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: Among 4,300 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).
Results: 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 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 HR 2.49, 95% CI 1.45-4.29, p < 0.001). Notably, with high levels of low-density lipoprotein (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 significant early impact on coronary arteries, revealing new measurable coronary atherosclerosis, mainly with unstable plaque, in proximal lesions.
Conclusions: 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.
Keywords: Atherosclerosis; Clonal haematopoiesis; Low-density lipoprotein cholesterol; Synergy.
In this cohort study of 4,300 asymptomatic community-dwelling Korean adults, we demonstrated a detailed interplay between clonal haematopoiesis of indeterminate potential (CHIP) and conventional risk factors in the development of atherosclerotic cardiovascular disease (ASCVD).The presence of CHIP significantly increased the risk of ASCVD in the general population, displaying a notable synergistic effect with high levels of low-density lipoprotein (LDL) cholesterol.Analyses of serial coronary computed tomography angiography scans revealed that CHIP, in conjunction with high LDL cholesterol levels, may contribute to the promotion of “early” stage in coronary atherosclerosis, providing new insights into CHIP-associated atherosclerosis in the primary prevention.
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