Cellular basis for long QT, transmural dispersion of repolarization, and torsade de pointes in the long QT syndrome

Genetic studies have identified four forms of congenital long QT syndrome (LQTS) caused by mutations in ion channel genes located on chromosomes 3 (LQT3), 7 (LQT2), 11 (LQT1), and 21 (LQT5). Preliminary clinical studies have reported different phenotypic electrocardiographic patterns and different sensitivity to pacing or pharmacological therapy for each genotype. A transmural electrocardiogram and transmembrane action potentials from epicardial, M, and endocardial cells were simultaneously recorded from an arterially perfused wedge of canine left ventricle. Isoproterenol (100 nmol/L) in the presence of chromanol 293B (30 mu mol/L), an I-Ks blocker (LQT1 model), produced a preferential prolongation of M-cell action potential duration (APD), resulting in an increase in transmural dispersion of repolarization (TDR) and a broad-based T wave, as commonly seen in LQT1 patients. D-Sotalol (100 mu mol/L), an I-Kr blocker (LQT2 model), and ATX-II (20 nmol/L), an agent that augments late I-Na (LQT3 model), also produced a preferential prolongation of M-cell APD, an increase in TDR, and low-amplitude T wave with a bifurcated appearance (LQT2), and late-appearing T wave (LQT3), respectively. APD-, QT-, and TDR-rate relations were much sleeper in the LQT3 model than in either the LQT1 or LQT2 model, whereas the rate relations in the LQT1 and LQT2 models were both steeper than those under control conditions. Spontaneous and programmed electrical stimulation-induced tor sade de pointes (TdP) were observed in all 3 models. Propranolol (1 mu mol/L), a beta blocker, completely prevented the effect of isoproterenol to persistently or transiently increase TDR and to induce TdP in the LQT1 and LQT2 models, but facilitated TdP in the LQT3 model. Mexiletine, a class IB Na+ channel blocker, dose-dependently (2-20 mu mol/L) abbreviated the QT and APD more in the LQT3 model, but decreased TDR and suppressed TdP in the 3 models.