EXPERIMENTAL STUDIES
Differential effects of beta-adrenergic agonists and antagonists in LQT1, LQT2 and LQT3 models of the long QT syndrome
Wataru Shimizu, MD, PhDa and
Charles Antzelevitch, PhD, FACCa
a Masonic Medical Research Laboratory, Utica, New York, USA
Manuscript received July 30, 1999;
revised manuscript received September 21, 1999,
accepted November 3, 1999.
Reprint requests and correspondence: Dr. Charles Antzelevitch, Masonic Medical Research Laboratory, 2150 Bleecker Street, Utica, New York 13501-1787
ca{at}mmrl.edu
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 (APD90), transmural dispersion of repolarization (TDR) and the development of Torsade de Pointes (TdP) in models of LQT1, LQT2 and LQT3 forms of LQTS.
RESULTS
IKs block with chromanol 293B (LQT1) homogeneously prolonged APD90 of the three cell types without increasing TDR. Addition of isoproterenol prolonged QT and APD90 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. IKr block with d-sotalol (LQT2) and augmentation of late INa with ATX-II (LQT3) prolonged APD90 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 APD90 of M but always abbreviated EPI, thus transiently increasing TDR and the incidence of TdP. In LQT3, isoproterenol always abbreviated APD90 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.
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Abbreviations and Acronyms
| | APD | = action potential duration | | APD90 | = action potential duration measured at 90% repolarization | | APD100 | = APD measured at full repolarization | | BCL | = basic cycle length | | EAD | = early afterdepolarization | | ECG | = electrocardiogram | | Icl(ca) | = calcium activated chloride current | | Ikr | = rapidly activating delayer rectifier current | | Iks | = slowly activating delayed rectifier current | | INa-Ca | = Na+/Ca2+ exchange current | | late INa | = late sodium current | | LQTS | = long QT syndrome | | PES | = programmed electrical stimulation | | S1 | = basic stimuli | | S2 | = premature stimuli | | TdP | = Torsade de Pointes | | TDR | = transmural dispersion of repolarization |
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