REVIEW

Obesity and Heart Failure: Focus on the Obesity

Paradox
Salvatore Carbone, MS; Carl J. Lavie, MD; and Ross Arena, PhD, PT

Abstract

The escalating prevalence of obesity has been linked to substantial increases in both metabolic and
cardiovascular disease. Nevertheless, the direct effects of obesity on cardiovascular health and function
require further exploration. In particular, the relationship between obesity and cardiac function has
received intense scrutiny. Although obesity increases the risk for development of heart failure (HF), it
appears to exert a protective effect in patients in whom HF has already been diagnosed (the “obesity
paradox”). The protective effects of obesity in patients with previously diagnosed HF are the focus of
particularly intense research. Several explanations have been proposed, but most studies are limited by
the use of body mass index to classify obesity. Because body mass index does not distinguish between
fat mass, fat-free mass, and lean mass, individuals with similar body mass indices may have vastly
different body composition. This article discusses the roles of body composition, diet, cardiorespiratory
fitness, and weight loss in the development of cardiac dysfunction and HF and the potential protective
role that body composition compartments might play in improving HF prognosis. Based on an
intensive literature search (Pubmed, Google Scholar) and critical review of the literature, we also discuss
how a multidisciplinary approach including a nutritional intervention targeted to reduce systemic
inflammation and lean massetargeted exercise training could potentially exert beneficial effects for
patients with HF.
ª 2016 Mayo Foundation for Medical Education and Research n Mayo Clin Proc. 2016;nn(n):1-14

O
besity (ie, body mass index [BMI; In this review, we describe the role of obesity
calculated as weight in kilograms in the development of HF and the possible
divided by height in meters squared], mechanism(s) through which obesity may exert From the Pauley Heart

30 kg/m2) has increased to epidemic propor- protective effects in HF. We also discuss the role Center, Victoria Johnson
Research Laboratories,
tions since 1980.1 In 2014, nearly 1.9 billion of diet and systemic inflammation and their Virginia Commonwealth
adults worldwide were overweight, and more involvement in cardiac dysfunction as well University, Richmond, VA
than 600 million were obese.1,2 Obesity is an as potential body compositione, diet-, and (S.C.); Department of
Experimental Medicine,
independent risk factor for several chronic systemic inflammationetargeted therapeutic Sapienza University of
noncommunicable diseases (NCDs) including strategies. Rome, Rome, Italy (S.C.);
John Ochsner Heart and
diabetes, cancer, and cardiovascular disease Vascular Institute, Ochsner
(CVD), the lattermost which includes heart fail- MATERIAL AND METHODS Clinical School-The Uni-
ure (HF). This cluster of NCDs collectively rep- For this critical review, we identified articles by versity of Queensland
resents the major causes of death worldwide.1-6 searching original studies, review articles, and School of Medicine, New
Orleans, LA (C.J.L.); and
In this context, there clearly appears to be a editorials published in peer-reviewed journals Department of Physical
cause and effect relationship between obesity indexed in PubMed and Google Scholar be- Therapy, College of
Applied Health Sciences,
and the increased risk for development of one tween January 1, 1960, and March 30, 2016. University of Illinois at
or more NCDs. The comprehensive electronic literature search Chicago, Chicago, IL
The interplay between obesity and HF is included the use of key words and their combi- (R.A.).
complex. Paradoxically, although obesity in- nation: obesity, heart failure, heart failure with
creases the risk of HF, once a diagnosis is reduced ejection fraction, heart failure with pre-
confirmed, patients with HF who are also served ejection fraction, obesity and heart failure,
obese have a better prognosis compared with obesity paradox, obesity paradox in heart failure,
their leaner counterparts. This phenomenon body composition, body composition and heart
has been termed the obesity paradox.6-9 failure, lean mass, weight loss and heart failure,

Mayo Clin Proc. n XXX 2016;nn(n):1-14 n http://dx.doi.org/10.1016/j.mayocp.2016.11.001 1

www.mayoclinicproceedings.org n ª 2016 Mayo Foundation for Medical Education and Research

