Hematopoietic somatic mutations in atherosclerotic cardiovascular disease

Age-related somatic mosaicism in the hematopoietic system is increasingly recognized as a risk factor for atherosclerotic cardiovascular disease. The most prominent example is clonal hematopoiesis of indeterminate potential (CHIP), defined as the expansion of hematopoietic clones carrying acquired mutations in genes recurrently mutated in myeloid hematological malignancies, typically at a variant allele fraction ≥2%. Across large human cohorts, CHIP is associated with increased risk of coronary artery disease and other atherosclerosis-related outcomes, although the magnitude of the association varies substantially by mutated gene and clone size. Complementary experimental studies in hyperlipidemic mice support a causal contribution to atherosclerosis for several CHIP drivers and reveal mutation-specific inflammatory mechanisms. These mechanistic insights are beginning to inform the design of genotype-guided, anti-inflammatory prevention strategies. In parallel, loss of the Y chromosome (LOY), the most frequent somatic chromosomal alteration detected in blood in aging men, has been associated with myocardial infarction and adverse cardiovascular outcomes, yet its causal role in atherosclerosis remains unproven. Here, we summarize current evidence for CHIP and LOY as heterogeneous, mutation-dependent contributors to atherosclerotic cardiovascular disease, highlighting methodological considerations that influence the observed associations, and outlining key knowledge gaps that must be addressed to allow for clinical translation.