European Heart Journal Advance Access published December 18, 2015

REVIEW

European Heart Journal doi:10.1093/eurheartj/ehv509

Controversies in cardiovascular medicine

Obesity and cardiovascular disease: friend or foe? Seong Hwan Kim 1, Jean-Pierre Despre´s 2, and Kwang Kon Koh 3,4* 1 Division of Cardiology, Korea University Ansan Hospital, Ansan, Republic of Korea; 2Department of Kinesiology, Faculty of Medicine, Quebec Heart and Lung Institute, Universite´ Laval, Quebec, Canada; 3Division of Cardiology, Department of Cardiovascular Medicine, Heart Center, Gachon University Gil Medical Center, 774 Beongil 21, Namdongdaero, Namdong-Gu, Incheon 405-760, Republic of Korea; and 4Gachon Cardiovascular Research Institute, Incheon, Republic of Korea

Received 23 May 2015; revised 26 August 2015; accepted 7 September 2015

----------------------------------------------------------------------------------------------------------------------------------------------------------Keywords

Obesity † Metabolically healthy obesity † Obesity paradox † Cardiovascular disease † Cardiometabolic syndrome

Introduction During the last three decades, the worldwide prevalence of obesity has nearly doubled, and the mean body mass index (BMI) has increased worldwide by 0.4 kg/m2 per decade for men and 0.5 kg/m2 per decade for women.1 Although obesity is merely one of various cardiovascular disease (CVD) risk factors, it has received a lot of medical attention lately as the prevalence of obesity continues to increase globally.2 Although some argue that obesity could be classified as a disease,3 many issues regarding assessment/management of obesity remain to be addressed. The first issue is that obesity is measured by various means, such as BMI, waist circumference (WC), waist-to-hip ratio, or by assessing visceral adiposity by imaging techniques. This means that the diagnosis of obesity could be influenced by the index used. It is already well established that there are considerable variations in the WC and visceral adipose tissue (AT) at any given BMI value.4,5 The second issue is that although WHO proposed lower BMI cut-off points for obesity among Asians,6 cohort studies about

the relationships between BMI and mortality do not seem to consistently support the need for lower BMI thresholds for the Asian population.7 – 9 Finally, within the Asian population itself, there may be differences in body composition/AT distribution. Another issue is the heterogeneity of obesity as a phenotype as it has been proposed by some investigators that there may even be a healthy form of obesity referred to as ‘metabolically healthy obesity’ (obesity which is characterized by a normal metabolic risk profile).10 In addition, the reported protective effect of obesity in patients with CVD, commonly referred to as the ‘obesity paradox’, poses an additional challenge to the CV risk assessment and management of the obese population.11 Finally, the suggested protective role of subcutaneous AT also support the importance of AT quality and function rather than just the level of adiposity per se in the regulation of lipid and carbohydrate metabolism and related cardiometabolic risk profile.2,12 – 14 Despite the unique characteristics of AT as an essential endocrine organ to maintain energy homeostasis, obesity definitely leads to increased risk of mortality at the population level.15 – 17 However, the

* Corresponding author. Tel: +82 32 460 3683, Fax: +82 32 467 9302, Email: [email protected] Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2015. For permissions please email: [email protected].

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Obesity is currently one of the greatest public health issues worldwide. However, despite its known deleterious effects on the cardiovascular system and its association with numerous cardiovascular diseases (CVD), recent findings leading to the development of concepts such as metabolically healthy obesity, the obesity paradox, and protective subcutaneous fat depots have raised a lively debate on the disparate effects of obesity on health outcomes. Regarding the concept of metabolically healthy obesity, by presumably labelling a subset of obese people as metabolically healthy, physicians may not feel pressed to curb the current obesity epidemic and prevent the next generation of people from becoming obese. Another issue is that the most commonly used anthropometric index to define obesity, the body mass index, is at the core of the controversy because of its limitations including its inability to discriminate between fat mass and muscle mass. Many recent epidemiological and metabolic studies have used other indices such as waist–hip ratio, waist circumference, and imaging (computed tomography or magnetic resonance imaging) measurements of visceral adiposity and of ectopic fat depots. In addition, emerging evidence supports the importance of cardiorespiratory fitness, skeletal muscle mass and strength in patients with obesity as useful variables to predict CVD risk beyond adiposity. In this review, we will discuss the complex and disparate effects of obesity on CVD, particularly focusing on whether, under given circumstances, it could be harmful, potentially harmless or neutral, or even possibly protective.