ARTICLE HIGHLIGHTS
d Obesity is an independent risk factor for the development of
heart failure.
d Heart failure affects about 38 million people worldwide, almost
6 million in the United States alone.
d Although obesity increases the risk of heart failure, overweight
or obesity exert protective effects in patients with a confirmed
heart failure diagnosis, describing an obesity paradox.
d Body mass index does not distinguish between fat mass, fat-free
mass, and lean mass.
d The obesity paradox may not be present in sarcopenic obese
patients.
d Body composition assessment should be performed in patients
with heart failure for better risk stratification.
d Interventions aimed at increasing lean mass and reducing
systemic inflammation may be protective in heart failure.
diet and heart failure, diet and cardiac function,
inflammation and heart failure, sarcopenia,
sarcopenia and heart failure, sarcopenic obesity,
sarcopenic obesity and heart failure, and inflam-
mation and heart failure. Of more than 1000
articles found, 139 were considered to be rele-
vant to the scope of this critical review. The
search was restricted to articles published
in English. The reference lists of the chosen
studies were also reviewed to identify potential
additional pertinent articles.
OBESITY AND HF: DEFINITIONS AND
EPIDEMIOLOGY
The World Health Organization defines
obesity and overweight as “an abnormal or
excessive fat accumulation.to the extent
that health may be impaired.”1 However, uni-
versal cutoffs of body fat to diagnose over-
weight and obesity have not been established.
Therefore, overweight and obesity are usually
diagnosed in individuals with a BMI of
25 kg/m2 or higher and a BMI of 30 kg/m2
or higher, respectively. Visceral obesity, often
considered a better tool than BMI to determine
a more complete cardiometabolic risk,10,11 is
defined as a waist circumference of more
than 102 cm in males and more than 88 cm
in females, although race-related cutoffs have
been proposed.12
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2 Mayo Clin Proc.
MAYO CLINIC PROCEEDINGS
Heart failure is “a complex clinical syn-
drome that results from any structural or func-
tional impairment of ventricular filling and/or
ejection of blood.”13 Heart failure affects about
38 million people worldwide, almost 6 million
in the United States alone with nearly 915,000
new cases every year.14 Moreover, it is the
most common reason for hospital admissions
in patients aged 65 years or older.14,15
Although the survival rate in patients with
HF has improved in recent history, the death
rate remains very high: more than 30% of
patients die within 5 years of an HF
diagnosis.14,15
Approximately half of the patients with
HF have a reduced left ventricular (LV) ejec-
tion fraction (LVEF) or systolic dysfunction
(ie, HF with reduced ejection fraction
[HFrEF]), while the remaining half present
with preserved LVEF (ie, HF with preserved
ejection fraction [HFpEF]),13,16 usually char-
acterized by the presence of diastolic dysfunc-
tion, also known as diastolic HF. These 2
forms of HF have very different pathophysio-
logic mechanisms, which are highlighted by
the fact that beneficial therapeutic strategies
in HFrEF have failed to improve outcomes
in HFpEF.13-18 For instance, in HFrEF, the
renin-angiotensin-aldosterone system repre-
sents a target for several drugs proven to
reduce mortality and complications.13,19
However, similar pharmacological approaches
targeting the renin-angiotensin-aldosterone
system failed to produce beneficial effects in
patients with HFpEF.
Despite sharing very similar signs and
symptoms, such as fluid retention, shortness
of breath, and exercise intolerance, HFpEF
and HFrEF differ not only on the differences
in LVEF but also in epidemiology and clinical
characteristics.13,15-18 Heart failure with pre-
served ejection fraction is more prevalent in
women and it more characteristically associ-
ates with obesity; up to 85% of patients with
HFpEF are in fact obese,6,20 while in HFrEF,
obesity prevalence is usually lower than
50%.21,22
As mentioned previously, obesity increases
the risk of HF4,5,23 (Figure 1). Overall, approx-
imately 38% of patients with HF are obese.20
The mechanism(s) behind the association of
obesity with HF, particularly with HFpEF, are
not well known, although several plausible
