Abstract
The democratization of genomic technologies has revealed profound sex biases in expression patterns in every adult tissue, even in organs with no conspicuous differences, such as the heart. With the increasing awareness of the disparities in cardiac pathophysiology between males and females, there are exciting opportunities to explore how sex differences in the heart are established developmentally. Although sexual dimorphism is traditionally attributed to hormonal influence, expression and epigenetic sex biases observed in early cardiac development can only be accounted for by the difference in sex chromosome composition, i.e., XX in females and XY in males. In fact, genes linked to the X and Y chromosomes, many of which encode regulatory factors, are expressed in cardiac progenitor cells and at every subsequent developmental stage. The effect of the sex chromosome composition may explain why many congenital heart defects originating before gonad formation exhibit sex biases in presentation, mortality, and morbidity. Some transcriptional and epigenetic sex biases established soon after fertilization persist in cardiac lineages, suggesting that early epigenetic events are perpetuated beyond early embryogenesis. Importantly, when sex hormones begin to circulate, they encounter a cardiac genome that is already functionally distinct between the sexes. Although there is a wealth of knowledge on the effects of sex hormones on cardiac function, we propose that sex chromosome-linked genes and their downstream targets also contribute to the differences between male and female hearts. Moreover, identifying how hormones influence sex chromosome effects, whether antagonistically or synergistically, will enhance our understanding of how sex disparities are established. We also explore the possibility that sexual dimorphism of the developing heart predicts sex-specific responses to environmental signals and foreshadows sex-biased health-related outcomes after birth.
Highlights
Biological sex has long been known to affect the epidemiology, clinical manifestation, pathophysiology, and response to treatment for cardiovascular disorders [1], yet the basic mechanisms underlying these differences remain unknown
In view of the sex differences in baseline cardiac function, it is not surprising that biological sex is a significant determinant in the development, presentation and progression of cardiovascular disease [28,29,30]
Variants of Y chromosome loci affect cardiac function [60], and the Y chromosome-linked genes TBL1Y and KDM5D have been reported to be involved in cardiac differentiation in human embryonic stem cells [61, 62]
Summary
Biological sex has long been known to affect the epidemiology, clinical manifestation, pathophysiology, and response to treatment for cardiovascular disorders [1], yet the basic mechanisms underlying these differences remain unknown. Filling this knowledge gap and elucidating sex-biased protective factors should lead to better, more selective treatments for. Studies have included both sexes without sufficient power to perform meaningful comparisons [3]. Sex chromosomes are often excluded from genomic analyses and association studies, limiting the ability to identify sexbiased risk factors. Many cardiovascular diseases are polygenic and multifactorial, posing additional challenges for understanding the mechanisms leading to sex disparities (Figure 1)
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