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EXPERIMENTAL STUDIES

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

^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

I_Ks 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. I_Kr block with d-sotalol (LQT2) and augmentation of late I_Na 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.

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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