Epigenetic regulation of cardiac physiology and pathophysiology: biological sex matters

Cardiovascular disease (CVD) is the leading cause of global morbidity and mortality, with epigenetic mechanisms playing a pivotal role in its pathogenesis. This review synthesizes current evidence on sex-specific epigenetic regulation in cardiac health and disease, highlighting DNA methylation, histone modifications, and non-coding RNAs as key mediators. Epigenetic processes govern cardiac development, remodeling, and responses to injury, with sex chromosomes, sex hormones, and environmental factors contributing to dimorphic patterns. Developmental programming establishes early sex biases in chromatin architecture while aging and clonal hematopoiesis amplify these differences via mutations in epigenetic modulators. Therapeutic strategies targeting epigenetic regulators hold promise but require sex-tailored approaches to optimize efficacy and minimize off-target effects. This review underscores the critical need for sex-stratified research to advance precision medicine for CVD.