Obesity, CAD and Heart Failure: A Triple Jeopardy

121
CHAPTER
Obesity, CAD and Heart
Failure: A Triple Jeopardy
SN Routray, Debasish Das,
TK Mishra, SS Mishra
INTRODUCTION
Last decade has witnessed an “obesity epidemic” with WHO
estimation of around 300 million worldwide. The incidence of
obesity has tripled over past 20 years in developing countries and
projections predict that there will be 2.3 billion overweight and
700 million obese individuals worldwide by 2015. 8.9% of adult
men and 13.1% of adult women are clinically obese and 10% of the
world’s children are currently overweight or obese. Obesity being
a genetic and metabolic cardiovascular (CV) risk factor1 with 41
genetic loci induces adaptive alteration in cardiac structure and
function in response to excess adiposity. Abdominal obesity is an
important risk factor for cardiovascular disease (CVD) worldwide
with android (apple) obesity being more adiposopathic than
gynecoid (pear-shaped) obesity generating the “FitFat Model”.
Obese CV platform constitutes the triad of coronary artery
disease (CAD), heart failure (HF) and sudden cardiac death
(SCD) with a favorable landing zone of obesity paradox. Global
epidemic of diabetes and obesity has put forth a new concept of
“diabetisity” accentuating this CV spectrum. WHO categorizes
obesity according to body mass index (BMI) in kg/m2 as
underweight (< 18.5), normal weight (18.5–24.9), overweight
(25–29.9), obese Class I (30–34.9), obese Class II (35–39.9) and
obese Class III (40 or more). Metabolically they are divided
as metabolically obese obese (MOO), metabolically obese
nonobese (MONO), and metabolically healthy obese (MHO) and
metabolically healthy nonobese (MHNO) individuals. Although
landmark epidemiological studies like Framingham has clearly
shown a close relationship between obesity and an increased
risk of CVD, a U- or J-curve is observed in relation to mortality,
being higher in individuals with a low and very high BMI. The
genesis of CAD and HF in obesity arises amidst clustered CV
risk factors like dyslipidemia, hypertension, glucose intolerance,
inflammatory markers, obstructive sleep apnea/hypoventilation
and the prothrombotic state, the story is an amalgam of jeopardy
and paradox.
WITH A VERY HEAVY HEART: OBESITY
AND CARDIOVASCULAR DISEASE
Obesity giving way to dyslipidemia, insulin resistance,
hypertension, CAD, HF, arrhythmia, SCD with a panoply of
associated comorbidities is better described as “obesity disease”.
Hyperleptinemia plays a central role in inflicting vascular and
myocardial injury in obesity—the key event behind the genesis of
CAD and HF.
ADIPOSE TISSUE IS AN
ENDOCRINE ORGAN
The adipose tissue is not simply a passive storehouse for fat but
an endocrine organ that is capable of synthesizing and releasing
tumor necrosis factor (TNF)-a, interleukin (IL)-6, plasminogen
activator inhibitor-1 (PAI-1), resistin, lipoprotein lipase, acylation
stimulating protein, cholesteryl-ester transfer protein (CETP),
retinal binding protein, estrogens, leptin, angiotensinogen,
adiponectin, insulin-like growth factor-I (IGF-I), insulin like
growth factor binding protein 3 (IGFBP3), and monobutyrin
playing important role in CV homeostasis.2
MYOCARDIAL INJURY
Myocardial Lipotoxicity
Secondary to loss of plasticity in substrate utilization and
compensatory increase of fatty acid oxidation (FAO) causes
mitochondrial uncoupling and reduced cardiac efficiency with
CHAPTER 121: Obesity, CAD and Heart Failure: A Triple Jeopardy
oxygen wasting and an increase of reactive oxygen species (ROS),
in production that ultimately leads to cell apoptosis.3 Increased
FAO disrupts the insulin-mediated signal for the promotion of
glucose uptake and oxidation, this lack of flexibility is negative
in critical conditions such as ischemia and high workload when
glucose oxidation is preferable for lower myocardial oxygen
consumption. Lipotoxicity induces elaboration of inflammatory
molecules including C-reactive protein (CRP) which induce
atherogenesis.
ROLE OF PERICARDIAL FAT
Increased risk of CAD has recently been associated with the
accumulation of intrapericardial fat (IPF). IPF is supplied
by branches of coronary arteries and shares the same
microcirculation of the myocardium, while this is not true for
extrapericardial fat (EPF). IPF directly affects vascular remodeling
and plaque complications than EPF through paracrine signaling.
