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81ISSN 1479-667810.2217/FCA.13.84 © 2014 Future Medicine Ltd Future Cardiol. (2014) 10(1), 81–91

ABSTRACT: An inverse association between BMI and mortality has been reported in patients with coronary heart disease and heart failure. This ‘obesity paradox’ has recently been reported in other disease states, including stroke, hypertension, incident diabetes, atrial fibrillation, hemodialysis and transcatheter aortic valve replacement. Cardiorespiratory fitness influences the obesity paradox and this inverse association may be present only in individuals with low fitness levels. Intentional weight loss, exercise training and improving lean mass are important and should be advised to all patients. Recent studies have also explored the association between measures of central obesity and direct measures of body fat with mortality. This review will summarize the evidence, controversies and mechanisms associated with the puzzling obesity paradox.

1Department of Internal Medicine, Division of Cardiovascular Diseases, Mayo Clinic, Rochester, MN, USA 2Department of Cardiovascular Diseases, John Ochsner Heart & Vascular Institute & Ochsner Clinical School–The University of Queensland School of Medicine, 1514 Jefferson Hwy, New Orleans, LA 70121, USA 3Division of Cardiology, University of Ottawa Heart Institute, Ottawa, ON, Canada 4The Department of Preventive Medicine, Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, LA, USA *Author for correspondence: Tel.: +1 504 842 1281; Fax: +1 504 842 5875; [email protected]

Obesity paradox in different populations: evidence and controversies

REVIEW

Kashish Goel1, Francisco Lopez-Jimenez1, Alban De Schutter2,

Thais Coutinho3 & Carl J Lavie*2,4

KEYWORDS• body fat • cardiorespiratory fitness • central obesity • coronary heart disease • fitness • heart failure • mortality • obesity paradox • other populations

Obesity is a precursor to the development of cardiovascular (CV) disease (CVD) and is associ-ated with increased mortality in general healthy populations [1]. This is an expected observa-tion, since obesity is associated with hyperlipidemia and increased atherosclerotic burden [2]. However, in the last decade, counterintuitive findings have been reported wherein persons with elevated BMI were found to have a survival advantage over individuals with normal BMI, a phenomenon termed as the ‘obesity paradox’ [1,3,4]. This paradox was initially described in patients with coronary heart disease (CHD) and heart failure (HF), but subsequently reported in a large number of subpopulations, including hypertension (HTN), patients referred for tread-mill testing, stroke, atrial fibrillation (AF), hemodialysis, incident diabetes mellitus (DM) and recently in patients undergoing transcatheter aortic valve replacement (TAVR) (Box 1). Recently, a large systematic review and meta-analysis of 97 studies including 2.88 million individuals reported that overweight (BMI 25 to <30 kg/m2) and moderate obesity (BMI 30 to <35 kg/m2) were significantly associated with lower all-cause mortality even in the general population [5]. The evidence behind this paradox has increased over the last decade; however, the underlying mechanisms remain unclear. Several hypotheses have been presented, including the possibil-ity of selection bias and residual confounding, and inability of BMI to differentiate between central and peripheral fat deposits. This review will present the literature on obesity paradox in different populations and summarize the potential reasons behind this phenomenon. We will also discuss the impact of cardiorespiratory fitness and weight loss on the obesity paradox, and associated controversies.

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REviEW Goel, Lopez-Jimenez, De Schutter, Coutinho & Lavie

Obesity paradox & CHDCHD is a major cause of morbidity and mor-tality in the USA and worldwide [6]. Most of the recent studies report an obesity paradox with BMI in patients with CHD. A large meta-analysis of 40 cohort studies including >250,000 patients with CHD showed that overweight (BMI 25 to <30 kg/m2) individu-als had a significantly lower risk of all-cause mortality, and a trend towards decreased CV mortality than individuals with normal BMI (Figure 1) [7]. In another meta-analysis involving >15,000 CHD patients, Coutinho et al. reported

