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Journal of Hypertension:
doi: 10.1097/HJH.0b013e32834905ee
Editorial commentaries

Obesity can break your heart and more so when you are a woman

Haufe, Sven; Jordan, Jens

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Institute of Clinical Pharmacology, Hannover Medical School, Hannover, Germany

Correspondence to Jens Jordan, MD, Institute of Clinical Pharmacology, Hannover Medical School, Carl-Neuberg-Strasse 1, 30625 Hannover, Germany E-mail: jordan.jens@mh-hannover.de

The growing prevalence of obesity imposes an increasing burden on health systems in many countries. Perhaps more importantly, obesity limits the quality as well as the quantity of life. Obesity-induced changes in cardiac structure and function are particularly important in this regard. Obesity is associated with increased left ventricular mass, a potential contributor to heart failure, cardiovascular events, and mortality. In the Framingham Heart Study, the heart failure risk increased by 5% in men and 7% in women with each 1 kg/m2 increment in BMI [1]. Compared with normal weight individuals, heart failure risk was doubled in obese individuals. Physical inactivity further increases heart failure risk [2]. Typically, heart failure in obesity is mediated through increased left ventricular mass and impaired left ventricular diastolic filling, rather than systolic dysfunction. As left ventricular hypertrophy and increased left ventricular filling pressure predispose to atrial fibrillation, it is no surprise that obesity increases the risk for chronic atrial fibrillation [3]. An increased BMI is also a risk factor for new onset atrial fibrillation after surgery [4]. Heart failure patients are particularly dependent on left atrial contraction for left ventricular filling. Thus, atrial fibrillation often worsens heart failure symptoms.

Obesity promotes left ventricular hypertrophy through various mechanisms. Hemodynamic mechanisms including intravascular volume expansion and increased cardiac output produce left ventricular hypertrophy [5]. Concomitant obesity-associated arterial hypertension [6] and neurohumoral activation [7–9] further exacerbate changes in cardiac structure and function. Inflammatory cytokines, such as tumor necrosis factor-α, interleukin-1, and interleukin-6, are elevated in heart failure and are able to modulate cardiac remodeling by a variety of mechanisms, including induction of myocardial hypertrophy, fibrosis, and apoptosis [10]. The low-grade systemic inflammation associated with obesity [11,12] could conceivably promote changes in cardiac structure and function.

Obesity may elicit abnormalities in myocardial metabolism and function through intramyocardial triglyceride deposition and lipotoxicity [13]. Previous studies demonstrated lipid accumulation in failing human hearts, particularly in obese diabetics [14]. 1H magnetic resonance spectroscopy can be applied to quantify myocardial triglyceride content in humans. In subsequent studies, myocardial triglyceride content was excessive in type 2 diabetic patients and tended to be increased in obese nondiabetic individuals [15]. Myocardial triglycerides were independent predictors of diastolic dysfunction [16,17]. Furthermore, recent animal studies suggest that cardiac insulin resistance is an early event in response to obesity and develops before changes in whole-body glucose homeostasis occur [18]. The impairment in cardiac insulin signaling predisposes to cardiac hypertrophy and contractile dysfunction [19]. Finally, adiponectin, which is suppressed in abdominal adiposity, protects against cardiac hypertrophy [20,21]. Thus, obesity can compromise cardiac function through changes in left ventricular structure as well as changes in metabolism as illustrated in the schematic Fig. 1. Yet, the expression of all this mechanisms differs profoundly from patient to patient. Sex may contribute to the variability.

Fig. 1
Fig. 1
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In this issue, De Simone et al. [22] examined the relationship between left ventricular mass determined by echocardiography and body composition in women and in men. The investigators included data from 2919 participants of the Strong Heart Study. All were American Indians residing in Arizona, Oklahoma, and South and North Dakota in the United States. Body composition was assessed in different ways. The authors calculated BMI and the waist-to-hip ratio, which distinguishes between abdominal and peripheral fat distribution. Abdominal fat distribution is often associated with excessive abdominal visceral fat mass. Finally, the authors applied the bioelectric impedance method to determine adipose and fat-free mass. These detailed studies were important, as body composition with increasing BMI differed markedly between women and men. Men showed much greater increases in lean body mass with increasing BMI. In contrast, women showed a greater increase in adipose mass at a given increase in BMI. Blood pressure, which was similarly elevated in obese men and women, was positively correlated with left ventricular mass. After adjusting for age, hypertension, SBP, and diabetes, left ventricular mass indexed for height or for fat-free mass were greater in obese women than in obese men. Remarkably, waist-to-hip ratio and adipose mass contributed to the variability in left ventricular mass in women but not in men. The investigators observed a similar phenomenon in an earlier study in another ethnic group [23].

