Sodium channel block with mexiletine is effective in reducing dispersion of repolarization and preventing torsade de pointes in LQT2 and LQT3 models of the long-QT syndrome

Background This study examines the contribution of transmural heterogeneity of transmembrane activity to phenotypic T-wave patterns and the effects of pacing and of sodium channel block under conditions mimicking HERG and SCN5A defects linked to the congenital long-QT syndrome (LQTS). Methods and Results A transmural ECG and transmembrane action potentials from epicardial, M, and endocardial or Purkinje cells were simultaneously recorded in an arterially perfused wedge of canine left ventricle. d-Sotalol was used to mimic LQT2, whereas ATX-II mimicked LQT3. dSotalol caused a preferential prolongation of the M cell action potential duration (APD(90), 291 +/- 14 to 354 +/- 35 ms), giving rise to broad and sometimes low-amplitude bifurcated T waves and an increased transmural dispersion of repolarization (TDR, 51 +/- 15 to 72 +/- 17 ms). QT interval increased from 320 +/- 13 to 385 +/- 37 ms. ATX-II produced a preferential prolongation of the M cell APD(90) (280 +/- 25 to 609 +/- 49 ms) and caused a marked delay in the onset of the T wave and a sharp rise in TDR (40 +/- 5 to 168 +/- 40 ms). QT-, APD(90)-, and dispersion-rate relations were much steeper in the ATX-II than in the d-sotalol model. Mexiletine (2 to 20 mu mol/L) dose-dependently abbreviated the QT interval and APD(90) of all cell types, more in the ATX-II than in the d-sotalol model, but decreased TDR equally in the two models. Mexiletine 2 to 5 mu mol/L totally suppressed spontaneous torsade de pointes (TdP) and reduced the vulnerable window during which single extrastimuli could induce TdP in both models. Higher concentrations of mexiletine (10 to 20 mu mol/L) totally suppressed stimulation-induced Td. Conclusions Our results suggest that although pacing and sodium channel block are very effective in abbreviating the QT interval and TDR in LQT3, these therapeutic approaches may also be valuable in reducing the incidence of arrhythmogenesis in LQT2.