Biological age acceleration and bradyarrhythmia: evidence from clinical and epigenetic perspectives

To date, effective preventive and therapeutic strategies for early-stage bradyarrhythmia remain limited. We first calculated two well-established biological aging (BA) measures (Klemera-Doubal Method [KDM] and Phenotypic Age [PhenoAge]), with BA acceleration defined as the residual from regressing each BA measure on chronological age. Cox proportional hazards models were used to evaluate the effects of BA acceleration on bradyarrhythmia risk. We then conducted epigenetic Mendelian randomization (MR) and colocalization analyses to prioritize aging-related DNA methylation CpG sites for bradyarrhythmias. In the UK Biobank cohort of 298,214 individuals, per 1-SD increase in PhenoAge acceleration and KDM-BA acceleration were significantly associated with a 13% (HR = 1.13, 95% CI 1.11–1.15, P < 0.001) and 11% (HR = 1.11, 95% CI 1.09–1.13, P < 0.001) higher incidence of bradyarrhythmia. Epigenetic MR and colocalization analyses suggested that cg11410859 (SCN5A), cg18249173 (TBX20), cg07185587 (AKAP6), cg16555537 (TRIP6), cg10459018, cg03473532 (MKLN1), and cg13654588 (PRLHR) were associated with a reduced risk of bradyarrhythmias, whereas cg25286333 (RNF207) and cg02447380 (RAB42) were associated with an increased risk of bradyarrhythmias. In summary, our study elucidated the role of accelerated biological aging and underlying epigenetic modifications in bradyarrhythmia, providing novel insights into its prevention and treatment.