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 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 syndrome, chronic arthritis, as well as other chronic conditions. (Table 1) (20,32,41). In fact, studies on older (e.g., age, >60 yr) cohorts of patients also have identified a survival advantage of higher weight status (e.g., BMI of 25 to 35 kg·m−2) 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 fitness-versus-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.
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 kg·m−2) and Class III (BMI, ≥40 kg·m−2) obesity, as those with Class I obesity (BMI, 30 to 34.9 kg·m−2) had a trend toward lower mortality than those with normal BMI (18.5 to 24.9 kg·m−2), and the overweight group (BMI, 25 to 29.9 kg·m−2) 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, <18.5 kg·m−2) 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 kg·m−2) 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 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 (<25 kg·m−2) and low body fat (BF), including BF <25% in men and <35% 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 >19 kg·m−2 in men and >15 kg·m−2 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 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 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 at-risk 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 meta-analysis 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 meta-analysis 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 > 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, <14 mL O2·kg−1·min−1) 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 kg·m−2) having the worst prognosis and the obese patients (BMI, ≥30 kg·m−2) 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, ≥14 mL O2·kg−1·min−1) had a good prognosis, 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 (≥6 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).
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 min·wk−1 of moderate PA or 75 min·wk−1 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).
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.
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