al.9
2008
2006
2008
Post PCI for
STEMI
Acute MI
Post PCI
9633
3076
894
22 cohort
publications
Poludasu
et al.66
Sarno
et al.15
2009
Post PCI
777
2010
Post PCI
1707
Shechtera
et al.8
2010
ACS
5751
Timoteo
et al.12
Wang
et al.16
2011
2009
Post PCI for
STEMI
Post PCI
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)
1–5-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
(%)
25–30
>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)
Similar across all groups
Ref.
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.
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 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
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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 hypertension.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 independent predictor of HRCA. Long-term (30–36 months) mortality 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 earlier, a potential explanation for the obesity paradox.
A similar study by Niraj et al.24 reported a negative correlation 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 therapy 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 demonstrated 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 stable 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 independent 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 atherosclerosis.34 In healthy-weight populations, levels of
C-reactive protein (CRP) correlate to CAC.35 However, in
the obese population this correlation attenuates to insignificance and high levels of CRP do not indicate high levels of
CAC.36 Inflammation and the concurrent vascular endothelial damage play an important role in the pathogenesis of
CAD. Large-scale trials and meta-analyses have demonstrated that CRP and fibrinogen are predictors of CAD.37,38
BMI and CRP correlate strongly, with increasing BMI leading to higher levels of CRP in both genders, with a particularly 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 atherosclerosis. Their study demonstrated that the association between
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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.
Obesity and endothelial function
Paradoxically, obese individuals have also been shown to
have better endothelial function than nonobese individuals. In a study assessing vascular function, inflammatory
markers, and CD34+KDR+/CD133+ endothelial progenitor cells (known markers of vascular health/protection) in
71 healthy participants,45 it was demonstrated that flowmediated dilation was higher in severely obese than in
obese and normal-weight individuals (p=0.019 and
p=0.011 respectively). Intima–media thickness was lower
in severely obese than in obese individuals (p=0.040).
Although CRP levels and leptin were higher in severely
obese than in obese and normal-weight individuals,
CD34+KDR+ endothelial progenitor cells were significantly higher in severely obese vs. obese individuals
(p=0.039), possibly providing vascular protection against
atherosclerosis.45
Obesity and acute STEMI
Wienbergen and colleagues46 evaluated the relationship
between BMI and the occurrence and outcome of acute
STEMI in 10 534 consecutive patients with STEMI in the
German MITRA (Maximal Individual Therapy of Acute
MI) PLUS registry. Obese patients with their first STEMI
were reported to be younger (62.5 vs. 65.7 years; p<0.0001),
had lower in-hospital (6.0%) and long-term mortality
(4.8%) of all compared to nonobese groups.46 Obesity has
also been linked with a smaller infarct size in STEMI
patients, a possible explanation for better outcomes.
Pingitore et al.47 used magnetic resonance imaging to measure infarct size in 89 patients with a first MI (of whom 80%
had a STEMI). A smaller infarct size was observed in obese
patients (11±4% of left ventricular myocardium) than in
those with normal bodyweight (16±9% of left ventricular
myocardium; p=0.03).47 Similarly, cardiac fat, including
epicardial adipose tissue and pericardial adipose tissue,
measured by transthoracic echocardiography was found to
be associated with smaller infarct size.48
To better understand the impact of ‘extreme’ obesity
(BMI >40 mg/m2) and outcomes of STEMI, Das and colleagues49 investigated 50,149 patients with morbid obesity from the National Cardiovascular Data Registry
(NCDR) Acute Coronary Treatment and Intervention
Outcomes Network (ACTION) Registry and found that
these patients present with STEMI at a younger age
(median age 55 years for class III obese vs. 66 years for
normal weight) and have less extensive CAD and better
left ventricular systolic function. Surprisingly, despite
these, class III obesity was independently associated with
higher in-hospital mortality.49 Unadjusted outcomes saw a
U-shaped bimodal distribution with extremes of weight
demonstrating worst outcomes. When adjusted for confounding influences, only class III obesity demonstrated
increased mortality rates. Medical practices were similar
across all treatment groups, suggesting that only extreme
obesity increased in-hospital mortality post PCI (adjusted
1.64, 95% CI 1.32–2.03).49 Despite being at lower a priori
risk and receiving similar care, morbidly obese patients
had worse outcomes, the mechanism of which has not
been elucidated yet. The investigators speculated that
class III obesity might be related to other comorbidities
not captured by the registry or might be associated with an
intrinsic hazard that needs further elucidation by further
robust studies. These studies also highlight the importance of primary prevention aimed at reducing obesity and
metabolic syndrome in young people to avoid the early
occurrence of STEMI.
