Curr Heart Fail Rep

DOI 10.1007/s11897-015-0265-5

EPIDEMIOLOGY OF HEART FAILURE (J. HO, SECTION EDITOR)

Cardiometabolic Disease Leading to Heart Failure: Better Fat

and Fit Than Lean and Lazy
Ambarish Pandey 1 & Jarett D. Berry 1 & Carl J. Lavie 2

# Springer Science+Business Media New York 2015

Abstract High body mass index (BMI) and low cardiorespi- Abbreviations
ratory fitness (CRF) are important modifiable risk factors for BMI Body mass index
heart failure (HF). While the individual contributions of CRF CCLS Cooper Center for Longitudinal Study
and BMI toward risk for HF are well established, the interre- CHD Coronary heart disease
lationship between BMI and CRF in modifying long-term HF CRF Cardiorespiratory fitness
risk is more complex and not well understood. In this review, CV Cardiovascular
we discuss and summarize the available evidence-base on CVD Cardiovascular disease
individual and joint contributions of obesity and low CRF DM Diabetes mellitus
toward HF risk, including the potential mechanisms through HF Heart failure
which these lifestyle risk factors may lead to HF. We also HTN Hypertension
discuss the role of interventions aimed at intentional loss of LV Left ventricle or ventricular
weight or CRF improvement as potential HF preventive strat- LVH Left ventricular hypertrophy
egies. Finally, the article also highlights the modifying effects MET Metabolic equivalent
of CRF on survival in relation to the obesity paradox in pa- MetS Metabolic syndrome
tients with established HF. PA Physical activity

Keywords Obesity . Heart failure . Cardiorespiratory fitness . Introduction

Physical activity . Exercise
Heart failure (HF) is a growing public health concern affecting
This article is part of the Topical Collection on Epidemiology of Heart
more than 5 million Americans and is the only manifestation
Failure
of cardiovascular (CV) disease (CVD) that has been increas-
* Carl J. Lavie
ing in recent years [13], largely attributed to the aging pop-
clavie@ochsner.org ulation and increased survival following acute coronary heart
Ambarish Pandey
disease (CHD) events [2]. Furthermore, increasing prevalence
ambarish.pandey@outlook.com of lifestyle risk factors, such as obesity and physical inactivity,
Jarett D. Berry
are also contributing to the HF epidemic [47]. Novel preven-
Jarett.Berry@utsouthwestern.edu tive approaches focused on early modification of these risk
factors are urgently needed to reduce the growing burden of
1
HF.
Division of Cardiology, Department of Internal Medicine, University
of Texas Southwestern Medical Center, Dallas, TX, USA
Prevalence of overweight and obesity has increased signif-
2
icantly in the USA over the past few decades [810]. More
Department of Cardiovascular Diseases, John Ochsner Heart &
Vascular Institute, Ochsner Clinical School, University of
than 70 % of the US population is overweight to obese, and
Queensland School of Medicine, 1514 Jefferson Highway, New approximately 3 % have morbid or class III obesity [body
Orleans, LA 70121, USA mass index (BMI)>40 kg/m2] [79]. Concurrent with the