that overweight, obese (BMI 30 to <35 kg/m2) and severely obese (≥BMI 35 kg/m2) patients had a significantly lower risk of mortality compared with those with normal BMI [4]. Bucholz et al. also reported similar findings in a prospective registry of 6359 patients with acute myocardial infarction (MI) [8]. Most recently, Azimi et al. found that overweight patients had the lowest risk of mortality in a study of 37,573 patients with known atherosclerosis [9]. Numerous stud-ies have shown the paradoxical association of BMI with mortality for the overweight and obese categories [4,7,9,10]. However, most of these stud-ies show that patients with extreme obesity (BMI ≥40 kg/m2) have increased mortality compared with normal BMI patients [7,9,11]. One exception is a recent study that found decreased mortal-ity with extreme obesity in >400,000 patients hospitalized with acute MI [12]. These discrepan-cies reflect the limitations of BMI as a marker of obesity, and the importance of measuring body fat (BF) directly. In a study of 581 stable CHD patients, Lavie et al. found that both low BMI and low BF (measured by skinfolds) were associ-ated with a significantly higher 3-year mortality [13]. Interestingly, patients with a combination of low BMI and low BF were at the highest mortal-ity risk compared with other groups with higher BMI and/or BF (Figure 2) [13]. Recently, it was also demonstrated that both low BF (<25% in men and <35% in women) and lean mass were inversely associated with mortality in stable CHD [10,14].

Obesity paradox & percutaneous coronary interventionGruberg et al., in one of the first studies to explore the obesity paradox (n = 9633), reported that obese patients undergoing percutaneous coronary intervention (PCI) had a significantly lower incidence of in-hospital complications (including CV death) and 1-year mortality, compared with normal BMI patients despite similar angiographic success rates [3]. Another study of 4880 consecutive PCI patients also found a survival advantage in obese patients [15]. In a meta-analysis of ten studies, Oreopou-los et al. reported that overweight, obese and severely obese individuals had significantly lower short- and long-term mortality compared with normal BMI patients undergoing PCI [16]. Fur-thermore, in a pooled patient-level data analysis of 11 independent and prospective clinical stud-ies (including eight randomized clinical trials)

Box 1. Conditions associated with the obesity paradox.

● Coronary heart disease ● Percutaneous coronary intervention ● Heart failure ● Stroke ● Hypertension ● Referral population for stress testing ● Diabetes ● Atrial fibrillation ● Transcatheter aortic valve replacement ● Hemodialysis ● Pulmonary hypertension

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Figure 1. Obesity paradox described in a meta-analysis involving >250,000 patients with coronary heart disease. Overweight and obese patients with coronary heart disease have the lowest mortality as compared with other BMI groups. RR: Relative risk. Reproduced with permission from [7].

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of patients undergoing PCI, Korean investi-gators found that obese Asian patients had a significantly lower adjusted hazard ratio of major adverse CV events and all-cause mortal-ity compared with patients with normal BMI (22.5 to <25 kg/m2) [17]. On the other hand, few other studies found no association between obesity and target vessel revascularization in PCI patients [18].

Recently, Danish investigators reported that overweight patients undergoing PCI had sig-nificantly lower hazards of all-cause mortality, cardiac death or nonfatal MI after adjustment of multiple risk factors in 6332 patients. However, this paradox with increased BMI was neutralized after adjusting for optimal medical therapy for all outcomes, except nonfatal MI. The authors concluded that more optimal medical treatment in obese patients may explain the obesity para-dox in patients undergoing PCI [19]. However, other studies have reported comparable use of evidence-based therapies among different classes of BMI groups [11]. In a retrospective study of over 5000 PCI and cardiac catheterizations, Cox et al. reported a significantly lower rate of vascu-lar complications in those with a BMI >30 kg/m2 [20]. Another study replicated these findings, showing that patients with higher BMI have lesser incidence of femoral hematomas or major bleeding requiring transfusions [21]. Therefore, evidence suggests that overweight and obese (by BMI) patients undergoing PCI have signifi-cantly lower rates of in-hospital complications and short- and long-term outcomes. Limited data are available in this patient population for measures of central obesity and BF.

Obesity paradox & HFAlthough obesity adversely affects cardiac sys-tolic and diastolic function, multiple studies report an inverse association between various measures of obesity including BMI [1], central obesity [22] or BF [23], and mortality in patients with established HF. In a meta-analysis of 28,209 patients with HF, Oreopoulous et al. found that overweight and obese (defined by BMI) patients had a significantly lower all-cause and CV mortality [24]. We have recently pub-lished a detailed review on the association of obesity and HF [25].

