European Heart Journal: Acute Cardiovascular Care http://acc.sagepub.com/ 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 The online version of this article can be found at: http://acc.sagepub.com/content/early/2014/02/13/2048872614523349 Published by: European Society of Cardiology ESC Working Group on Acute Cardiac Care and http://www.sagepublications.com Additional services and information for European Heart Journal: Acute Cardiovascular Care can be found at: Email Alerts: http://acc.sagepub.com/cgi/alerts Subscriptions: http://acc.sagepub.com/subscriptions Reprints: http://www.sagepub.com/journalsReprints.nav Permissions: http://www.sagepub.com/journalsPermissions.nav >> OnlineFirst Version of Record - Feb 13, 2014 What is This? Downloaded from acc.sagepub.com at Uni of Southern Queensland on October 9, 2014 523349 research-article2014 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 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav 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] Downloaded from acc.sagepub.com at Uni of Southern Queensland on October 9, 2014 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 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 Downloaded from acc.sagepub.com at Uni of Southern Queensland on October 9, 2014 3 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 Downloaded from acc.sagepub.com at Uni of Southern Queensland on October 9, 2014 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 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 Downloaded from acc.sagepub.com at Uni of Southern Queensland on October 9, 2014 5 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 Downloaded from acc.sagepub.com at Uni of Southern Queensland on October 9, 2014 6 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 Downloaded from acc.sagepub.com at Uni of Southern Queensland on October 9, 2014 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. References 1. NHS Information Centre Lifestyles Statistics. Statistics on obesity, physical activity and diet: England 2012. London: NHS Information Centre Lifestyles Statistics, 2012. 2. Krauss RM, Winston M, Fletcher BJ, et al. Obesity: impact on cardiovascular disease. Circulation 1998; 98: 1472–1476. 3. Scarborough PBP, Wickramasinghe K, Smolina K, et al. Coronary heart disease statistics. London: British Heart Foundation, 2010. 4. Clark AL, Chyu J and Horwich TB. The obesity paradox in men vs. women with systolic heart failure. Am J Cardiol 2012; 110: 77–82. 5. Curtis JP, Selter JG, Wang Y, et al. The obesity paradox: body mass index and outcomes in patients with heart failure. Arch Intern Med 2005; 165: 55–61. 6. Dhoot J, Tariq S, Erande A, et al. 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