Professional Documents
Culture Documents
Accepted Manuscript: 10.1016/j.pcad.2018.05.005
Accepted Manuscript: 10.1016/j.pcad.2018.05.005
PII: S0033-0620(18)30095-1
DOI: doi:10.1016/j.pcad.2018.05.005
Reference: YPCAD 893
To appear in:
Received date: 25 May 2018
Accepted date: 25 May 2018
Please cite this article as: Tamara B. Horwich, Gregg C. Fonarow, Adrienne L. Clark ,
Obesity and the Obesity Paradox in Heart Failure. (2018), doi:10.1016/j.pcad.2018.05.005
This is a PDF file of an unedited manuscript that has been accepted for publication. As
a service to our customers we are providing this early version of the manuscript. The
manuscript will undergo copyediting, typesetting, and review of the resulting proof before
it is published in its final form. Please note that during the production process errors may
be discovered which could affect the content, and all legal disclaimers that apply to the
journal pertain.
ACCEPTED MANUSCRIPT
T
Gregg C. Fonarow is a Professor of Medicine / Cardiology at the David Geffen School of
IP
Medicine at University of California, Los Angeles.
CR
Adrienne L. Clark is an Instructor of Medicine at Harvard Medical School in Boston, MA
US
From the University of California, Los Angeles David Geffen School of Medicine
AN
Disclosures/COI:None
M
ED
thorwich@mednet.ucla.edu
ACCEPTED MANUSCRIPT
Abstract:
Obesity continues to be a public health problem in the general population, and also
significantly increases the risk for the development of new-onset heart failure (HF). However, in
patients with already-established, chronic HF, overweight and mild to moderate obesity is
associated with substantially improved survival compared to normal weight patients; this has
T
been termed the "obesity paradox". The majority of studies measure obesity by body mass index,
IP
but studies utilizing less-frequently used measures of body fat and body composition, including
CR
waist circumference, waist-hip ratio, skinfold estimates, and bioelectrical impedance analysis
also confirm the obesity paradox in HF. Other areas of investigation such as the relationship of
US
the obesity paradox to cardiorespiratory fitness, gender, and race are also discussed. Finally, this
AN
review explores various explanations for the obesity paradox, and summarizes the current
Key words:
Heart failure
CE
Obesity paradox
Waist circumference
AC
ACCEPTED MANUSCRIPT
Abbreviations
T
Computed tomography (CT)
IP
Cardiovascular disease (CVD)
CR
Dual energy x-ray absorptiometry (DEXA)
Obesity is a growing public health problem in the United States (US) and worldwide. The
percentage of obese individuals as identified by body mass index (BMI) in the US in the last half
century has nearly tripled, from BMI ≥ 30 in 13.4% and BMI ≥ 40 in 0.9% of the population in
T
During this time, the percentage of overweight (BMI 25.0-29.9 kg/m2) remained stable at
IP
approximately one-third of the population, meaning that the distribution of BMI in the US is now
CR
significantly shifted toward higher values. Overweight and obesity, as defined by BMI, are also
highly prevalent in heart failure (HF) populations. While prevalence varies by demographics of
US
the cohort studied, approximately 29-40% of HF patients are overweight (BMI 25.0-29.9 kg/m2)
AN
and 30 – 49% of HF patients are obese 32-49% (BMI ≥ 30 kg/m2).2 Of note, obesity is
significantly more prevalent in HF patients with preserved ejection fraction (HFpEF) compared
M
to HF with reduced ejection fraction (HFrEF), with over 80% of HFpEF patients having BMIs in
ED
Obesity as measured by elevated BMI is a major risk factor for the development of HF,
CE
both HFpEF and HFrEF.5 Among 5,881 patients in the Framingham Heart Study, BMI was
found to correlate with HF risk in a dose-dependent fashion: HF risk increased by 5% for men
AC
and 7% for women for each single unit increase in BMI, even after adjustment for demographics
and other known risk factors such as diabetes, hypertension, and cholesterol.6 This positive
correlation between BMI and HF risk for both overweight and obese was confirmed in the larger
Physicians’ Health Study of 21,094 men without known coronary artery disease, where
overweight participants had a 49% increase in HF risk compared with lean participants and obese
ACCEPTED MANUSCRIPT
participants had a 180% increase (95% CI, 124-250)7. These same trends have been
link between BMI and HF risk, with multivariable-adjusted hazard ratios of HF for normal,
overweight, and obese BMI of 1.00, 1.25, and 1.99 for men and 1.00, 1.33, and 2.06 for women,
T
80,630 Swedish men and women; not only higher BMI but higher waist circumference (WC),
IP
waist-hip ratio , and waist to height ratio were associated with higher risk of HF hospitalization
CR
and mortality.9 Lastly, it may be that distribution of adiposity plays a critical role in obesity’s
impact on HF incidence; for example, in one magnetic resonance imaging ( MRI) study, visceral
US
but not subcutaneous adipose tissue was significantly related to adverse cardiac remodeling and
AN
adverse hemodynamics.10
Although elevated BMI is well established as a risk factor for HF, a surprising
ED
relationship between BMI and outcomes in those with established HF has been observed.