obesity epidemic, there has been a marked decline in the phys-
ical activity (PA) levels during the past five decades, and [5]
PA is the strongest modifiable determinant of cardiorespirato-
ry fitness (CRF), and both higher BMI as well as lower CRF/
PA levels are independently associated with an increased
long-term risk for HF [6, 1113]. However, the interrelation-
ship between BMI and CRF in modifying long-term HF risk is
more complex, and the contributions of CRF in reducing HF
risk among obese vs. lean population is not well understood.
In this review, we discuss the independent and joint contribu-
tions of CRF and BMI toward HF risk. We also evaluate the
relative importance of high CRF levels vs. overweight and
obesity for overall CV health and, particularly, HF prevention.
Physical Inactivity, Low CRF, and Risk of HF
Large-scale observational cohort studies have consistently
shown that higher levels of self-reported PA is associated with
lower risk for HF [12, 1416]. More recently, in a pooled
meta-analysis of such cohort studies, we demonstrated a con-
sistent inverse dose-dependent relationship between levels of
self-reported PA and risk of HF [14]. In a recent study from the
Cooper Center for Longitudinal Study (CCLS), we observed
that higher levels of CRF in midlife are associated with lower
risk of HF after age of 65 [11]. Khan et al. in a Finnish cohort
of middle-aged men also reported similar inverse association
between CRF levels and HF risk [17]. Furthermore, risk of HF
associated with low CRF or PA levels appears to be modifi-
able with improvement in CRF [13]. Kraigher-Krainer et al.
[18] observed that greater decline in PA levels over time is
associated with a higher risk of HF. Similarly, we have report-
ed that each one metabolic equivalent (MET) improvement in
CRF between two consecutive examinations is associated
with a 17 % reduction in HF risk at a later age [hazard ratio
per 1 MET increase = 0.83 (0.74=0.93)] [13]. Taken together,
findings from these observational studies suggest that low
CRF is an independent modifiable risk factor for HF [19].
There are several mechanisms through which low CRF
may predispose to an increased risk of HF. One potential
mechanism is through the indirect effects of lower CRF on
both CVD and non-CVD risk factors. Low CRF is associated
with increased downstream prevalence of CVD risk factors,
such as diabetes mellitus (DM), hypertension (HTN), and
obesity that might promote the development of HF in older
age directly [13, 20]. However, in a recent analysis from the
CCLS, we observed that lower midlife CRF was associated
with a higher risk for HF hospitalization independent of inter-
val development of CVD and non-CVD risk factors [13]. An-
other potential mechanism through which CRF in middle age
might lower HF risk in later life is through more direct effects
of exercise and increased PA on cardiac structure and function
[2123]. Subclinical abnormalities in left ventricular (LV)
Curr Heart Fail Rep
systolic function, diastolic function, and abnormal remodeling
are important intermediate phenotypes in the natural history of
symptomatic HF [20, 24]. In a cross-sectional analysis of
healthy participants from CCLS, we observed a significant
inverse association between CRF levels and prevalence of
diastolic dysfunction and abnormal concentric remodeling
[22]. Similarly, Kosmala et al. [25] demonstrated that low
CRF is independently associated with subclinical abnormali-
ties in systolic as well as diastolic LV function. These findings
are supported by a recent mechanistic study that demonstrated
increased LV end-diastolic stiffness among participants with
sedentary lifestyle and low CRF, similar to that observed
among patients with symptomatic HF [26]. These findings
suggest that HF risks associated with low CRF may reflect
the direct effects of exercise on cardiac structure and function
independent of development of HF risk factors.
Obesity and Risk of HF
Overweight and obesity has been implicated as a major risk
factor for CVD such as HTN, CHD, atrial fibrillation, and HF
[7]. Several cohort studies have demonstrated an increased
risk of HF among overweight and obese participants as com-
pared with normal weight participants. In a seminal study of
participants from the Framingham Heart Study, Kenchaiah
et al. [12] demonstrated a 57 % increase in HF incidence
for every 1 kg/m [2] increase in BMI, with graded increase
in risk of HF noted across all BMI categories. Similarly, Hu
et al. [27] observed that overweight and obese middle-age
participants of a Finnish study cohort had significantly greater
risk for HF as compared with the normal weight participants
[Hazard ratio (95 %) overweight men 1.25 (1.121.39); obese
men 1.99 (1.742.27)].
These epidemiological observations of increased HF risk
with higher BMI may be partially explained by increased
downstream development of metabolic risk factors. For exam-
ple, in a study of participants without DM at baseline, BMI
was not associated with increased HF risk, whereas metabolic
syndrome (MetS) was associated with 2.5-fold higher HF risk
[28]. Furthermore, metabolically healthy obese participants
had a lower HF risk as compared with normal weight patients
with MetS. In a Swedish cohort study, Ingelsson et al. [29]
reported that the relationship between obesity and HF risk is
attenuated after adjustment for measures of insulin resistance.
Similarly, Bahrami et al. [30] observed that the association
between BMI and HF incidence was attenuated after adjust-
ment for inflammatory markers. In contrast, Morkedal et al.
[31] reported that among participants of the HUNT study, risk
of HF was similarly increased in metabolically healthy and
unhealthy obese participants, suggesting that metabolic risk
factors may not play a central role in mediating obesity-
related risk of HF.
Curr Heart Fail Rep
Obesity has been associated with significant abnormalities
in CV structure and function that may contribute to increased
HF risk (Fig. 1). Increased adiposity is associated with in-
creases in total blood volume, stroke volume, and cardiac
output that may result in abnormal LV remodeling and LV
hypertrophy (LVH) over time [6, 32]. While older studies
suggested that obesity predisposes to eccentric LV remodeling
[33], more recent studies have demonstrated a predominance
of concentric remodeling and LVH among obese patients [34].
Higher baseline BMI and increases in BMI with aging have
also been associated with abnormalities in LV systolic and
diastolic function in middle age [34, 35] [36]. These adverse
effects of obesity on cardiac structure and function may be
mediated by several metabolic abnormalities, such as
lipotoxicity and lipoapoptosis, insulin resistance with
hyperinsulinemia, leptin resistance, and hyperleptinemia [6,
32]. Furthermore, obesity-related pro-inflammatory state, ac-
tivation of the sympathetic nervous system, and activation of
the renin-angiotensin-aldosterone system may also contribute
to cardiac structural and functional abnormalities [6, 37, 38].
Fig. 1 Pathophysiology of
obesity-associated abnormalities
in cardiac structure and function.
LV left ventricle, RV right
ventricle. Reprinted from Lavie
et al. [6] with permission from the
publishers
Combined Effects of CRF and BMI on HF Risk
Several studies have evaluated the modifying effect of CRF on
obesity-related risk for CVD and all-cause mortality. Wessel
et al. [39] reported that among women undergoing diagnostic
coronary angiography, higher baseline CRF, but not obesity,
was associated with risk of downstream adverse CVD events
[HR (95 % CI) CRF 0.93 (0.900.96) per 1 MET increase;
BMI 1.01 (0.991.02)]. Furthermore, in a recent meta-
analysis of epidemiological cohort studies, Barry et al. [40]
demonstrated that mortality risk in overweight and obese-fit
individuals was not significantly higher as compared with
normal weight fit individuals [HR (95 % CI) overweight fit
1.13 (1.001.27); obese fit 1.21 (0.95 to 1.52)], suggesting
that higher levels of CRF may significantly attenuate the
long-term CV adverse effects associated with obesity. These
findings are also supported by recent studies from the Aerobic
Center for Longitudinal Study by Lee et al. that demonstrated
a significant attenuation in the negative effects of weight gain
on incidence of CVD risk factors and mortality with

