Clonal Hematopoiesis of Indeterminate Potential in Cardiovascular Disease: Gene-Specific Mechanisms and Therapeutic Implications

Clonal hematopoiesis of indeterminate potential (CHIP) denotes the age-associated expansion of hematopoietic clones carrying acquired somatic variants, conventionally identified at a variant allele frequency of at least 2% in people without overt hematologic malignancy. Once viewed mainly through the lens of premalignant hematology, CHIP is now repeatedly linked to excess cardiovascular morbidity and mortality. The earliest cardiovascular signal centered on atherosclerotic cardiovascular disease (ASCVD), but the phenotype has broadened to include calcific aortic valve disease, atrial fibrillation, heart failure, stroke, and venous thromboembolism. Cardiovascular biology also differs substantially by driver gene. TET2 loss-of-function favors inflammasome-linked IL-1β/IL-6 signaling and has been connected to plaque vulnerability and myocardial inflammation; DNMT3A mutations reshape myeloid epigenetic programs through overlapping but non-identical inflammatory states; ASXL1 mutations promote myeloid-skewed hematopoiesis and have been associated with adverse cardiac remodeling and arrhythmia susceptibility; and JAK2 V617F, a prototypic gain-of-function lesion, produces a particularly thromboinflammatory profile through amplified NET formation. Although these drivers diverge upstream, several CHIP subtypes ultimately converge on inflammatory effector pathways involving IL-1β and IL-6, supporting the concept of anti-inflammatory precision prevention. Exploratory CANTOS analyses suggest that IL-1β inhibition may be especially beneficial in TET2-CHIP carriers, but this observation remains hypothesis-generating and requires adequately powered, CHIP-stratified outcome trials. Current translational work includes CHIP-enriched studies of inflammasome and IL-1-pathway blockade, ongoing large outcome trials targeting IL-6 in residual inflammatory risk, and gene-informed strategies for thromboinflammatory CHIP subtypes. This article is a narrative review that synthesizes mechanistic, epidemiologic, and translational evidence rather than a systematic review based on a formal search strategy. This review develops a gene-centric framework that connects molecular mechanisms, cardiovascular phenotypes, and emerging therapeutic opportunities, while emphasizing the evidence gaps that must be closed before CHIP-directed precision cardiology can be considered clinically actionable.