Obesity as measured by BMI and various other indices has been linked to improved HF survival
PT
outcomes and traditional risk factors, sometimes termed “reverse epidemiology” or “obesity
paradox,” has now been well documented in the HF medical literature.11 In one of the first
AC
followed at a single university transplant center, patients with higher BMI (>27.8 kg/m2) were
outcomes were seen in the underweight group, followed closely by normal weight HF patients.
An analysis of a large, randomized controlled trial of 7,599 patients with symptomatic HFpEF
ACCEPTED MANUSCRIPT
and HFrEF showed that there was a graded decreased risk of death with increasingly higher BMI
categories; the group with the highest BMI (>35 kg/m2) had similar risk to those with BMI 30.0-
34.9 kg/m2).13 An analysis of BMI and its relationship to in-hospital mortality for 108,927
patients with decompensated HF identified a 10% reduction in mortality for every 5-unit increase
T
(n=22,807) investigated the relationship between BMI and all-cause mortality, cardiovascular
IP
disease (CVD) mortality, and HF hospitalizations; those at highest risk of the three outcomes had
CR
low BMI (<20 kg/m2) while those at lowest risk were in the overweight category (BMI 25 – 29.9
kg/m2). Mortality risk was similar in the obese and severely obese groups (Figure 1).15
US
Most studies of the obesity paradox have used BMI to estimate body composition and
AN
identify overweight and obese patients, for reasons of widespread acceptance and ease of use.
However, the reliability of BMI as an accurate measure of adiposity has been questioned.
M
Numerous alternate techniques may be more accurate to define body composition (fat vs. lean
ED
obesity include WC, waist-hip ratio, skinfold estimates of percent body fat (BF), and
PT
bioelectrical impedance analysis (BIA) of body composition. Dual energy x-ray absorptiometry
CE
(DEXA) is useful for assessment of BF and body compartments, but has limited application due
to expense, radiation, and required technical expertise.16, 17 The current gold standards for
AC
assessing body composition are computed tomography (CT) and MRI, which are thought to
provide the most accurate qualitative and quantitative information on adiposity and lean mass,
but application of these methods are also limited by expense and radiation (CT).18
ACCEPTED MANUSCRIPT
WC is a simple and inexpensive way to assess for abdominal obesity, and an established
predictor of CVD risk in the general population.19, 20 Not only higher BMI but also higher WC
has been shown to be associated with improved outcomes in both men and women with
advanced HFrEF. In fact, patients with both overweight or obese BMI and high WC (defined as
T
≥88 cm in women and ≥102 cm in men) had the best survival in a cohort of advanced systolic
IP
HF patients at a university transplant referral center.21, 22 However, a more recent analysis of a
CR
HFpEF population showed that abdominal obesity as defined by WC was associated with an
approximate 50% increase in both all-cause and CVD mortality after multivariable adjustment,
US
raising the possibility that abdominal obesity and / or visceral adiposity play a more detrimental
AN
role in the pathophysiology of HFpEF.23 Thus, as put forth by Lavie et al., further investigation is
necessary, particularly aimed at understanding whether WC may have more import in certain
M
A study of 209 HF patients used the average of three skinfolds to measure BF (thigh,
chest, and abdomen skin folds in men; thigh, triceps, and suprailiac in women).25 Increased
PT
absolute increase in percent BF measured via skinfold thickness was associated with a >13%
reduction in major clinical events (P=0.002). Those patients in the highest BF quintile (mean
AC
37.7%) had the lowest rate of death / urgent heart transplant (5%), compared to an event rate of
22% in the patients in the lowest body fat quintile (mean 16.4%).
