Genetic Variants Associated With Nonpulmonary Vein Triggers of Atrial Fibrillation

BACKGROUND: Atrial fibrillation (AF) originating from non-pulmonary vein (non-PV) foci is a major cause of postablation recurrence; however, its underlying mechanisms remain poorly understood. OBJECTIVES: The purpose of this study was to identify genetic variants and electrophysiological features associated with AF originating from non-PV foci. METHODS: We performed a genome-wide association study in 1,091 patients with paroxysmal AF undergoing first catheter ablation. AF triggers were classified into PV or non-PV groups based on standardized electrophysiological testing with isoproterenol provocation. AF originating from the posterior wall of the left atrium, including the PV antrum, was categorized into the PV group. Associations between genetic variants and non-PV AF triggers were assessed and validated in an independent cohort (n = 371). RESULTS: ; OR: 1.98; 95% CI: 1.49-2.62). This association was replicated under Firth's penalized logistic regression adjusted for age and sex (OR: 3.31; 95% CI: 1.40-7.55; P = 0.007). Non-PV AF was associated with significantly longer intra-atrial conduction times, although rs117203318 showed no correlation with conduction parameters. CONCLUSIONS: The rs117203318 variant, near genes associated with myocardial fibrosis and cellular stress responses, is associated with AF originating from non-PV foci. These findings suggest that there may be distinct substrates for non-PV AF and this could inform strategies to improve ablation outcomes.