Sex-Related Effects on Cardiac Development and Disease

Abstract

Cardiovascular diseases (CVD) are the leading cause of morbidity and mortality. Interestingly, male and female patients with CVD exhibit distinct epidemiological and pathophysiological characteristics, implying a potentially important role for primary and secondary sex determination factors in heart development, aging, disease and therapeutic responses. Here, we provide a concise review of the field and discuss current gaps in knowledge as a step towards elucidating the "sex determination-heart axis". We specifically focus on cardiovascular manifestations of abnormal sex determination in humans, such as in Turner and Klinefelter syndromes, as well as on the differences in cardiac regenerative potential between species with plastic and non-plastic sexual phenotypes. Sex-biased cardiac repair mechanisms are also discussed with a focus on the role of the steroid hormone 17β-estradiol. Understanding the "sex determination-heart axis" may offer new therapeutic possibilities for enhanced cardiac regeneration and/or repair post-injury.

Keywords: 17β-estradiol; biological sex; development; injury; regeneration; repair; sex chromosome disorders; sex determination.

Figure 1

Complete or partial loss of one X chromosome in TS is associated with cardiac abnormalities. These dysfunctions vary, with hypoplastic left heart syndrome being the most common among patients with TS. Multiple factors related to the missing X chromosome have been associated with the TS phenotype. Haplo-insufficiency of TIMP1, “reader” and “writer” enzymes, and abnormalities in 17β-estradiol production are only part of a general genetic and hormonal instability observed in patients with TS. Figures were produced using Servier medical art.

Figure 2

Sex determination–heart axis: sex determination is associated with cardiac regenerative capacity. Organisms with fluid sex determination, such as amphibians, zebrafish, newts and axolotls, retain cardiac regenerative capacity post-injury. In contrast, in mammalian organisms, where sex determination is permanent and takes place during development, cardiomyocyte renewal capacity is lost shortly after birth. Figures were produced using Servier medical art.