Table 1 Potential reasons for the obesity paradox in cardiovascular
diseases
Non-purposeful 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 cardiorespiratory fitness
Unmeasured confounding factors
Adapted from Lavie et al. [59] with permission from the publishers
improvement in CRF among healthy middle-aged participants
[41, 42].
The interaction between CRF and BMI in mediating HF
risk has not been well reported in the literature. In a prospec-
tive cohort study of 21,094 men, Kenchaiah et al. [12] ob-
served that the risk of HF among obese active participants
was lower than that of obese inactive subjects [HR (95 %
CI) 2.68 (2.083.45) vs. 3.93 (2.605.96), reference group:
lean and active participants] during a mean follow-up of
20 years. Similarly, Hu et al. [27] found that higher levels of
PA are associated with lower risks of long-term HF in partic-
ipants with high BMI. More recently, Kraigher-Krainer et al.
assessed the longitudinal relationship between changes in
BMI and PA levels and HF risk [18] among Framingham
Heart Study participants who attended consecutive follow-
up examinations. The authors reported that decrease in PA
levels between these examinations was significantly associat-
ed with an increased risk of HF regardless of an increase or
decrease in BMI [HR (95 %CI) BMI increase/PA decrease
Fig. 2 Obesity paradox among heart failure patients stratified by their
body mass index and cardiorespiratory fitness levels. Left panel shows the
Kaplan-Meier analysis plot according to body mass index in the low fit
group (peak oxygen consumption <14 ml/kg/min). Right panel shows the
Curr Heart Fail Rep
1.82 (1.15 to 2.87); BMI decrease/PA decrease 1.76 (1.13 to
2.76, ref group: BMI decrease/PA decrease)]. However, these
studies were limited by use of self-reported PA levels, as op-
posed to more precisely measuring PA with pedometers and
accelerometers. In a recent study using the CCLS database, we
have reported that CRF in midlife, measured using maximal
exercise treadmill test, is inversely associated with risk for HF,
and this relationship is minimally attenuated after adjustment
for baseline BMI and interval development of obesity [13].
We further characterized this relationship in a recent follow-up
study and demonstrated that compared with lean and low fit
individuals, risk of HF at a later age was significantly lower
among overweight fit (event rate 5.3 vs. 13.6 per 1000 person-
years, p value <0.001) and obese-fit individuals (event rate 5.7
vs. 13.6 per 1000 person-years, p value <0.01) [43]. Taken
together, findings from these studies suggest that higher levels
of CRF and PA are inversely associated with long-term risk of
HF across all BMI strata. Furthermore, this protective effect of
higher CRF and PA levels substantially attenuates the risk of
HF associated with higher BMI.
Weight Loss, CRF Improvement, and HF Risk
Effect of lifestyle interventions aimed at purposeful weight
loss and CRF improvements on HF risk is not well under-
stood. Supervised exercise training in The LookAHEAD trial
published in 2003 evaluated the impact of intensive lifestyle
intervention of dietary weight loss counseling and moderate
exercise vs. usual care on CV endpoints in more than 5000
overweight patients with type 2 DM [44]. Despite modest but
significant weight loss and improvements in CRF among the
study participants that underwent intensive lifestyle interven-
tions, there was no significant benefit of intensive lifestyle
interventions in reducing adverse atherosclerotic CVD events,
Kaplan-Meier analysis plot according to BMI in the high fit group (peak
oxygen consumption 14 ml/kg/min). Adapted from data in Lavie et al.
[66], reproduced from Lavie et al. [70] with permission from the
publishers
Curr Heart Fail Rep
such as myocardial infarction, revascularization, and CVD
mortality [44]. This lack of benefit could be related to the
recently observed inter-individual variability in CRF and
weight changes in response to such intensive lifestyle inter-
vention [45, 46] [47]. However, intensive lifestyle interven-
tion was associated a numerically lower number of HF events
(n=99) as compared with the usual care (n=119) with a trend
toward significance (hazard ratio (95 % CI)=0.80 (0.61
1.04)).
Despite the lack of definitive clinical trials supporting in-
tentional weight loss to reduce HF risk, several diet and exer-
cise studies have reported favorable changes in LV structure
and function with intentional weight loss [4850]. These fa-
vorable effects are most dramatic among patients undergoing