composition, although not widely available in the clinical setting.26 In a community-based study
in the United Kingdom, 1025 patients with chronic HF underwent BIA; percent BF, fat mass,
ACCEPTED MANUSCRIPT
and fat-free mass were associated with increased risk and percent BF was a significant predictor
of mortality in a multivariable model (P=0.04).27 BIA has now been shown to be safe for use
with pacemakers and defibrillators, broadening its potential use in advanced HF populations.28
Visceral fat deposited around the heart is known as epicardial adipose tissue (EAT),
which can be imaged with CT or MRI. Increased EAT is associated with insulin resistance,
T
central adiposity, dyslipidemia, and decreased adiponectin levels from this biochemically active
IP
organ.29, 30 Data from both the Framingham Heart Study and Multi-Ethnic Study of
CR
Atherosclerosis reveals that in general populations, EAT is linked to both metabolic syndrome
and increased CVD burden.31, 32 In one study of HF patients, those with more severe disease had
US
lower levels of EAT, with a stepwise decrease in EAT with disease progression: patients with
AN
lower left ventricular ejection fraction ( LVEF;<35%) had significantly decreased EAT
compared to patients with LVEF 35%-55% (P <0.05), 33 which was independent of BMI.
M
Decrease in EAT was associated with statistically significant higher risk of HF mortality
ED
(P=0.02), possibly representing a novel component of the obesity paradox.34 However, a more
recent study assessing pericardial fat (including both EAT and paracardial layers) by MRI
PT
showed that higher pericardial fat was associated with increased risk of malignant arrhythmias in
CE
Cachexia, or progressive weight loss with body composition alterations and disturbed
homeostasis of several body systems, is a poorly understood syndrome that carries a devastating
prognosis in HF and other disease states. In one HF population studied in 1997, 50% of those
with cachexia (defined as non-intentional documented weight loss of at least 7.5% of previous
normal weight over 6 months) had died at 18 months follow-up (HR 3.73, 95% CI 1.93-7.23
ACCEPTED MANUSCRIPT
compared to those without cachexia).36 Even in a modern cohort of HF patients in which over
90% of patients were on beta-blockers (which are thought to be anti-cachexia), weight loss of 5%
or more over one year occurred in 17% of patients and was associated with significant mortality
risk.37 While the cause of cachexia is unclear, a recent paper demonstrated more right ventricle
(RV) dysfunction in those with cachexia and lower fat/lean body mass ratio, suggesting an
T
association between poor RV function and cachexia and highlighting the possible protective role
IP
of adipose tissue in HF.38
CR
However, more severe obesity may also impact prognosis. One study from the Cleveland
Clinic demonstrated that patients with class III obesity (BMI ≥ 40 kg/m2) experienced the highest
US
all-cause mortality/transplant (hazard ratio 2.46; 95% CI 1.4-4.30), far greater than that of the
AN
non-obese group (hazard ratio HR 1.44; 95% CI 1.09-1.91), when both groups were compared to
HFpEF showed increased risk above BMI of 30 kg/m2, although in HFrEF, the risk levelled out
ED
at BMI of 30 kg/m2.40 It is possible that severely obese patients, particularly those with HFpEF,
may benefit from different weight loss goals than their overweight and less obese counterparts.
