Cellular basis for the Brugada syndrome and other mechanisms of arrhythmogenesis associated with ST-segment elevation

Background-The Brugada syndrome is characterized by marked ST-segment elevation in the right precordial ECG leads and is associated with a high incidence of sudden and unexpected arrhythmic death. Our study examines the cellular basis for this syndrome. Methods and Results-Using arterially perfused wedges of canine right ventricle (RV), we simultaneously recorded transmembrane action potentials from 2 epicardial and 1 endocardial sites, together with unipolar electrograms and a transmural EGG. Loss of the action potential dome in epicardium but not endocardium after exposure to pinacidil (2 to 5 mu mol/L), a K+ channel opener, or the combination of a Na+ channel blocker (flecainide, 7 mu mol/L) and acetylcholine (ACh, 2 to 3 mu mol/L) resulted in an abbreviation of epicardial response and a transmural dispersion of repolarization, which caused an ST-segment elevation in the ECG. ACh facilitated loss of the action potential dome, whereas isoproterenol (0.1 to 1 mu mol/L) restored the epicardial dome, thus reducing or eliminating the ST-segment elevation. Heterogeneous loss of the dome caused a marked dispersion of repolarization within the epicardium and transmurally, thus giving rise to phase 2 reentrant extrasystole. which precipitated ventricular tachycardia (VT) and ventricular fibrillation (VF), Transient outward current (I-to) block With 4-aminopyridine (1 to 2 mmol/L) or quinidine (5 mu mol/L) restored the dome. normalized the ST segment, and prevented VT/VF. Conclusions-Depression or loss of the action potential dome in RV epicardium creates a transmural voltage gradient that may be responsible for the ST-segment elevation observed in the Brugada syndrome and other syndromes exhibiting similar ECG manifestations. Our results also demonstrate that extrasystolic activity due to phase 2 reentry can arise in the intact wall of the canine RV and serve as the trigger for VT/VF. Our data point to I-to block (4-aminopyridine, quinidine) as an effective pharmacological treatment.