Matters of the heart: Cellular sex differences

Area of Science:

• Cardiovascular Biology
• Cellular and Molecular Medicine
• Sex Differences Research

Background:

• Cardiovascular diseases exhibit significant sexual dimorphisms in prevalence, presentation, and outcomes.
• Historically, clinical trials and animal studies have often overlooked or combined data from both sexes, leading to underrepresentation of female biology.
• Cellular sex differences within the heart, including non-myocyte populations, are understudied, with a bias towards using male cells in in vitro experiments.

Purpose of the Study:

• To explore intrinsic and acquired differences between male and female mammalian heart cells.
• To investigate the impact of the cardiac microenvironment and hormones on sexually dimorphic cellular phenotypes and functions.
• To highlight recent findings on sex differences in cardiac cell-type composition and provide recommendations for future research models.

Main Methods:

• Review and synthesis of existing literature on cellular sex differences in the mammalian heart.
• Analysis of studies examining the influence of hormones and microenvironment on cardiac cell function.
• Inclusion of recent single-cell sequencing data revealing sex-based variations in cardiac cell populations.

Main Results:

• Inherent differences in genotype (XX vs. XY) and acquired factors like hormones contribute to distinct male and female cardiac cellular phenotypes.
• The cardiac microenvironment modulates cellular sex phenotypes, and secretory profiles are dependent on cellular sex.
• Single-cell sequencing reveals previously unrecognized sex differences in the composition of cardiac cell types.

Conclusions:

• Cellular sex is a critical determinant of cardiac health and disease, necessitating its consideration in research.
• Understanding sexually dimorphic cellular mechanisms, including gene expression and epigenetic remodeling, is vital for advancing cardiovascular medicine.
• Future bioengineered in vitro models of heart disease must incorporate cellular sex differences for improved translational relevance.