PT
Given the heterogeneity of those affected by HF, recent studies have made efforts to
better characterize the obesity paradox in specific subgroups. Because systolic HF is more
AC
common in men, the majority of research has been conducted in predominantly male
populations. This selection bias extends into studies of the obesity paradox in HF despite
accepted variations in fat distribution by sex: women may make up as little as 13% of a study
population or sex of participants may not be reported.41, 42 One investigation identified BMI <25
kg/m2 and normal WC (<102 cm in men and <88 cm in women) as strong independent predictors
ACCEPTED MANUSCRIPT
of increased mortality in men (relative risk for BMI 1.34, 95% CI 1.13-1.58; WC 2.02, 1.18-
3.45).22 However, only BMI and not WC was significant for the subgroup of women (1.38, 1.02-
1.89). This study may have been limited by small sample size (n=469 with recorded WC),
pointing to the need for further investigation of HF outcomes in women. On the other hand, in
one study of 30-day mortality rates in hospitalized HF patients, the obesity paradox was not
T
affected by race / ethnicity.40, 43
IP
VI. The Obesity Paradox, Cardiorespiratory Fitness (CRF), and HF Prognosis
CR
CRF, measured variously as peak oxygen uptake (VO2) or minute ventilation (VE)/carbon
dioxide production (VCO2), has been identified as an important predictor of survival in HF.44, 45
US
Chase et al. studied a cohort of 744 HF patients and found that patients with obese BMI had
AN
significantly lower VE/VCO2 slopes than patients with normal and overweight BMI, and
ultimately found that VE/VCO2 was a strong independent predictor of improved survival
M
irrespective of BMI.44 Several groups have now demonstrated that CRF level may modify the
ED
obesity paradox.46 Lavie et al. showed that in 2066 patients with systolic HF, BMI was a
significant predictor of age- and sex-adjusted survival in the group with low peak VO2 (<14
PT
mL/O2/kg) (P=0.03), but not in the high CRF group.47 Clark et al similarly found that high BMI
CE
was associated with improved prognosis only in those with low fitness levels48. (Figure 2) Most
recently, in a mixed HFrEF / HFpEF population from the Henry Ford Exercise Testing Project,
AC
there was no relationship between BMI and mortality in the subgroup with exercise tolerance at
or above 4 metabolic equivalents (METS), while the obesity paradox was preserved in the low
exercise capacity group.49 These findings indicate that CRF might mitigate or even negate the
obesity paradox phenomenon in HF, perhaps by improving the prognosis of those with lower
BMI. CRF lowers CVD risk factors such as blood pressure and inflammation and increases
ACCEPTED MANUSCRIPT
strength and muscle mass.50 In summary, exercise training to improve CRF is reasonable for HF
Various competing and often contradictory mechanisms have been proposed to explain the HF
obesity paradox (Table 1). HF is a catabolic state, and overweight and obesity may represent
T
metabolic reserve while patients at lower BF levels may suffer from unintentional weight loss
IP
resulting in “cardiac cachexia,” known to be associated with a poor prognosis.51, 52 Obese
CR
patients may also experience greater functional impairment and have more impaired quality of
life in part from their increased body mass, and thus present earlier in their disease course,
US
leading to earlier implementation of life-saving therapies. This association of obesity with better
AN
outcomes in patients with established HF may represent survival bias, index event bias, or
reverse causation.
M
Obesity is linked to lower circulating levels of B-type natriuretic peptide, suggesting the
ED
presence of a more favorable hemodynamic profile.53 These patients are also thought to have a
beneficial attenuated response to the renin-angiotensin-aldosterone system, yet at the same time
PT
can maintain higher blood pressures, which may preserve renal function and permit them to
CE
inhibitors.54 Obese patients may also benefit from the protective effects of various anti-
inflammatory adipokines, including soluble tumor necrosis factor-alpha receptor, which could
neutralize some component of the inflammation. Obese patients may have higher lipoprotein
levels, which may also neutralize circulating inflammatory endotoxin which characterizes
advanced HF.55 Lastly, obesity is associated with lower levels of adiponectin, which can increase
ACCEPTED MANUSCRIPT
energy expenditure and induce weight loss, and which is undesirable in the catabolic state of
HF.56-58
As discussed, given the limitations of various indices of BF, it is also quite plausible that
some of the patients identified as “obese” may actually have increased muscle mass and
muscular strength compared to their “normal weight” counterparts.17 BMI may not accurately
T
distinguish between percent BF and lean mass, and the relationship between BMI and BF varies
IP
with age, sex, and ethnicity.59-61 The accuracy of BMI in identifying obesity appears to be
CR
particularly limited in the intermediate BMI ranges, as well as in men and in the elderly. This is
important because the obesity paradox was first identified in these intermediate ranges of BMI
US
(overweight individuals) and because white men make up the majority of most HF study
AN
cohorts.12 Furthermore, obesity is a heterogeneous condition. Increased visceral fat depots have
high-density lipoprotein, and elevated low-density lipoprotein, whereas obese patients with low
ED
levels of visceral adipose tissue and increased subcutaneous or gluteofemoral obesity had
“normal” metabolic risk profiles.62, 63 The suggestion that higher lean mass may be protective is
PT
bolstered by the recent findings discussed above that obesity paradox is not strongly observed in
CE
those patients with greater levels of CRF.47 Lastly, obesity is associated with higher levels of
circulating stem cells,64 raising the hypothesis that perhaps these stem cells repopulate in areas of
AC
myocardial injury.