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OBESITY, BODY COMPOSITION, AND HEART FAILURE
hypotheses have been proposed.6-9,24-27 In
the following sections, we will focus our atten-
tion on the potential contribution of body
composition to the development of HF in obese
individuals and how body composition, rather
than BMI, may be a better predictor of out-
comes once HF has been diagnosed.
OBESITY-INDUCED HEMODYNAMIC AND
STRUCTURAL CHANGES
The pathophysiology of HF is very complex.
Ventricular remodeling resulting in hemody-
namic and structural changes, neurohormonal
system activation, systemic inflammation, and
abnormalities in calcium fluxes are involved in
the development and progression of the dis-
ease.16 In particular, hemodynamic abnormal-
ities and structural cardiac changes have been
reported in obese patients6-9,24-27 (Figure 2).
The hemodynamic changes include increased
central blood volume and stroke volume and
ultimately increased cardiac output6-9,24-30
proportional to the degree of obesity but not
body surface area.31 The increased blood vol-
ume seems to result from the increased
amount of lean mass seen in most obese pa-
tients.8,9,24,31 In fact, although obesity by defi-
nition is characterized by a higher amount of
fat mass,1 the classic obesity phenotype also
presents with a preserved or increased amount
of lean mass.7-9,24,32 The main component of
lean mass is skeletal muscle.33,34 Although
the terms lean mass and skeletal muscle mass
are often used interchangeably, the correct
definition of lean mass is the sum of bone
mineral mass, skeletal muscle mass, and resid-
ual mass.34 Clinically, an accurate measure-
ment of skeletal muscle mass is very
challenging, and therefore, it is often estimated
from the measurement of lean mass.
The fact that the blood flow requirement
for skeletal muscle mass is significantly higher
than that for fat mass is particularly relevant.35
Specifically, higher amounts of skeletal muscle
mass, and not fat mass, with the associated
increase in blood flow and central blood vol-
ume seem to be a main contributors to the
increased stroke volume seen in the obese
HF phenotype. Because heart rate is either
not augmented or, at a maximum, just moder-
ately increased due to the sympathetic system
activation in obese patients,6,9,24 the increased
cardiac output appears to mainly result from
Mayo Clin Proc. n XXX 2016;nn(n):1-14 n http://dx.doi.org/10.1016/j.mayocp.2016.11.001
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2.5
Risk of heart failure (HR)
#
2.0 #
#
1.5
#
1.0
Women Men
BMI 18.5–24.9 kg/m2 BMI 25–29.9 kg/m2 BMI ≥30 kg/m2
FIGURE 1. Risk of heart failure according to categories of body mass index
(BMI). Considering a BMI of 18.5 to 24.9 kg/m2 as the reference category,
overweight and obese individuals had an increased risk of heart failure with
reduced and preserved ejection fraction, described as hazard ratio (HR).
# ¼ P<.01 vs BMI of 18.5 to 24.9 kg/m2. Data from N Engl J Med.4
the increased stroke volume. The sustained
increase in cardiac output due to increased
preload, however, leads to an initial LV dilata-
tion followed by a compensatory hypertrophic
response evident at both a cellular and organ
level.20,32 In fact, LV hypertrophy is often pre-
sent in obese patients.7-9,31,36-41
Interestingly, although impairment in dia-
stolic function and increased filling pressures
were at first considered to be the result of
the increased LV mass, it has been reported
that obese patients may present with diastolic
dysfunction without LV hypertrophy,42,43 sug-
gesting potential alternative mechanisms
involved. Indeed, LV hypertrophy may even
be protective by reducing wall stress. Obese
patients with HFpEF have increased relative
wall thickness and reduction of the size of car-
diac cavities17,43-46 even in the absence of
increased LV mass,6,41,47-50 which is referred
to as LV concentric remodeling and appears to
carry similar, if not worse, prognostic informa-
tion (ie, higher cardiovascular complications
or death) in patients with HF.51,52 Moreover,
the increase in BMI in obese patients positively
correlates with cardiac output as well as
with LV end-diastolic pressure, right atrial
pressure, and pulmonary capillary wedge
pressure.6,53-55
These hemodynamic and structural
changes may represent compensatory mecha-
nisms that may, however, lead to detrimental
3
 MAYO CLINIC PROCEEDINGS

