Introduction

Clonal hematopoiesis of indeterminate potential (CHIP)-associated mutations lead to hematopoietic malignancy. Accumulating evidence suggest that CHIP-related mutations contribute to development of atherosclerosis. However, their frequency and gene mutational discrepancy in patients with dilated (DCM) or ischemic cardiomyopathy (ICM) is unclear. In this study, we aim to examine the incidence and clinical significance of CHIP-related mutations in DCM and ICM patients.

Methods

Twenty-two ICM and 20 DCM patients were recruited through the Heart Failure Registry at the University Hospital Jena (ICM vs. DCM: age: 68±10 vs. 61 ±19 years; BMI: 26.6±3.7 vs. 29.4±6.1 kg/m²; NYHA: 2.2±0.4 vs. 2.2±0.7; p=not significant). Genomic DNA (gDNA) was isolated from peripheral blood and next-generation sequencing was performed with the TruSight Myeloid Sequencing Panel using the MiniSeq™ System (Illumina). Data was analyzed using VariantStudio™ 3.0 (Illumina). Somatic mutation was confirmed with the gDNA from buccal swabs.

Results

Sequencing was performed with a sensitivity of 5% and an amplicon mean coverage of 11812±2584.CHIP-associated somatic mutations is found in 10% of individuals older than 65 years old. However, our study revealed that somatic mutations were detected in 17% of all patients examined, with higher frequency in DCM patients (mutations in ICM vs. DCM: 5% vs. 30%, p=0.027). CHIP-related mutations are age-dependent; however, a higher frequency of CHIP-related mutations was observed in younger subjects with heart failure (mutations in age≤65 vs. age>65: 25% vs. 9.1%, p=0.17). Among all mutations identified, DNMT3A was the most commonly mutated gene and its mutation was detected in 11.9% of total patients analyzed. Additional mutations that were detected included TET2 and PHF6. No difference in clinical presentation was found in relation to the incidence of CHIP-related mutations among ICM and DCM patients.

Conclusion

CHIP-associated somatic mutations are identified in both ICM and DCM patients. Furthermore, the mutation rate is higher in DCM patients and such mutation is independent of age. Among all the mutated genes identified, DNMT3A has the highest mutation frequency. A larger cohort will be necessary to confirm the current finding and to delineate if mutation incidence is associated with mortality and hospitalization rate.