Obesity causes hemodynamic changes and cardiac structural remodeling, the best
treatment for which is intentional weight loss.65 Weight reduction decreases left ventricular mass,
lowers arterial pressures and left and right sided cardiac filling pressures, and decreases systemic
ACCEPTED MANUSCRIPT
oxygen consumption and cardiac output.66 Despite the benefit of weight loss in the prevention of
adverse cardiac remodeling, HF, and other cardiac disease, weight loss recommendations aimed
at other populations may not be appropriate for HF, and there are currently no clear consensus
recommends management of overweight and obese patients with HF as per guidelines for
T
general cardiovascular disease prevention, but acknowledges the gaps in evidence.67 The
IP
American College of Cardiology and American Heart Association Heart Failure clinical practice
CR
guidelines acknowledge the lack of evidence and do not make a recommendation.68
A small group of studies on diet, exercise, and bariatric surgery in patients with obesity
US
and HF have been performed, but have been generally small, short term, and inconclusive.
AN
Evangelista et al. randomized 14 HF patients with systolic HF, elevated BMI (≥27 kg/m2) and
type 2 diabetes to 12 weeks of a high protein diet, standard protein diet, or control. Both
M
quality of life, although greatest reductions in waist circumference and percent BF were seen
with the high protein diet.69 However, neither group experienced change in cardiac structure or
PT
diet, walking program, and educational sessions versus no intervention, but found no significant
Both interventions were well tolerated, suggesting that larger scale investigations are safe for
obese HF groups; however, there was no difference in physical exam, laboratory values, quality
of life questionnaire, six minute walk, or brachial ultrasound between the two groups. Likewise,
the HF-ACTION study demonstrated that moderate levels of exercise were both safe and
fit HF patients across BMI categories, although no association with weight loss was identified.71
However, exercise was significantly associated with improved quality of life.72 While severe HF
12 morbidly obese patients (BMI 53 ± 7 kg/m2) with systolic HF demonstrated significant one-
year reductions in hospitalization and NYHA class as compared to matched controls, and
T
improvement in LVEF from 21.7% ± 6.5 to 35.0% ± 14.8 (P<0.01).73 Similarly, another
IP
retrospective investigation at the same center showed that 14 systolic HF patients who underwent
CR
bariatric surgery experienced significant improvements in BMI and LVEF over a six month
period (from 50.8 ± 2.04 kg/m2 to 36.8 ± 1.72 kg/m2 and from 23% ± 2% to 32% ± 4%,
respectively).74
US
AN
Given the current state of the evidence and expert recommendations, it is reasonable to
state that weight loss should not be the primary therapeutic goal for overweight and obese HF
M
patients, but that diets aimed at mild to moderate weight loss may be reasonable in severely
ED
obese patients with the goal of weight stabilization or mild weight reduction with the aim of
Conclusions
CE
The association of obesity and improved survival in HF patients is well established across
multiple measures of adiposity. However, more complete understanding of this relatively robust
AC
survival benefit is needed and thus calls for further investigation. Better characterization of the
role of visceral and ectopic fat depots and their biochemical activity will be important in
of the role of CRF may lead to better risk assessment. Furthermore, while intentional weight loss
is known to improve hemodynamic function and cardiac structure in non-HF patients, further
ACCEPTED MANUSCRIPT
HF.
T
IP
CR
US
AN
M
ED
PT
CE
AC
ACCEPTED MANUSCRIPT
References
1. Fryar CD, Carrol MD, Ogden CL. Prevalence of overweight, obesity, and extreme
obesity among adults: United States, trends 1960-1962 through 2015-2016. NCHS Health
E-Stat. 2016.
2. Bozkurt B, Aguilar D, Deswal A, et al. Contributory Risk and Management of
Comorbidities of Hypertension, Obesity, Diabetes Mellitus, Hyperlipidemia, and
Metabolic Syndrome in Chronic Heart Failure: A Scientific Statement From the
American Heart Association. Circulation. 2016;134:e535-e578.
3. Lewis GA, Schelbert EB, Williams SG, et al. Biological Phenotypes of Heart Failure
T
With Preserved Ejection Fraction. Journal of the American College of Cardiology.
IP
2017;70:2186-2200.
4. Ather S, Chan W, Bozkurt B, et al. Impact of Noncardiac Comorbidities on Morbidity
CR
and Mortality in a Predominantly Male Population With Heart Failure and Preserved
Versus Reduced Ejection Fraction. Journal of the American College of Cardiology.
