Cellular Basis for Trigger and Maintenance of Ventricular Fibrillation in the Brugada Syndrome Model. High-Resolution Optical Mapping Study

Objectives: We examined how repolarization and depolarization abnormalities contribute to the development of extrasystoles and subsequent ventricular fibrillation (VF) in a model of the Brugada syndrome. Background: Repolarization and depolarization abnormalities have been considered to be mechanisms of the coved-type ST-segment elevation (Brugada-electrocardiogram [ECG]) and development of VF in the Brugada syndrome. Methods: We used high-resolution (256 × 256) optical mapping techniques to study arterially perfused canine right ventricular wedges (n = 20) in baseline and in the Brugada-ECG produced by administration of terfenadine (5 μmol/l), pinacidil (2 μmol/l), and pilsicainide (5 μmol/l). We recorded spontaneous episodes of phase 2 re-entrant (P2R)-extrasystoles and subsequent self-terminating polymorphic ventricular tachycardia (PVT) or VF under the Brugada-ECG condition and analyzed the epicardial conduction velocity and action potential duration (APD) restitutions in each condition. Results: Forty-one episodes of spontaneous P2R-extrasystoles in the Brugada-ECG were successfully mapped in 9 of 10 preparations, and 33 of them were originated from the maximum gradient of repolarization (GR_max: 176 ± 54 ms/mm) area in the epicardium, leading to PVT (n = 12) or VF (n = 5). The epicardial GR_max was not different between PVT and VF. Wave-break during the first P2R-extrasystole produced multiple wavelets in all VF cases, whereas no wave-break or wave-break followed by wave collision and termination occurred in PVT cases. Moreover, conduction velocity restitution was shifted lower and APD restitution was more variable in VF cases than in PVT cases. Conclusions: Steep repolarization gradient in the epicardium but not endocardium develops P2R-extrasystoles in the Brugada-ECG condition, which might degenerate into VF by further depolarization and repolarization abnormalities.