EXERCISE IS MEDICINE

Obesity and Prognosis in Chronic Diseases V Impact of Cardiorespiratory Fitness in the Obesity Paradox Carl J. Lavie, MD1,2; Alban De Schutter, MD,MSc1; Edward Archer, PhD, MS3; Paul A. McAuley, PhD4; and Steven N. Blair, PED5 increased prevalence of impaired fasting glucose, metabolic syndrome, and type 2 diabetes mellitus; it also adversely impacts lipids and is linked to inflammation and leads to additional physical inactivity, all of which worsen overall CV risk (2,25,29,32). Considering the adverse effects that obesity has on CV risk factors and on CV structure and function, including adversely affecting systolic, and especially, diastolic ventricular function, it is not surprising that almost all CVD are increased in the setting of obesity, including hypertension (HTN), coronary heart disease (CHD), heart failure (HF), atrial fibrillation (AF), peripheral arterial disease (PAD), as well as many other CVD (2,25,29,32). Additionally obesity adversely impacts other potentially important aspects of chronic health, including increasing the risk of certain cancers, arthritic conditions and overall mobility, psychological factors, and overall quality of life (QoL) (20,32). There is no question that efforts to reduce overweight and obesity in the first place would be advantageous for preventing many long-term health consequences. However despite the impact of obesity to increase CVD risk factors and overall CVD, many have demonstrated a very strong obesity paradox among cohorts with established CVD, including HTN, CHD, HF, AF, and PAD, where lean patients (e.g., those with body mass index (BMI) in the ‘‘normal’’ range) with these same conditions appear to have a worse CVD prognosis and overall survival compared with that of their heavier counterparts with the same CVD (29,32). Although probably most of the emphasis and research in the area of the obesity paradox has been directed at CVD, this obesity paradox also has been noted in many other groups of patients with chronic diseases, including end-stage renal disease (41), chronic obstructive pulmonary disease (COPD), cancers, immune deficiency diseases such as human immunodeficiency virus (HIV) or acquired immune deficiency

Abstract The effects of overweight and obesity on chronic diseases, particularly on cardiovascular disease (CVD), and its impact on increasing CVD risk factors and total CVD are reviewed. However despite the adverse effects of obesity on CVD risk factors and CVD, obesity has a surprising association with prognosis in patients with established diseases, often showing an ‘‘obesity,’’ where overweight (body mass index (BMI), 25 to 29.9 kgImj2) and obese patients (BMI, Q30 kgImj2) with established CVD frequently have a better prognosis than that of their leaner counterparts (BMI, G25 kgImj2) with the same diseases. Fitness-versus-fatness debate is summarized also, including the critical role that fitness plays to alter the relationship between adiposity and subsequent prognosis.

Substantial evidence suggests that obesity takes a ‘‘heavy’’ toll on overall health and, especially, on the cardiovascular (CV) disease (CVD) risk factors and increases the prevalence of overall CVD events and mortality (29,32). Increases in body weight typically increase levels of arterial blood pressure, which adversely impact CV structure and function, including left ventricular hypertrophy (2,3,29,32). Obesity also increases the resistance to the actions of insulin, leading to an 1

Department of Cardiovascular Diseases, John Ochsner Heart and Vascular Institute, Ochsner Clinical School V University of Queensland School of Medicine, New Orleans, LA; 2Department of Preventive Medicine, Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, LA; 3Office of Energetics, School of Public Health, University of Alabama at Birmingham, Birmingham, AL; 4Department of Health, Physical Education, and Sports Sciences, Winston-Salem State University, Winston-Salem, NC; and 5Department of Exercise Science and Department of Epidemiology and Biostatistics, Arnold School of Public Health, University of South Carolina, Columbia, SC Address for correspondence: Carl J. Lavie, MD, FACC, FACP, FCCP, Exercise Laboratories, John Ochsner Heart and Vascular Institute, Ochsner Clinical School V University of Queensland School of Medicine, 1514 Jefferson Highway, New Orleans, LA 70121-2483; E-mail: [email protected]. 1537-890X/1304/240Y245 Current Sports Medicine Reports Copyright * 2014 by the American College of Sports Medicine

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Obesity, Fitness, and Prognosis

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Table 1. Adverse effects of obesity.

