Effect of clonal hematopoiesis of indeterminate potential on long-term survival in patients with arrhythmias

Clonal hematopoiesis of indeterminate potential(CHIP), defined by somatic mutations within hematopoietic clones, has emerged as a novel risk factor for cardiovascular disease. While cardiac arrhythmias are a major global health concern, the factors contributing to outcome variability remain unclear. The study aimed to investigate the association between CHIP and mortality in patients with arrhythmias. This study analyzed UK Biobank participants hospitalized with arrhythmias who had whole-exome sequencing data. Arrhythmia subtypes were classified using ICD-10 codes. Outcomes, including all-cause, cardiovascular, and cancer-related mortality, were obtained from national registries. CHIP was defined as any CHIP as variant allele fraction(VAF) ≥ 2%, large CHIP as VAF ≥ 10%. Cox regression models adjusted for confounders were used. Among 53,149 individuals (median age 69 years), 3,315 carried CHIP mutations. Both any and large CHIP were independently associated with higher mortality: adjusted hazard ratios (HRs) for all-cause mortality were 1.26 (1.19–1.34) and 1.44 (1.33–1.55), respectively; for cardiovascular mortality, 1.14 (1.02–1.27) and 1.31 (1.14–1.52); and for cancer-related mortality, 1.36 (1.23–1.51) and 1.65 (1.45–1.87). Associations persisted across arrhythmia subtypes, with the strongest effects in ventricular arrhythmias. In gene-specific analyses, TET2, TP53 and spliceosome genes appeared to be the strongest deleterious genes for all-cause mortality [large TET2 CHIP: HR 1.63 (1.40–1.90); large TP53 CHIP: 1.83 (1.18–2.84); large spliceosome CHIP: HR 1.85 (1.32–2.59)]. CHIP is independently associated with increased mortality in patients with arrhythmias across different subtypes. These findings suggest that CHIP may serve as a potential prognostic marker and therapeutic target. Clonal hematopoiesis of indeterminate potential (CHIP) is a novel cardiovascular risk factor. As cardiac arrhythmia is an increasing global health burden, particularly with advancing age, the relationship between CHIP and mortality remains unclear.