Sex is a potent modifier of the cardiovascular system

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 sex-dependent 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 α1-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.