Body weight and body mass index

Fat mass Lean mass

Blood volume

Stroke volume
Proinflammatory
adipokines release ≅ Heart rate SVR

Cardiodepressant factors
release (IL-1β, TNF-α, IL-18)
Cardiac output

Western diet
Cardiac workload CRF

Cardiac dysfunction Initial LV dilatation

Improved performance
Concentric remodeling

Concentric LVH

Heart failure

Improved outcomes in HF

FIGURE 2. Proposed mechanisms driving obesity to heart failure (HF) and to the obesity paradox once
HF is diagnosed. The dark blue arrows indicate the potential detrimental effects of body composition
components (fat mass and lean mass) on cardiac function and eventually HF development. The light blue
arrows indicate the potential mechanisms by which body composition improves cardiorespiratory fitness
(CRF). IL ¼ interleukin; LV ¼ left ventricular; LVH ¼ LV hypertrophy; SVR ¼ systemic vascular resistance;
TNF-a ¼ tumor necrosis factor a.

changes, describing a paradoxical effect
(Figure 2).
OBESITY, DIET, AND HFPEF
A form of HF that has been increasing in inci-
dence in the past few decades is characterized
by impaired diastolic function associated with
preserved LVEF and no major coronary artery,
valvular, or arrhythmic disease. This syn-
drome is referred to as HFpEF or diastolic
HF.17,20,56 Most patients with HFpEF are
obese and have evidence of metabolic derange-
ments such as insulin resistance and dia-
betes.17,56 It is therefore conceivable that
n n
4 Mayo Clin Proc.
obesity and diastolic dysfunction are causally
linked.
The mechanisms by which obesity may
induce diastolic dysfunction and therefore
increase the risk of HFpEF are still unclear.
Several hypotheses have been proposed
including a potential involvement of direct
cardiodepressant factors produced by the adi-
pose tissue.18,57 The adipose tissue is an active
endocrine organ able to synthesize a number
of hormones or active molecules called adipo-
kines.58-60 In particular, the adipose tissue pro-
duces proinflammatory cytokines such as
interleukin (IL) 1b, tumor necrosis factor a,
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OBESITY, BODY COMPOSITION, AND HEART FAILURE
and IL-18,59 which induce diastolic dysfunc-
tion in preclinical animal models.59,61,62 In
support of these hypotheses, pilot studies
with targeted anti-inflammatory treatment
have reported promising results in HF,
including HFpEF.61,63,64 In these pilot studies,
short-term IL-1 blockade strategies with a
human recombinant IL-1 receptor antagonist
improved cardiorespiratory fitness (CRF) in
patients with HFrEF63 and HFpEF,64 and
both studies found a significant increase of
peak oxygen consumption (VO _ 2 ), an indepen-
dent predictor of outcomes in HF.
Furthermore, obesity is considered the
result of an unhealthy diet. Recent studies
have found that a high-sugar (30% of total
calories) and highesaturated fat (12.8% of to-
tal calories) diet resembling a typical diet of
Western countries (Western diet) can directly
impair cardiac diastolic and systolic function
in experimental animals,65,66 providing a po-
tential link between diet-induced inflamma-
tion and cardiac dysfunction (Figure 2).
Moreover, returning to a healthy diet low in
saturated fat and sugar induced significant
improvements in cardiac function, high-
lighting a major ability of the diet to modulate
both systolic and diastolic function.65-69
Sugars and saturated fat can activate proin-
flammatory pathways; specifically, they can
induce the synthesis and activation of the
macromolecular complex Nod-like receptor
pyrin domainecontaining protein 3 inflam-
masome70-72 responsible for the production
of IL-1 and IL-18, cytokines with well-
known cardiodepressant properties. A diet
low in sugars and saturated fat could perhaps
improve cardiac function and CRF by limiting
the synthesis and activation of the macromo-
lecular complex Nod-like receptor pyrin
domainecontaining protein 3 inflammasome
and of cytokines IL-1 and IL-18.
THE OBESITY PARADOX IN HF
Although the risk of HF increases with BMI,
patients with HFrEF who are overweight or
obese commonly have better outcomes than
those who are normal weight or under-
weight,7-9,24-26,73-79 even when high BMI man-
ifests several years before an HF diagnosis.80 A
secondary analysis of the Meta-analysis Global
Group in Chronic Heart Failure (MAGGIC)
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included 31 studies, both randomized
controlled trials and observational studies.
This meta-analysis revealed a relationship be-
tween BMI and mortality in both HFrEF and
HFpEF, with the lowest mortality rate seen in
those with class 1 obesity81 (Figure 3). A later
meta-analysis including about 22,000 patients
who had chronic HF (HFrEF and HFpEF)
with a mean follow-up of almost 3 years re-
ported a similar outcome; overweight patients
presented with the lowest total and CV mortal-
ity rate compared with those who were normal
weight, while underweight patients had the
highest mortality rate and patients with class
2 and higher obesity had an intermediate prog-
nosis with lower total and CV mortality despite
increased HF hospitalizations.82 Recently, it
has also been observed that the obesity
paradox is particularly relevant in women
with advanced HF.83
Based on these data, researchers have
started to explore potential mechanisms for
the obesity paradox. A plausible explanation
is related to the inaccuracy of the BMI in
characterizing the severity of obesity.84-90
The World Health Organization definitions
of obesity imply that every individual with a
BMI of 25 kg/m2 or higher, and even more
so when BMI is 30 kg/m2 or higher, have
increased fat mass.1 However, this implication
is not necessarily true. Body mass index has
in fact several limitations, and as such it
should be considered more of a measurement
of heaviness than body composition. Patients
with increased BMI may not necessarily have
increased fat mass (eg, athletes),91,92 while
having a normal BMI (
18.5 kg/m2 and
<25 kg/m2) does not preclude an individual
from having increased fat mass and thus
increased metabolic and CVD risk.93 Thus,
an accurate measurement of body composi-
tion, rather than BMI, that defines body
weight components (ie, fat mass, fat-free
mass, lean mass) likely plays a crucial role
in the development and progression of
CVD, including HF. Nevertheless, at least at
a population level, BMI has predicted CVD
and all-cause survival,94,95 and more specific
fat distribution measures, such as waist
circumference and waist to hip ratio, do not
outperform BMI in predicting the incidence
of HF.96
5
 MAYO CLINIC PROCEEDINGS

