(Circulation. 1998;98:2314-2322.)
© 1998 American Heart Association, Inc.
Basic Science Reports |
Cellular Basis for the ECG Features of the LQT1 Form of the Long-QT Syndrome
Effects of ß-Adrenergic Agonists and Antagonists and Sodium Channel Blockers on Transmural Dispersion of Repolarization and Torsade de Pointes
From the Masonic Medical Research Laboratory, Utica, NY.
Correspondence to Dr Charles Antzelevitch, Masonic Medical Research Laboratory, 2150 Bleecker St, Utica, NY 13501-1787. E-mail ca{at}mmrl.edu
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 ß-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 IKs blocker, dose-dependently (1 to 100 µmol/L) prolonged the QT interval and action potential duration (APD90) 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 APD90 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 IKs 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 APD90 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 IKs alone does not induce TdP but that the addition of ß-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 IKs in epicardial and endocardial cells but not in M cells, in which IKs is intrinsically weak. Our data provide a mechanistic understanding of the cellular basis for the therapeutic actions of ß-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.
Key Words: long-QT syndrome • arrhythmia • KvLQT1 • chromanol 293b • isoproterenol
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