Editorial. Future Cardiology. ...the current body of evidence strongly suggests excess bodyweight is protective in patients with heart failure...

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1 For reprint orders, please contact: The obesity paradox and outcome in heart failure: is excess bodyweight truly protective?...the current body of evidence strongly suggests excess bodyweight is protective in patients with heart failure... Ross Arena & Carl J Lavie Author for correspondence: Department of Physical Therapy, Box , Virginia Commonwealth University, Health Sciences Campus, Richmond, VA , USA Tel.: Fax: raarena@.vcu.edu Editorial Future Cardiology Excess bodyweight is convincingly linked to physical inactivity, hypertension, dyslipidemia and Type 2 diabetes mellitus (DM) in addition to being a well-established independent risk factor for the development of cardiovascular disease (CVD) and mortality [1,2]. More troubling is the continuing rise in individuals classified as being overweight (BMI = kg/m 2 ) or obese (BMI 30 kg/m 2 ). As such, significant healthcare efforts are being directed toward the promotion of weight loss in the general population [3]. However, there is a large and continually growing body of evidence indicating excess bodyweight confers a lower risk for adverse events in patients with CVD, including the heart failure (HF) population. This pheno menon has been termed the obesity paradox, given that excess bodyweight significantly increases the risk for initially developing HF [4]. This paper addresses the current body of evidence supporting improved prognosis in patients with HF who are overweight or obese; the potential mechanisms for the obesity paradox; and current clinical recommendations and future research pursuits regarding bodyweight in patients with HF. Evidence supporting the obesity paradox in heart failure The majority of the well-conducted body of research supporting the obesity paradox in HF was collectively analyzed in a recent meta-analysis by Oreopoulus et al. [5]. The nine studies assessed in the final analysis, cumulatively including more than 28,000 subjects, consistently found patients with HF who were overweight (BMI = kg/m 2 ; relative risk [RR]: 0.84; 95% CI: ) or obese (BMI 30 kg/m 2 ; RR: 0.67; 95% CI: ) had a significantly lower (p < 0.001) mortality risk compared with those subjects who presented with a normal weight (BMI = kg/m 2 ). Moreover, prognosis was more favorable in obese patients compared with those who were overweight. These findings were consistent in both unadjusted and adjusted prognostic models, the latter of which controlled for other baseline factors such as age, sex and New York Heart Association (NYHA) class. A subgroup analysis revealed that even subjects classified as being in the moder ate severe obese range (BMI 35 kg/m 2 ; RR: 0.62; 95% CI: ; p < 0.001) enjoyed a more favorable prognosis compared with those who were normal weight. Conversely, a second subgroup analysis revealed subjects who were considered underweight/low-normal weight (BMI <23.0 kg/m 2 ; relative risk: 1.25; 95% CI: ; p < 0.001) presented with a significantly worse prognosis compared to the normal weight cohort. Fonarow et al. assessed the impact of BMI on in-hospital mortality for patients admitted with acute HF decompensation [6]. The registry included 237 hospitals in the USA and more than 100,000 hospitalizations. The overall group was divided into quartiles according to BMI ( , , and kg/m 2 ), resulting in more than 27,000 subjects per quartile. Numerous differences in baseline characteristics were apparent according to BMI grouping, including a significantly lower age and significantly higher left ventricular (LV) ejection fraction and DM prevalence in the kg/m 2 quartile. B-type natriuretic peptide (BNP) also significantly decreased from the lowest to highest BMI quartile ( to pg/ml; p < 0.001). part of /FCA Future Medicine Ltd Future Cardiol. (2010) 6(1), 1 6 ISSN

2 Editorial Arena & Lavie The incidence in in-hospital mortality significantly decreased as BMI increased ( to %; p < 0.001) and improved prognosis with higher BMI persisted after adjustment for age, sex, blood urea nitrogen, blood pressure, creatinine, sodium, heart rate and dyspnea at rest. Lastly, each increase in 5 kg/m 2 equated to a 10% reduction in mortality....a higher percent of body fat was the strongest independent predictor of event-free survival, with every 1% reduction in percent body fat equating to a 13% increase in risk for adverse events. Assessment of body composition through BMI is limited by its inability to accurately quantify percent body fat. Lavie et al. addressed this limitation by examining the prognostic value of different measures of body composition, including direct assessment of percent body fat via the skinfold technique [7]. This analysis revealed a higher percent of body fat was the strongest independent predictor of event-free survival, with every 1% reduction in percent body fat equating to a 13% increase in risk for adverse events. Consistent with other investigations, a higher BMI also equated to improved survival. The results of this investigation indicate that the improved survival consistently associated with higher BMI is in fact linked to body fat in patients with HF. Anker et al. assessed the prognostic value of the longitudinal change in