Abstract 16649: Clonal Hematopoiesis as a Predictor of Left Ventricular Reverse Remodeling in Non-Ischemic Dilated Cardiomyopathy

Abstract

Background: Clonal hematopoiesis of indeterminate potential (CHIP) is an independent risk factor of major adverse cardiovascular events, including heart failure (HF) with reduced left ventricular ejection fraction (LVEF). Although genetic mutations are known to affect clinical prognosis and left ventricular reverse remodeling (LVRR) in non-ischemic dilated cardiomyopathy (DCM), the prevalence and clinical significance of CHIP in DCM remain elusive. Objectives: The principal aim of this study is to delineate the distribution and prognostic impact of CHIP in non-ischemic DCM. Methods: We included 198 cases of DCM with LVEF ≤ 40% and no identifiable cause for left ventricular systolic dysfunction from the Japanese multi-center cohort. Whole exome sequencing was performed for germline analysis, and deep target sequencing focusing on CHIP driver genes for somatic analysis was conducted. We detected cardiomyopathy-related pathogenic mutations and CHIP driver mutations using GATK best practices and Mutect2, respectively. The primary endpoint was LVRR, defined as an absolute increase in LVEF by ≥ 10% at a one-year follow-up echocardiogram. Results: Twenty-seven CHIP driver mutations were detected in 24 (12%) of the DCM patients. The mean read coverage for CHIP driver mutation was 2156. DNMT3A was the most frequent mutated gene in CHIP, followed by TET2 . Ninety-two (46%) patients have cardiomyopathy-related pathogenic mutations. TTN was the most frequent mutated gene, followed by LMNA . Although the CHIP-positive group showed similar LVEF and prevalence of cardiomyopathy-related pathogenic mutations compared with the CHIP-negative group, the occurrence of LVRR was significantly lower in the CHIP-positive group (47.0% vs. 20.8%, P=0.018). Multivariate logistic regression analysis revealed that CHIP (odds ratio (OR): 0.23, P=0.022) and cardiomyopathy-related pathogenic mutations (OR: 0.28, P<0.001) were independent negative predictors of LVRR. Conclusions: Determining germline and somatic mutations in DCM significantly predict clinical prognosis.