Abstract 13052: Clonal Hematopoiesis of Indeterminate Potential Predicts Incident Cardiac Arrhythmias

Abstract

Background: Clonal hematopoiesis of indeterminate potential (CHIP), the age-related expansion of blood cells with preleukemic mutations, is associated with atherosclerotic cardiovascular disease and heart failure. Whether CHIP independently predicts new-onset arrhythmias is unknown. Methods: UK Biobank participants without prevalent arrhythmias were included. Co-primary study outcomes were supraventricular arrhythmias, bradyarrhythmias, and ventricular arrhythmias. Secondary outcomes were cardiac arrest, atrial fibrillation, and any arrhythmia. Associations of any CHIP (variant allele fraction [VAF] ≥2%), large CHIP (VAF ≥10%) and gene-specific CHIP subtypes with incident arrhythmias were tested using multivariable-adjusted Cox regression. Associations of CHIP with myocardial interstitial fibrosis (T1 times on cardiac magnetic resonance [CMR]) were also tested. Results: This study included 410,879 participants (CHIP: n =13,901 [3.4%]; large CHIP: n =9,197 [2.2%]). Any and large CHIP were associated with adjusted HRs of 1.11 (95%CI, 1.04-1.18; P <0.001) and 1.14 (95%CI, 1.05-1.22; P <0.001) for supraventricular arrhythmias, 1.09 (95%CI, 1.01-1.19; P =0.029) and 1.13 (95%CI, 1.03-1.25; P =0.011) for bradyarrhythmias, and 1.15 (95%CI, 1.00-1.33; P =0.054) and 1.22 (95%CI, 1.03-1.45; P =0.023) for ventricular arrhythmias, respectively. Associations were independent of coronary artery disease and heart failure. Associations were also heterogeneous across arrhythmia subtypes and strongest for cardiac arrest. Gene-specific analyses revealed increased risk of arrhythmias across mutations in driver genes other than DNMT3A ( Figure ) . Large CHIP was associated with 1.30-fold odds (95%CI, 1.07-1.59; P =0.009) of being in the top quintile of myocardial fibrosis by CMR. Conclusions: CHIP may represent a novel risk factor for incident arrhythmias, indicating a potential target for modulation toward arrhythmia prevention and treatment. 1