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Obesity and Heart Failure Focus On The Obesity
Obesity and Heart Failure Focus On The Obesity
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,
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
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 obesity and diastolic dysfunction are causally
(Figure 2). linked.
The mechanisms by which obesity may
OBESITY, DIET, AND HFPEF induce diastolic dysfunction and therefore
A form of HF that has been increasing in inci- increase the risk of HFpEF are still unclear.
dence in the past few decades is characterized Several hypotheses have been proposed
by impaired diastolic function associated with including a potential involvement of direct
preserved LVEF and no major coronary artery, cardiodepressant factors produced by the adi-
valvular, or arrhythmic disease. This syn- pose tissue.18,57 The adipose tissue is an active
drome is referred to as HFpEF or diastolic endocrine organ able to synthesize a number
HF.17,20,56 Most patients with HFpEF are of hormones or active molecules called adipo-
obese and have evidence of metabolic derange- kines.58-60 In particular, the adipose tissue pro-
ments such as insulin resistance and dia- duces proinflammatory cytokines such as
betes.17,56 It is therefore conceivable that 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- included 31 studies, both randomized
tion in preclinical animal models.59,61,62 In controlled trials and observational studies.
support of these hypotheses, pilot studies This meta-analysis revealed a relationship be-
with targeted anti-inflammatory treatment tween BMI and mortality in both HFrEF and
have reported promising results in HF, HFpEF, with the lowest mortality rate seen in
including HFpEF.61,63,64 In these pilot studies, those with class 1 obesity81 (Figure 3). A later
short-term IL-1 blockade strategies with a meta-analysis including about 22,000 patients
human recombinant IL-1 receptor antagonist who had chronic HF (HFrEF and HFpEF)
improved cardiorespiratory fitness (CRF) in with a mean follow-up of almost 3 years re-
patients with HFrEF63 and HFpEF,64 and ported a similar outcome; overweight patients
both studies found a significant increase of presented with the lowest total and CV mortal-
peak oxygen consumption (VO _ 2 ), an indepen- ity rate compared with those who were normal
dent predictor of outcomes in HF. weight, while underweight patients had the
Furthermore, obesity is considered the highest mortality rate and patients with class
result of an unhealthy diet. Recent studies 2 and higher obesity had an intermediate prog-
have found that a high-sugar (30% of total nosis with lower total and CV mortality despite
calories) and highesaturated fat (12.8% of to- increased HF hospitalizations.82 Recently, it
tal calories) diet resembling a typical diet of has also been observed that the obesity
Western countries (Western diet) can directly paradox is particularly relevant in women
impair cardiac diastolic and systolic function with advanced HF.83
in experimental animals,65,66 providing a po- Based on these data, researchers have
tential link between diet-induced inflamma- started to explore potential mechanisms for
tion and cardiac dysfunction (Figure 2). the obesity paradox. A plausible explanation
Moreover, returning to a healthy diet low in is related to the inaccuracy of the BMI in
saturated fat and sugar induced significant characterizing the severity of obesity.84-90
improvements in cardiac function, high- The World Health Organization definitions
lighting a major ability of the diet to modulate of obesity imply that every individual with a
both systolic and diastolic function.65-69 BMI of 25 kg/m2 or higher, and even more
Sugars and saturated fat can activate proin- so when BMI is 30 kg/m2 or higher, have
flammatory pathways; specifically, they can increased fat mass.1 However, this implication
induce the synthesis and activation of the is not necessarily true. Body mass index has
macromolecular complex Nod-like receptor in fact several limitations, and as such it
pyrin domainecontaining protein 3 inflam- should be considered more of a measurement
masome70-72 responsible for the production of heaviness than body composition. Patients
of IL-1 and IL-18, cytokines with well- with increased BMI may not necessarily have
known cardiodepressant properties. A diet increased fat mass (eg, athletes),91,92 while
low in sugars and saturated fat could perhaps having a normal BMI (18.5 kg/m2 and
improve cardiac function and CRF by limiting <25 kg/m2) does not preclude an individual
the synthesis and activation of the macromo- from having increased fat mass and thus
lecular complex Nod-like receptor pyrin increased metabolic and CVD risk.93 Thus,
domainecontaining protein 3 inflammasome an accurate measurement of body composi-
and of cytokines IL-1 and IL-18. tion, rather than BMI, that defines body
weight components (ie, fat mass, fat-free
THE OBESITY PARADOX IN HF mass, lean mass) likely plays a crucial role
Although the risk of HF increases with BMI, in the development and progression of
patients with HFrEF who are overweight or CVD, including HF. Nevertheless, at least at
obese commonly have better outcomes than a population level, BMI has predicted CVD
those who are normal weight or under- and all-cause survival,94,95 and more specific
weight,7-9,24-26,73-79 even when high BMI man- fat distribution measures, such as waist
ifests several years before an HF diagnosis.80 A circumference and waist to hip ratio, do not
secondary analysis of the Meta-analysis Global outperform BMI in predicting the incidence
Group in Chronic Heart Failure (MAGGIC) of HF.96
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 cardiac output. However, whether systemic
PROTECTIVE EFFECTS IN HF vascular resistance is reduced only in obese
Although we have described the potential patients with preserved or increased skeletal
involvement of body composition components muscle mass or if this also occurs in patients
in the initial cardiac abnormalities leading to with reduced skeletal muscle mass requires
increased HF risk, increased skeletal muscle further investigation.