Page 2 of 11 presence of the obesity paradox in CVD has left some clinicians quite perplexed about the ‘identity’ of obesity. Although the underlying mechanisms governing these disparate effects of obesity on CVD are complex and not completely understood, a variety of factors, such as different anthropometric indices, body fat distribution, body composition, muscle mass and strength, and cardiorespiratory fitness (CRF), appear to play a critical role in explaining the paradoxical association of obesity with clinical outcomes. In this review, we will attempt to examine the complex and disparate effects of obesity on CVD. We will discuss whether or not metabolically healthy obesity exists and examine factors potentially involved in explaining the obesity paradox.

Obesity and cardiovascular pathophysiology: obesity is a foe!

Obesity and adipokines Considerable data from experimental, epidemiological, and clinical studies support the notion that obesity has independent adverse effects on haemodynamics and CV structure and function through AT dysfunction and abnormal inflammatory pathways. The adipocyte as an active endocrine secretory cell as well as an immune organ produces many different adipokines to modulate inflammation and various metabolic processes.18,19 Under normal physiologic circumstances, adipocytes release anti-inflammatory factors such as adiponectin, transforming growth factor-beta, interleukin-10, and nitric oxide, which promote insulin-sensitivity and anti-atherogenic effects.18,19 At the population level, adiponectin could be found in high levels in the blood of lean healthy individuals whereas its concentration was markedly reduced among individuals with type 2 diabetes, coronary heart disease (CHD), or with a high risk form of overweight/obesity.20 Thus, adiponectin has generally been perceived as an antidiabetogenic/antiatherosclerotic adipokine. In contrast, pathologic hypertrophied adipocytes caused by excessive body weight release pro-inflammatory cytokines such as leptin, tumour necrosis factor-alpha, resistin, and interleukin-6, contributing to the development of various metabolic diseases.21 According to the results from clinical and population surveys, although increased levels of adiponectin have been linked to higher mortality in older adults or patients with CVD, which is termed as the ‘adiponectin paradox’,19 hypoadiponectinemia in obese patients without CVD contributes to the development of obesity-related CVD through insulin resistance, inflammation, endothelial dysfunction, and atherosclerosis.18,20 On the other hand, plasma leptin levels increase with obesity, resulting in the term ‘leptin resistance’.21 Generally, leptin is known to produce opposing effects on atherogenesis, CV hypertrophy, metabolism, and inflammation. These contrasting effects are maintained in balance in a normal state. However, hyperleptinemia in obese individuals is associated with unfavourable CV outcomes via vascular inflammation, oxidative stress, atherothrombosis, left ventricular (LV) hypertrophy, and

insulin resistance.21 On the other hand, recent data reported that increase in leptin level had conferred some beneficial effects on coronary endothelial function in morbidly obese group (BMI ≥40 kg/m2), but not in the obese group (BMI 30–39 kg/m2).22 In addition, plasma endocannabinoids released from the AT, such as anandamide and 2-arachidonoylglycerol (2-AG), remain a focus of attention in obesity research. Endocannabinoids involved in feeding behaviour, energy metabolism as well as glucose and lipid metabolism are increased via insulin resistance and inflammation in obese individuals, which may stimulate the overexpression of cannabinoid receptors in a pathophysiological manner contributing to excessive visceral fat accumulation and decreases in adiponectin level.23 It is recognized that endocannabinoids may play a key role in the pathogenesis of obesity-related complications, such as nephropathy, atherosclerosis, and cardiac dysfunction through inflammationmediated reactive oxygen species. Lifestyle interventions leading to weight loss and loss of visceral AT have been shown to reduce anandamide and 2-AG levels in the blood of abdominally obese, dyslipidaemic men with features of the metabolic syndrome.24 A recent study has also shown that gastric bypass-induced weight loss in morbid obesity normalized coronary circulatory function through the decrease in endocannabinoid levels and a marked increase in adiponectin concentrations.25 Overall, the findings from laboratory, clinical, and population data on obesity-related CV complications strongly support the pathogenic roles of various adipokines secreted from AT in the development of CVD. Such links are, however, difficult to isolate, particularly considering the large number of secretory products from AT and their complex interactions.

