Sex differences in cardiovascular disease (CVD) are increasingly recognized. These are traditionally attributed to hormonal influences, but recent evidence underscores the potential role of sex chromosomes. This review describes the involvement of sex chromosomes in CVD, through loss of chromosomes, genetic variation and altered expression. Mosaic loss of Y chromosome (mLoY) is the most well-characterized mechanism linking sex chromosomes to CVD, with substantial evidence in heart failure. Also, involvement of mLoY in CVD mechanisms such as myocardial fibrosis and cardiac macrophage infiltration, both mediated by TGF-β signaling, have been demonstrated. mLoY could serve as both a biomarker or causal factor for CVD, with potential implications for risk stratification and therapeutic intervention. X chromosome inactivation escape, which leads to higher expression of specific X-linked genes in females, holds additional promise as an explanation for sex differences in CVD. Animal models have already provided insight into the mechanisms underpinned by this phenomenon, but further research is needed to clarify its impact on cardiovascular outcomes in humans. Overall, this review underscores the complexity of sex chromosome-related mechanisms in CVD and the need to further unravel their role in disease etiology.
© The Author(s) 2025. Published by Oxford University Press on behalf of the European Society of Cardiology.