40 HFrEF <22.5 40 HFpEF <22.5

HFrEF 22.5-24.9 HFpEF 22.5-24.9
HFrEF 25-29.9 HFpEF 25-29.9
HFrEF 30-34.9 HFpEF 30-34.9
HFrEF ≥35 HFpEF ≥35
30 30
Mortality (%)

Mortality (%)
20 20

10 10

0 1 2 3 0 1 2 3
Years Years
No. at risk No. at risk
HFrEF <22.5 2282 1867 1238 935 HFrEF <22.5 907 584 463 359
HFrEF 22.5-24.9 3465 2357 1605 1213 HFrEF 22.5-24.9 1094 746 630 507
HFrEF 25-29.9 6667 4695 3388 2625 HFrEF 25-29.9 2239 1627 1399 1090
HFrEF 30-34.9 2603 1998 1630 1265 HFrEF 30-34.9 1229 926 835 649
HFrEF ≥35 939 758 651 503 HFrEF ≥35 584 488 452 304

FIGURE 3. Total mortality stratified by body mass index (BMI) and heart failure (HF). Patients with HF and higher BMI had a lower
mortality rate than those with a lower BMI. Heart failure is categorized as HF with reduced ejection fraction (HFrEF) or HF with
preserved ejection fraction (HFpEF). Adapted from Int J Obes (Lond),81 with permission from Nature Publishing Group.