Obesity paradox & strokeSimilar to CHD, studies have elicited the pres-ence of the obesity paradox in acute stroke

patients. In a prospective study of 2785 patients admitted with first-ever acute stroke, Vemmos et al. reported that obese and overweight patients (by BMI) had significantly lower mortality as early as the first week to 10 years of follow-up [26]. Similar findings were demonstrated in the post hoc analysis of the TEMPiS trial, in which obese patients not only had significantly lower mortality than normal BMI patients, but also lower incidence of functional nonfatal outcomes and recurrent stroke after adjustment of multiple confounding factors [27]. Furthermore, a recent study on 29,326 patients with first-ever stroke showed that being overweight or obese was asso-ciated with a significantly lower all-cause mor-tality and lower risk of readmission for recurrent stroke [28]. As the etiology of stroke is similar to CVD and CHD, the inverse association of BMI with outcomes could just be a ‘class effect’ with similar mechanisms.

Obesity paradox & HTNUrestsky et al. evaluated 22,576 patients with HTN and CHD and demonstrated that over-weight patients had almost 40% lower mor-tality rates, and those with a BMI >30 kg/m2 had a 26% lower all-cause mortality than their leaner counterparts [29]. Obese HTN patients may paradoxically have a better prognosis, pos-sibly because of having lower systemic vascular resistance and plasma renin activity compared

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Figure 2. Kaplan-Meier curves for combined analysis of BMi and body fat in stable coronary heart disease patients. Combination of low BF and low BMI confers the highest mortality risk in patients with stable coronary heart disease. *p < 0.001 compared with other groups. BF: Body fat. Reproduced with permission from [13].



with more lean HTN patients [1]. However, in a recent prespecified analysis of the ACCOM-PLISH trial, Weber et al. showed that the obesity paradox was limited to the patients randomized to the benazepril–hydrochlorothiazide arm, and was not present among patients taking benazepril–amlodipne [30]. HTN in obese indi-viduals may therefore be mediated by increased plasma volume and cardiac output, so diuretic use may be of more benefit in obese individuals [30].

Obesity paradox & referral/general populationIn a study of over 12,000 veterans who were referred for exercise testing, McAuley et al. found that obese and overweight individuals had sig-nificantly lower mortality during a mean follow-up of 7.7 years [31]. Veterans have a higher muscle mass contributing to a higher BMI, which may in part explain the obesity paradox. In another cohort of over 30,000 patients with preserved ejection fraction, Lavie et al. reported that obese individuals had a significantly lower all-cause mortality than nonobese persons, even though obese individuals had a higher prevalence of left ventricular structural abnormalities [32]. These findings were recently extended to the gen-eral healthy population as well, as Flegal et al. reported lower all-cause mortality in overweight and moderately obese individuals in a worldwide meta-analysis of 2.88 million persons [5]. Possi-ble explanations include an aggressive treatment strategy, earlier presentation and possibly higher metabolic reserves in obese patients [5].

Other populationsThe gamut of the obesity paradox has extended to many populations; however, the overall evidence is less robust.

●● Diabetes mellitusIn a recent meta-analysis of 2625 participants from five different large cohort studies from the USA who developed incident DM during follow-up, Carnethon et al. reported that over-weight and obese persons with new-onset DM had a significantly lower total CV and non-CV mortality than normal weight individuals after adjusting for blood pressure, waist circumfer-ence (WC), smoking and lipids [33]. The results could be explained by greater lean mass in the overweight/obese category leading to better insulin sensitivity, and possible presence of sarcopenia in normal weight individuals [34].

●● Atrial fibrillationA post hoc analysis of the AFFIRM trial showed that overweight and obese individuals had a sig-nificantly lower risk of all-cause and CV mortal-ity than normal BMI patients [35]. The reduction of inflammation associated with soluble TNF-a receptors, and a smaller rennin–angiotensin response to stress and sarcopenia may be the possible explanations for this paradox in patients with AF [35].

●● Transcatheter aortic valve replacementIn recent years, TAVR is emerging as an effective alternative to aortic valve replacement for patients who are considered as extremely high risk for CV surgery. In 940 patients undergoing TAVR, van der Boon et al. reported that BMI as a continu-ous variable was associated with a significant reduction in 30-day mortality after adjusting for differences in baseline and procedural charac-teristics [36]. However, there was no significant difference in outcomes for long-term mortality. This obesity paradox in short-term mortality could be explained by the fact that obese patients were younger, had greater prevalence of preserved ventricular and renal function and, probably, a higher metabolic reserve [36].

