Clonal haematopoiesis of indeterminate potential and incident cardiomyopathy

Abstract Background Both clonal haematopoiesis of indeterminate potential (CHIP) and cardiomyopathy are gene and inflammation-related conditions. This study aimed to explore the association of CHIP with newly onset cardiomyopathy. Methods The prospective cohort study used data from the UK Biobank, including 456,246 participants without baseline cardiomyopathy, and determined CHIP status through whole-exome sequencing. Cox proportional hazard models were performed to assess the associations of CHIP mutations with cardiomyopathy and three subtypes: dilated cardiomyopathy (DCM), hypertrophic cardiomyopathy (HCM), and restrictive cardiomyopathy (RCM). Gene-specific CHIP mutations and cardiac magnetic resonance (CMR) phenotypes were also evaluated. Additionally, the clonal haematopoiesis risk score (CHRS) was applied to evaluate the risk of incident cardiomyopathy. Results During a median follow-up of 13.4 years, 2,685 (0.6%) participants developed cardiomyopathies. In multivariable-adjusted model, CHIP was independently associated with a 44% (95% CI, 23%-68%) increased risk for cardiomyopathies, especially for DCM (HR 1.39, 1.08-1.79) and RCM (HR 3.71, 1.41-9.78). Gene-specific CHIP mutations, including DNMT3A, TP53, NF1 and SRSF2, were associated with DCM, and DNMT3A was also associated with RCM. Analyses on CMR phenotypes revealed CHIP was associated with decreased left ventricle ejection fraction and strain, along with increased pericardial fat accumulation. Associations of gene-specific CHIP were heterogeneous across CMR phenotypes. Furthermore, a dose-response association between CHRS and incident cardiomyopathy was observed, with the 1.39 (1.17-1.64) fold and 1.76 (1.22-2.54) fold increased risk of cardiomyopathy for low risk and intermediate-high risk categories, respectively, compared to participants with no CHIP . Conclusions CHIP could be a novel risk factor for the onset of cardiomyopathies, particularly DCM and RCM, providing new insights on pathogenic mechanisms and therapeutic strategies.The assciations of CHIP with CMs  Associations of CHIP with CMR phenotypes