(Circulation. 1997;96:2038-2047.)
© 1997 American Heart Association, Inc.
Articles |
Sodium Channel Block With Mexiletine Is Effective in Reducing Dispersion of Repolarization and Preventing Torsade de Pointes in LQT2 and LQT3 Models of the Long-QT Syndrome
From the Masonic Medical Research Laboratory, Utica, NY.
Correspondence to Charles Antzelevitch, PhD, Masonic Medical Research Laboratory, 2150 Bleecker St, Utica, NY 13501-1787. E-mail ca{at}mmrl.edu
Background This study examines the contribution of transmural heterogeneity of transmembrane activity to phenotypic T-wave patterns and the effects of pacing and of sodium channel block under conditions mimicking HERG and SCN5A defects linked to the congenital long-QT syndrome (LQTS).
Methods and Results A transmural ECG and transmembrane action potentials from epicardial, M, and endocardial or Purkinje cells were simultaneously recorded in an arterially perfused wedge of canine left ventricle. d-Sotalol was used to mimic LQT2, whereas ATX-II mimicked LQT3. d-Sotalol caused a preferential prolongation of the M cell action potential duration (APD90, 291±14 to 354±35 ms), giving rise to broad and sometimes low-amplitude bifurcated T waves and an increased transmural dispersion of repolarization (TDR, 51±15 to 72±17 ms). QT interval increased from 320±13 to 385±37 ms. ATX-II produced a preferential prolongation of the M cell APD90 (280±25 to 609±49 ms) and caused a marked delay in the onset of the T wave and a sharp rise in TDR (40±5 to 168±40 ms). QT-, APD90-, and dispersion-rate relations were much steeper in the ATX-II than in the d-sotalol model. Mexiletine (2 to 20 µmol/L) dose-dependently abbreviated the QT interval and APD90 of all cell types, more in the ATX-II than in the d-sotalol model, but decreased TDR equally in the two models. Mexiletine 2 to 5 µmol/L totally suppressed spontaneous torsade de pointes (TdP) and reduced the vulnerable window during which single extrastimuli could induce TdP in both models. Higher concentrations of mexiletine (10 to 20 µmol/L) totally suppressed stimulation-induced TdP.
Conclusions Our results suggest that although pacing and sodium channel block are very effective in abbreviating the QT interval and TDR in LQT3, these therapeutic approaches may also be valuable in reducing the incidence of arrhythmogenesis in LQT2.
Key Words: long-QT syndrome • torsade de pointes • arrhythmia • electrophysiology • pharmacology
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W. Zareba, A. J. Moss, P. J. Schwartz, G. M. Vincent, J. L. Robinson, S. G. Priori, J. Benhorin, E. H. Locati, J. A. Towbin, M. T. Keating, et al. Influence of the Genotype on the Clinical Course of the Long-QT Syndrome N. Engl. J. Med., October 1, 1998; 339(14): 960 - 965. [Abstract] [Full Text] [PDF]
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M. Chinushi, M. Restivo, E. B. Caref, and N. El-Sherif Electrophysiological Basis of Arrhythmogenicity of QT/T Alternans in the Long-QT Syndrome : Tridimensional Analysis of the Kinetics of Cardiac Repolarization Circ. Res., September 21, 1998; 83(6): 614 - 628. [Abstract] [Full Text] [PDF]
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M. A. Vos, S. H. M. de Groot, S. C. Verduyn, J. van der Zande, H. D. M. Leunissen, J. P. M. Cleutjens, M. van Bilsen, M. J. A. P. Daemen, J. J. Schreuder, M. A. Allessie, et al. Enhanced Susceptibility for Acquired Torsade de Pointes Arrhythmias in the Dog With Chronic, Complete AV Block Is Related to Cardiac Hypertrophy and Electrical Remodeling Circulation, September 15, 1998; 98(11): 1125 - 1135. [Abstract] [Full Text] [PDF]
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W. Shimizu, T. Kurita, K. Matsuo, K. Suyama, N. Aihara, S. Kamakura, J. A. Towbin, and K. Shimomura Improvement of Repolarization Abnormalities by a K+ Channel Opener in the LQT1 Form of Congenital Long-QT Syndrome Circulation, April 28, 1998; 97(16): 1581 - 1588. [Abstract] [Full Text] [PDF]
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N. G. Kambouris, H. B. Nuss, D. C. Johns, G. F. Tomaselli, E. Marban, and J. R. Balser Phenotypic Characterization of a Novel Long-QT Syndrome Mutation (R1623Q) in the Cardiac Sodium Channel Circulation, February 24, 1998; 97(7): 640 - 644. [Abstract] [Full Text] [PDF]
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F. G. Akar, G.-X. Yan, C. Antzelevitch, and D. S. Rosenbaum Unique Topographical Distribution of M Cells Underlies Reentrant Mechanism of Torsade de Pointes in the Long-QT Syndrome Circulation, March 12, 2002; 105(10): 1247 - 1253. [Abstract] [Full Text] [PDF]
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K. Gima and Y. Rudy Ionic Current Basis of Electrocardiographic Waveforms: A Model Study Circ. Res., May 3, 2002; 90(8): 889 - 896. [Abstract] [Full Text] [PDF]
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