bodyweight in approximately 2500 patients (~1900 in initial cohort and ~600 in validation set) with HF [8]. All subjects survived at least 4 months and mean follow-up was 35 months. Approximately 40% of the subjects in the initial data set had a weight loss of 5% or more at follow-up. Moreover, spontaneous reversal of weight loss occurred in less than 2% of the subjects who lost weight at follow-up. While all percent weight loss thresholds assessed were prognostic for increased mortality risk ( 5, 6, 7.5, 10 and 15%), the greater than or equal to 6% threshold was p rognostically optimal. Cardiopulmonary exercise testing is a standard of care in patients with HF [9] and, as such, several large HF cohorts who have undergone this procedure are available for analysis. Arena et al. recently examined the prognostic value of BMI in more than 1000 patients referred for cardiopulmonary exercise testing [10]. Absolute peak oxygen consumption (VO 2 in l/min) significantly increased from normal to overweight to obese subgroups, although expression in relative terms (mlo 2 kg -1 min -1 ) was comparable. Ventilatory efficiency (VE; i.e., the VE/VCO 2 slope), a powerful prognostic marker in patients with HF irrespective of BMI [11,12], was significantly worse in the normal weight subgroup compared with both overweight and obese subgroups. In the overall group, the overweight and obese subjects again had a significantly lower risk for adverse events compared with those who were normal weight as defined by BMI. However, this prognostic trend was not consistent according to the etiology of HF. In patients with an ischemic HF etiology, only subjects classified as obese had a significantly better prognosis while overweight and normal weight subjects presented with comparable and higher adverse event rates. Conversely, overweight and obese subjects with a nonischemic HF etiology presented with a comparable and significantly more favorable prognosis compared with normal weight subjects. In the ischemic HF group, a dichotomous BMI classification of obese versus overweight/normal weight was retained in a multivariate prognostic model including the VE/VCO 2 slope (strongest independent predictor) and peak VO 2. In the nonischemic HF group, a dichotomous BMI classification of obese/overweight versus normal weight was again retained in a multivariate prognostic model including the VE/VCO 2 slope (strongest independent predictor), ejection fraction and age. This appears to be the first investigation to suggest that the impact of bodyweight on prognosis is modulated by HF etiology. Potential explanations for the obesity paradox in heart failure There are several plausible hypotheses accounting for the link between increasing bodyweight and improved survival in patients with HF. Increasing HF severity is often paralleled by a higher catabolic burden. The cardiac cachexia (i.e., wasting) observed in end-stage HF is associated with abnormal cytokine and neurohormone levels [13] and indicative of higher mortality risk [14]. It is therefore not surprising that underweight patients with HF have the worst prognosis compared with all other weight classifications [5]. Therefore, one explanation for the obesity paradox is that patients progressing to higher levels of HF disease severity while carrying excess bodyweight have a greater metabolic reserve and are more resistant to the increasing 2 Future Cardiol. (2010) 6(1)

3 The obesity paradox & outcome in heart failure: is excess body weight truly protective? Editorial catabolic burden [15]. Along these lines, tumor necrosis factor a (TNF a), a proinflammatory cytokine with catabolic effects, is elevated in patients with HF and is also significant p redictor of adverse events [16,17]. In patients with an ischemic HF etiology, only subjects classified as obese had a significantly better prognosis while overweight and normal weight subjects presented with comparable and higher adverse event rates. Adipose tissue has been shown to produce TNF α receptors, the production of which positively correlates with the level of body fat [18]. Therefore, overweight and obese patients with HF may therefore be afforded a protective buffer from the negative impact of increasing TNF α by producing higher levels of these receptors compared with those who are normal or underweight. Interestingly, patients with ischemic HF appear to have significantly higher TNF α concentrations compared with those with a nonischemic etiology [16]. Perhaps this variation is a plausible hypothesis for the observed differences in the interaction between BMI and prognosis according to HF etiology [10]. Specifically, patients with ischemic HF and the highest level of TNF α require adipose tissue levels only realized in the obese range to improve prognosis. Conversely, patients with nonischemic HF and a lower TNF α level may produce the receptors via adipose tissue needed to favorably impact prognosis at a lower bodyweight (i.e., overweight). Bacterial lipopolysaccharides (LPS) provide a strong stimulus for inflammatory cytokine release and are also elevated in patients with HF [19]. It has been posited that cholesterol and triglyceride-rich lipoproteins have the ability to bind to and detoxify LPS [20]. The higher levels of cholesterol observed in overweight and obese patients with HF may therefore counteract the higher level of