Clonal haematopoiesis is associated with major adverse cardiovascular events in patients with hypertrophic cardiomyopathy

Abstract

Background & Aims: The heterogeneous phenotype of hypertrophic cardiomyopathy (HCM) is still not fully understood. Clonal haematopoiesis (CH) is emerging as a cardiovascular risk factor potentially associated with adverse clinical events. The prevalence, phenotype and outcomes related to CH in HCM patients was evaluated. Methods: Patients with HCM and available biospecimens from the Peter Munk Cardiac Centre Cardiovascular Biobank were subjected to targeted sequencing for 35 myeloid genes associated with CH. CH prevalence, clinical characteristics, morphological phenotypes assessed by echocardiogram and cardiac magnetic resonance and outcomes were assessed. All patients were evaluated for a 71-plex cytokines/chemokines, troponin I and B-type natriuretic peptide analysis. Major cardiovascular events (MACE) were defined as appropriate ICD shock, stroke, cardiac arrest, orthotopic heart transplant and death. Results: Among the 799 patients, CH was found in 183 (22.9%) HCM patients with sarcomeric germline mutations. HCM patients with CH were more symptomatic and with a higher burden of fibrosis than those without CH. CH was associated with MACE in those HCM patients with sarcomeric germline mutations [adjusted HR of 3.46 (95% CI 1.25-9.52; p=0.016)], with the highest risk among those that had DNMT3A, TET2 and ASXL1 mutations [adjusted HR of 7.23 (95% CI 1.79-29.13) p=0.005]. Several cytokines (IL-1ra, IL-6, IL-17F, TGFa, CCL21, CCL1, CCL8, and CCL17), and troponin I were upregulated in gene-positive HCM patients with CH. Conclusions: These results indicate that CH in patients with HCM is associated with worse clinical outcomes. In the absence of CH, gene-positive patients with HCM have lower rates of MACE.