A. Increases in insulin resistance 1) Glucose intolerance 2) Metabolic syndrome 3) Type 2 diabetes mellitus B. HTN C. Dyslipidemia 1) Elevated total cholesterol 2) Elevated triglycerides 3) Elevated low-density lipoprotein cholesterol 4) Elevated non-high-density lipoprotein cholesterol 5) Elevated apolipoprotein-B 6) Elevated small dense LDL particles 7) Decreased high-density lipoprotein cholesterol 8) Decreased apolipoprotein-A1 D. Abnormal left ventricular geometry 1) Concentric remodeling 2) Left ventricular hypertrophy E. Endothelial dysfunction F. Increased systemic inflammation and prothrombotic state G. Systolic and diastolic dysfunction H. HF I. CHD J. AF K. Obstructive sleep apnea/sleep-disordered breathing L. Albuminuria M. Osteoarthritis N. Cancers (Reprinted from Lavie CJ, Milani RV, Ventura HO. Obesity and cardiocascular disease: risk factor, paradox, and impact of weight loss. J. AM Coll. Cardiol. 2009; 53:1925Y32. Copyright * 2009 Elsevier. Used with permission.)

syndrome, chronic arthritis, as well as other chronic conditions. (Table 1) (20,32,41). In fact, studies on older (e.g., age, 960 yr) cohorts of patients also have identified a survival advantage of higher weight status (e.g., BMI of 25 to 35 kgImj2) among the elderly (9,17). Until recently, cardiorespiratory fitness (CRF), which is a powerful CVD risk factor and may be impacted adversely by weight gain, has been overlooked as a potential modifier of the inverse relationship between obesity and prognosis, particularly in patients with known or suspected CVD (38). In this article, several aspects of the obesity paradox are reviewed, including aspects of body composition and fatness versus contributions of CRF, including the fitnessversus-fatness debate. The lack of physical activity (PA) as a major cause of obesity is discussed also, as well as the contributions of PA and exercise training (ET) toward improving levels of CRF in overall prognosis. www.acsm-csmr.org

Controversies Regarding Obesity and Prognosis Various studies have suggested different contributions of obesity to overall prognosis (15,19,36). A high-profile study suggests that nearly 20% of all mortality in the United States and the Western World could be attributed to obesity (36). On the other hand, a recent meta-analysis from 97 studies and 2.9 million people including more than 270,000 deaths suggests that although obesity was associated with increased mortality at least in the nonelderly subjects, all this was due to Class II (BMI, 35 to 39.9 kgImj2) and Class III (BMI, Q40 kgImj2) obesity, as those with Class I obesity (BMI, 30 to 34.9 kgImj2) had a trend toward lower mortality than those with normal BMI (18.5 to 24.9 kgImj2), and the overweight group (BMI, 25 to 29.9 kgImj2) actually had the best survival, with 6% lower mortality than that in subjects with normal BMI (15). Nevertheless, another report suggested that there was no such thing as metabolically healthy obesity, as this group still had a 24% higher mortality than that in lean patients who also were metabolically healthy (19). On the other hand, lean or obese patients who were ‘‘metabolically unhealthy’’ had two- to threefold increased mortality rates (19,25). All of these studies discussed previously only assess mortality and/or major CVD events, and none assess the other contributions of obesity to long-term health outcomes or overall QoL, which may be impacted adversely by obesity. Moreover these studies did not assess adequately the contributions of PA and no study quantified the potentially extremely important contribution of CRF to the impact of adiposity on health outcomes (25,29,38). Obesity Paradox in CVD During the past decade, numerous studies have identified low body weight, especially among the underweight (BMI, G18.5 kgImj2) but also in those with higher levels of BMI, as associated with the worst prognosis among patients with CVD; it also was identified that overweight and even mildly to moderately obese groups (BMI, 30 to 35 kgImj2) have a better prognosis than that of the patients of normal weight having the same CVD (29,32). The obesity paradox in CVD prognosis probably is understood best in the setting of HF (12,21). Certainly this is understood more easily in patients with advanced HF, with the leanest patients with HF including the frail and cachectic having a particularly poor prognosis (23). Frailty is defined as a biological syndrome characterized by declining overall function and loss of resistance to stresses, and this has a well-known association with considerable morbidity and mortality as well as health care utilization among elderly populations who have a high prevalence of HF (23). Cachexia, or unintentional weight loss, predicts poor prognosis in many conditions, including HF (23). Clearly unintentional weight loss is an extremely bad sign, predicting poor prognosis in many medical conditions, including HF. To an extent, overweight and obesity may represent the opposite of cachexia in HF and other chronic CV or medical conditions, which some have termed ‘‘reverse causality’’ (30,40). In addition to the obesity paradox that has been demonstrated clearly in many HF studies and meta-analyses (34), the same holds true for many other groups with various Current Sports Medicine Reports

