Abstract 15798: Clonal Hematopoiesis of Indeterminate Potential is Associated With Pro-Inflammatory Markers in Patients With Established Coronary Artery Disease

Abstract

Introduction: Progression of atherosclerosis is a result of systemic inflammation. Clonal hematopoiesis of indeterminate potential (CHIP) has been shown to be associated with atherosclerosis, but pathways that lead to this are still not fully elucidated. Hypothesis: CHIP may contribute to atherosclerosis by facilitating low-grade inflammatory response. Methods: 130 patients younger than 80 years, who were hospitalized for acute coronary syndrome or for myocardial revascularization were included in this study and followed for 18 months post-intervention. Targeted next-generation sequencing (NGS) was performed on peripheral blood mononuclear cells to detect CHIP mutations with a variant allelic fraction > 2% in 92 genes. Subsequently, multiplexed proteomic analysis with extension proximity assays (EPA) was used to quantify circulating pro-inflammatory biomarkers potentially related to CHIP. Results: Some 17.6 % (23) of 130 patients were detected with CHIP mutations. Patients with mutations in either DNA methyltransferase 3alpha (DNMT3A) or Tet methylcytosine dioxygenase 2 (TET2) showed significantly higher body mass index (BMI) ( p =0.010), inflammatory markers (high sensitivity C-reactive protein p =0.015, interleukin- 6 p =0.002, chemerin p =0.034) as well as higher markers of myocardial overload (troponin T p =0.022 and NT-proBNP). In multivariable model adjusted for BMI, age, and gender we found that the inflammatory markers HGF, IL10RB, IL5RA, IL18, OSM, PD-L1, TNFRSF9, and TNFSF14 presented statistically significant association with CHIP (p<0.01). Interestingly, these differently expressed proteins form an overlapping network between TET2 and DNMT3A mutations pointing to cytokine receptor activity, inflammatory response, and leucocyte activation pathways. Conclusions: There is a significant association between CHIP and enhanced inflammatory response in patients with coronary artery disease, even after adjustment for age and BMI.