2012;59:998-1005.
5. Dunlay SM, Roger VL, Redfield MM. Epidemiology of heart failure with preserved
US
ejection fraction. Nature Reviews Cardiology. 2017;14:591.
6. Kenchaiah S, Evans J, Levy D, et al. Obesity and the risk of heart failure. N Engl J Med.
2002;347:305-313.
AN
7. Kenchaiah S, Sesso HD, Gaziano JM. Body mass index and vigorous physical activity
and the risk of heart failure among men. Circulation. 2009;119:44-52.
8. Hu G, Jousilahti P, Antikainen R, Katzmarzyk PT, Tuomilehto J. Joint effects of physical
M
activity, body mass index, waist circumference, and waist-to-hip ratio on the risk of heart
failure. Circulation. 2010;121:237-244.
ED
Ventricular Structure and Function: Neeland et al: Fat Distribution and Cardiac
Morphology. Circulation. Cardiovascular imaging. 2013;6:800-807.
11. Lavie CJ, Sharma A, Alpert MA, et al. Update on Obesity and Obesity Paradox in Heart
CE
2001;38:789-795.
13. Kenchaiah S, Pocock SJ, Wang D, et al. Body mass index and prognosis in patients with
chronic heart failure: insights from the Candesartan in Heart failure: Assessment of
Reduction in Mortality and morbidity (CHARM) program. Circulation. 2007;116:627-
636.
14. Fonarow G, Srikanthan P, Costanzo M, Cintron G, Lopatin M, Investigators ASACa. An
obesity paradox in acute heart failure: analysis of body mass index and inhospital
mortality for 108,927 patients in the Acute Decompensated Heart Failure National
Registry. American heart journal. 2007;153:74-81.
ACCEPTED MANUSCRIPT
15. Sharma A, Lavie CJ, Borer JS, et al. Meta-Analysis of the Relation of Body Mass Index
to All-Cause and Cardiovascular Mortality and Hospitalization in Patients With Chronic
Heart Failure. The American journal of cardiology. 2015;115:1428-1434.
16. Volgyi E, Tylavsky FA, Lyytikainen A, Suominen H, Alen M, Cheng S. Assessing body
composition with DXA and bioimpedance: effects of obesity, physical activity, and age.
Obesity (Silver Spring). 2008;16:700-705.
17. Oreopoulos A, Kalantar-Zadeh K, McAlister F, et al. Comparison of direct body
composition assessment methods in patients with chronic heart failure. Journal of cardiac
failure. 2010;16:867-872.
18. Cornier MA, Despres JP, Davis N, et al. Assessing Adiposity: A Scientific Statement
T
From the American Heart Association. Circulation. 2011.
IP
19. Bigaard J, Frederiksen K, Tjonneland A, et al. Waist circumference and body
composition in relation to all-cause mortality in middle-aged men and women. Int J Obes
CR
(Lond). 2005;29:778-784.
20. Janssen I, Katzmarzyk PT, Ross R. Waist circumference and not body mass index
explains obesity-related health risk. The American journal of clinical nutrition.
2004;79:379-384.
US
21. Clark AL, Fonarow GC, Horwich TB. Waist circumference, body mass index, and
survival in systolic heart failure: the obesity paradox revisited. Journal of cardiac failure.
2011;17:374-380.
AN
22. Clark AL, Chyu J, Horwich TB. The obesity paradox in men versus women with systolic
heart failure. The American journal of cardiology. 2012;110:77-82.
23. Tsujimoto T, Kajio H. Abdominal Obesity Is Associated With an Increased Risk of All-
M
24. Lavie CJ, Milani RV, Ventura HO. Adipose Composition and Heart Failure Prognosis:
Paradox or Not?∗. Journal of the American College of Cardiology. 2017;70:2750-2751.
25. Lavie CJ, Osman AF, Milani RV, Mehra MR. Body composition and prognosis in
chronic systolic heart failure: the obesity paradox. The American journal of cardiology.
PT
2003;91:891-894.
26. Paterna S, Di Pasquale P, Parrinello G, et al. Changes in brain natriuretic peptide levels
and bioelectrical impedance measurements after treatment with high-dose furosemide and
CE
31. Mahabadi AA, Massaro JM, Rosito GA, et al. Association of pericardial fat, intrathoracic
fat, and visceral abdominal fat with cardiovascular disease burden: the Framingham Heart
Study. European heart journal. 2009;30:850-856.
