Sex differences in cardiovascular research

Abstract

Historically, the lack of appreciation for the impact of sex on cardiovascular outcomes has allowed for women's health in the cardiovascular arena to be largely ignored. In fact, cardiovascular disease is the number one cause of death in both women and men. Although female sex does appear to be associated with cardioprotection, aging and menopause are major risk factors for cardiovascular disease. In fact, specific cardiovascular diseases, such as heart failure with preserved ejection fraction, occur more frequently in women than men by a proportion of 2:11. As our current population ages, the number of women living with cardiovascular disease is ever increasing, imposing a major economic burden on global health care systems. Therefore, a better understanding of the effects of gender on disease progression, pharmacogenomics, therapeutic and environmental responses may allow for the development of gender-specific therapeutics. Aging is associated with a reduced capacity for the heart to repair itself. Since stem cells aid in mediating endogenous repair, cardiovascular disease might be, in part, a failure of stemcell mediated cardiac repair. Indeed, we found that as both men and women age, there is a decrease in the frequency of blood circulating stem cells that express the stem cell marker, CD34 which differs between the sexes, decreasing at a much earlier age in males than females. This is mimicked in animal models of atherosclerotic disease where a sexdifference decrease in CD34+ cells with age is inversely correlated with progression of disease. These cells play an important role in mediating new blood vessel growth after myocardial ischemic episodes due to coronary artery disease. Aging is also associated with altered inflammatory responses, and patients with multiple risk factors for cardiovascular disease development demonstrate a significant increase in inflammation. Sex differences in inflammation also exist and the functionality of progenitor cells is higher in middle-aged women than in middle-aged men. In fact, we found that delivery of female reparative inflammatory cells into male mice having atherosclerotic disease, results in an increase in male reparative cell number and response suggesting that female inflammatory cells may confer protection. Indeed, we found that stem cells from female mice exposed to ischemia, exhibit decreased apoptosis, decreased cytokines and growth factors such as tumor necrosis factor (TNF), interleukin-6 (IL-6), and increased vascular endothelial growth factor (VEGF) expression. Other studies have shown that female stem cells offer greater protection after ischemia/reperfusion injury than do male cells. Clinical studies have shown that hearts from women are protected against ischemia/ reperfusion injury with a decrease in TNF, IL-1 and IL-6 inflammatory cytokines. The heart itself may also differ in men and women. For example, during pregnancy women must functionally compensate for an increase in blood volume and for rapid reduction in blood volume after delivery. The inability to compensate for these changes can cause heart failure associated pregnancy2. Interestingly, we have found that extracellular matrix of female hearts is actually stiffer than male hearts which may be related to genderspecific hormones. Indeed, administration of estrogen limits undesirable extracellular matrix remodeling in blood volume overloaded hearts3. The mechanisms for these sex differences are unclear. Since menopause is a major risk factor cardiovascular disease development, it is postulated that hormones such as estrogen play an important role in mediating these sex differences. However, the use and efficacy of replacement hormone therapy in post-menopausal women has proven controversial and in some trials, ineffective reducing the incidence of disease. This suggests that gender-specific hormones may not be the only mechanism for sex differences in disease outcomes. Interestingly, prepubescent male and female children also have differences in their inflammatory cytokine responses suggesting th t the X chromosome, itself and genes escaping X chromosome inactivation may contribute to sex differences. A greater understanding of sex differences in cardiovascular disease will inevitably lead to therapeutics limiting disease progression and decreasing mortality for women.