Impact of clonal hematopoiesis on atherosclerotic cardiovascular disease according to low-density lipoprotein cholesterol levels

BackgroundClonal hematopoiesis of indeterminate potential (CHIP), defined as a clonal expansion of hematopoietic stem cells with age-related recurrent somatic mutations, has recently emerged as a novel cardiovascular risk factor. However, the pathogenic mechanism of CHIP in atherosclerotic cardiovascular disease (ASCVD) development is not yet fully understood. MethodsIn a cohort comprising 4,300 asymptomatic Korean participants aged 40-79 years, we investigated the risks associated with ASCVD by CHIP and the interplay of CHIP with other traditional risk factors for developing ASCVD. Using coronary computed tomography angiography (CCTA), we noninvasively assessed the changes in coronary arteries to evaluate CHIP-associated atherosclerosis. ResultsCHIP was present in 368 participants (8.6%). The most commonly mutated genes in CHIP included DNMT3A, TET2, and ASXL1. During follow-up (median, 4.7 years), 18 ASCVD cases (4.9%) were observed in CHIP carriers vs. 62 (1.6%) in non-carriers (p<0.001). The presence of CHIP was associated with an increased risk of ASCVD (adjusted hazard ratio [HR] 2.54, 95% confidence interval [CI] 1.48-4.37, p<0.001) after adjusting for other conventional cardiovascular risk factors. Particularly, in participants with high levels of low-density lipoprotein (LDL) cholesterol, CHIP enhanced the risk of ASCVD development (adjusted HR 4.18, 95% CI 1.99-8.77, p<0.001), demonstrating a significant synergism between CHIP and LDL cholesterol (S-index, 4.61; 95% CI 1.04-20.57, p=0.045). Serial CCTAs supported our findings by displaying de novo measurable coronary atherosclerosis with unstable plaque and in proximal lesions only in CHIP carriers with high LDL cholesterol. ConclusionThe presence of CHIP was significantly associated with the risk of ASCVD through synergy with LDL cholesterol in the general population, which might promote the early stage of coronary atherosclerosis.