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CVD. Certainly many studies and large meta-analyses also have demonstrated a strong obesity paradox in patients with CHD, where overweight and mildly obese patients have a considerably better prognosis than that in their leaner counterparts with CHD (14,21,25,29,32). Most recently, investigators have questioned whether this relationship represents a true obesity paradox as opposed to an ‘‘overweight paradox,’’ (6,24) since similar to the data in the study of Flegal et al. (15), overweight patients with CHD seem to have a particularly good prognosis (6,24). This relationship may represent even a ‘‘lean paradox,’’ since it seems that the leaner CHD patients, including those with low BMI (G25 kgImj2) and low body fat (BF), including BF G25% in men and G35% in women, have a particularly bad prognosis (26). Although both low BMI and low BF are independent predictors of increased mortality, data from Ochsner in New Orleans show that those patients with combined low BMI and low BF are the only patients with higher mortality in CHD (26). Most recently, it was demonstrated that low BF and low lean mass (or non-fat mass) are independent predictors of higher mortality, with the best prognosis noted in those with both a high BF and high lean mass (e.g., lean mass index 919 kgImj2 in men and 915 kgImj2 in women) and the worst survival in those with combined low BF and low lean mass (27). In another study, those with underweight BF had the worst prognosis in CHD, whereas the overweight BF had the best prognosis (13). Mechanisms of Obesity Paradox Although some investigators continue to stress the importance of confounders as causes of the obesity paradox, especially emphasizing the potentially important role of smoking and smoking-induced COPD in this process (43), many studies have found a strong obesity paradox even when correcting for COPD and other confounders (26,27). The exact mechanism for this puzzling obesity paradox, however, remains poorly understood (29,32), but several Table 2. Potential reasons for the obesity paradox in CVD.

Nonpurposeful weight loss Younger age at presentation Lower prevalence of smoking Greater metabolic reserves Less cachexia Lower atrial natriuretic peptides Attenuated response to renin-angiotensin-aldosterone system High blood pressure, allowing for more cardiac medications Differing etiology, associated with a better prognosis Increased muscle mass and muscular strength Implications regarding CRF

Figure 1: Obesity paradox and fitness in CHD. Joint effects of cardiorespiratory fitness and BMI (A), WC (B), and percentage of BF (C) on all-cause mortality. Hazard ratios (boxes) and 95% confidence intervals (error bars represent values) after adjusting for age, baseline examination year, PA (active or inactive), smoking status (currently smoking or not), alcohol intake (914 drinks per week or not), hypercholesterolemia, HTN, and diabetes (present or not for each), and family history of CVD. Low fitness was defined as the bottom tertile of fitness based on age and gender, whereas high fitness was defined as all others not in the bottom tertile. (Reprinted from McAuley PA, Artero EG, Sui X, et al. The obesity paradox, cardiorespiratory fitness and coronary heart disease. Mayo Clin. Proc. 2012; 87:443Y57. Copyright * 2012 Elsevier, Inc. Used with permission.)

Unmeasured confounding factors (Reprinted from Lavie CJ, McAuley PA, Church TS, et al. Obesity and cardiovascular diseases: implications regarding fitness, fatness and severity in the obesity paradox. J. Am. Coll. Cardiol, 2014; in press. Copyright * 2014 Elsevier. Used with permissions.)

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potential mechanisms are listed in Table 2 (29). In some situations, higher BF may provide reserves to fight a serious chronic disease, which would be logical for some serious cancers, HIV, or advanced HF, but this would seem hardly Obesity, Fitness, and Prognosis

