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

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 mol/L), a K ϩ channel opener, or the combination of a Na ϩ channel blocker (flecainide, 7 mol/L) and acetylcholine (ACh, 2 to 3 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 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 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. (Circulation. 1999;100:1660-1666.)

Defective Epidermal Barrier in Neonatal Mice Lacking the C-Terminal Region of Connexin43

“…Similar ECG abnormalities with ST-elevation and QT-prolongation as an overlap of Brugadaand Long-QT-syndrome have been described in association with mutations in the SCN5A sodium channel gene (Priori et al, 2000;Rivolta et al, 2001). Interestingly, the elevation of the ST-segment typical for the Brugada syndrome is explained by a changed transmural voltage gradient caused by an abbreviation of epicardial action potential duration (Yan and Antzelevitch, 1999). Thus, the accumulation of Cx43K258stop and impairment in its colocalization with sodium channels in intercalated discs (Kucera et al, 2002) could provide a potential explanation for the repolarization abnormalities found.…”

Brugada syndrome: clinical and genetic findings

“…36 This explains the greater ST segment elevation recorded in vagal settings and the incidence of ventricular arrhythmias at night.…”

Brugada syndrome and ischemia-induced ST-segment elevation. Similarities and differences

“…Phase 2 reentry-induced extrasystoles leading to polymorphic VT or VF was also anticipated [9,20,21], In addition, the presence of a much greater I to in right-vs left ventricular epicardium has also been proposed to account, at least in part, for the RV nature of this disease [15].…”