Abstract
BACKGROUND: Acute coronary syndrome (ACS) remains a leading global cause of mortality despite advances in revascularization therapies. METHODS: This prospective cohort study investigated the synergistic prognostic impact of clonal hematopoiesis of indeterminate potential (CHIP) and atherogenic index of plasma (AIP) in 1396 ACS patients undergoing primary percutaneous coronary intervention at Fuwai Hospital (2017-2020). Using deep targeted sequencing (42 genes, median depth 14,219 ×), we identified CHIP mutations (VAF ≥ 2%) in 14.5% of participants, with DNMT3A (23.7%), TET2 (2.8%), and ASXL1 (1.9%) being most prevalent. RESULTS: High-AIP patients stratified by cutoff value were younger (57.8 vs. 63.2 years), had elevated hs-CRP (7.2 vs. 5.8 mg/L), and higher smoking rates, suggesting accelerated atherosclerosis. Multivariable Cox regression revealed that in patients with AIP ≥ cutoff, CHIP carriers exhibited significantly higher all-cause mortality, particularly for TET2 mutations (HR 5.20, CI 95%: 1.75-15.41; p = 0.003) and TET2/ASXL1 co-mutations (HR 5.5, CI 95%: 2.02-13.15; p = 0.001). Among individuals in the high AIP group, any CHIP (Fig. 3A, HR 2.38, 95% CI 1.18-4.81; P log-rank = 0.015) and common CHIP (Fig. 3B, HR 2.74, 95% CI 1.30-5.08; P log-rank = 0.008) mutation experienced a higher risk of mortality than individuals absence of CHIP mutation. CONCLUSION: These findings establish AIP as a critical modifier of CHIP-related cardiovascular risk, potentially through enhanced inflammatory pathways in younger ACS populations. The study highlights the clinical utility of combining lipid-based (AIP) and genetic (CHIP) biomarkers for precision prognostication, though validation in larger cohorts and mechanistic investigations of the AIP-CHIP interplay are warranted to guide targeted therapies.