Cellular Basis for the ECG Features of the LQT1 Form of the Long-QT Syndrome: Effects of β-Adrenergic Agonists and Antagonists and Sodium Channel Blockers on Transmural Dispersion of Repolarization and Torsade de Pointes

Abstract

Background —This study examines the cellular basis for the phenotypic appearance of broad-based T waves, increased transmural dispersion of repolarization (TDR), and torsade de pointes (TdP) induced by β-adrenergic agonists under conditions mimicking the LQT1 form of the congenital long-QT syndrome. Methods and Results —A transmural ECG and transmembrane action potentials from epicardial, M, and endocardial cells were recorded simultaneously from an arterially perfused wedge of canine left ventricle. Chromanol 293B, a specific I Ks blocker, dose-dependently (1 to 100 μmol/L) prolonged the QT interval and action potential duration (APD 90 ) of the 3 cell types but did not widen the T wave, increase TDR, or induce TdP. Isoproterenol 10 to 100 nmol/L in the continued presence of chromanol 293B 30 μmol/L abbreviated the APD 90 of epicardial and endocardial cells but not that of the M cell, resulting in widening of the T wave and a dramatic accentuation of TDR. Spontaneous as well as programmed electrical stimulation (PES)-induced TdP was observed only after exposure to the I Ks blocker and isoproterenol. Therapeutic concentrations of propranolol (0.5 to 1 μmol/L) prevented the actions of isoproterenol to increase TDR and to induce TdP. Mexiletine 2 to 20 μmol/L abbreviated the APD 90 of M cells more than that of epicardial and endocardial cells, thus diminishing TDR and the effect of isoproterenol to induce TdP. Conclusions —This experimental model of LQT1 indicates that a deficiency of I Ks alone does not induce TdP but that the addition of β-adrenergic influence predisposes the myocardium to the development of TdP by increasing transmural dispersion of repolarization, most likely as a result of a large augmentation of residual I Ks in epicardial and endocardial cells but not in M cells, in which I Ks is intrinsically weak. Our data provide a mechanistic understanding of the cellular basis for the therapeutic actions of β-adrenergic blockers in LQT1 and suggest that sodium channel block with class IB antiarrhythmic agents may be effective in suppressing TdP in LQT1, as they are in LQT2 and LQT3, as well as in acquired (drug-induced) forms of the long-QT syndrome.