Background: Advanced Coronary Artery Disease (CAD) represents one of the leading causes of death worldwide. Only parts of cases can be explained by established cardiovascular risk factors. Clonal hematopoiesis of indeterminate potential (CHIP) is characterized by a monoclonal proliferation of a somatic leukocyte without meeting criteria for malignancy. Recently, CHIP has been shown to be associated with an increased risk for coronary artery disease, myocardial infarction, and mortality by heart failure. The mechanisms and vascular phenotype driven by CHIP mutations remain unknown.

Aim: To investigate the coronary plaque morphology and immunological phenotype associated with CHIP+ and non-CHIP patients with acute coronary syndromes.

Methods: We performed deep targeted amplicon sequencing of known CHIP-associated genes in bone marrow derived mononuclear cells (PBMC) from 117 NST-ACS and STE-ACS patients within the OPTICO-ACS study cohort. All patients underwent comprehensive morphological characterization by intracoronary high-resolution optical coherence tomography (OCT) imaging of the culprit lesion and additional functional flow assessment by quantitative flow ratio (QFR) measurements of all non-culprit vessels to characterize the individual panvascular coronary atherosclerosis. Furthermore, a comprehensive immunophenotyping at the culprit site was performed including FACS-analyses and bead assays for inflammatory cytokine assessment.

Results: Out of 117 sequenced samples, 36 (30.8%) carried CHIP-mutations with a VAF >1% (CHIP+). We found 15 different CHIP-mutations, the most frequent ones being DNMT3A (38.9%) and TET2 (13.9%). CHIP+ patients are characterized by a cardiovascular risk profile comparable to ACS patients without carrying a CHIP mutation (CHIP-). While no relevant difference in the ACS-causing mechanism (Plaque Rupture (RFC) and Erosion (IFC) were observed among the CHIP status (RFC CHIP+ 46.4%, IFC CHIP+ 46.9%, p=0.95). CHIP+ACS patients are characterized by more pronounced coronary calcifications (Mean calcium arc 61° vs 50°, p<0.05; max calcium arc: 104° vs 83°, p=0.05). In contrast, Non-culprit-vessels of CHIP+ ACS patients had higher quantitative flow ratios (QFR 0.95 vs 0.92, p=0.02. FACS analyses revealed no significant differences in leukocyte subpopulations between CHIP+/ and CHIP- ACS patients. Interestingly, higher levels of serum soluble CD40 ligand (sCD40L) were detected in culprit coronary blood samples of CHIP+patients. (317 vs 156 pg/ml, p=0.04)