32. McAuley PA, Hsu FC, Loman KK, et al. Liver attenuation, pericardial adipose tissue,
obesity, and insulin resistance: the Multi-Ethnic Study of Atherosclerosis (MESA).
Obesity (Silver Spring). 2011;19:1855-1860.
33. Khawaja T, Greer C, Chokshi A, et al. Epicardial fat volume in patients with left
ventricular systolic dysfunction. The American journal of cardiology. 2011;108:397-401.
34. Doesch C, Suselbeck T, Leweling H, et al. Bioimpedance analysis parameters and
epicardial adipose tissue assessed by cardiac magnetic resonance imaging in patients with
T
heart failure. Obesity (Silver Spring). 2010;18:2326-2332.
IP
35. Wu C-K, Tsai H-Y, Su M-YM, et al. Pericardial fat is associated with ventricular
tachyarrhythmia and mortality in patients with systolic heart failure. Atherosclerosis.
CR
2015;241:607-614.
36. Anker S, Ponikowski P, Varney S, et al. Wasting as independent risk factor for mortality
in chronic heart failure. Lancet. 1997;349:1050-1053.
US
37. Zamora E, Díez‐López C, Lupón J, et al. Weight Loss in Obese Patients With Heart
Failure. Journal of the American Heart Association. 2016;5.
38. Melenovsky V, Kotrc M, Borlaug BA, et al. Relationships between Right Ventricular
Function, Body Composition and Prognosis in Advanced Heart Failure. J Am Coll
AN
Cardiol. 2013.
39. Nagarajan V, Cauthen CA, Starling RC, Tang WH. Prognosis of morbid obesity patients
with advanced heart failure. Congestive heart failure. 2013;19:160-164.
M
40. Lin G-M, Li Y-H, Yin W-H, et al. The Obesity-Mortality Paradox in Patients With Heart
Failure in Taiwan and a Collaborative Meta-Analysis for East Asian Patients. The
ED
cardiology. 2008;101:348-352.
45. Mancini DM, Eisen H, Kussmaul W, Mull R, Edmunds LH, Jr., Wilson JR. Value of
peak exercise oxygen consumption for optimal timing of cardiac transplantation in
ambulatory patients with heart failure. Circulation. 1991;83:778-786.
46. Lavie CJ, De Schutter A, Parto P, et al. Obesity and Prevalence of Cardiovascular
Diseases and Prognosis—The Obesity Paradox Updated. Progress in Cardiovascular
Diseases. 2016;58:537-547.
47. Lavie CJ, Alpert MA, Arena R, Mehra MR, Milani RV, Ventura HO. Impact of obesity
and the obesity paradox on prevalence and prognosis in heart failure. JACC: Heart
Failure. 2013;1:93-102.
ACCEPTED MANUSCRIPT
48. Clark AL, Fonarow GC, Horwich TB. Impact of Cardiorespiratory Fitness on the Obesity
Paradox in Patients With Systolic Heart Failure. The American journal of cardiology.
2015;115:209-213.
49. McAuley PA, Keteyian SJ, Brawner CA, et al. Exercise Capacity and the Obesity
Paradox in Heart Failure: The FIT (Henry Ford Exercise Testing) Project. Mayo Clinic
Proceedings. 2018.
50. Oktay AA, Lavie CJ, Kokkinos PF, Parto P, Pandey A, Ventura HO. The Interaction of
Cardiorespiratory Fitness With Obesity and the Obesity Paradox in Cardiovascular
Disease. Progress in Cardiovascular Diseases. 2017;60:30-44.
51. Davos CH, Doehner W, Rauchhaus M, et al. Body mass and survival in patients with
T
chronic heart failure without cachexia: the importance of obesity. Journal of cardiac
IP
failure. 2003;9:29-35.
52. Anker SD, Negassa A, Coats AJ, et al. Prognostic importance of weight loss in chronic
CR
heart failure and the effect of treatment with angiotensin-converting-enzyme inhibitors:
an observational study. Lancet. 2003;361:1077-1083.
53. Mehra MR, Uber PA, Park MH, et al. Obesity and suppressed B-type natriuretic peptide
levels in heart failure. J Am Coll Cardiol. 2004;43:1590-1595.
US
54. Lavie CJ, Milani RV, Ventura HO. Obesity and cardiovascular disease: risk factor,
paradox, and impact of weight loss. J Am Coll Cardiol. 2009;53:1925-1932.