Cardiac adaptations to obesity The study of the development of heart failure (HF) and LV changes associated with excessive weight gain has provided clues about the existence of obesity cardiomyopathy from asymptomatic subclinical LV changes to overt dilated cardiomyopathy, irrespective of coexisting conditions such as hypertension and diabetes mellitus.26 Altered haemodynamics due to increased total blood volume and a higher cardiac output, predispose overweight/obese individuals to LV remodelling and to an increase in LV wall stress.27 Histologically, cardiomyocyte hypertrophy, myocardial fat infiltration, and myocardial fibrosis have been confirmed by post-mortem studies.28 These haemodynamic and histological alterations contribute to the development of LV remodelling and left atrial enlargement. Consequently, LV diastolic dysfunction can occur at an earlier stage of obesity cardiomyopathy, independently or in conjunction with systolic dysfunction.26 Clinical studies using new echocardiographic indices, such as tissue Doppler imaging or strain/strain rate, have indicated that there was a graded decrease in LV systolic and/or diastolic function across BMI categories, already observed among overweight individuals, compared with normal weight subjects.29 These associations were also observed when WC, waist-to-hip ratio (WHR), or cross-sectional area of visceral AT was used as indices of obesity instead of the BMI.30,31 In addition to LV impairment associated with excessive adiposity, recent studies have highlighted the importance of body fat distribution and body composition on LV adaptations to obesity. In the Dallas Heart Study, a cohort of 2710 participants without CVD,

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At the population level, there is no doubt that obesity is harmful and is associated with a plethora of health problems. The following sections will explore how obesity could be related to cardiovascular outcomes.

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Obesity paradox and heart disease

Ectopic fat accumulation around the heart has been also reported to be related to CV risk, despite the fact that these cardiac fat cells represent a very small proportion of total body AT.33 A growing body of evidence has indicated that fat depots around the heart and myocardial steatosis are associated with the development and progression of coronary atherosclerosis34 and cardiomyopathy35 through mainly paracrine and endocrine effects.36 Fat depots around the heart are classified into four types according to their location: intramyocardial fat, epicardial AT (EAT), pericardial AT (PAT), and paracardial AT located outside of the pericardium.37 Coronary artery perivascular AT (PVAT) is defined as fatty tissue surrounding the major conduit coronary arteries within the EAT. In a study by Rosito et al.,38 the amount of PAT was positively associated with coronary artery calcification, even after adjustment for visceral adiposity in 1155 participants from the Framingham Heart Study. In addition, PAT was also associated with paroxysmal and persistent atrial fibrillation, independently from CV risk factors including the BMI.39 Although the data on the vascular effect of PVAT are limited and contradictory, it seems to be dependent on anatomic location (noncoronary artery vs. coronary artery) and body phenotype. 40,41 Currently, it has been suggested that non-coronary artery PVAT could release factors modulating both vasodilation and vasoconstriction,42,43

Figure 1 Body composition and left ventricular (LV) structure and function according to different combinations of tertiles (T) of visceral fat area (VFA) and appendicular skeletal muscle mass index (ASM/Wt). The increases in LV mass index (A) and E/Ea ratio (B) and the decrease in tissue Doppler imaging (TDI) early diastolic mitral annulus (Ea) velocity (C) were most pronounced in the highest VFA and the lowest ASM/Wt group. Reproduced with permission from Park et al. 31

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visceral AT measured by magnetic resonance imaging was associated with concentric LV remodelling and adverse haemodynamics, such as lower cardiac output and higher systemic vascular resistance. In contrast, lower-body subcutaneous fat assessed by dual-energy X-ray absorptiometry was associated with eccentric LV remodelling, a higher cardiac output, and lower systemic vascular resistance. Consequently, the markedly divergent effects on the CV system of upper-body vs. lower-body AT provide evidence of the protective role of some subcutaneous regional fat depots.32 We have recently produced additional evidence of the association between visceral adiposity (assessed by computed tomography) and skeletal muscle mass (assessed by dual-energy X-ray absorptiometry) on LV structure and function.31 In a relatively healthy cohort of 1941 participants, skeletal muscle mass was found to be positively associated with LV diastolic function but negatively associated with LV mass index. Interestingly, the combination of excess visceral adiposity and of lower skeletal muscle mass was synergistically associated with subclinical deterioration in LV structure and diastolic function (Figure 1). These findings support the notion that both body fat distribution and lean body mass may contribute to explain the obesity paradox in patients with established CVD, a notion to be discussed later in this review.