Possibly, influences of sex on the mechanisms driving left ventricular hypertrophy could contribute to the apparent ‘fat sensitivity’ of female myocardium. Indeed, in one study, severity of hyperglycemia was more strongly related to left ventricular mass in women than in men. The sex difference was attenuated but persisted after adjusting for BMI [24]. A study in diabetic nonobese Goto-Kakizaki rats suggests that the phenomenon could be explained in part by a sex difference in cardiac insulin resistance [25]. Aging female Goto-Kakizaki rat hearts exhibited more hypertrophy, insulin resistance, and sensitivity to ischemic injury than male rat hearts. Surprisingly, even in healthy young women, myocardial glucose uptake determined by PET was reduced compared with healthy young men [26]. In a subsequent study, a similar methodology was applied to assess influences of adiposity on cardiac structure, metabolism, and efficiency in a sex-specific fashion [27]. Nonobese men and women had an almost identical left ventricular mass per fat-free mass. In contrast, left ventricular mass per fat-free mass was approximately 11% greater in obese women compared with obese men [27]. Overall, myocardial efficiency was lower in women compared with men. Yet, female sex independently predicted lower myocardial glucose utilization. Adipose tissue releases molecules, such as fatty acid-binding protein 4, that directly suppress myocardial contractile function in vitro [28]. At least in one study, sex did not have an influence on circulating fatty acid-binding protein 4 concentrations in patients with type 2 diabetes mellitus [29]. Finally, some of the mechanisms promoting obesity-associated changes in left ventricular structure and function may be less activated in women. For example, we observed that abdominal fat distribution is related to sympathetic activity in men, but not or to a lesser degree in women [30]. Overall, sex appears to affect structural and metabolic adaptations to obesity in a complex fashion that deserves to be studied in more detail.

It is tempting to speculate that the sex difference in the myocardial response to adiposity translates into a sex difference in overt cardiovascular disease. Indeed, among heart failure patients identified in the Euro Heart Failure survey program, 45% of women and 22% of men had normal left ventricular systolic function [31]. Thus, diastolic dysfunction is a particularly common cause of heart failure in women.

As obesity affects cardiac structure, metabolism, and function, obesity treatment may be a good way to halt heart disease progression. Weight reduction through lifestyle interventions substantially reduces left ventricular mass independently of blood pressure [32–34]. Regression in left ventricular mass can also be observed in obese patients treated with weight-loss medications [35,36] or with bariatric surgery [34]. Reduction in left ventricular mass with weight loss is accompanied by improvements in myocardial metabolism and in left ventricular diastolic as well as systolic function measures [32,37]. Improvements in sympathetic nervous system and renin–angiotensin system [7,38], adiponectin deficiency, insulin resistance, and systemic inflammation may contribute to the beneficial response. Reductions in circulating concentrations of the potential endogenous cardiodepressant fatty acid-binding protein 4 with weight loss [39] might also be involved. Notably, the left ventricular mass regression observed with moderate weight loss compares favorably with the regression on antihypertensive medications including renin–angiotensin inhibitors [40,41]. One important implication of the sex difference in how obesity affects the heart, as observed by De Simone et al. [22] and others, is that men and women may require different treatments. Given the more pronounced influence of increasing adiposity on left ventricular mass and the particularly large proportion of women with diastolic heart failure, women might benefit more from weight-loss interventions in terms of heart failure prevention. Because diastolic heart failure is not a benign condition and may not respond to conventional heart failure remedies, this idea should be studied in larger prospective studies with meaningful clinical end points. Clearly, scientific projects on obesity-associated cardiovascular disease should always control for the potentially confounding variable sex.

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