55. Niebauer J, Volk H-D, Kemp M, et al. Endotoxin and immune activation in chronic heart
AN
failure: a prospective cohort study. The Lancet. 1999;353:1838-1842.
56. Kalantar-Zadeh K, Block G, Horwich T, Fonarow GC. Reverse epidemiology of
conventional cardiovascular risk factors in patients with chronic heart failure. J Am Coll
M
Cardiol. 2004;43:1439-1444.
57. Mohamed-Ali V, Goodrick S, Bulmer K, Holly JM, Yudkin JS, Coppack SW. Production
ED
of soluble tumor necrosis factor receptors by human subcutaneous adipose tissue in vivo.
The American journal of physiology. 1999;277:E971-975.
58. Packer M. Leptin-Aldosterone-Neprilysin Axis. Identification of Its Distinctive Role in
the Pathogenesis of the Three Phenotypes of Heart Failure in People With Obesity.
PT
2018;137:1614-1631.
59. Jackson A, Stanforth P, Gagnon J, et al. The effect of sex, age and race on estimating
percentage body fat from body mass index: The Heritage Family Study. Int J Obes Relat
CE
65. Rider OJ, Francis JM, Ali MK, et al. Beneficial cardiovascular effects of bariatric
surgical and dietary weight loss in obesity. J Am Coll Cardiol. 2009;54:718-726.
66. Poirier P, Giles TD, Bray GA, et al. Obesity and cardiovascular disease:
pathophysiology, evaluation, and effect of weight loss. Arteriosclerosis, thrombosis, and
vascular biology. 2006;26:968-976.
67. McMurray JJ, Adamopoulos S, Anker SD, et al. ESC guidelines for the diagnosis and
treatment of acute and chronic heart failure 2012: The Task Force for the Diagnosis and
Treatment of Acute and Chronic Heart Failure 2012 of the European Society of
Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the
ESC. European journal of heart failure. 2012;14:803-869.
T
68. Yancy CW, Jessup M, Bozkurt B, et al. 2013 ACCF/AHA Guideline for the Management
IP
of Heart Failure: A Report of the American College of Cardiology Foundation/American
Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2013.
CR
69. Evangelista LS, Heber D, Li Z, Bowerman S, Hamilton MA, Fonarow GC. Reduced
body weight and adiposity with a high-protein diet improves functional status, lipid
profiles, glycemic control, and quality of life in patients with heart failure: a feasibility
study. The Journal of cardiovascular nursing. 2009;24:207-215.
US
70. Pritchett AM, Deswal A, Aguilar D, et al. Lifestyle Modification with Diet and Exercise
in Obese Patients with Heart Failure - A Pilot Study. Journal of obesity & weight loss
therapy. 2012;2:1-8.
AN
71. Horwich TB, Broderick S, Chen L, et al. Relation among body mass index, exercise
training, and outcomes in chronic systolic heart failure. The American journal of
cardiology. 2011;108:1754-1759.
M
72. Flynn KE, Pina IL, Whellan DJ, et al. Effects of exercise training on health status in
patients with chronic heart failure: HF-ACTION randomized controlled trial. JAMA : the
ED
74. McCloskey CA, Ramani GV, Mathier MA, et al. Bariatric surgery improves cardiac
function in morbidly obese patients with severe cardiomyopathy. Surgery for obesity and
related diseases : official journal of the American Society for Bariatric Surgery.
CE
2007;3:503-507.
AC
ACCEPTED MANUSCRIPT
T
IP
CR
Legends
US
Figure 1. Total mortality, cardiac mortality, and hospitalization in 6 studies combined in a meta-
analysis of published studies on BMI and outcomes in heart failure.
AN
Figure 2. Survival at 2 years by BMI in PKVO2 subgroups: (A) High PKVO2 and (B) Low
M
PKVO
ED
PT
CE
AC
ACCEPTED MANUSCRIPT
T
IP
CR
US
Figure 1. from ref 14
AN
M
ED
PT
CE
AC
ACCEPTED MANUSCRIPT
T
IP
CR
Figure 2 from ref 20. US
AN
M
ED
PT
CE
AC
ACCEPTED MANUSCRIPT
T
IP
CR
US
AN
M
ED
PT
CE
AC
T
Higher blood pressure leading to more optimized cardioprotective medications
IP
Differential etiologies of heart failure
CR
Increased muscle mass and muscular strength in those with high body mass index