Differential effects of beta-adrenergic agonists and antagonists in LQT1, LQT2 and LQT3 models of the long QT syndrome

OBJECTIVES To define the cellular mechanisms responsible for the development of life-threatening arrhythmias in response to sympathetic activity in the congenital and acquired long QT syndromes (LQTS). METHODS Transmembrane action potentials (AP) from epicardial (EPI), M and endocardial (ENDO) cells and a transmural electrocardiogram were simultaneously recorded from an arterially perfused wedge of canine left ventricle. We examined the effect of beta-adrenergic agonists and antagonists on action potential duration (APD(90)), transmural dispersion of repolarization (TDR) and the development of Torsade de Pointes (TdP) in models of LQT1, LQT2 and LQT3 forms of LQTS. RESULTS I-Ks block with chromanol 293B (LQT1) homogeneously prolonged APD(90) of the three cell types without increasing TDR. Addition of isoproterenol prolonged QT and APD(90) of M but abbreviated that of EPI and ENDO, causing a persistent increase in TDR; Torsade de Pointes developed or could be induced only in the presence of isoproterenol. I-Kr block with d-sotalol (LQT2) and augmentation of late I-Na with ATX-II (LQT3) prolonged APD(90) of M more than EPI and ENDO, causing increases in QT and TDR. TdP developed in the absence of isoproterenol. In LQT2 isoproterenol initially prolonged, then abbreviated, the APD(90) of M but always abbreviated EPI, thus transiently increasing TDR and the incidence of TdP. In LQT3, isoproterenol always abbreviated APD(90) of the three cell types, causing a persistent decrease in TDR and suppression of TdP. The arrhythmogenic as well as protective actions of isoproterenol were reversed by propranolol. CONCLUSIONS Our data suggest that beta-adrenergic stimulation induces TdP by increasing transmural dispersion of repolarization in LQT1 and LQT2 but suppresses TdP by decreasing dispersion in LQT3. The data indicate that beta-blockers are protective in LQT1 and LQT2 but may facilitate TdP in LQT3. (C) 2000 by the American College of Cardiology.