bariatric surgery and among those with severe obesity [48].
Similarly, recent studies have demonstrated that supervised
high intensity exercise training is associated with significant
weight loss, CRF improvement, and improvements in LV sys-
tolic and diastolic function [51]. These findings are encourag-
ing and highlight the need for future studies to better evaluate
the role of intentional weight loss and high intensity exercise
training strategies for HF prevention.
CRF and Obesity Paradox in HF: Survival
of the Fittest or the Fattest?
Despite the association of overweight and obesity with in-
creased incidence of CVD risk factors as well as CVD, such
as HF, several studies have reported the phenomenon of obe-
sity paradox, where overweight and obese patients with
established HF have better clinical outcomes as compared
with normal weight patients [52]. In a recent study of 6142
patients with acute decompensated HF followed up across 4
continents, Shah et al. demonstrated that every 5 kg/m [2]
increase in BMI was associated with 11 % decrease in
30 day mortality and 9 % decrease in 1 year mortality [53].
Similar findings were also reported by Fonarow et al. among
hospitalized acute decompensated HF patients in the AD-
HERE registry [54]. A recent large meta-analysis has con-
firmed the obesity paradox, especially in the overweight, on
CVD and all-cause survival and HF hospitalizations [55]. Fur-
thermore, premorbid obesity before HF development has also
been associated with lower mortality after HF diagnosis [56].
Several mechanisms have been proposed to explain this
obesity paradox among HF patients (Table 1) [5759]. First,
HF is a catabolic state and patients with higher BMI may have
greater metabolic reserve as compared with normal weight
patient and thus have a more favorable prognosis [60, 61].
Second, adipose tissue is known to produce soluble tumor
necrosis factor alpha (TNF-alpha) receptors that may neutral-
ize the adverse effects of TNF-alpha in HF patients [62].
Third, overweight and obese patients have reduced expression
of circulating natriuretic peptides, which may lead to greater
symptom burden and thus earlier presentation at less severe
stages of HF [63]. Finally, overweight and obese patients have
higher blood pressure levels as compared with normal weight
patients and may tolerate more evidence-based HF therapies
such as beta-blockers, angiotensin converting enzyme inhibi-
tors, and aldosterone antagonists [7].
Recent studies suggest that CRF levels may significantly
modify the relationship between adiposity and outcomes in
HF patients [6468]. In a study of 2066 systolic HF patients,
an obesity paradox was observed only among low fit patients
(peak oxygen consumption <14 ml/kg/min) and higher CRF
was associated with better prognosis irrespective of BMI
(Fig. 2) [66]. Clark et al. [64] also reported attenuation of
the obesity paradox among patients with higher CRF levels
in a younger cohort of 1675 systolic HF patients. The findings
from these studies suggest that CRF has a strong modifying
effect on the relationship between adiposity and prognosis in
HF patients. Thus, management strategies aimed at improving
CRF may be useful strategy not only for HF prevention but
also to improve outcomes among patients with established
disease [45, 65, 69].
Conclusion
Low levels of CRF and obesity are significant risk factors for
HF. Maintaining a lean body weight and high CRF levels
would be ideal to reduce the growing burden of CVD, partic-
ularly HF. Furthermore, increasing body of evidence suggest
that among overweight and obese participants, higher levels of
CRF may significantly attenuate the BMI-associated in-
creased risk of HF at a later age. Future studies are needed
to evaluate the effectiveness of intentional weight loss and
CRF improvement in preventing HF incidence among at risk
participants. In patients with established HF, higher BMI ap-
pears to be associated with protection against future adverse
events in only low CRF patients. In contrast, higher levels of
CRF are associated with better outcomes across all body
weight categories. Taken together, the weight of evidence
suggests that low CRF is an important target for prevention as
well as management of HF.
Compliance with Ethics Guidelines
Conflict of Interest Ambarish Pandey: None
Jarett D. Berry: None
Carl J. Lavie has received personal fees outside of the submitted work.
Human and Animal Rights and Informed Consent This article does
not contain any studies with human or animal subjects performed by any
of the authors.

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