HEMODYNAMIC
REPERCUSSION OF OBESITY
Obesity produces an increment in total blood volume and cardiac
output that is caused in part by the increased metabolic demand
induced by excess body weight. In obesity, the Frank-Starling
curve is shifted to the left because of incremental increases in
left ventricular (LV) filling pressure and volume, which over time
may produce chamber dilation leading to increased wall stress,
which increase the myocardial mass and eccentric left ventricular
hypertrophy (LVH). Left atrial enlargement may also occur in
the setting of increased left ventricular end diastolic pressure
(↑ LVEDP) which in turn increases the risk of atrial fibrillation.
Obese patients may also demonstrate higher right heart filling
pressures and pulmonary vascular resistance index.
VASCULAR INJURY
Adipokines induce endothelial dysfunction with decreased
expression of endothelial nitric oxide (NO), circulating lipid
peroxides and myeloperoxidase reduce available vasodilators,
elevated plasma free fatty acids (FFAs) increase intercellular
adhesion molecule (ICAM)-1, myeloperoxidase and, PAI1, thromboxane A2 (TXA2) expression along with inherent
prothrombotic risk in obese segregate into an atherosclerotic
milieu. These inflammatory molecules, oxidant species, lipotoxicity
and hyperglycemic wave front mediated endothelial injury due to
associated diabetes sets in atherosclerosis in obese individuals.
OBESITY AND CORONARY
ARTERY DISEASE
Obesity is an independent risk factor for development of CAD
with a 3 or more fold increase in the risk of fatal and nonfatal
myocardial infarction (MI). The association of obesity with CAD
is blatant in two classical highly consulted prospective studies: (1)
the Framingham Heart Study and (2) the Nurses’ Health Study.
The relative risk for CAD for adults with BMI 21–22.9 kg/m²
increased from 1.19 to 3.56 in patients with BMI higher than 29 kg/
m². The Asia Pacific Cohort Collaboration Study found an increase
of 9% in ischemic cardiac events for each unit of change in BMI.
The EUROASPIRE investigators identified that 33% of women
and 23% of men with CAD were obese. Higher BMI is associated
with elevated concentrations of CRP, suggesting a state of lowgrade systemic inflammation in overweight and obese persons.
This effect of “smouldering arteries” partly mediate the effects of
obesity on CAD, a concept showing that obesity is independently
associated with coronary endothelial dysfunction irrespective
of the presence of CAD. PDAY (Pathobiological Determinants
of Atherosclerosis in Youth) study in individuals within
15–34 years of age revealed that the extent of atherosclerosis in the
right coronary artery (RCA) and abdominal aorta were associated
with obesity and size of the abdominal panniculus with equal
incidence in male and female and with more prevalence in blacks.
Importantly, BMI more than 30 kg/m2 was associated with raised
lesions in the RCA only among individuals with a large panniculus
thickness (≥17 mm), which reinforces the concept that central fat
distribution is more important than total fat4 behind genesis of
atherosclerosis. Also maximal density of macrophages/mm2 in
the lesions was associated with visceral obesity. Of note, coronary
atherosclerosis in young women lagged behind those seen in
young men by 10–20 years due to preferential central deposition
of fat after menopause. PDAY study provides convincing evidence
that obesity accelerates the progression of atherosclerosis decades
before the appearance of clinical manifestations. Prospective
studies that with follow-up data over more than 2 decades, such as
Framingham Heart Study, the Manitoba Study, and the Harvard
School of Public Health Nurses Study, have documented that
obesity is an independent predictor of clinical CHD. Cumulative
effects of childhood obesity persist into adulthood as evidenced
by childhood levels of BMI are associated with carotid intimalmedial thickness (IMT) only among obese adults.
OBESITY MYOCARDIAL
INFARCTION PARADOX
Among 6,661 EPHESUS participants it was found that obesity
was associated with reduced all-cause mortality among postacute myocardial infarction (AMI) patients with left ventricular
systolic dysfunction (LVSD) and HF attributed to younger age
of obese patients. Each unit increase in BMI was associated
with 5% reduction in 1-year mortality. In patients with known
CVD, obesity is inversely related to mortality. Characteristics of
the obese patients in the catheterization laboratory are younger
age and more single-vessel disease5 which offers a favorable
outcome. In CARDIA (Coronary Artery Risk Development in
Young Adults) study abdominal obesity correlated with coronary
artery calcification and obese patients were referred for coronary
angiography at an earlier age had a lower CAD burden lending
further credence to the existence of an apparent “obesity paradox”.