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logical for stable HTN or CHD, for example. Another possibility is genetic selection bias, in that some overweight and obese may have not developed CVD in the first place if weight gain had been prevented, whereas the thin patients who still develop the same CVD do so for another reason (e.g., genetic predisposition) that may be associated with a worse prognosis despite having a more favorable overall CVD risk factor profile. One of the theories to explain partly the obesity paradox is the relatively poor accuracy of BMI in representing true at-risk body fatness. Other parameters of body composition, including waist circumference (WC) and central obesity, waist-to-hip ratio, percentage of BF, and especially BF compartments (e.g., visceral adiposity may reflect more atrisk obesity, whereas subcutaneous fat actually may be protective), may predict risk in patients with CVD better than BMI alone (25,29,32). However there are inconsistencies in the data, and some studies have indicated an obesity paradox with both BMI and percentage of BF in both CHD and HF (13,21,26,27,31,33) and in CHD, even with WC (the latter at least in those with low levels of CRF, discussed below) (37). CRF, Fatness, and the Obesity Paradox During the past three decades, numerous prospective studies have reported the independent effects of CRF and adiposity on all-cause mortality (8,11,18,35). Prior studies suggest that obesity, as assessed by BMI, increased mortality risk independently by between 20% and 30%, whereas higher CRF is associated with markedly lower risk of CV events and all-cause mortality (7). In fact, a very large metaanalysis from Kodama et al. (18) demonstrated that for every 1-metabolic equivalent (MET) increase in precisely measured CRF, CV events and all-cause mortality were reduced by 15% and 13%, respectively. However considerable debate regarding the relative influences of obesity versus fitness and their relative contributions to all-cause mortality has occurred (7). In this regard, Barry et al. (7) recently performed a metaanalysis to assess the relative importance of CRF and fatness on all-cause mortality. They reviewed 10 prospective studies that assessed CRF, BMI, and all-cause mortality. In this

meta-analysis including almost 100,000 participants, they demonstrated that compared with fit individuals with normal weight (generally defined as fitness level 9 bottom 20%), unfit individuals (generally defined as the bottom quintile of CRF) had nearly twice the mortality regardless of the level of adiposity. On the other hand, overweight and obese, but fit, individuals had survival similar to that of the fit individuals with normal weight. They suggested that the obesity paradox may not influence those individuals with relatively preserved levels of CRF. Other studies have assessed the impact of CRF on the relationship of adiposity and survival in cohorts with CVD, including both CHD and HF (21,29). Clearly CRF is a powerful prognostic factor in the general population, and the same is true for patients with CVD. McAuley et al. (37) recently evaluated 9,563 subjects with known or suspected CHD stratified by BMI as well as WC and BF percentage and followed this cohort for 13 years for all-cause and CVD mortality. After adjusting for age, baseline assessment, PA, smoking, dyslipidemia, diabetes status, and family history of CVD, they found an obesity paradox associated with all three measures of body composition for those in the bottom third of CRF status (based on age and gender), but there was excellent prognosis and no obesity paradox noted in those with more preserved CRF (Fig. 1) (37). Other studies in patients with known or suspected CHD also found that CRF markedly alters the relationship between adiposity and clinical prognosis (16,39). Recently similar findings were noted in a cohort of 2,066 patients with systolic HF who were followed up for 5 years (22). Patients with low peak oxygen consumption (V˙O2peak, G14 mL O2Ikgj1Iminj1) on a cardiopulmonary stress test (CPX) had a high rate of mortality, and there was a strong obesity paradox, with the patients with normal BMI (18.5 to 25 kgImj2) having the worst prognosis and the obese patients (BMI, Q30 kgImj2) having the best prognosis. It should be noted, however, that there were few patients with systolic HF who had moderate and severe obesity in this study, and in our experience, such patients seem to have a difficult time performing CPX. On the other hand, those with more preserved exercise capacity (V˙O2peak, Q14 mL O2Ikgj1Iminj1) had a good prognosis,

Figure 2: Obesity paradox and fitness in HF. Kaplan-Meier analyses according to BMI with the group with low CRF (O2 consumption, G14 mL O2Ikgj1Iminj1; log rank, 11.7; P = 0.003) (A) and group with high CRF (O2 consumption, e14 mL O2Ikgj1Iminj1; log rank, 1.72; P = 0.42) (B). [Adapted from Lavie CT, Cahalin LP, Chase P. et al. Impact of cardiorespiratory fitness in the obesity paradox in patients with heart failure. Mayo Clin. Proc. 2013; 88:251Y8. Copyright * 2013 Elsevier, Inc. Used with permission.] (Reprinted from Lavie CJ, De Shutter A, Patel DA, Milani RV. Does fitness completely explain the obesity paradox? Am. Heart J. 2013; 166:1Y3. Copyright * 2013 Elsevier, Inc. Used with permission.) www.acsm-csmr.org

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and there was no obesity paradox (Fig. 2) (22). Therefore in CHD and HF, substantial evidence indicates that CRF markedly alters the obesity paradox. However a recent study by Uretsky et al. (44) on over 5,000 patients referred for nuclear stress testing and found to have normal perfusion scans demonstrated an obesity paradox regardless of the level of CRF. Nevertheless those with more preserved CRF (Q6 estimated METs) had extremely low mortality of less than 1% yearly, although the group with normal BMI had a higher mortality than that of the overweight and obese (1.4%, 0.9%, and 0.6% yearly, respectively) (28,44).