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whereas coronary artery PVAT may be associated with endothelial dysfunction through the alterations in gene expression and protein levels including adiponectin, leptin, resistin, tumour necrosis factor-a, and inteleukin-6.44 However, how these factors are delivered to the coronary endothelial and vascular smooth muscle cells to impair endothelial-dependent vasodilation and potentiate coronary contraction will require further investigation.

Metabolically healthy obesity: can obesity be really healthy?

Table 1

Various criteria for metabolically healthy obesity Meigs et al. 47

Stefan et al. 45

Aguilar-Salinas et al. 46

Karelis et al. 48

Mexico (n ¼ 716, M ¼ 26.4%)

Canada (n ¼ 154, M ¼ 0%)

Wildman et al. 54

Park et al. 52

............................................................................................................................................................................... Study population

USA (n ¼ 2902, M ¼ 45%)

Germany (n ¼ 314, M ¼ 38.5%)

USA (n ¼ 5440, M ¼ 47.9%)

Korea (n ¼ 2540, M ¼ 49.6%)

. . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . Metabolic components WC (cm)

≥102 (M) ≥88 (F)

BP (mmHg)

≥130/85 or treatment

,140/90 and no treatment

≥130/85 or treatment

,130/85 and no treatment

FPG (mg/dL)

≥100 or treatment

,126 and no treatment

≥100 or treatment

,100 and no treatment

TG (mg/dL)

≥150

HDL (mg/dL)

,40 (M) ,50 (F)

,150

≥150

,150

≥40

≥50

,40 (M) ,50 (F)

≥40 (M) ≥50 (F)

,3 of the above

WBISI .75th percentile All of the above

All of the above

,1.95 TC ,200 mg/dL LDL ,100 mg/dL ≥4 of the above

.90th percentile hsCRP .90th percentile ,2 of the above

All of the above

≥30

≥30

≥30

≥30

≥30

≥25

HOMA-IR Others MH criteria

,90 (M) ,80 (F)

. . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . Obesity component BMI (kg/m2)

Modified from Velho et al. 55 BMI, body mass index; BP, blood pressure; F, female; FPG, fasting plasma glucose; HOMA-IR, homeostasis model assessment of insulin resistance index; hsCRP, high-sensitivity C-reactive protein; M, male; MH, metabolically healthy; TC, total cholesterol; TG, triglycerides; WBISI, whole-body insulin sensitivity index; WC, waist circumference.

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Although being overweight and obese are well-established risk factors for CVD, there are substantial individual differences observed in the cardiometabolic risk profile of subjects within the same BMI category. Based on favourable metabolic features observed in some obese patients such as high levels of insulin sensitivity and HDL-cholesterol as well as low levels of fasting triglycerides and fasting glucose, a unique obesity phenotype known as ‘metabolically healthy obesity’ was introduced.45,46 Early studies suggested that metabolically healthy obesity was not associated with an increased risk of CV mortality compared with normal weight individuals.47 Such early data have been interpreted by some as providing evidence that these apparently metabolically healthy obese people would not need to receive preventive therapies, because they would appear unlikely to experience long-term morbidity on the basis of their seemingly normal cardiometabolic risk profile.48 However, considerable controversy exists about the criteria and levels to be used to define metabolically healthy obesity and whether

obesity can be healthy. Recent studies with long-term follow-up information have refuted the existence of metabolically healthy obesity by demonstrating that these individuals are nevertheless associated with an increased risk of CVD.49 In addition, a series of cross-sectional studies have shown that metabolically healthy obesity was associated with subclinical target organ changes including increased carotid intima media thickness50 and coronary artery calcium scores,51 subtle impairment of LV structure and function,52 and impaired vasoreactivity.53 Several potential explanations for these conflicting results have been proposed in recent years. Firstly and as previously mentioned, there is no standard definition for metabolically healthy obesity (Table 1). Although Hinnouho et al.56 suggested that metabolically healthy obese individuals were at increased risk of mortality, irrespective of various definitions used, these different definitions still make the comparison of findings among studies, such as prevalence rates and the long-term health effects, difficult.54,55 Secondly, the issue of a difference in the follow-up duration between studies is another crucial factor affecting the study results. Most studies supporting the existence of metabolically healthy obese phenotype have had a relatively short follow-up period of ,10 years, whereas data by Arnlov et al.49 have shown that there was an increased risk for CVD events in metabolically healthy obese subjects when a follow-up period beyond 10 years and up to 30 years was used (Figure 2). Similarly, our study demonstrated that the metabolically healthy obese group showed a similar risk of incident hypertension during the first 4-year follow-up compared with metabolically healthy normal weight controls.57 However, an increased risk of developing hypertension began to be observed only after 6-year