●● HemodialysisA meta-analysis of over 81,000 patients from four studies showed that a BMI ≥25 kg/m2 was associ-ated with a significantly lower all-cause mortal-ity, and this effect remained in the risk-adjusted sensitivity analysis. The authors proposed that stable hemodynamic status, cytokines and neuro-hormonal alternations contributed to this paradox in hemodialysis patients [37].

●● Pulmonary HTNZafrir et al. found that obese (BMI ≥30 kg/m2) patients had a significantly higher survival com-pared with nonobese patients with known pulmo-nary HTN in a study of 61 patients [38]. As this was a very small study, future studies are required in this group of patients to analyze the effect of obesity on outcomes.

Mechanisms behind the obesity paradoxSeveral explanations and mechanisms have been proposed to explain the obesity paradox (Box 2). Some of the mechanisms that are specific to patient populations have been mentioned in their respective sections, although most of these mech-anisms also apply to other groups. In the early

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2000s when the obesity paradox was described, it was considered as a result of selection bias and inability to control for non-measurable confound-ing factors. Underweight individuals are known to have increased mortality due to sarcopenia and the presence of comorbidities such as can-cer [13,39]. Some of the studies grouped under-weight (BMI <18.5 kg/m2) patients with those with normal BMI, leading to false-positive results of increased mortality in these normal weight patients. However, as data accumulated over the last decade, evidence behind the obesity paradox has increased, even after adjusting for various confounding factors. The following factors may explain the obesity paradox.

●● Aggressive medical treatmentObese individuals have a higher risk of develop-ing HTN, DM, hyperlipidemia and renal disease. Therefore, they present early for medical inter-vention, which may result in early recognition of their diseased state (CHD and HF, among oth-ers). This leads to more aggressive treatment and reduction of long-term risk factors in obese indi-viduals compared with their leaner counterparts [40–43]. Multiple studies have also shown that patients with higher BMI received more optimal medical treatment after PCI compared with those with a normal BMI [19,44].

●● Coronary anatomyRubinshtein et al. reported that the prevalence of high-risk coronary anatomy, defined as 50% stenosis of the left main coronary artery and/or significant three-vessel coronary artery disease (70% narrowing), was significantly lower in obese patients (BMI >30 kg/m2) [43]. Small reference diameter vessels are associated with a higher inci-dence of major adverse CV events and have lesser chances of successful percutaneous revascular-ization compared with large diameter vessels [45]. O’Connor et al. reported that higher body surface area and BMI were associated with a larger mid-left anterior descending coronary artery luminal diameter in patients who underwent coronary artery bypass grafting [46]. A recent study of 149 consecutive acute MI patients who underwent carotid Dopplers showed that patients in the high-est tertile of BMI had a significantly lower burden of unstable plaque in the carotids. As unstable plaque is implicated in most acute coronary syn-dromes, this may be a plausible explanation. How-ever, the mechanism behind this finding is not clear and needs validation in larger studies [47].

●● Biological mechanismsAdipose tissue produces soluble TNF-a receptors [48], which may neutralize the effects of TNF-a on the myocardium [49]. Consequently, obese per-sons with HF have lower levels of TNF and other inflammatory cytokines [50].

●● Metabolic reserveObese individuals have a higher metabolic reserve, which may help counteract the chronic effects of inf lammation and cachexia [51,52]. Other mechanisms that may offer protection in adiposity include improved endothelial function [53], and better metabolic and regenerative capac-ity [54,55], referred to as a ‘healthy fat’ phenotype by Andreotti et al. [56]. They hypothesize that obesity may offer protection in the setting of acute MI by protecting the myocardium against prolonged ischemia.

Box 2. Mechanisms associated with the obesity paradox.

