The Relevance of Clonal Hematopoiesis of Indeterminate Potential for Cardiovascular Disease

Background and Aims: Clonal hematopoiesis of indeterminate potential (CHIP) is associated with a higher incidence of late-onset diseases, including myocardial infarction. This study investigates the impact of CHIP on mortality in patients with coronary artery disease (CAD) and explores underlying mechanisms.

Methods: We screened >7,500 CAD patients using deep DNA sequencing with a 13-gene panel, identifying 2,002 individuals with at least one CHIP-defining mutation (variant allele frequency ≥2%) and complete follow-up. These CHIP carriers were matched 1:1 with non-CHIP carriers. We assessed 3-year mortality and analyzed arterial plaques and macrophages from TET2 mutation carriers to explore underlying mechanisms.

Results: CHIP carriers exhibited a significantly higher 3-year mortality compared to non-CHIP carriers (HR 1.48, 95% CI 1.23-1.78, p<0.0001). Specific mutations in TET2, ASXL1, DNMT3A, PPM1D, SF3B1, SRSF2, and U2AF1 were associated with increased mortality. CHIP mutations were detected in leukocytes within coronary atherosclerotic plaques. Proteomic analysis of TET2 mutation carriers' plaques showed upregulation of inflammatory and metabolic pathways, including lipid metabolism. RNA sequencing of monocyte-derived macrophages from an independent cohort revealed CAD severity in TET2 mutation carriers. In vitro studies demonstrated increased uptake of low-density lipoprotein (LDL) and oxidized LDL-cholesterol in TET2-mutated macrophages, along with heightened inflammatory pathways.

Conclusions: CHIP is a significant prognostic factor in CAD patients, associated with increased mortality and CAD complexity. TET2 mutations specifically alter macrophage behavior, leading to heightened inflammation and increased LDL-cholesterol uptake. These findings underscore the relevance of CHIP in CAD prognosis and the mechanistic role of TET2 mutations in exacerbating CAD pathology.