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follow-up. In addition, our findings refuted the concept of ‘benign obesity’ by demonstrating that a higher proportion of metabolically healthy obese group deteriorated metabolically over time. Indeed, we observed a progressive conversion of metabolically healthy obese subjects from being healthy to becoming unhealthy over the follow-up period of our study.57 Thus, these results emphasize the long-term CV hazards of being characterized by an apparently benign obesity phenotype and the necessity to follow these patients over the long-term. In other words, although younger individuals may have metabolically healthy obesity, they may nevertheless develop insulin resistance, diabetes, dyslipidaemia, and arterial hypertension called metabolic syndrome with increasing age. Recently, two meta-analyses concluded that the metabolically healthy obese phenotype should no longer be considered as a benign condition. One analysis, including eight studies in 61 386 people with a follow-up period of .10 years, reported that metabolically healthy obesity was associated with an increased risk for all-cause mortality and CVD events.58 Other study also demonstrated similar findings. In a meta-analysis of 14 studies involving 299 059 individuals, a 100% increased risk for CVD events was observed in the metabolically healthy obese group.59 The risk of clinical outcomes was much worse when only considering studies with .15-year follow-up. Accordingly, by labelling a subset of obese people as metabolically healthy, a strategy of only offering treatment to obese patients with overt metabolic derangements would seem to provide a short-sighted view to the current obesity epidemic.60 In addition, according to a recent study by Ortega et al.,61 when physical activity or fitness was considered as one of the confounders, the adverse effect of metabolically healthy obese phenotype on all-cause and CVD mortality was significantly attenuated or even not observed.

In other words, as a high level of CRF was associated with a low incidence of metabolic syndrome and attenuated the magnitude of the relationship between the metabolic syndrome and mortality regardless of weight status,62 these results suggest that the metabolically healthy obese phenotype is clearly associated with a higher level of CRF.63 These findings could provide useful information to physicians in assessing the risk stratification of obese individuals. Thus, the prevalence of the metabolically healthy obesity phenotype is probably much lower than expected and levels of physical activity/CRF are probably some of the key factors, in addition to body composition and level of visceral adiposity/ectopic fat, to explain this phenomenon. Our suggestion would be to define metabolically healthy not only on the basis of absence of any criteria of the metabolic syndrome but rather as having all usual risk factors being at optimal levels, otherwise, any slight increase in any of the risk factors increases risk of CVD.

Obesity paradox: can obesity be a friend? Yesterday’s enemy is today’s friend

As previously mentioned in this paper, there is strong evidence showing that an elevated BMI predisposes individuals to most CVD and has been associated with a greater risk of mortality. In a 10-year follow-up study of 527 265 U.S. men and women in the National Institutes of Health-American Association of Retired Persons (AARP) cohort between the ages of 50 and 71 years,15 a J-shaped relationship between BMI and the risk of death was observed, showing that underweight and excess body weight, including overweight,

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Figure 2 Cardiovascular events in different body mass index without metabolic syndrome. An increased incidence of cardiovascular events in metabolically healthy obesity started to emerge only after 10 years. Reproduced with permission from Arnlo¨v et al. 49

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Obesity paradox and heart disease Coronary heart disease In 2002, Gruberg et al.10 proposed that there was an ‘obesity paradox’ in patients with CHD. According to an analysis of 9633 patients undergoing percutaneous coronary intervention, optimal survival was observed in overweight and obese patients. On the other hand, underweight and normal weight patients were at increased risk for cardiac death and for 1-year mortality. A systematic review of 40 cohorts involving a total of 250 000 CHD patients also concluded that overweight patients were characterized by the lowest risks for total and CVD mortality.66 In addition, an increased mortality risk was not observed in class I obesity. However, CHD patients with substantial level of obesity (BMI ≥35 kg/m2) were found to display increased total mortality risk. According to this systematic review and meta-analysis, because overweight CHD patients were found to have the optimal CV and all-cause mortality risk, it could have been proposed that we should rather refer to an ‘overweight paradox’ rather than to an ‘obesity paradox’. However, another recent longitudinal study has reported the lowest mortality rate in class I obese patients with ST-segment elevation myocardial infarction.67 Thus, the concept of the obesity paradox is still debated in CHD. Although there is evidence supporting the mortality benefit in class III obese (BMI ≥40 kg/m2) patients with CHD,68 other

