Gender Differences in Obesity-Associated Cardiac Remodeling

Abstract

The prevalence of obesity has been increasing globally, with important implications for cardiovascular morbidity and mortality. Obesity is linked to changes in cardiac morphology that collectively play a role in the development of heart failure in this population, as hemodynamic and metabolic alterations lead to cardiac hypertrophy and chamber enlargement. Over time subclinical abnormalities in contractile function occur and could progress to overt clinical heart failure. Understanding the relationship between obesity and alterations in cardiac structure and function has important implications for the development of lifestyle and pharmacologic interventions targeting this modifiable risk factor. There is also a growing awareness of the importance of understanding gender differences in obesity. Gender-specific patterns of adiposity and fat distribution in addition to the distinctive hormonal environments of men and women may lead to sex-specific differences in the degree of cardiometabolic risk associated with obesity. Imaging studies have shown that ventricular remodeling in response to obesity differs among the sexes, and these differences may play a role in the female predominance of heart failure with a preserved ejection fraction.

Introduction

The prevalence of obesity has been increasing globally over the past several decades; in the United States more than one-third of adults are considered obese, and an additional one-third are overweight.^1,2 This rising burden of obesity has important implications for cardiovascular morbidity and mortality, as obesity has been identified as a major risk factor for hypertension and coronary heart disease.^3,4 Obesity has also been linked with changes in cardiac morphology that collectively play a critical role in the development of heart failure in this population.^5–8 In 2005 the American Heart Association and American College of Cardiology issued updated guidelines for the diagnosis and treatment of heart failure, and for the first time described heart failure as a continuum. ⁹ In this new framework, individuals with obesity are classified as Stage A “at high risk for HF [heart failure] but without structural heart disease or symptoms.” Stage B occurs when individuals develop structural heart disease but are not yet symptomatic, a recognition that changes in cardiac morphology collectively play a critical role in the development of heart failure.^3,5–8 Understanding how obesity leads to alterations in cardiac structure and function en route to symptomatic heart failure, Stages C and D, is important for the development of lifestyle and pharmacologic interventions targeting this modifiable risk factor.

There is also a growing awareness of the importance of understanding gender differences in the development of cardiovascular disease, as men and women often manifest different signs and symptoms of cardiovascular illness. The role of the hormonal environment and how body composition mediates the mechanism, timing, and prominence of physiologic adaptations to obesity must be considered to understand the implications of the obese state fully, and to develop and apply preventative and therapeutic measures effectively. This review discusses the impact of obesity on cardiac structure and function as well as the different patterns of cardiac remodeling that occur in men and women.

Association Between Obesity and Maladaptive Cardiac Remodeling

Cardiac remodeling is the process by which alterations in ventricular architecture, including changes in cavity size and wall thickness, occur. Classically described following a myocardial infarction, remodeling has subsequently been described in response to a variety of forms of myocardial injury and increased wall stress.^10,11 As it shifts from normal geometry, the left ventricular (LV) adaptive response can be classified in 1 of 3 patterns: (1) concentric remodeling (increased relative wall thickness with normal LV mass index); (2) eccentric hypertrophy (normal relative wall thickness with an increased LV mass index); or (3) concentric hypertrophy (increased relative wall thickness and LV mass index).^12,13

Many studies have shown that obesity is independently associated with the development of LV remodeling and hypertrophy, and abnormal LV geometry is associated with increased morbidity and mortality.^12–14 This pathologic thickening of cardiac muscle is likely multifactorial in the setting of direct fatty infiltration of the myocardium, hemodynamic alterations associated with obesity, and the metabolic effects of elevated leptin and insulin.^15–17

Regarding hemodynamic alterations, eccentric hypertrophy has classically been described in individuals with obesity; adiposity leads to increased circulating blood volume due to alterations in salt retention and activation of the renin–angiotensin–aldosterone system, ultimately resulting in increased cardiac output, wall stress, and dilatation.^17–19 However, recent large studies have demonstrated that obesity is associated with a predominance of concentric hypertrophy with increased wall thickness relative to the chamber size.^8,14,20–22 Although some studies have suggested that the development of concentric hypertrophy is related to coexisting hypertension, others have suggested that an independent portion of this geometric change is likely attributable to body composition rather than to blood pressure.^8,13 In an attempt to harmonize the different patterns of remodeling that have been described, it seems likely that the LV remodeling that occurs as a result of obesity is initially concentric in nature. As the obese state becomes chronic, persistent volume and pressure overload lead to further chamber enlargement and LV hypertrophy, with both eccentric and concentric hypertrophy occurring.

In addition to the hemodynamic changes seen in obesity, metabolic stimuli also affect cardiac remodeling and function. Increased levels of leptin, an adipokine secreted by adipose tissue, can both induce hypertrophy and attenuate systolic contraction, and have also been implicated in cardiac interstitial fibrosis and early diastolic dysfunction.^15,17,23 Leptin has also been associated with upregulation of the renin–angiotensin–aldosterone system that might contribute to the sodium retention and blood volume expansion seen in obesity. ²⁴ Because many obese individuals have comorbid metabolic syndrome, hyperinsulinemia can contribute to cardiomyocyte hypertrophy through the growth factor effect of insulin. ²⁵ Additionally insulin may increase sodium retention through direct interactions with renal tubules and with arteriolar vasoconstriction, contributing to volume expansion and comorbid hypertension. ¹⁷