mass seen in obese individuals may actually
also exert protective effects related to better OBESITY PHENOTYPES AND OUTCOMES
outcomes in HF. Hypothesizing a major protective role of skel-
With respect to HF pathophysiology, char- etal muscle mass in patients with HF is consis-
acterized by reduced or inadequate cardiac tent with what has already been observed in
output and increased systemic vascular resis- other disease states, such as diabetes and can-
tance,13 it is plausible that obese individuals cer, in which reduced lean mass is associated
with preserved skeletal muscle mass have a with poor outcomes and metabolic abnormal-
better prognosis secondary to increased stroke ities, a muscle deficiency condition known as
volume and thus cardiac output (ie, improved sarcopenia.97 When sarcopenia is paralleled
tissue perfusion) compared with their counter- by an increase in fat mass (obesity), it is
parts who have reduced lean mass and lower termed sarcopenic obesity, bringing together
stroke volume and cardiac output. Moreover, body composition abnormalities of both con-
obese patients tend to have lower systemic ditions, sarcopenia and obesity.98,99 Sarcopenic
vascular resistance, especially those who are obesity is becoming extremely prevalent and is
normotensive.6-9,24,35 Reduction in the after- related to poor outcomes in a number of
load results in improved forward flow and chronic diseases. A recent meta-analysis of
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OBESITY, BODY COMPOSITION, AND HEART FAILURE
_ 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
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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 with better outcomes in HF may be the corre-
more importantly, loss of lean mass that is lation of increased body fat with greater
expected in cachectic patients. Rapid weight muscular strength.134,135
loss can, in fact, be associated with a reduction Because the effects of weight loss in HF
in lean mass.132,133 Because lean mass has are currently unclear, interventions should
been hypothesized to exert protective effects focus on improving CRF in obese patients
in HF, its reduction could increase the risk with HF, regardless of the effect on body
for development of sarcopenia and sarcopenic weight. Exercise training (ET) and increased
obesity, paradoxically increasing mortality physical activity have indeed produced bene-
risk. Large randomized controlled trials assess- ficial effects, and better CRF correlates with
ing the direct effect of intentional weight loss better outcomes, regardless of BMI.136 Addi-
should be encouraged, accurately assessing tionally, physical activity, ET, and higher
body composition to determine whether the CRF have been reported to reduce the devel-
intervention induced changes in fat mass and opment of HF in the first place.137 Although
lean mass rather than just focusing on body aerobic-type exercise is usually recommended
weight. Because of the lack of strong evidence, as the primary approach, it is unknown
however, major guidelines do not recommend whether this form of training is superior to
weight loss in HF but rather suggest avoiding resistance ET. Based on the knowledge that
unintentional weight loss.16 Although large lean mass, particularly appendicular lean
studies are lacking, it may be reasonable to hy- mass, may exert protective effects, resistance
pothesize that intentional weight lossdprefer- ET aimed to increase muscle mass and
ably of fat mass while preserving or increasing strength may be helpful (Figure 6).134,138
lean massdcould exert beneficial effects. Additionally, this strategy may also prove
However, it should be recognized that one of helpful for obese patients with very advanced
the reasons why obesity may be associated HF when LV assist devices are being used,
ACKNOWLEDGMENTS
Heart failure We thank Antonio Abbate, MD, PhD, and
Raffaella Buzzetti, MD, for their help and valu-
able comments on the manuscript during the
Pharmacological therapy
Lifestyle
writing process.
(ACE inhibitors, ARBs,
modification
diuretics) and device therapy
Abbreviations and Acronyms: BMI = body mass index;
CRF = cardiorespiratory fitness; CVD = cardiovascular dis-
ease; ET = exercise training; HF = heart failure; HFpEF = HF
Low sugar and low ↑ PhysicaI activity and with preserved ejection fraction; HFrEF = HF with reduced
saturated fat diet exercise training
ejection fraction; LV = left ventricular; LVEF = left ventric-
ular ejection fraction; NCD = noncommunicable disease;
_ VCO
VE/ _ 2 = minute ventilation/carbon dioxide production;
Improved cardio- ↑ Resistance Aerobic _ 2 = oxygen consumption
VO
respiratory fitness exercise exercise
Grant Support: Dr Carbone is supported by a Mentored
Clinical and Population Research Award from the American
↑ Lean mass Heart Association.
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OBESITY, BODY COMPOSITION, AND HEART FAILURE
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