studies have generated robust evidence that morbid obesity is a phenotype associated with a poor prognosis.67,69 Interestingly, the obesity paradox is observed even in the presence of a deteriorated metabolic profile, such as higher levels of fasting glucose and triglycerides as well as a lower level of HDL-cholesterol, in overweight/ obese patients with CHD.70 However, in contrast to overweight or class I obesity paradox, there are other studies demonstrating no protective effect or even worse prognosis among CHD patients with increased BMI values.71 Above all these inconsistent findings, a key factor to consider in the interpretation of the obesity paradox in patients with CHD is the remarkable selection bias. Indeed, in the absence of being overweight or obese, subjects who nevertheless develop CHD may have inherited an exquisite susceptibility to CHD compared with individuals who developed CHD because of their obesity. Thus, once a cohort only including CHD patients is studied, it is of no surprise to find that patients who got CHD through obesity are less susceptible to a recurrent event than those who got the disease without being overweight or obese. Thus, there is a tremendous selection bias in the study of risk factors for recurrent CHD and such bias should be taken into consideration in the interpretation of the obesity paradox.2

Heart failure Many epidemiological studies showed that obesity is a major risk factor for the development of HF. In a study of 5 881 participants from the Framingham Heart Study,13 each one unit increment of BMI was associated with an increase in HF risk of 5% for men and 7% for women. Despite a clear relationship between BMI and incident HF in a dose-dependent manner, overweight and obese patients with established HF, as assessed by BMI, have also been reported to show a paradoxical decrease in mortality like in CHD patients. Among all manifestations of CVD that have been reported to contribute to the theory of the obesity paradox, advanced HF seems to be particularly associated with the obesity paradox phenomenon. In 2001, Horwich et al.72 described for the first time that excess body weight (BMI .27.8 kg/m2) was not associated with increased mortality in patients with HF. Rather, underweight or normal weight HF patients appeared to have the worst prognosis. Another study of 7788 patients with symptomatic chronic HF also found that overweight and obese patients were associated with better HF survival rates when compared with normal weight patients.73 The first meta-analysis of nine observational HF studies in 28 209 patients demonstrated lower relative risks of all-cause and CV mortality in overweight and obese patients, compared with patients with normal BMI.74 In addition to chronic HF, the obesity paradox also appeared to exist in acute decompensated HF.75 According to the Acute Decompensated Heart Failure Registry, the odds of risk-adjusted mortality was 10% lower for every 5 kg/m2 increase of BMI in hospitalized acute HF patients. However, controversies remain regarding whether an obesity paradox could be observed regardless of HF aetiology (ischaemic vs. non-ischaemic). One study confirmed the obesity paradox in obese patients, irrespective of HF aetiology, but the mortality benefit in overweight patients was observed only in non-ischaemic HF.76 Another study reported that there was an obesity paradox only among obese patients with non-ischaemic

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were associated with higher rates of death than normal weight. However, a recent meta-analysis from prospective studies of general populations reported a statistically significant 6% lower allcause mortality in overweight persons compared with normal weight subjects. Although the mortality risk was increased in overall obesity including all classes (class I, II, and III combined) and class II (BMI 35 – 40 kg/m2) and class III obesity (BMI ≥40 kg/m2), class I obesity (BMI 30 –35 kg/m2) was not associated with higher mortality compared with normal weight individuals.64 However, considering the fact that the mortality rate for a BMI between 19 and 20 kg/m2 is higher than a BMI between 24 and 25 kg/m2 where the lowest mortality is observed, the use of a wide range of BMI between 18.5 and 25 kg/m2 as the presumably ‘normal weight’ reference group in a study by Flegal et al.64 could explain the protective effect conferred by overweight and class I obesity in the general population. Recent data from the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) confirmed that the protective effect of obesity on all-cause mortality was not observed after excluding individuals with BMI ,22 kg/m2 who are clearly at increased risk compared with subjects in a normal but higher BMI range such as 22–25 kg/m2.65 Nevertheless, there is accumulating evidence that obesity in patients with established CVD, including CHD, HF, hypertension, and atrial fibrillation, plays a protective role against both all-cause and CV mortality, findings which contributed to feed the ‘obesity paradox’ hypothesis in the field of cardiology.66 However, because this obesity paradox is being reported in a variety of chronic diseases including end stage renal disease, chronic obstructive pulmonary disease, and type 2 diabetes mellitus, it does not appear to be specific for only CVD. We will briefly review the obesity paradox observed in overweight and mildly obese patients with CHD or HF as well as the potential mechanisms that have been suggested to explain this phenomenon.

