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

Background-This study examined the role of phase 2 early afterdepolarizatio n (EAD) in producing a trigger to initiate torsade de pointes (TdP) with QT prolongation induced by dl-sotalol and azimilide. The contribution of tran smural 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, midmyo cardium, and endocardium were recorded simultaneously, together with a tran smural EGG, in arterially perfused canine and rabbit left ventricular prepa rations. dE-Sotalol preferentially prolonged action potential duration (APD ) in M cells dose-dependently (1 to 100 mu mol/L), leading to QT prolongati on and an increase in TDR. Azimilide, however, significantly prolonged APD and QT interval at concentrations from 0.1 to 10 mu mol/L but shortened the m at 30 mu mol/L. Unlike dl-sotalol, azimilide (>3 mu mol/L) increased epic ardial APD markedly, causing a diminished TDR. Although both dl-sotalol and azimilide rarely induced EADs in canine left ventricles, they produced fre quent EADs in rabbits, in which more pronounced QT prolongation was seen. A n increase in TDR by dl-sotalol facilitated transmural propagation of EADs that initiated multiple episodes of spontaneous TdP in 3 of 6 rabbit left v entricles. Of note, although azimilide (3 to 10 mu mol/L) increased APD mor e than dl-sotalol, its EADs often failed to propagate transmurally, probabl y because of a diminished TDR. Conclusions-This study provides the first direct evidence from intracellula r 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.