The Impact of Sex Chromosomes on Cardiovascular Disease: A Systematic Review

Abstract

Background: Cardiovascular disease (CVD) remains the leading cause of death worldwide for both men and women. While most research on CVD sex differences focuses on sex hormones, the role of sex chromosomes is less understood. This systematic review examines how sex chromosome abnormalities and variations—loss of chromosome X (LOX) and Y (LOY), X chromosome inactivation (XCI) skewing and escape, and X and Y chromosome variations—affect CVD risk and outcomes.

Methods: A systematic search was conducted in PubMed on September 4, 2024, using Medical Subject Heading (MeSH) terms related to CVDs and sex chromosomes, excluding congenital sex chromosome disorders. After removing duplicates, records were screened for relevance based on predefined criteria, focusing on clinical and population-based studies. Data extraction included study characteristics, population details, sex chromosome abnormalities, and key findings. Records were categorized by type of chromosomal abnormality: LOX, XCI skewing, X chromosome variations, LOY, and Y chromosome variations.

Results: 29 studies were included, examining the role of sex chromosomes in CVD. There was only one study on LOX and CVD, which found no significant association between the two. Three studies on XCI skewing identified connections to thrombosis in essential thrombocythemia patients and atherosclerotic CVD risk in the general population. Additionally, XCI skewing in atherosclerotic patients was linked to plaque hemorrhage and peripheral artery events. One study on X chromosome variation linked maternal family history to hypertension. Seven studies indicated that LOY negatively affects cardiovascular outcomes and all-cause mortality. Seventeen studies investigated Y chromosome haplogroups (e.g. P, K, R, YAP, I); some identified associations with CVD risk, while others found no significant links.

Conclusion: Sex chromosome abnormalities and variations—particularly XCI skewing, LOY, and Y chromosome haplogroups—are associated with CVD. However, the causal relationships remain unclear, highlighting the need for further research to elucidate underlying mechanisms and enhance CVD risk assessment.