passages.id: 17849
passages.type: title
passages.text: Phase 2 early afterdepolarization as a trigger of polymorphic ventricular tachycardia in acquired long-QT syndrome : direct evidence from intracellular recordings in the intact left ventricular wall.
passages.id: 17850
passages.type: abstract
passages.text: BACKGROUND: This study examined the role of phase 2 early afterdepolarization (EAD) in producing a trigger to initiate torsade de pointes (TdP) with QT prolongation induced by dl-sotalol and azimilide. The contribution of transmural dispersion of repolarization (TDR) to transmural propagation of EAD and the maintenance of TdP was also evaluated. METHODS AND RESULTS: Transmembrane action potentials from epicardium, midmyocardium, and endocardium were recorded simultaneously, together with a transmural ECG, in arterially perfused canine and rabbit left ventricular preparations. dl-Sotalol preferentially prolonged action potential duration (APD) in M cells dose-dependently (1 to 100 micromol/L), leading to QT prolongation and an increase in TDR. Azimilide, however, significantly prolonged APD and QT interval at concentrations from 0.1 to 10 micromol/L but shortened them at 30 micromol/L. Unlike dl-sotalol, azimilide (>3 micromol/L) increased epicardial APD markedly, causing a diminished TDR. Although both dl-sotalol and azimilide rarely induced EADs in canine left ventricles, they produced frequent EADs in rabbits, in which more pronounced QT prolongation was seen. An increase in TDR by dl-sotalol facilitated transmural propagation of EADs that initiated multiple episodes of spontaneous TdP in 3 of 6 rabbit left ventricles. Of note, although azimilide (3 to 10 micromol/L) increased APD more than dl-sotalol, its EADs often failed to propagate transmurally, probably because of a diminished TDR. CONCLUSIONS: This study provides the first direct evidence from intracellular action potential recordings that phase 2 EAD can be generated from intact ventricular wall and produce a trigger to initiate the onset of TdP under QT prolongation.