3096 – MUTATIONAL LANDSCAPE OF CLONAL HEMATOPOIESIS IN CHRONIC HEART FAILURE PATIENTS WITH DISTINCT RISK GENES FOR INCREASED MORTALITY

Somatic mutations in hematopoietic stem cells can lead to the expansion of mutated blood cells, known as clonal hematopoiesis (CH). Mutations in the most prevalent genes DNMT3A and TET2 with a variant allele frequency (VAF)≥2% (CHIP) have been associated with atherosclerosis and chronic heart failure (CHF). However, the mutational landscape in CHF and the effects in CH-driver genes other than DNMT3A and TET2 with low VAF≤2% on CHF are still unknown. Therefore we analyzed bone marrow and blood cells from 399 CHF patients by deep error-corrected targeted sequencing of 56 genes and associated mutations with the long-term mortality (3.95 years median follow-up). We detected 1113 mutations with a VAF≥0.5% in 347 patients (87%). Despite a high prevalence of mutations in the most frequently mutated genes DNMT3A and TET2, mutations in the genes CBL, CEBPA, EZH2, GNB1, PHF6, SMC1A and SRSF2 were associated with increased death compared to the average death rate of all patients (20%). To avoid confounding effects caused by the presence of DNMT3A and TET2 CHIP mutations, we excluded patients with CHIP-related mutations (VAF≥2%) for further analyses. Kaplan-Meier survival analyses revealed a significantly higher mortality in patients with mutations in the seven genes (53 patients), combined as the CH risk gene set for CHF. These patients showed no significant differences in any parameter including patient age, confounding diseases or blood parameters except for a reduced number of platelets. However, carrying a mutation in any of the risk genes remained significant after multivariate cox regression analysis (HR, 3.1; 95% CI, 1.8-5.4; p<0.001), whereas platelet numbers did not. Somatic mutations with low VAF in these risk genes are prevalent in young CHF patients and comprise an independent risk factor for the outcome, potentially providing a novel tool for risk assessment in CHF. Somatic mutations in hematopoietic stem cells can lead to the expansion of mutated blood cells, known as clonal hematopoiesis (CH). Mutations in the most prevalent genes DNMT3A and TET2 with a variant allele frequency (VAF)≥2% (CHIP) have been associated with atherosclerosis and chronic heart failure (CHF). However, the mutational landscape in CHF and the effects in CH-driver genes other than DNMT3A and TET2 with low VAF≤2% on CHF are still unknown. Therefore we analyzed bone marrow and blood cells from 399 CHF patients by deep error-corrected targeted sequencing of 56 genes and associated mutations with the long-term mortality (3.95 years median follow-up). We detected 1113 mutations with a VAF≥0.5% in 347 patients (87%). Despite a high prevalence of mutations in the most frequently mutated genes DNMT3A and TET2, mutations in the genes CBL, CEBPA, EZH2, GNB1, PHF6, SMC1A and SRSF2 were associated with increased death compared to the average death rate of all patients (20%). To avoid confounding effects caused by the presence of DNMT3A and TET2 CHIP mutations, we excluded patients with CHIP-related mutations (VAF≥2%) for further analyses. Kaplan-Meier survival analyses revealed a significantly higher mortality in patients with mutations in the seven genes (53 patients), combined as the CH risk gene set for CHF. These patients showed no significant differences in any parameter including patient age, confounding diseases or blood parameters except for a reduced number of platelets. However, carrying a mutation in any of the risk genes remained significant after multivariate cox regression analysis (HR, 3.1; 95% CI, 1.8-5.4; p<0.001), whereas platelet numbers did not. Somatic mutations with low VAF in these risk genes are prevalent in young CHF patients and comprise an independent risk factor for the outcome, potentially providing a novel tool for risk assessment in CHF.