AIMS Clonal haematopoiesis of indeterminate potential (CHIP), defined as a clonal expansion of age-related recurrent somatic mutations, has recently emerged as a novel cardiovascular risk factor. However, the precise role of CHIP in the development of atherosclerotic cardiovascular disease (ASCVD) remains unclear.

METHODS AND RESULTS Among 4300 asymptomatic Korean participants aged 40-79 years, we investigated the risk of ASCVD by CHIP and the interplay between CHIP and conventional risk factors in ASCVD development. Additionally, we assessed changes in coronary arteries based on the presence of CHIP using coronary computed tomography angiography (CCTA). CHIP was present in 363 participants (8.4%), and its prevalence increased with age. Commonly mutated genes were DNMT3A, TET2, and ASXL1, in order. During the follow-up (median 4.7 years), 18 ASCVD cases (5.0%) were observed in CHIP carriers vs. 62 (1.6%) in non-carriers (P < 0.001), indicating an elevated risk of ASCVD associated with CHIP [adjusted hazard ratio (HR) 2.49; 95% confidence interval (CI) 1.45-4.29; P < 0.001]. Notably, with high levels of LDL cholesterol, CHIP enhanced the risk of ASCVD (adjusted HR 6.20; 95% CI 3.14-12.23; P < 0.001), demonstrating synergism between CHIP and LDL cholesterol levels (S-index 4.94; 95% CI 1.08-22.53; P = 0.039). Serial CCTAs confirmed that CHIP, in conjunction with high LDL cholesterol levels, had a significant early impact on coronary arteries, revealing new measurable coronary atherosclerosis, mainly with unstable plaque, in proximal lesions.

CONCLUSION The presence of CHIP was significantly associated with the risk of ASCVD, promoting the early stage of atherosclerosis through synergy with high LDL cholesterol in the general population.