Bias ● Selection ● Confounding factors ● Baseline genetic differences

Cardiorespiratory fitness ● Higher fitness levels ● Lean mass

Treatment approach ● Early treatment ● Aggressive treatment ● More revascularization ● More optimal medical therapy

Coronary anatomy ● Lower risk of multivessel disease ● Bigger coronary size ● Easier stent placement ● Lesser burden of unstable plaque

Biological mechanisms ● Increased TNF-a receptors ● Decreased effects of inflammation on myocardium

Metabolic reserve ● Less catabolic state ● Reduced endothelial dysfunction ● Increased regenerative capacity

Others ● Lower atrial natriuretic peptides and renin ● Smoking and pulmonary disease ● Nonpurposeful weight loss ● Body fat distribution



Effect of cardiorespiratory fitness on the obesity paradoxCardiorespiratory fitness is associated directly with improved survival in healthy populations and patients with CHD [39,57]. Cardiorespira-tory fitness has been shown to influence the obesity paradox in a number of recent studies. In a study of 859 patients with known CHD, we showed that the obesity paradox was pres-ent only in patients with low cardiorespiratory fitness (Figure 3) defined by peak exercise oxygen consumption [39]. These data were replicated in a recent study of over 9000 men with docu-mented or suspected CHD, where McAuley et al. found that there was no obesity paradox in the high cardiorespiratory fitness group; although a strong paradox was noted in low cardiorespi-ratory fitness patients by BMI, BF and central obesity [58]. In addition, Lavie et al. reported similar findings in a recent analysis of 2066 sys-tolic HF patients, where the BMI paradox was present only in the low cardiorespiratory fitness group [22]. Based on the available data, it can be confidently stated that cardiorespiratory fit-ness significantly alters the obesity paradox and is one of the most important factors determining long-term survival. Future studies evaluating the obesity paradox should include cardiorespiratory fitness in their outcome models to prevent con-founding, and the effect of exercise training [59,60]

and muscular strength [61] should be emphasized in CHD patients.

Impact of weight loss on the obesity paradoxThe presence of the obesity paradox does not mean that weight reduction is not beneficial in the above-mentioned high-risk populations. Some epidemiological studies have suggested that pur-poseful weight loss is associated with increased mortality [49,62]. However, multiple studies have suggested that unintentional weight loss rather than purposeful weight loss, and loss of BF rather than weight reduction, is associated with lower mortality. Allison et al. reported, in two differ-ent prospective population-based cohort stud-ies, that weight loss increased the mortality rate, whereas loss of BF decreased the mortality rate over 8–16 years of follow-up [63]. Furthermore, a large study of 1669 patients found that inten-tional weight loss over a period of 6 months was associated with a significantly lower incidence of CHD over 4 years of follow-up [64]. Specifically, in patients with known CHD who are known to have the obesity paradox, Mayo Clinic inves-tigators showed that intentional weight loss in patients attending cardiac rehabilitation was asso-ciated with a 38% reduction in the composite end point of all-cause mortality and CV events [65]. In addition, the favorable outcomes were seen both in normal weight and overweight patients [65]. Similarly, Lavie et al. have shown that intentional weight loss after attending a cardiac rehabilitation program was associated with significant improve-ments in cardiorespiratory fitness, LDL choles-terol, HDL cholesterol, triglycerides, C-reactive protein and fasting glucose [66].

Myers et al. observed that unintentional weight loss was associated with a higher mortality in 3834 men referred for exercise testing during a mean follow-up of 7 years [67]. However, it was noted that >60% of the persons in the weight loss group died due to conditions associated with muscle wasting, compared with only 27% in the weight gain group. The authors concluded that unintentional weight loss secondary to occult diseases might be responsible for the obesity par-adox observed in these patients [67]. These data are further substantiated by a subanalysis of the ACLS study, where improvement in cardiorespi-ratory fitness over a period of 6.3 years was asso-ciated with a significant improvement in CVD mortality and all-cause mortality, independent of the change in BMI; however, the vice versa was

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Figure 3. Risk-adjusted hazard ratio in a combined analysis of cardiorespiratory fitness and BMi in 855 coronary heart disease patients. An obesity paradox with BMI was noted only in patients with low cardiorespiratory FIT, where there was no paradox in patients with high cardiorespiratory FIT. FIT: Fitness. Reproduced with permission from [39].



not demonstrated [68]. It is clear that intentional weight loss is beneficial despite the obesity para-dox, compared with unintentional weight loss, which is associated with sarcopenia and loss of lean mass.