SKELETAL MUSCLE MASS AND ITS
PROTECTIVE EFFECTS IN HF
Although we have described the potential
involvement of body composition components
in the initial cardiac abnormalities leading to
increased HF risk, increased skeletal muscle
mass seen in obese individuals may actually
also exert protective effects related to better
outcomes in HF.
With respect to HF pathophysiology, char-
acterized by reduced or inadequate cardiac
output and increased systemic vascular resis-
tance,13 it is plausible that obese individuals
with preserved skeletal muscle mass have a
better prognosis secondary to increased stroke
volume and thus cardiac output (ie, improved
tissue perfusion) compared with their counter-
parts who have reduced lean mass and lower
stroke volume and cardiac output. Moreover,
obese patients tend to have lower systemic
vascular resistance, especially those who are
normotensive.6-9,24,35 Reduction in the after-
load results in improved forward flow and
n n
6 Mayo Clin Proc.
cardiac output. However, whether systemic
vascular resistance is reduced only in obese
patients with preserved or increased skeletal
muscle mass or if this also occurs in patients
with reduced skeletal muscle mass requires
further investigation.
OBESITY PHENOTYPES AND OUTCOMES
Hypothesizing a major protective role of skel-
etal muscle mass in patients with HF is consis-
tent with what has already been observed in
other disease states, such as diabetes and can-
cer, in which reduced lean mass is associated
with poor outcomes and metabolic abnormal-
ities, a muscle deficiency condition known as
sarcopenia.97 When sarcopenia is paralleled
by an increase in fat mass (obesity), it is
termed sarcopenic obesity, bringing together
body composition abnormalities of both con-
ditions, sarcopenia and obesity.98,99 Sarcopenic
obesity is becoming extremely prevalent and is
related to poor outcomes in a number of
chronic diseases. A recent meta-analysis of
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OBESITY, BODY COMPOSITION, AND HEART FAILURE
prospective cohort studies including more
than 35,000 patients found that sarcopenic
obese patients had a 24% increased risk for
all-cause mortality compared with those
who were nonsarcopenic and obese. Another
analysis highlighted the importance of identi-
fying patients with sarcopenic obesity as early
as possible to begin interventions directed to-
ward improving body composition, with the
goal of improving outcomes.100 A recent
study reported that sarcopenia was associated
with lower muscle strength and exercise ca-
pacity and worse quality of life in patients
with HFpEF.101 However, whether these re-
sults translate into similar long-term out-
comes in HF, as seen in non-HF patients,
requires further study.
OBESITY, BODY COMPOSITION, AND CRF
Lean mass and skeletal muscle mass, particu-
larly appendicular muscle mass (ie, the
amount of skeletal muscle mass in the arms
and in the legs) has been suggested to be a
major determinant of CRF in patients with
HF.102 Peak oxygen consumption assessed
by a cardiopulmonary exercise test is the cri-
terion standard assessment of CRF and is an
independent predictor of outcomes in HF.
The minute ventilation/carbon dioxide pro-
duction (VE/_ VCO
_ 2) slope, which quantifies
ventilatory efficiency, is also a primary predic-
tor of outcomes in patients with HF.103,104 In
fact, a number of investigations have indicated
_ VCO
that the VE/ _ 2 slope is a stronger indepen-
dent prognostic marker than peak VO _ 2,
although both measures assessed in combina-
tion improve prognostic resolution.105-107 A
higher peak VO _ 2 and lower VE/ _ VCO
_ 2 slope
correlates with better outcomes in patients
with HF.103,104 A peak VO _ 2 of less than
1
10 mL∙kg ∙min and VE/1 _ VCO_ 2 slope of
45 or higher are particularly disconcerting,
irrespective of body habitus.107
Obesity contributes to exercise intoler-
ance, particularly in patients with HFpEF,
and not necessarily by directly affecting car-
diac function.108 Obese patients seem to
have a lower peak VO _ 2 than leaner individ-
uals,109,110 however, only if the peak VO _ 2 is
corrected for body weight, without adjusting
for body composition compartments.102,111
When corrected for lean mass or skeletal mus-
cle mass, at least in patients with HFrEF, these
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differences do not persist.102,112 Moreover, it
has been suggested that correcting peak VO _ 2
for lean mass or skeletal muscle mass, rather
than body weight, may improve risk stratifica-
tion in patients with HF.6-9,24,102,111 In partic-
ular, appendicular muscle mass positively
correlates with peak VO _ 2 in noncachectic pa-
102
tients with HFrEF. Lean mass can be
assessed easily and accurately by dual-energy
x-ray absorptiometry that allows for the esti-
mation of appendicular muscle mass.34
Based on the previous findings, it would be
reasonable to assume that higher amounts of
lean mass exert protective effects in patients
with HF. Although most of the studies on
obesity, body composition, and HF have
been performed in patients with HFrEF, a
retrospective analysis of more than 47,000
patients with HFpEF reported a significant
protective effect of lean mass in predicting
all-cause mortality, regardless of BMI or fat
mass.113 An initial analysis of this study113
suggested that higher BMI and fat mass were
associated with lower mortality. When
adjusted for lean mass index (kg/m2), however,
these associations were not supported, there-
fore suggesting that the protective component
of high body weight and BMI was not fat
mass but lean mass. This study has some lim-
itations characteristic of most studies assessing
body composition in HF, mainly because of
the technique used to determine body compo-
sition. A skinfold caliper was used to assess fat
mass with a consequent subtraction from the
total body weight to calculate the estimated
amount of lean mass, or the fat mass was calcu-
lated with a validated predictive equation tak-
ing into account body weight and BMI
without an actual assessment of body compo-
sition. We can, however, speculate that sarco-
penic obese patients, characterized by
increased fat mass and reduced appendicular
lean mass, would have worse cardiac function
and CRF than obese patients with a preserved
or increased amount of appendicular lean
mass, independent of BMI (Figure 4).57,114-118
It has been also proposed that the quality
of lean mass may play an important role. In
fact, despite a similar amount of lean mass,
elderly patients with HF have reduced skeletal
muscle oxidative function compared with age-
matched healthy controls.116 Moreover, sarco-
penia and sarcopenic obesity are characterized
7
 MAYO CLINIC PROCEEDINGS