LPS more efficiently, serving as another hypothesis for the link between excess bodyweight and improved survival [21]. In conclusion, the exact physiologic mechanism(s) explaining the link between excess bodyweight and improved prognosis in HF has not yet been elucidated. However, there is a compelling amount of evidence to indicate adipose tissue and circulating lipoproteins play a role in r educing s ystemic inflammation and its deleterious effects. Other lines of evidence suggest that the obesity paradox may partially be the result of selection bias. Overweight and obese patients may present earlier with less severe HF and may also have comorbidities treated in a more aggressive fashion [5,22]. Two lines of evidence appear to support this premise. First, excess bodyweight may cause dyspnea for reasons not related to HF (deconditioning and restrictive pulmonary disease), thus leading to a HF presentation at an earlier stage [22]. Similar to this, obesity may lead to peripheral edema owing to non-hf reasons (e.g., venous insufficiency and increased total blood volume), that may also lead to HF presenting at a less severe stage. Second, it has been demonstrated that excess bodyweight decreases BNP expression in patients with HF [23,24]. Reduced levels of circulating BNP may lead to increased volume and symptoms of dyspnea that are more so independent of the degree of systolic and diastolic dysfunction in patients with HF who possess excess bodyweight. The link between lower BNP and excess volume may be another potential reason as to why overweight/ obese patients with HF present earlier with less severe HF, are managed more effectively, and enjoy better prognosis. Even though selection bias may contribute to the obesity paradox in patients with HF, models adjusted for different baseline patient characteristics and clinical management strategies still suggest excess bodyweight is, in itself, protective, lending support to a physiologic mechanism [5]. Current state of the clinical approach & future research pursuits in bodyweight management in patients with heart failure Clinicians are rightfully trained/conditioned to council patients who are overweight or obese to strongly consider strategies that would assist in weight loss. This approach stems from the overwhelming evidence supporting the negative impacts of excess bodyweight on multiple facets of health, quality of life and prognosis. To now suggest that clinicians council HF patients to gain weight if their BMI falls within the normal range to achieve overweight or obese levels, or maintain current weight if already classified as overweight or obese, would therefore be counterintuitive and should not be endorsed. However, based upon an overwhelming amount of scientific evidence, the fact that obese and, to a lesser degree, overweight patients with HF enjoy a more favorable prognosis compared with their normal and underweight counterparts 3

4 Editorial Arena & Lavie cannot be ignored in the current clinical environment. As such, the following current clinical paradigm and future research pursuits are put forth for consideration....adipose tissue and circulating lipoproteins play a role in reducing systemic inflammation and its deleterious effects. Clinicians responsible for the management of patients with HF should consider bodyweight, via BMI, when assessing an individual s prognostic outlook. Determining prognosis in HF is complex and entails multivariate modeling (i.e., age, hemodynamics, cardiopulmonary exercise test data, echocardiography, neurohormonal markers and other variables). Along these lines, there is clearly value in crosssectionally considering BMI for prognostic purposes. An obese classification should currently be considered a favorable prognostic marker, perhaps irrespective of HF etiology. Conversely, etiology may impact the prognostic status of an overweight classification with only those diagnosed with nonischemic HF having a lower risk for adverse events. A normal weight or underweight designation, particularly the latter, carries u nfavorable prognosis irrespective of etiology. Last, from a longitudinal perspective, unintentional weight loss of 6% or more of initial bodyweight should be considered an ominous prognostic marker. In the original investigations currently supporting the prognostic benefit of excess bodyweight in HF, subjects in the normal and underweight categories presumably did not reach these levels through intentional weight loss practices (i.e., diet and exercise). The limited research examining weight changes longitudinally also indicates that unintentional reductions in bodyweight is prognostically disconcerting [8]. Therefore, counseling overweight and obese patients with HF on intentional weight loss through healthy lifestyle practices such as the initiation of regular exercise and/or dietary modifications should not be overlooked [15]. Moreover, weight gain strategies should be considered for patients who are found to be underweight and at the greatest risk for future adverse events. A substantial amount of additional research is needed to solidify optimal clinical practice patterns with respect to weight management in patients with HF. A primary objective is to more accurately identify the mechanism(s) by which excess bodyweight is protective in this chronic disease population. Initial evidence