ControversiesBMI is a surrogate marker of obesity and does not differentiate between central and periph-eral obesity or between lean mass and BF [1]. A major point of debate in the obesity paradox literature has been the association of central obesity parameters with outcomes in CHD patients. An individual patient data meta-ana-lysis of over 15,000 patients with CHD showed that central obesity was directly associated with all-cause mortality, and that central obesity or BF distribution may be more applicable for risk stratification compared with generalized obesity measured by BMI [4]. On the other hand, data from the ACLS study showed that patients (9563 men with known or suspected CHD) in the sec-ond and third tertiles of WC had a significantly lower mortality compared with the first tertile [58]. These contradictory findings in the meta-analysis [4] and the ACLS study [58] were most likely secondary to inherent differences in the patient populations (nonveterans vs veterans), gender distribution (only men in ACLS) and the use of different measures of central obesity (waist-to-hip ratio and WC vs WC only), respec-tively. A post hoc analysis of the MERLIN-TIMI 36 trial reported an inverse association between increasing BMI or WC and short-term outcomes (CV death, MI or recurrent ischemia). However, WC was directly associated with worse outcomes at 1 year. Of note, the authors found that the combination of high WC and low BMI con-ferred the highest mortality risk [69]. Zeller et al. found no obesity paradox with BMI or WC in 2229 patients with acute MI; however, the high-est risk of mortality was observed in patients with high WC and low BMI [70]. Congruent to these findings, our group has recently reported the concept of ‘normal weight central obesity’ show-ing that patients with normal BMI but elevated measures of central obesity were at the highest mortality risk compared with other patterns of adiposity. These data indicate that a combina-tion of BMI and measures of central obesity is superior to documenting BMI alone for risk stratification in CHD patients (Figure 4) [71].

Comparisons between BMI and directly mea-sured BF percentage in patients with CHD have

shown that BMI correlates only moderately (rho coefficient: 0.6) with BF [72,73]. De Schutter and colleagues demonstrated that BMI ≥30 kg/m2

had a good specificity (95%), but a poor sensi-tivity (43%) to detect obesity by BF [74]. In this direction, Lavie et al. found an inverse association between BF and mortality in CHD patients as reported above [13]. In light of these emerging data, it can be stated that an obesity paradox definitely exists when BMI is used as a measure of obesity in patients with CHD; however, fur-ther studies are required to confirm these find-ings with measures of central obesity and BF. Direct measurement of BF with dual-energy x-ray absorptiometry scan and abdominal fat by computed tomography or MRI will be more insightful [75].

ConclusionObesity is associated with adverse outcomes in the general healthy population. However, con-clusive evidence suggests that elevated BMI in patients with certain diseases, such as CHD, PCI, HF and HTN, is associated with lower all-cause mortality, defined as the obesity para-dox. Although data on direct measures of cen-tral obesity are conflicting, the combination of

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Figure 4. ‘Normal weight central obesity’ evaluated in over 15,000 coronary heart disease patients. Risk-adjusted hazard ratios in this individual patient data meta-analysis study showed that coronary heart disease patients with normal BMI but higher waist-to-hip ratio have the highest all-cause mortality. Reproduced with permission from [71].



EXECUTivE SUMMARYObesity paradox in coronary heart disease

● Numerous studies have reported an inverse association between BMI and all-cause mortality in patients with known coronary heart disease (CHD), stable CHD, acute myocardial infarction and those undergoing percutaneous coronary intervention. Patients with a BMI ≥40 kg/m2 have higher mortality rates compared with normal BMI (20–25 kg/m2) patients. Recent studies also report that low body fat percentage was associated a higher risk of mortality.

Obesity paradox in other diseased states

● In patients with heart failure, evidence suggests the presence of an obesity paradox with BMI, body fat and central obesity. Studies in other populations such as ischemic stroke, hypertension, incident diabetes mellitus, atrial fibrillation, transcatheter aortic valve replacement, hemodialysis and pulmonary hypertension also suggest an obesity paradox.

Mechanisms

● Some investigators and epidemiologists think that this association may be secondary to selection bias and residual confounding. However, multiple mechanisms have been proposed to explain the obesity paradox in different populations. These include aggressive medical treatment, low-risk coronary anatomy, higher metabolic reserve and presence of soluble TNF-a receptors in adipose tissue.

Cardiorespiratory fitness

● Cardiorespiratory fitness significantly alters the obesity paradox. Multiple studies have shown that an obesity paradox exists only in patients with low cardiorespiratory fitness. A high level of fitness and aerobic capacity is independently associated with increased survival.

