Somatic DNMT3A and TET2 mutations in explanted hearts from advanced heart failure show enrichment in myocarditis and inflammatory heart disease

Introduction Clonal haematopoiesis of indeterminate potential (CHIP) arises from somatic mutations in haematopoietic stem cells, most commonly in DNMT3A and TET2. CHIP has been linked to cardiovascular disease through inflammatory mechanisms, but its presence and potential role in advanced heart failure remain poorly characterised. Purpose This study investigated somatic mutations associated with CHIP in cardiac tissue from patients with advanced heart failure and evaluated their association with inflammatory cardiac disease phenotypes. Methods Whole-genome sequencing data from explanted cardiac tissue of 104 patients with advanced heart failure undergoing heart transplantation in the SwedeHeartSeq study were analysed (age 15–73 years, 25% women). Somatic mutations in known myeloid driver genes were identified using GATK Mutect2. Technical artefacts were removed by comparison with the 1000 Genomes Project and germline variants were filtered using the Genome Aggregation Database (gnomAD). Associations between CHIP mutations and clinical phenotypes were examined, including myocarditis and inflammatory heart disease (myocarditis, sarcoidosis, rheumatic heart disease and systemic lupus erythematosus). Enrichment was assessed using Fisher’s exact test. Results Potential CHIP-associated somatic mutations were identified in 5 of 104 patients with advanced heart failure (aged 46–59 years). Three patients carried DNMT3A variants (M364R, M513L, N802T) and two carried TET2 variants (K1197M and Q548R). Two of the three DNMT3A carriers were women despite women comprising 25% of the cohort. CHIP mutations were enriched in patients with prior myocarditis (3/5 vs 4/99; Fisher’s exact test odds ratio 32.2, p=0.0018) and with inflammatory heart disease (3/5 vs 6/99; odds ratio 21.7, p=0.004). Three CHIP carriers had a history of myocarditis, which was otherwise present in eight patients in the cohort. One patient with a DNMT3A mutation showed marked expansion of cardiac myeloid cells (2% to 27%). All CHIP carriers presented with dilated or hypertrophic cardiomyopathy or right ventricular failure without evidence of coronary artery disease upon angiography. Conclusions Potential CHIP-associated somatic mutations in DNMT3A and TET2 were detected in 5% of patients with advanced heart failure undergoing transplantation. CHIP mutations were strongly enriched in myocarditis and inflammatory heart disease, suggesting a potential link between clonal haematopoiesis and myocardial inflammation. These findings support further investigation of CHIP as a contributor to inflammatory mechanisms in advanced heart failure.