Association of Mutations Contributing to Clonal Hematopoiesis With Prognosis in Chronic Ischemic Heart Failure

Abstract

Importance: Somatic mutations causing clonal expansion of hematopoietic cells (clonal hematopoiesis of indeterminate potential [CHIP]) are increased with age and associated with atherosclerosis and inflammation. Age and inflammation are the major risk factors for heart failure, yet the association of CHIP with heart failure in humans is unknown.

Objective: To assess the potential prognostic significance of CHIP in patients with chronic heart failure (CHF) owing to ischemic origin.

Design, setting, and participants: We analyzed bone marrow-derived mononuclear cells from 200 patients with CHF by deep targeted amplicon sequencing to detect the presence of CHIP and associated such with long-term prognosis in patients with CHF at University Hospital Frankfurt, Frankfurt, Germany. Data were analyzed between October 2017 and April 2018.

Results: Median age of the patients was 65 years. Forty-seven mutations with a variant allele fraction (VAF) of at least 0.02 were found in 38 of 200 patients with CHF (18.5%). The somatic mutations most commonly occurred in the genes DNMT3A (14 patients), TET2 (9 patients), KDM6A (4 patients), and BCOR (3 patients). Patients with CHIP were older and more frequently had a history of hypertension. During a median follow-up of 4.4 years, a total of 53 patients died, and 23 patients required hospitalization for heart failure. There was a significantly worse long-term clinical outcome for patients with either DNMT3A or TET2 mutations compared with non-CHIP carriers. By multivariable Cox proportional regression analysis, the presence of somatic mutations within TET2 or DNMT3A (HR, 2.1; 95% CI, 1.1-4.0; P = .02, for death combined with heart failure hospitalization) and age (HR, 1.04; 95% CI, 1.01-1.07 per year; P = .005) but not a history of hypertension remained independently associated with adverse outcome. Importantly, there was a significant dose-response association between VAF and clinical outcome.

Conclusions and relevance: Our data suggest that somatic mutations in hematopoietic cells, specifically in the most commonly mutated CHIP driver genes TET2 and DNMT3A, may be significantly associated with the progression and poor prognosis of CHF. Future studies will have to validate our findings in larger cohorts and address whether targeting specific inflammatory pathways may be valuable for precision medicine in patients with CHF carrying specific mutations encoding for CHIP.

Figure 1.. Prevalence of Clonal Hematopoiesis of Indeterminate Potential (CHIP) According to Age and Proportion of Mutated Genes Leading to Clonal Hematopoiesis in Patients With Chronic Ischemic Heart Failure (CHF)

A, The number of patients with CHF analyzed per age group is given. P value is for analysis of variance test. B, CHIP-associated mutations in 56 analyzed genes that resulted in a variant allele fraction higher than 0.02 and remained positive after stringent unsupervised and supervised variant calling criteria are included. Because some patients carried more than 1 mutation, the total number of identified mutations leading to clonal expansion exceeds the number of patients with CHIP. The list of individual mutations can be found in eTable 3 in the Supplement.

Figure 2.. Association Between Mutated Genes and Incidence of Death Combined With Rehospitalization for Heart Failure and Kaplan-Meier Event-Free Survival Curves in Patients With Chronic Heart Failure (CHF)

A, Bubble size reflects the sample size of patients carrying each individual mutation, dashed line reflects incidence of death combined with rehospitalization for heart failure for patients who were not carriers of clonal hematopoiesis of indeterminate potential (CHIP). See eTable 1 in the Supplement for gene annotation. B, Overall survival of patients with DNMT3A or TET2 mutations with a variant allele fraction (VAF) of at least 0.02 vs non-CHIP patients. C, Event-free survival free of death or rehospitalization for heart failure with DNMT3A or TET2 mutations with a VAF of at least 0.02 vs non-CHIP patients. P values are for log-rank tests.

Figure 3.. Kaplan-Meier Event-Free Survival Curves for Non–Clonal Hematopoiesis of Indeterminate Potential (CHIP) Carriers and Patients With Clonal Hematopoiesis Caused by DNMT3A or TET2 Mutations at Low Variant Allele Fraction (VAF)

A, Overall survival of patients with DNMT3A or TET2 mutations with a VAF greater than 0.005 to 0.01; a VAF of at least 0.01 to 0.02; a VAF of at least 0.02; and non-CHIP patients reveals dose-response of clone size and clinical outcome; B, Event-free survival free of death or rehospitalization for heart failure with DNMT3A or TET2 mutations at various VAFs vs non-CHIP patients. P values are for log-rank tests.