A recent meta-analysis demonstrated that those patients who are
classed as overweight or obese have lower mortality rates post
percutaneous coronary intervention (PCI) following MI (both STelevation myocardial infarction (STEMI) and non-ST-elevation
myocardial infarction (NSTEMI).6 In contrast to common
beliefs, obesity is not associated with increased mortality rates
or postoperative cerebrovascular accident (CVA) after coronary
artery bypass grafting (CABG). Obesity paradox is now being
extended to even cardiac stress testing.
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SECTION 12: Dyslipidemia and Cardiometabolism
OBESITY AND HEART FAILURE
Congestive heart failure (CHF) is a common complication
of obesity, even in the absence of hypertension or ischemic
disease with higher LV cavity size and end-systolic wall stress.
Approximately 11% of cases of HF among men and 14% among
women in the community are attributable to obesity alone.
Framingham Heart Study clearly showed that obesity and
overweight are highly predictive of later clinical HF. Elevated
BMI predisposes to CHF by promoting hypertension, diabetes,
and CHD. There is an increase in the risk of CHF of 5% for men and
7% for women for each increment of 1 U of BMI.7
EFFECTS ON VENTRICULAR FUNCTION
Eccentric LVH, commonly present in morbidly obese patients
(BMI ≥40 kg/m2), is often associated with LV diastolic dysfunction.
The finding that ejection fraction (EF) of less than 40% are seen
in 42% of obese as compared to 54% of normal-weight patients
with HF confirms that diastolic HF is the more common type of
LV dysfunction among the obese. Moreover, as with increased LV
mass, longer durations of obesity are associated with poorer LV
systolic function. Lipid deposition can impair cardiac function in
two possible ways: (1) The size of fat pads modify cardiac function
either by simple physical compression or secretion of adipokines
and (2) lipid accumulation in non-adipose cells leading to cell
dysfunction or death, a phenomenon known as “lipotoxicity”.
Abnormal cellular adaptations unfavorably affect the cardiac
muscle in several mechanisms leading to cardiomyopathy.
CARDIOMYOPATHY OF OBESITY
(ADIPOSITAS CORDIS)
Obesity cardiomyopathy was described by Cheyne in 1818
from the reported case of Cheyne-Stokes respiration. Fatty
heart probably is a metaplastic phenomenon with adaptative
substitution of cells which are better able to withstand the adverse
environment. Cords of cells gradually accumulate fat between
muscle fibers causing myocyte degeneration. Occasionally, a
pattern of restrictive cardiomyopathy develops as a result of
pressure-induced atrophy from the intervening fat. An alternative
explanation could be the lipotoxicity of the myocardium induced
by FFAs causing apoptosis of cardiomyocytes. Thus, through
different mechanisms (increased total blood volume, increased
cardiac output, LVH, LV diastolic dysfunction, adipositas cordis),
obesity predispose to HF.
THE “OBESITY PARADOX” AND HEART
FAILURE: THE STORY CONTINUES
In spite of adverse effects of obesity on LV structure and function
obese patients with HF have better prognosis than do their leaner
counterparts.8 BMI is inversely related to mortality over long term
in patients with chronic HF justify the use of the term “reverse
epidemiology”.9 An analysis from 7,767 patients with stable HF
in the Digitalis Investigation Group (DIG) trial reported that
higher BMI was associated with lower mortality risk. For each 1%
absolute increase in the percentage of body fat, there is more than
13% decrease in severe clinical events. Obese HF patients have
19% reductions in CV mortality. In obese people heart failure
with preserved ejection fraction (HFpEF) survival is better in
overweight and underweight, but there is a U-shaped survival
curve in patients with LVSD. In fact, for every 5-unit increase in
BMI, the risk of mortality was 10% lower. However, in patients
with a BMI of more than 35 kg/m2, there was an excess risk for CV
mortality without any increase in total mortality. Hence obesity
should not be ruled out as a risk factor just because of the existence
of the “obesity paradox” and it continues to be a risk factor for HF
or coronary disease. Following mechanisms exist which might
explain the apparent paradox.10
•• Natriuretic peptide concentrations are depressed in patients
with HF causing early appearance of dyspnea and early health
care access and slow subsequent evolution.
