Sex is a potent modifier of the cardiovascular system

Abstract

Despite the growing number of reports in the literature identifying sex-related differences in cardiac function in both rodents and humans, the underlying mechanisms have yet to be determined. Here, variables of experimental studies such as diet, animal model utilized, and age, in addition to sex hormones and other factors that may play a role in sex-related variations in cardiac responses to various pathophysiological conditions are discussed, suggesting that current approaches used in the study of cardiac disease require reevaluation.There are numerous health problems that are affected by gender. Women are more susceptible than men to depression, osteoporosis, asthma, lung cancer due to smoking, and autoimmune disease (1). Gender effects in disease are complex, however, as exemplified by the observation that while the incidence of melanoma is slightly higher among women than men, mortality from melanoma is higher in men. Not all medical problems show gender dimorphism. For example, males do not differ from females in terms of their responses to infection (1). When it comes to heart disease, generally, of those individuals diagnosed with heart disease, women fare much better than men. Little is known about the basis for this difference in cardiovascular disease. Much focus has been placed on the potential cardioprotective role of estrogen. However, the recent finding that estrogen replacement in postmenopausal women actually increased heart disease has challenged this view (2).Deriving a coherent view of potential players in sexdependent differences in the heart requires analysis of both the clinical literature and the literature on sex-dependent differences in the cardiovascular system of laboratory animals. There is a major limiting factor in comparing rodent laboratory studies: the vast majority have been carried out on males only. However, this limitation appears to be changing. In the past year, a number of studies have appeared in which both males and females have been analyzed. An article in a recent issue of the JCI by O'Connell et al. (3) provided a glimpse into what promises to be a new way of thinking about genetic sex. In this report, the authors found that the α 1 -adrenergic receptors are critical in determining heart size and the ability of the heart to respond to both pathologic and physiologic stimuli, but only in male animals. Intriguingly, this sex-related difference did not disappear following ovariectomy of females. This article will discuss the fact that sex is an extremely potent modifier of the myocardium and will identify which pathways have been implicated in some of these differences. I hope it will become clear that future research should focus on the mechanisms by which both sex and diet can modify cardiovascular phenotypes.Sex-related differences in normal male and female hearts in human cardiac disease What are the sexually dimorphic cardiovascular differences to which I refer? Before puberty, there are no statistically significant sex-related differences in heart size (4). After ...

Ablation of cyclase-associated protein 2 (CAP2) leads to cardiomyopathy

“…The exact molecular mechanism is still unknown, but the hypothesis is that estrogen prevents the development of cardiovascular diseases that could culminate into CHF [37]. However, this was challenged by the findings that estrogen replacement in postmenopausal women actually increased heart disease [46]. Thus, our Cap2 gene-trap model may serve as a good addition to current DCM models to understand the molecular basis of DCM and sex differences in DCM progression.…”

Prenatal androgen exposure causes hypertension and gut microbiota dysbiosis

“…Reduced insulin sensitivity or upregulated expression of androgen receptor within the heart has been found to impair cardiac function. 104 , 105 The upregulation of androgen receptor that we observed within the PNA heart may alter the electrophysiology of the cardiomyocytes of the left ventricle by altering expression of receptors involved in the regulation of membrane potential. 106 , 107 Androgens may promote the development of cardiomyopathy by upregulating potassium channel regulatory subunits and reducing cardiomyocyte repolarization.…”

The Effects of Endogenous Sex Hormones and Acute Hypoxia on Vasoconstriction in Isolated Rat Pulmonary Artery Rings

“…In most cardiovascular diseases, premenopausal women have a much better prognosis than men [1]. It has also been demonstrated that females fare better than their male counterparts after cardiac ischemia-perfusion injury [2,3].…”

“…It has also been demonstrated that females fare better than their male counterparts after cardiac ischemia-perfusion injury [2,3]. On the other hand, women with idiopathic dilated cardiomyopathy have a poorer prognosis than males, and women are also more susceptible to alcohol-related heart disease [1]. Pulmonary arterial hypertension occurs twice as frequently in females as compared to males [4][5][6].…”