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HF.77 The obesity paradox in HF seems to be more evident for HF patients with a non-ischaemic aetiology.

Proposed mechanisms for the obesity paradox

Body fat distribution and body composition Although a higher BMI is paradoxically associated with lower mortality in patients with CHD or HF, there is no universal agreement on the basic mechanism responsible for this phenomenon. The first limitation that comes to mind is the use of BMI as the index of obesity in most studies showing the obesity paradox. A recent meta-analysis of six studies including 15 923 patients with CHD

directly compared the mortality risk of WC or WHR as indices of central obesity and BMI as a parameter of total adiposity.80 As expected, the relationship between BMI and mortality represented a negative association reflecting the typical ‘obesity paradox’ pattern. However, central obesity was positively associated with mortality, even among patients with an apparently normal BMI. These results provide evidence that we should refer to a ‘BMI paradox’ in lieu of an ‘obesity paradox’. Despite the fact that the BMI is a widely used and convenient anthropometric index of obesity at the population level, it has been heavily criticized because of its inability to discriminate between fat mass and lean body mass and as a totally inappropriate index of regional body fat distribution.2,11 In patients with CHD, the correlation coefficient between BMI and percent body fat in overweight and normal BMI groups has been reported to be low (r ¼ 0.17 for overweight and 0.10 for normal weight).81 There are also abundant papers for which Drs Kissebah in the USA and Bjo¨rntorp in Sweden were pioneers in the early 1980s that both showed that body shape mattered a much more than size (BMI) when it came the time to predict clinical outcomes.82,83 The work of these two investigators paved the way for almost three decades of metabolic and clinical studies which clearly showed that the amount and proportion of abdominal visceral AT is an important risk factor for the development of the features of the so-called metabolic syndrome for which insulin resistance is a central figure. Furthermore, this constellation of metabolic abnormalities resulting from too much fat stored at the wrong place has been found to be a powerful risk factor for CV outcomes, irrespective of the BMI.84 In a prospective population study of 2 493 Danish men and women, the WHR was the only index of obesity measured which was significantly associated with incident CVD.85 Similar conclusions

Figure 3 Body composition and coronary heart disease survival. All-cause mortality was the highest in low body fat (BF)/low lean mass index (LMI) group for 3-year follow-up. Reprinted from Lavie et al 87 with permission from Elsevier.

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A variety of mechanisms have been proposed to explain the obesity paradox in patients with CVD.78 Among potential causes for the obesity paradox, spontaneous weight loss, which is observed after the development of HF, is known to cause a bias associated with the timing of weight measurement. However, because a recent study from the Atherosclerosis Risk In Communities (ARIC) has suggested that the protective effect of obesity paradox is driven by pre-existing obesity,79 cardiac cachexia due to advanced HF does not appear to fully explain the obesity paradox in patients with established HF, although this phenomenon certainly contributes to the high mortality risk of very lean HF patients. Given that the obesity paradox is usually observed in the elderly with CVD, age-related changes of body fat distribution and also sarcopenia may be clues to the obesity paradox.2 Accordingly, the concept of being fat and fit has recently come into the spotlight as a potential reason for the obesity paradox. We will briefly review the data on the association between fatness, fitness, and mortality in CVD patients among whom the obesity paradox is observed.

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Figure 4 The lipid overflow-ectopic fat model. Excess visceral fat accumulation may be causally related to the features of insulin resistance, but it may also be a marker of a dysfunctional adipose tissue not being able to appropriately store the energy excess. Under this model, the body’s ability to cope with the surplus of calories (resulting from excess caloric consumption, a sedentary lifestyle, or, as often the case, a combination of both factors) may ultimately determine the individual’s susceptibility to develop features of the metabolic syndrome. There is evidence suggesting that, if the extra energy is channelled into insulin-sensitive subcutaneous adipose tissue (able to expand through hyperplasia), the subject in positive energy balance will nevertheless be protected against the development of the metabolic syndrome. However, in cases where the adipose tissue is absent, deficient, or insulin resistant with a limited ability to store the energy excess (hypertrophic adipose tissue), the triglyceride surplus will be deposited at undesirable sites such as the liver, the heart, the skeletal muscle, and in visceral adipose tissue, a phenomenon described as ectopic fat deposition. Factors associated with a preferential accumulation of visceral fat and with features of insulin resistance include, among others, smoking, the well-documented genetic susceptibility to visceral obesity and a permissive neuroendocrine profile related to a maladaptive response to stress. The resulting metabolic consequences of this defect in energy partitioning include visceral obesity, insulin resistance, an atherogenic dyslipidaemia, and a prothrombotic, inflammatory profile, which are features defining the metabolic syndrome. This constellation of abnormalities can be detected by the metabolic syndrome clinical criteria, the two simplest being the simultaneous presence of an elevated waist girth and fasting triglyceride levels, a condition that has been described as hypertriglyceridemic waist. FFA, free fatty acid. Reproduced with permission from Despre´s and Lemieux.12