Obesity and acute NSTEMI
The CRUSADE (Can Rapid Risk Stratification of Unstable
Angina Patients Suppress Adverse Outcomes with Early
Implementation of the American College of Cardiology/
American Heart Association Guidelines) study50 demonstrated a strong inverse relationship between BMI and age
of first presentation with NSTEMI on retrospective analysis of date from 189,065 patients with ACS. The age of
first NSTEMI occurred 3.5, 6.8, 9.4, and 12.0 years earlier
with increasing BMI (25.1–30.0, 30.1–35.0, 35.1–40.0,
and >40.0 kg/m2, respectively; p<0.0001). Obese patients
demonstrated an increase in all cardiac risk factors, which
was countered by an increased prescription of cardio protective drugs at baseline.50 The obese patients also received
more aggressive management following NSTEMI and,
except for the extremely obese, this resulted in a lower
incidence of death and reinfarction compared with normalweight individuals.51 Compared to the normal-weight
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European Heart Journal: Acute Cardiovascular Care
group, all obesity groups were more likely to undergo PCI
and were more likely to be treated with antiplatelet, statin,
beta-blocker, and angiotensin-converting enzyme inhibitor
therapy.51 A prospective study of NSTEMI and unstable
angina patients52 demonstrated that higher BMI groups
received higher rates of gold standard medical therapy and
had improved rates of all-cause mortality than normal BMI
groups. Obese patients more often received angiotensinconverting enzyme inhibitor (64 vs. 51%) or statin treatment (70 vs. 57%). After 3-year follow up, obese patients
(BMI >30 kg/m2) had less than half mortality when compared with normal BMI patients (hazard ratio, HR 0.38,
95% CI 0.18–0.81; p=0.012].52 Thus, although obesity
appears to increase the risk of developing unstable angina
and NSTEMI at a younger age, obese patients appear to
receive more aggressive medical and interventional management, resulting in better outcomes.
Obesity, gender, and percutaneous
coronary intervention
A significant number of studies have reported that women
present later with CAD than men.53 Also of concern is that
the number of young women presenting with CAD is
increasing and that the prevalence of women is highest in
the obese class III category.49,54 A retrospective study of
clinical records in Spain53 demonstrated that women
undergoing PCI were more likely to be obese (OR 1.8),
hypertensive (OR 2.9), and diabetic (OR 2.1) compared to
men. In a review of the British Columbia Cardiac
Registry,54 major bleeding rates and mortality after PCI in
38,346 consecutive patients during a 6-year period were
studied. Female gender was more prevalent at the extremes
of weight. A clear bimodal relationship between obesity
and outcomes was present for both genders (underweight
OR 1.98, 95% CI 1.6–2.5; p<0.0001) and morbidly obese
(OR 1.61, 95% CI 1.28–2.08; p<0.0001).54 Periprocedural
transfusion also showed the same bimodal distribution
and was associated with adverse outcomes (OR 2.86, 95%
CI 2.52–3.25; p<0.0001).55 This shows that women who
are morbidly obese are at much higher risk of bleeding
after PCI.
One hypothesis for the obesity paradox is that treatment is provided more readily to the overweight and
obese. Oestrogen is known to have a cardioprotective
effect and this adds further layers of complexity to the
process of atherogenesis.56 In men, age does not predict
likelihood of plaque rupture causing sudden cardiac
death. Yet in women, likelihood of sudden death by
plaque rupture increases with age with increasing BMI
linked to causing plaque rupture in cases of sudden cardiac death in women.57 Oestrogen offsets some of the risk
of obesity in premenopausal women. Yet for postmenopausal women, without this cardioprotective effect, rates
of plaque rupture increase.58
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
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7
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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