•• High circulating lipoproteins bind and detoxify circulating
lipopolysaccharides, including bacterial endotoxins which
release an array of inflammatory cytokines.
•• Adipose tissue releases more TNF-a receptors which
neutralizes the adverse biologic effects of cachexia molecule
TNF-a.
•• Obese have attenuated renin-angiotensin-aldosterone system
(RAAS) and sympathetic nervous system (SNS) activity, being
hypertensive tolerate cardioprotective antifailure measures
well.
•• Obese people have high metabolic reserves for which is they
are better able to deal with a catabolic situation such as HF.
•• Obesity can also produce symptoms of restrictive pulmonary
disease and deconditioning of it improves symptoms.
•• Obesity could also be associated with a more favorable
prognosis in other comorbidities, such as in end-stage
kidney disease undergoing dialysis, in chronic obstructive
pulmonary disease (COPD), liver cirrhosis or acquired
immunodeficiency syndrome (AIDS) as well as in those with
advanced cancer.
SUDDEN CARDIAC DEATH
The statement of Hippocrates is not to be forgotten:
“Sudden death is more common in those who are naturally fat
than in the lean.”
In the Framingham Study, the annual sudden cardiac
mortality rate in obese men and women was about 40 times higher
than non-obese population due to associated QT prolongation,
late potentials, elevated FFAs, catecholamine, hyperglycemiamediated cardiac repolarization, poor heart rate variability
(HRV) leading to development of ventricular tachyarrhythmias
and SCD.
IMPACT OF OBESITY ON TOTAL AND
CARDIOVASCULAR MORTALITY—
FACT OR FICTION
The relationship between obesity and CV morbidity and mortality
is still not entirely clear. Individuals with a low or high BMI are
at increased risk of total and CV mortality. In spite of existence
of puzzling obesity paradox, obese persons have a reduced life
expectancy of 2–4 years less than that compared with healthy
weight adults; adults with severe obesity (BMI >40) lose 8–10 years
of life expectancy, comparable to the effects of smoking. In the
CHAPTER 121: Obesity, CAD and Heart Failure: A Triple Jeopardy
Trandolapril Cardiac Evaluation (TRACE) register, the mortality
rate was increased 23% with abdominal obesity as compared
with patients who were not abdominally obese.
FITNESS VERSUS FATNESS
From “fitness” versus “fatness” for each unit of BMI increment,
the risk of CHD increases by 8%. On the other hand, each 1 MET
(metabolic equivalent) increase in activity score is associated with
an 8% decrease in CHD risk. Even modest weight loss of 5–10% can
reverse many of the comorbidities. It has been estimated that each
10% reduction in weight in men leads to a 20% reduction in coronary events. Weight reduction decrease blood volume, stroke volume, heart rate, cardiac output, LV mass, improve LV systolic and
diastolic dysfunction, decrease systemic arterial pressure, O2 consumption, decrease QT interval and improve heart rate variability.
MANAGEMENT
Obesity with co-existent CAD and HF represents a particularly
high-risk population who require aggressive management.
Behavioral, diet, exercise, drug treatments and bariatric surgery
have all been shown to be effective to some extent in treating
obesity especially when two or more approaches are used in
combination. Maintenance interventions involving continued
therapist contact to sustain weight loss and care of clustering
CV risk factors like hypertension, dyslipidemia, hyperglycemia
and other comorbidities bring down the fatal jeopardy of CAD
and HF combination with an illuminating favor from intriguing
obesity paradox. Bariatric surgery is currently the most effective
strategy for attaining significant and sustainable weight loss and
can reverse many obesity-related disease processes.11
SUMMARY AND CONCLUSION
Obesity has risen to its epidemic proportions. With clustering CV
risk factors like hypertension, dyslipidemia and hyperglycemia
it induces lipotoxic vascular and myocardial injury culminating
in CAD and HF. In spite of the intriguing concept of obesity
paradox, obesity plays an independent metabolic genetic risk
factor behind the fatal jeopardy of CAD and HF. The multiple
and ever increasing deleterious effects of obesity create a selfperpetuating cycle of illness and disability, sentences with
ischemia and LV dysfunction and ends the natural history of
this tragic epidemic with cardiac standstill. Multidisciplinary
approach including behavioral, diet, exercise, drugs and
bariatric surgery in selected patients will one day bring out a
slow sunset to this fat terrorism and triple jeopardy.
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