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

Circulation. 1999 Oct 12;100(15):1660-6. doi: 10.1161/01.cir.100.15.1660.


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 micromol/L), a K(+) channel opener, or the combination of a Na(+) channel blocker (flecainide, 7 micromol/L) and acetylcholine (ACh, 2 to 3 micromol/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 micromol/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 micromol/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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Acetylcholine / pharmacology
  • Action Potentials / drug effects
  • Adrenergic alpha-Agonists / pharmacology
  • Adrenergic beta-Agonists / pharmacology
  • Animals
  • Cardiac Complexes, Premature / complications
  • Cardiac Complexes, Premature / physiopathology*
  • Death, Sudden, Cardiac / etiology*
  • Dogs
  • Electrocardiography* / drug effects
  • Genetic Heterogeneity
  • Heart Conduction System / physiopathology*
  • Heart Ventricles / physiopathology
  • Humans
  • Isoproterenol / pharmacology
  • NAV1.5 Voltage-Gated Sodium Channel
  • Quinidine / pharmacology
  • Sodium Channels / genetics
  • Sodium Channels / physiology
  • Syndrome
  • Ventricular Fibrillation / etiology*
  • Ventricular Fibrillation / physiopathology


  • Adrenergic alpha-Agonists
  • Adrenergic beta-Agonists
  • NAV1.5 Voltage-Gated Sodium Channel
  • SCN5A protein, human
  • Sodium Channels
  • Quinidine
  • Isoproterenol
  • Acetylcholine