Atrial Fibrillation Initiation Arises From Reentry at Patient-Specific Regions With Steep Repolarization Gradients Identified During Sinus Rhythm.

BACKGROUND: The mechanism by which ectopic beats initiate atrial fibrillation (AF) remains undefined. OBJECTIVES: This study sought to define the mechanism and underlying substrate of AF initiation. METHODS: In 57 patients with AF and 24 controls, biatrial mapping with programmed extrastimulation during sinus rhythm was performed to characterize refractoriness, conduction, and AF inducibility. Multiple convergent electrophysiological parameters were assessed at initiation and noninitiation sites to define the mechanism of AF onset. In an exploratory cohort, 24 redo patients with durable pulmonary vein isolation (PVI; 50% with persistent AF) underwent ablation confined to mechanistically identified sites. RESULTS: AF was reproducibly induced and localized to discrete, patient-specific sites (1.8 ± 1.0 per patient), representing only 2.8% of tested locations. These sites were strongly associated with steep repolarization gradients (SRGs; AERP difference ≥50 ms over ≤10 mm), present in 91.7% of patients with AF vs 8.3% of controls (P < 0.001), accounting for 92.2% of all AF initiation episodes, and representing the strongest electrophysiological correlate of AF initiation. PV-associated SRGs predominated in paroxysmal AF, with increasing non-PV substrate in persistent AF and redo patients with durable PVI. Multiple convergent electrophysiological observations supported re-entry as the predominant mechanism, including narrow vulnerability windows, direction-dependent induction, and functional conduction delay and block preceding AF onset. In redo patients with durable PVI, ablation confined to mechanistically identified SRG sites achieved 87.5% freedom from atrial arrhythmia without antiarrhythmic drugs over a median follow-up of 489 days. CONCLUSIONS: AF initiation arises from a localized, patient-specific substrate capable of supporting re-entry that can be identified using programmed stimulation during sinus rhythm. These findings provide a mechanistic basis for transitioning from empiric to individualized, substrate-guided ablation strategies.