2. Alpert MA, Omran J, Mehra A, Ardhanari S. Impact of obesity and weight loss on cardiac performance and morphology in adults. Prog. Cardiovasc. Dis. 2014; 56:391Y400. 3. Alpert MA, Terry BE, Mulekar M, et al. Cardiac morphology and left ventricular function in normotensive morbidly obese patients with and without congestive heart failure and effect of weight loss. Am. J. Cardiol. 1997; 80:736Y40. 4. Archer E, Lavie CJ, McDonald SM, et al. Maternal inactivity: 45-year trends in mothers’ use of time. Mayo Clin. Proc. 2013; 88:1368Y77. 5. Archer ER, Shook RP, Thomas DM, et al. 45-Year trends in women’s use of time and household management energy expenditure. PloS One. 2013; 8:e56620. 6. 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. 2013; 99:655Y60. 7. Barry VW, Baruth M, Beets MW, et al. Fitness vs. fatness on all-cause mortality: a meta-analysis. Prog. Cardiovasc. Dis. 2014; 56:382Y90.

Impact of PA and ET Certainly increasing PA and regular ET as a way to improve CRF are essential for all patients, particularly for those with overweight or obesity. In fact, several recent articles demonstrate that lack of PA (occupational, household management, and leisure time) is likely the predominant cause of the obesity epidemic in the first place (4,5,10). Although CRF is determined also by genetic factors, the predominant determinant of CRF, which also is modifiable, is the level of PA and ET (45). National guidelines suggest that 150 minIwkj1 of moderate PA or 75 minIwkj1 of vigorous PA is needed by all individuals. The Institute of Medicine suggests 60 min of some PA on most days, with this amount of PA even more important for those who are overweight and obese. The role of PA and ET in obese patients has been reviewed in detail elsewhere (1,42). Clearly efforts to improve PA are needed throughout the health care system for the primary and secondary prevention of CVD (45) as well as the prevention and treatment of obesity (1,42). Conclusions The obesity paradox in chronic diseases, particularly CHD, HF, and CVD, was reviewed briefly. Although overweight and obesity appear to increase the prevalence of many chronic diseases, especially CVD, an obesity paradox clearly exists, where lean patients with certain chronic diseases have a worse prognosis than that of heavier patients with the same chronic disease. However CRF markedly alters the relationship between adiposity and clinical prognosis. High levels of fitness or CRF are likely to improve prognosis and all-cause mortality. Efforts to improve PA and CRF are needed throughout the health care system for the primary and secondary prevention of CVD as well as the prevention and treatment of obesity. C.J.L. has served as a consultant and speaker for the Coca-Cola Company (but on fitness/obesity and not on their products) and has published the Obesity Paradox book with potential royalties; E.A. has received honoraria for speaking engagements from the Coca-Cola Company and the International Life Sciences Institute; S.N.B. has served as a consultant for weight loss and fitness companies and for the Coca-Cola Company, who has provided him with unrestricted educational research grants.