Weight loss

● Intentional weight loss in patients with CHD is associated with significant improvements in cardiorespiratory fitness, lipid parameters, cardiovascular events and all-cause mortality. Loss of lean mass and nonintentional weight loss due to muscle wasting are associated with increased mortality. Weight reduction and exercise should be recommended to overweight and obese patients with CHD.

Controversies

● The lack of discriminatory power of BMI may be true to some extent, as it does not differentiate between central and peripheral obesity or lean mass and body fat. Studies on the association of central obesity and outcomes in patients with known CHD have mixed results. However, a combination of elevated central obesity and normal BMI has been shown to be associated with increased mortality in many studies and this high-risk phenotype is termed as ‘normal weight central obesity’.

elevated central obesity and normal/low BMI is definitely associated with a higher mortality risk. New emerging data in other subpopula-tions such as TAVR, DM, AF and pulmonary HTN needs validation in future studies. Cardio-respiratory fitness overrides the obesity paradox and development of lean mass may be benefi-cial. Intentional weight loss should be strongly recommended to obese patients with CHD and other diseases.

Future perspectiveProspective studies should be designed to assess the relative contributions of lean mass, BF and central obesity to better elucidate the exact mechanisms behind the obesity paradox. The impact of purposeful weight loss with dietary efforts, new pharmacologic therapies, as well as

weight loss surgeries needs further validation. Cardio respiratory fitness and the role of exer-cise training, including both aerobic/dynamic exercise and resistance/strength training in these overweight and obese patients is critical for reducing the long-term outcomes in these populations.

Financial & competing interests disclosureThe authors have no relevant affiliations or financial involvement with any organization or entity with a finan-cial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert t estimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

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ReferencesPapers of special note have been highlighted as:l● of interestl●●l● of considerable interest

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l●●l● Highest cited review article on the obesity paradox in cardiovascular diseases.

2 McGill HC Jr, McMahan CA, Herderick EE et al. Obesity accelerates the progression of coronary atherosclerosis in young men. Circulation 105(23), 2712–2718 (2002).

3 Gruberg L, Weissman NJ, Waksman R et al. The impact of obesity on the short-term and long-term outcomes after percutaneous coronary intervention: the obesity paradox? J. Am. Coll. Cardiol. 39(4), 578–584 (2002).

4 Coutinho T, Goel K, Correa de sa D et al. Central obesity and survival in subjects with coronary artery disease: a systematic review of the literature and collaborative ana lysis with individual subject data. J. Am. Coll. Cardiol. 57(19), 1877–1886 (2011).

l●●l● Individual patient data meta-ana lysis involving 15,293 patients with coronary heart disease (CHD) from three continents. Demonstrated an inverse association between BMI and mortality; however, found no obesity paradox for central obesity. Study suggests body fat distribution may provide more prognostic information compared with BMI alone.

5 Flegal KM, Kit BK, Orpana H, Graubard BI. Association of all-cause mortality with overweight and obesity using standard body mass index categories: a systematic review and meta-ana lysis. JAMA 309(1), 71–82 (2013).

l●●l● One of the largest meta-analyses to date involving 2.88 million healthy persons worldwide. Reported that being in the overweight category was associated with a significantly decreased mortality compared with normal BMI.

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7 Romero-Corral A, Montori VM, Somers VK et al. Association of bodyweight with total mortality and with cardiovascular events in coronary artery disease: a systematic review of cohort studies. Lancet 368(9536), 666–678 (2006).

l●●l● Largest meta-ana lysis on the obesity paradox in patients with CHD. This study found a U-shaped curve for the association between BMI and mortality, with transition point at a BMI of ≥35 kg/m2.

8 Bucholz EM, Rathore SS, Reid KJ et al. Body mass index and mortality in acute myocardial infarction patients. Am. J. Med. 125(8), 796–803 (2012).

9 Azimi A, Charlot MG, Torp-Pedersen C et al. Moderate overweight is beneficial and severe obesity detrimental for patients with documented atherosclerotic heart disease. Heart 99(9), 655–660 (2013).

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l●●l● In stable CHD patients, the authors reported that both low lean mass and low body fat were associated with a higher risk of all-cause mortality.

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l●●l● One of the first studies to assess the association of body fat percentage and outcomes in patients with stable CHD. The investigators found that a combination of low body fat and low BMI had the worst prognosis compared with other adiposity patterns.

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l●●l● Major review on the obesity paradox in patients with heart failure and proposed mechanisms.



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