Embryological Classification of Arrhythmogenic Triggers Initiating Atrial Fibrillation

Background: Atrial fibrillation (AF) is a prevalent multifactorial arrhythmia associated with specific single-nucleotide polymorphisms (SNPs). Pulmonary vein (PV) isolation is an established treatment for AF; however, recurrence risk remains caused by AF triggers beyond the PVs. Understanding the embryological origins of these triggers could improve treatment outcomes. Objectives: This study aimed to investigate the association between embryologically categorized AF triggers, clinical and genetic backgrounds, and postablation prognosis. Methods: In cohort 1, comprising 3,067 patients with AF undergoing PV isolation, the clinical characteristics and outcomes were analyzed. Among them, 815 patients underwent genetic analysis using AF-associated SNPs (cohort 2). Patients were delineated based on the developmental origin of the AF triggers: common PV, sinus venosus (SV), and primitive atrium (PA). Results: SV-origin extra-PV AF triggers occurred in 20.3% (n = 622) of patients, whereas PA-origin triggers occurred in 11.9% (n = 365) of patients in cohort 1. Multivariate analysis of cohort 2 revealed that female sex, lower body mass index, absence of hypertension, rs2634073 near PITX2, and rs6584555 in NEURL1 were associated with SV-AF, whereas nonparoxysmal AF and rs2634073 near PITX2 were predictors of PA-AF. The PA group had a significantly higher arrhythmia recurrence rate after repeated procedures than the common PV (HR: 1.75; 95% CI: 1.34-2.29; P < 0.001) and SV-AF (HR: 1.31; 95% CI: 1.19-1.45; P < 0.001) groups with more de novo AF triggers. However, the incidence of adverse events did not differ significantly among the 3 groups. Conclusions: SV-derived AF triggers may have hereditary factors with a favorable postablation prognosis, whereas PA-derived triggers are linked to AF persistence and poor ablation response. Variants near PITX2 may play a pivotal role in extra-PV triggers.