8. Blair SN, Kampert JB, Kohl HW 3rd. Influences of cardiorespiratory fitness and other precursors on cardiovascular disease and all-cause mortality in men and women. JAMA. 1996; 276:205Y10. 9. Childers DK, Allison DB. The ‘obesity paradox’: a parsimonious explanation for relations among obesity, mortality rate and aging? Int. J. Obes. (Lond). 2010; 34:1231Y8. 10. Church TS, Thomas DM, Tudor-Locke C, et al. Trends over 5 decades in U.S. occupation-related physical activity and their associations with obesity. PLoS One. 2011; 6:e19657. 11. Church TS, LaMonte MJ, Barlow CE, Blair SN. Cardiorespiratory fitness and body mass index as predictors of cardiovascular disease mortality among men with diabetes. Arch. Intern. Med. 2005; 165:2114Y20. 12. Clark AL, Fonarow GC, Horwich TB. Obesity and obesity paradox in heart failure. Prog. Cardiovasc. Dis. 2013; 56:409Y14. 13. De Schutter A, Lavie CJ, Patel DA, et al. Relation of body fat categories by Gallagher classification and by continuous variables to mortality in patients with coronary heart disease. Am. J. Cardiol. 2013; 111:657Y60. 14. De Schutter A, Lavie CJ, Patel DA, Milani RV. Obesity paradox and the heart: which indicator of obesity best describes this complex relationship? Curr. Opin. Clin. Nutr. Metab. Care. 2013; 16:517Y24. 15. Flegal KM, Kit BK, Orpana H, Graubard BL. Association of all-cause mortality with overweight and obesity using standard body mass index categories: a systematic review and meta-analysis. JAMA. 2013; 309:71Y82. 16. Goel K, Thomas RJ, Squires RW, et al. Combined effect of cardiorespiratory fitness and adiposity on mortality in patients with coronary artery disease. Am. Heart J. 2011; 161:590Y7. 17. Jahangir E, De Schutter A, Lavie CJ. Low weight and overweightness in older adults: risk and clinical management. Prog. Cardiovasc. Dis. 2014; doi: 10.1016/j.pcad.2014.01.001. 18. Kodama S, Saito K, Tanaka S, et al. Cardiorespiratory fitness as a quantitative predictor of all-cause mortality and cardiovascular events in healthy men and women: a meta-analysis. JAMA. 2009; 301:2024Y35. 19. Kramer CK, Zinman B, Retnakaran R. Are metabolically healthy overweight and obesity benign conditions?: a systematic review and meta-analysis. Ann. Intern. Med. 2013; 159:758Y769. 20. Lavie CJ. Obesity and prognosis V just one of many cardiovascular paradoxes? Prog. Cardiovasc. Dis. 2014; 56:367Y8. 21. Lavie CJ, Alpert MA, Arena R, et al. Impact of obesity and the obesity paradox on prevalence and prognosis in heart failure. JACC Heart Fail. 2013; 1:93Y102. 22. Lavie CJ, Cahalin LP, Chase P, et al. Impact of cardiorespiratory fitness on the obesity paradox in patients with heart failure. Mayo Clin. Proc. 2013; 88:251Y8. 23. Lavie CJ, De Schutter A, Alpert MA, et al. Obesity paradox, cachexia, frailty, and heart failure. Heart Fail. Clin. 2014;10:319Y326 http://dx.doi.org/ 10.1016/j.hfc.2013.12.002. 24. Lavie CJ, De Schutter A, Milani RV. Is there an obesity, overweight or lean paradox in coronary heart disease? Getting to the ‘fat’ of the matter. Heart. 2013; 99:596Y8. 25. Lavie CJ, De Schutter A, Milani RV. Healthy obese versus unhealthy lean: the obesity paradox. Nat. Rev. Endocrinol. 2014; in press. 26. Lavie CJ, De Schutter A, Patel D, et al. Body composition and coronary heart disease mortality V an obesity or a lean paradox? Mayo Clin. Proc. 2011; 86:857Y64.

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27. Lavie CJ, De Schutter A, Patel DA, et al. Body composition and survival in stable coronary heart disease: impact of lean mass index and body fat in the ‘‘obesity paradox.’’ J. Am. Coll. Cardiol. 2012; 60:1374Y80.

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28. Lavie CJ, De Schutter A, Patel DA, Milani RV. Does fitness completely explain the obesity paradox? Am. Heart. J. 2013; 166:1Y3.

37. McAuley PA, Artero EG, Sui X, et al. The obesity paradox, cardiorespiratory fitness, and coronary heart disease. Mayo Clin. Proc. 2012; 87:443Y51.

29. Lavie CJ, McAuley PA, Church TS, et al. Obesity and cardiovascular diseases: implications regarding fitness, fatness and severity in the obesity paradox. J. Am. Coll. Cardiol. 2014;63:1345Y1354.

38. McAuley PA, Beavers KM. Contribution of cardiorespiratory fitness to the obesity paradox. Prog. Cardiovasc. Dis. 2014; 56:434Y40.

30. Lavie CJ, Mehra MR, Milani RV. Obesity and heart failure prognosis: paradox or reverse epidemiology? Eur. Heart. J. 2005; 26:5Y7.

39. McAuley PA, Kokkinos PF, Oliveira RB, et al. Obesity paradox and cardiorespiratory fitness in 12,417 male veterans aged 40 to 70 years. Mayo Clin. Proc. 2010; 85:115Y21.

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45. Vuori IM, Lavie CJ, Blair SN. Physical activity promotion in the health care system. Mayo Clin. Proc. 2013; 88:1446Y61.

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Obesity and prognosis in chronic diseases--impact of cardiorespiratory fitness in the obesity paradox.

The effects of overweight and obesity on chronic diseases, particularly on cardiovascular disease (CVD), and its impact on increasing CVD risk factors...
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