Association Between Obesity and Reductions in Cardiac Function

Over time, the hemodynamic and structural changes seen with obesity lead to reduced cardiac function; classically diastolic dysfunction has been described, however there is also evidence to suggest that systolic dysfunction may occur as well.^7,8,26,27 Although many studies have failed to show a correlation between obesity and reduced systolic function as measured by ejection fraction, new imaging modalities allow for the identification of subclinical changes in cardiac function. Using more sensitive echocardiographic markers of systolic function—such as myocardial strain, as well as cross-sectional imaging with computerized tomography (CT) and magnetic resonance imaging (MRI)—contractile abnormalities have been identified in obese patients, and could become more clinically apparent over time.^7,8,26–31

Fewer studies have assessed the effect of obesity on the geometry and function of the right ventricle (RV), but there is evidence to suggest that both RV wall thickness and volume increase in obesity, and there might be associated decreases in RV systolic function.^30,32,33 Changes seen in the RV are thought to be due to similar mechanical and metabolic stimuli as those seen in the LV, but the RV could also be affected by increased RV pressure not only as a result of hypoxia from obesity-related sleep apnea but also progressive LV diastolic dysfunction. However, studies thus far have not correlated obesity-related changes in RV structure and function with the presence of ventilatory sleep disorders.^30,33

Gender Differences in Obesity

It has been well-established that women have greater adiposity than men, but with a different distribution.^34,35 While men have increased visceral fat, women tend to have peripheral fat distribution and more subcutaneous adipose tissue. However, as women age and estrogen production decreases, there is a preferential increase in abdominal fat, and a shift toward visceral adiposity and a more “male” fat distribution. ³⁶ Typically, visceral adiposity has been associated with higher cardiometabolic risk, and this difference could partially account for the more significant cardiovascular risk that is seen at a younger age in men. ³⁷

The increased adiposity seen in women also leads to increased levels of circulating leptin, which could impact the degree of cardiac hypertrophy that occurs in response to obesity. ¹⁵ Additionally there are estrogen and androgen receptors on cardiac myocytes that might mediate changes in cardiac remodeling. Most evidence indicates that testosterone increases myocyte proliferation while estrogen has antiproliferative properties, which could also explain the increasing LV mass seen as women age and become postmenopausal. ¹⁵

Evidence of Gender Differences in Cardiac Remodeling of Obesity

Given evidence of significant physiologic differences among men and women, several studies have examined the gender differences of obesity on cardiac remodeling. Bello et al. examined echocardiograms of an elderly biracial cohort of individuals without coronary heart disease or heart failure, and noted that although both concentric and eccentric hypertrophy occurred in obesity, obese women were more likely to show abnormal LV geometry, compared to men. ³⁸ Additionally while obesity was not associated with reduced ejection fraction in either sex, subclinical cardiac dysfunction was identified and seemed to affect women predominantly. Circumferential strain, an impairment of systolic function, was associated with obesity in women but not in men, and obese women also had worse diastolic function, compared to men. This increased prevalence of diastolic dysfunction in obese women, compared to men, is consistent with the results demonstrated in other studies.^8,20 Several studies also noted that obese women had more pronounced concentric hypertrophy with more significant increases in LV mass than obese men.^8,28,39 Other investigators have found that obese subjects who were not hypertensive had eccentric rather than concentric type hypertrophy more frequently. ³⁸

Cross-sectional imaging with CT and MRI has also been used to evaluate the effect of obesity and gender on cardiac remodeling, as there are concerns regarding the limitations of acoustic windows with echocardiography in the obese population and with the geometric assumptions associated with 2D imaging. ¹⁶ Rider et al. examined cardiac structural differences in subjects without identifiable cardiovascular risk factors with MRI, and found a strong positive correlation between obesity and LV mass. ¹⁶ However, while both sexes had concentric hypertrophy in response to increasing body mass index, the degree of hypertrophy was greater in males, and females showed more significant cavity dilatation. Other studies using MRI reported similar findings of a predominance of concentric hypertrophy in obese individuals ²¹ while a recent study by Corden et al. similarly found increased wall thickness in obese men and cavity dilatation in obese women. ⁴⁰

There are fewer data regarding gender differences in RV structure and function. Data from an echocardiographic study by Bello et al. did not reveal gender differences in RV structure or function. ³⁸ However, Rider et al. used MRI, a more-sensitive imaging modality in individuals with obese body habitus, to evaluate changes in RV structure and found sex-specific differences in the RV response to obesity. Although both obese men and women developed concentric RV hypertrophy, women developed more RV cavity dilatation and eccentric RV hypertrophy than men. ³² Women also had a more significant hypertrophic response than men, which was attributed to increased adiposity. There was evidence of reduced RV function with obesity in both sexes, with a reduced ejection fraction noted in men more than women.

Conclusion

As we move away from the conceptualization of cardiovascular disease as a predominantly male disorder, we must also evaluate the ways in which gender specific differences in pathophysiology can alter approaches to preventative and therapeutic interventions. The changes in myocardial structure seen with obesity have important implications on cardiac function and cardiovascular outcomes in a growing proportion of both men and women, but there is evidence to suggest that gender differences in body composition could alter this effect.

Specifically, women and men may have differential tendencies toward hypertrophic geometries; although both sexes develop significant increased ventricular wall thickness and mass in response to obesity, obese women appear to develop more significant cavity dilatation and appear to have more significant impairment in diastolic function. These differences may play roles in the discrepancy in the prevalence of heart failure with a preserved ejection fraction seen among the sexes, with a higher incidence of heart failure with a preserved ejection fraction among women, compared to men. Additional studies are needed to evaluate these differences further to develop therapies that target gender-specific pathophysiology better.