_ 2 cutoff
stratified by CRF level using a peak VO
of 14 mL∙kg1∙min1, the protective effects
of high BMI disappear, highlighting the more
Body prominent role of CRF, rather than BMI, in
composition defining HF prognosis. Those patients with
and obesity impaired but relatively higher peak VO _ 2 and
phenotypes
a higher degree of lean mass and CRF tend
to have a better clinical trajectory, regardless
of BMI. Similar findings have been reported
in metabolically healthy obesity, which is
Normal Nonsarcopenic Sarcopenic defined as obesity according to BMI criteria
Athlete
weight obese obese
but without metabolic syndrome characteris-
BMI (kg/m2) 18.5-25 >30 >30 >30 tics such as glucose abnormalities and
Fat mass Normal Decreased Increased Increased hypertension.124,125
Lean mass Normal Increased Increased Decreased
Cardiac Mild Severe WEIGHT LOSS IN HF
Normal Normal
function dysfunction? dysfunction? Intentional weight loss, through a combina-
Cardio-
Mild Severe
tion of diet and exercise, is often considered
respiratory Normal Increased the best therapeutic approach for patients
impairment? impairment?
fitness
with obesity and related comorbidities, partic-
ularly metabolic diseases such as type 2 dia-
FIGURE 4. Hypothetical relationship between obesity phenotypes, cardiac
betes, in which weight loss is associated with
function, and cardiorespiratory fitness in patients with heart failure. The
improvements in glucose control and a reduc-
figure highlights the proposed major role of body composition, obesity
phenotypes, and lean mass in the development and progression of cardiac tion in CVD risk.126 Whether weight loss is
dysfunction and cardiorespiratory fitness abnormalities. BMI ¼ body mass also beneficial in obese patients with HF is un-
index. Adapted from EC Cardiol.114 clear at this time. A recent study reported that
caloric restriction and/or exercise interven-
tions for 20 weeks induced favorable effects
on body weight, body composition, and CRF
by low-grade chronic systemic inflamma- in patients with HFpEF,127 suggesting benefi-
tion.119-121 As described earlier, systemic cial effects of intentional weight loss. Addi-
inflammation (ie, IL-1, IL-18) negatively and tional evidence suggests that intentional
directly affects cardiac function and exercise weight loss resulting from diet, physical activ-
capacity in patients with HF.61,63,64 Therefore, ity, bariatric surgical interventions, or a
it is plausible to hypothesize that increased combination thereof may positively affect
systemic inflammation in individuals with sar- hemodynamics and cardiac morphology, inde-
copenia and sarcopenic obesity contributes to pendent of age, sex, BMI, and comorbid-
worsening prognosis. It is also possible that ities.128 Long-term data documenting
increased low-grade systemic inflammation improved survival in patients with HF
contributes to the progressive loss of lean following weight loss are, however, still lack-
mass, which in turn increases even the proin- ing. Weight loss in HF is often considered
flammatory state further. the result of a cachectic process and is related
to poor outcomes.129,130 Pocock et al131
assessed the effects of 6-month body weight
CRF AND THE OBESITY PARADOX changes 33 months after baseline assessment
It is well known that CRF represents an in HF. Interestingly, the degree of weight loss
important prognostic factor in patients with was positively associated with increased mor-
HF. tality, regardless of initial body weight or
Studies have found that the obesity BMI, even in obese individuals. This study,
paradox does not persist in patients with HF however, did not assess whether weight loss
who have a relatively preserved CRF level, was intentional or unintentional. Moreover, a
_ 2 of 14 mL∙kg1∙min1
defined by a peak VO body composition assessment was not per-
or higher (Figure 5).122,123 When patients are formed to assess whether weight loss was
n n
8 Mayo Clin Proc. XXX 2016;nn(n):1-14 http://dx.doi.org/10.1016/j.mayocp.2016.11.001
www.mayoclinicproceedings.org
OBESITY, BODY COMPOSITION, AND HEART FAILURE

1.0 1.0

0.8 0.8
Cumulative survival

Cumulative survival
0.6 0.6

0.4 0.4

0.2 0.2
BMI of 30.0 or greater BMI of 30.0 or greater
BMI of 25.0 to 29.9 BMI of 25.0 to 29.9
BMI of 18.5 to 24.9 BMI of 18.5 to 24.9
0.0 0.0

0 10 20 30 40 50 60 0 10 20 30 40 50 60
Months Months

FIGURE 5. Obesity paradox and cardiorespiratory fitness (CRF). Kaplan-Meier analysis according to body mass index (BMI) in the
low CRF group (peak oxygen consumption <14 mL∙kg1∙min1) (left) and in the high CRF group (peak oxygen consumption
>14 mL∙kg1∙min1) (right). This figure describes the absence of the obesity paradox in patients with relatively high CRF (right)
compared with those who have low CRF, in which the obesity paradox is apparent. From Mayo Clin Proc.122

