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. d-Sotalol caused a preferential prolongation of the M cell action potential duration (APD90, 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 APD90 (280±25 to 609±49 ms) and caused a marked delay in the onset of the T wave and...