indicates adipose tissue, either directly through TNF α receptor production or indirectly through promotion of increased circulating lipoprotein concentrations, helps to counteract the systemic inflammatory catabolic cascade precipitated by HF. This mechanistic line of research seems promising and should continue. If the adipose tissue-inflammatory link is more firmly supported, the clinically relevant question becomes how can the increase in systemic inflammation in HF be treated while maintaining a normal bodyweight? This issue is currently being addressed by examining the impact of anti-inflammatory pharmacologic agents and exercise training in patients with HF. While the results from the initial pharmacologic trials have been disappointing, there is consensus that other agents with a primary anti-inflammatory mechanism should be explored [25,26]. In fact, statin therapy may improve prognosis in HF, potentially through the anti-inflammatory properties of this drug class [27]. From a lifestyle perspective, exercise training also appears to have an anti-inflammatory effect in patients with HF, reducing TNF α and IL-1 and 6 within skeletal muscle [28]. There is also the largely unexplored issue of intentional versus unintentional weight loss in patients with HF....patients progressing to higher levels of HF disease severity while carrying excess bodyweight have a greater metabolic reserve and are more resistant to the increasing catabolic burden. It is currently believed that unintentional weight loss through the catabolic effects of HF is the primary reason that lower bodyweight is linked to poor prognosis. Little has been carried out to comprehensively examine the physiologic, clinical and prognostic effects of intentional weight loss in this patient population. Clearly in HF, despite the obesity paradox, trials have indicated that purposeful weight reduction has led to reductions in LV mass, as well as improvements in both systolic and, particularly, diastolic LV function. Alpert et al. did find gastric bypass surgery significantly improved cardiac structure and function as well as clinical symptoms in 14 morbidly obese patients (defined as greater than or equal to two-times ideal bodyweight) diagnosed with HF [29]. Much more research is 4 Future Cardiol. (2010) 6(1)

5 The obesity paradox & outcome in heart failure: is excess body weight truly protective? Editorial needed to assess the safety and efficacy of intentional weight loss in HF, in particular, lifestyle approaches such as exercise training and diet. Lastly, current clinical patterns should be examined to determine if selection bias in HF management helps to explain the obesity paradox. If patients with HF and excess bodyweight are in fact presenting earlier in the disease process and therefore managed more effectively, elucidation of the reason for this pattern is needed to develop strategies to ensure similar practice patterns in normal-weight patients. Conclusion To answer the question put forth in the title of this article: the current body of evidence strongly suggests excess bodyweight is protective in patients with HF, thus providing a scientific foundation for the obesity paradox. However, this conclusion does not indicate that clinicians should promote the maintenance or attainment of bodyweight that would classify an individual as overweight or obese. Rather, the scientific community should work diligently to determine the mechanism(s) behind the obesity paradox and develop clinical approaches that would allow normal-weight patients to enjoy the prognostic advantages presently observed in those who are overweight or obese. Financial & competing interests disclosure The authors have no relevant affiliations or financial involvement with any organization or entity with a financial 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 testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript. Bibliography 1. 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6 Editorial Arena & Lavie 23. Lavie CJ, Mehra MR, Milani RV: Obesity and heart failure prognosis: paradox or reverse epidemiology? Eur. Heart J. 26(1), 5 7 (2005). 24. Mehra MR, Uber PA, Park MH et al.: Obesity and suppressed B-type natriuretic peptide levels in heart failure. J. Am. Coll. Cardiol. 43(9), (2004). 25. Aukrust P, Yndestad A, Ueland T, Damas JK, Gullestad L: Anti-inflammatory trials in chronic heart failure. Heart Fail. Monit. 5(1), 2 9 (2006). 26. Gullestad L, Aukrust P: Review of trials in chronic heart failure showing broad-spectrum anti-inflammatory approaches. Am. J. Cardiol. 95(11 Suppl. 1), (2005). 27. Raina A, Pickering T, Shimbo D: Statin use in heart failure: a cause for concern? Am. Heart J. 152(1), (2006). 28. Gielen S, Adams V, Möbius-Winkler S et al.: Anti-inflammatory effects of exercise training in the skeletal muscle of patients with chronic heart failure. J. Am. Coll. Cardiol. 42(5), (2003). 29. Alpert MD, Terry MD, Mulekar P 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. 80(6), (1997). Affiliations Ross Arena Departments of Internal Medicine, Physiology & Physical Therapy, Virginia Commonwealth University, Richmond, VA , USA Tel.: Fax: raarena@.vcu.edu Carl J Lavie Stress Testing Laboratory Ochsner Heart & Vascular Institute, 1514 Jefferson Highway, New Orleans, LA 70121, USA Tel.: Fax: clavie@ochsner.org 6 Future Cardiol. (2010) 6(1)