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Cardiorespiratory fitness Over the last two decades, substantial evidence has been published to support the notion that CRF is associated with a better prognosis and survival than weight status.89,90 This theory known as the ‘fat and fit’ hypothesis also implies that the obesity paradox may be partially explained by concomitant variation in CRF and by its key influence on all-cause and CV mortality, but not by an obesity index (mostly BMI). 78 For instance, a study of 9563 men with CHD from the Aerobics Center Longitudinal Study, found that over a 14-year follow-up, the obesity paradox remained across categories of BMI, per cent body fat, and even WC in men with low CRF. In contrast, patients with high levels of CRF had a good prognosis regardless of the obesity index considered.91 Another subsequent study reported similar findings in an analysis of 2066 patients with systolic HF. The HF patients with low CRF defined by a peak oxygen consumption ,14 mL/kg/min were characterized by the typical obesity paradox pattern, whereas no obesity paradox was found in the high CRF group.92 A recent meta-analysis of 10 studies examining the joint associations of CRF and BMI on mortality concluded that there was no obesity paradox phenomenon among fit individuals, whereas unfit individuals showed a more than two-fold higher risk for mortality, regardless of BMI, compared with their normal weight fit individuals.93 Among unfit individuals, only overweight unfit individuals had the lowest mortality risk while normal weight and obese unfit individuals had a higher risk of death. Although some data have suggested that the obesity paradox may exist even in highly fit healthy individuals or CAD patients with high fitness,94 the risk of death has been shown to be related to fitness level but not to BMI

in most studies. These findings suggest that individuals who are fat but fit could be at low CVD risk. In addition to the huge selection bias and the lack of control for body composition (particularly the presence or not of a preferential accumulation of healthy subcutaneous AT), the concomitant variation in CRF may represent a key factor to explain what is left of the obesity paradox theory in cardiology.

Conclusions At the population level, it is clear that obesity is an established risk factor for the development of CVD such as hypertension, diabetes mellitus, CHD, and HF. In addition, multiple biological mechanisms linking obesity and CVD events have been identified. However, the possible existence of a metabolically healthy obese phenotype (which could be more appropriately be referred to as a lower risk form of obesity), the important role of regional body fat distribution and ectopic fat accumulation, and the presence of an obesity (BMI) paradox in patients with CHD are all observations which emphasize the remarkable heterogeneity of obesity. At the population level, these complex obesity-related issues have remained the biggest challenge for clinicians dealing with numerous obese phenotypes. There is, however, robust evidence indicating that a subset of overweight and moderately obese individuals with a high level of fitness may be protected from obesity-related health outcomes. Thus, although it is clear that at the population level, there is a strong link between the BMI and the incidence of various clinical outcomes, whether reducing the BMI should be the primary target at the clinical level remains debated. It has rather been suggested that targeting key behaviours such as improving nutritional quality and improving CRF through regular physical activity would be legitimate approaches contributing to generate ‘healthy weight loss modalities’.63 Further investigations should consider both metabolic risk and CRF in addition to the selection of appropriate obesity index to better identify and manage patients who are ‘at risk’ for the development of CVD.

Authors’ contributions S.H.K., J.-P.D., and K.K.K.: conceived and designed the research, drafted the manuscript, and made critical revision of the manuscript for key intellectual content. Conflict of interest: J.-P.D. is the Scientific Director of the International Chair on Cardiometabolic Risk which is based at Universite´ Laval. He has received a research grant from Eli Lilly, has received speaker’s fees from Abbott, AstraZeneca, Merck, GlaxoSmithKline, and Pfizer Canada Inc., and is on the consultant/advisory board of Torrent Pharmaceuticals Ltd, Abbott, and Sanofi.

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