Cellular Basis for the Brugada Syndrome and Other Mechanisms of Arrhythmogenesis Associated With ST-Segment Elevation

TLDR

Brugada syndrome is marked by pronounced ST‑segment elevation in right precordial leads and a high risk of sudden arrhythmic death. The study investigates the cellular mechanisms underlying this syndrome. Using arterially perfused wedges of canine right ventricle, the authors recorded epicardial and endocardial transmembrane action potentials, unipolar electrograms, and a transmural ECG simultaneously. Loss of the epicardial action‑potential dome—induced by K⁺ channel opening or Na⁺ channel blockade plus acetylcholine—creates a transmural voltage gradient that elevates the ST segment; acetylcholine worsens, while isoproterenol restores the dome; heterogeneous dome loss generates phase‑2 reentry that triggers VT/VF, and blocking the transient outward current with 4‑aminopyridine or quinidine restores the dome, normalizes the ST segment, and prevents arrhythmias.

Abstract

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 ECG. Loss of the action potential dome in epicardium but not endocardium after exposure to pinacidil (2 to 5 μmol/L), a K + channel opener, or the combination of a Na + channel blocker (flecainide, 7 μmol/L) and acetylcholine (ACh, 2 to 3 μmol/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 μmol/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 μmol/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.