related to a reduction of fat mass and, perhaps
more importantly, loss of lean mass that is
expected in cachectic patients. Rapid weight
loss can, in fact, be associated with a reduction
in lean mass.132,133 Because lean mass has
been hypothesized to exert protective effects
in HF, its reduction could increase the risk
for development of sarcopenia and sarcopenic
obesity, paradoxically increasing mortality
risk. Large randomized controlled trials assess-
ing the direct effect of intentional weight loss
should be encouraged, accurately assessing
body composition to determine whether the
intervention induced changes in fat mass and
lean mass rather than just focusing on body
weight. Because of the lack of strong evidence,
however, major guidelines do not recommend
weight loss in HF but rather suggest avoiding
unintentional weight loss.16 Although large
studies are lacking, it may be reasonable to hy-
pothesize that intentional weight lossdprefer-
ably of fat mass while preserving or increasing
lean massdcould exert beneficial effects.
However, it should be recognized that one of
the reasons why obesity may be associated
with better outcomes in HF may be the corre-
lation of increased body fat with greater
muscular strength.134,135
Because the effects of weight loss in HF
are currently unclear, interventions should
focus on improving CRF in obese patients
with HF, regardless of the effect on body
weight. Exercise training (ET) and increased
physical activity have indeed produced bene-
ficial effects, and better CRF correlates with
better outcomes, regardless of BMI.136 Addi-
tionally, physical activity, ET, and higher
CRF have been reported to reduce the devel-
opment of HF in the first place.137 Although
aerobic-type exercise is usually recommended
as the primary approach, it is unknown
whether this form of training is superior to
resistance ET. Based on the knowledge that
lean mass, particularly appendicular lean
mass, may exert protective effects, resistance
ET aimed to increase muscle mass and
strength may be helpful (Figure 6).134,138
Additionally, this strategy may also prove
helpful for obese patients with very advanced
HF when LV assist devices are being used,

Mayo Clin Proc. n XXX 2016;nn(n):1-14 n http://dx.doi.org/10.1016/j.mayocp.2016.11.001 9

www.mayoclinicproceedings.org

Heart failure
Pharmacological therapy
Lifestyle
(ACE inhibitors, ARBs,
modification
diuretics) and device therapy
Low sugar and low ↑ PhysicaI activity and
saturated fat diet exercise training
Improved cardio- ↑ Resistance
respiratory fitness exercise
↑ Lean mass
FIGURE 6. Proposed nonpharmacological therapy for patients with heart
failure. In addition to standard of care, we hypothesize that a diet with low
proinflammatory effects (low sugars and low saturated fat) and increased
resistance training, potentially increasing the amount of lean mass, will
improve cardiorespiratory fitness and perhaps prognosis in patients with
heart failure. ACE ¼ angiotensin-converting enzyme; ARB ¼ angiotensin
receptor blocker.
especially as a potential bridge to heart
transplant.139
CONCLUSION
High BMI represents a risk factor for HF
but also exerts protective effects in certain
circumstances. The exact mechanisms related
to the increased risk of HF and the associated
protective effects once HF is diagnosed are
not well known. However, we believe that
lean mass plays a major role in outcome dif-
ferences seen in the HF population. As
such, a better risk stratification of HF patients
based on body composition rather than just
on BMI may be encouraged to identify pa-
tients at higher risk (ie, identifying those
with sarcopenia and sarcopenic obesity) in
whom strategic interventions aimed at preser-
ving or increasing lean mass may be clinically
beneficial. In addition to standard medical
treatment in patients with HF, a major focus
on improving CRF with ET, including resis-
tance ET to increase muscle mass and
strength, appendicular lean mass, and its
functionality, is recommended.
10 Mayo Clin Proc.
MAYO CLINIC PROCEEDINGS
ACKNOWLEDGMENTS
We thank Antonio Abbate, MD, PhD, and
Raffaella Buzzetti, MD, for their help and valu-
able comments on the manuscript during the
writing process.
Abbreviations and Acronyms: BMI = body mass index;
CRF = cardiorespiratory fitness; CVD = cardiovascular dis-
ease; ET = exercise training; HF = heart failure; HFpEF = HF
with preserved ejection fraction; HFrEF = HF with reduced
ejection fraction; LV = left ventricular; LVEF = left ventric-
ular ejection fraction; NCD = noncommunicable disease;
_ VCO
VE/ _ 2 = minute ventilation/carbon dioxide production;
Aerobic _ 2 = oxygen consumption
VO
exercise
Grant Support: Dr Carbone is supported by a Mentored
Clinical and Population Research Award from the American
Heart Association.
Potential Competing Interests: Dr Lavie has lectured for
the Coca Cola Company (but on exercise, fitness, and
obesity and not on their products) and he is the author
of the book, The Obesity Paradox.
Correspondence: Address to Salvatore Carbone, MS,
Pauley Heart Center, Virginia Commonwealth University,
West Hospital 5th Floor, Room 520, 1200 E Broad St,
PO Box 980204, Richmond, VA 23298 (salvatore.carbone@
vcuhealth.org).
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