Review: Sex chromosomes and cardiovascular disease

Anna E Spiering , Phebe J Groenheide , Michal Mokry , N Charlotte Onland-Moret , Mete Civelek , Karen Reue , Ernest Diez Benavente , Hester M den Ruijter Author Notes European Journal of Preventive Cardiology, European Journal of Preventive Cardiology, Volume 33, Issue 3, February 2026, Pages 316–326

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 the Y chromosome (mLoY) is the most well-characterized mechanism linking sex chromosomes to CVD, with substantial evidence in heart failure. Also, the involvement of mLoY in CVD mechanisms, such as myocardial fibrosis and cardiac macrophage infiltration, both mediated by transforming growth factor beta signalling, has been demonstrated. The mLoY could serve as a biomarker or a 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 aetiology.