(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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W. Han, Z. Wang, and S. Nattel Slow delayed rectifier current and repolarization in canine cardiac Purkinje cells Am J Physiol Heart Circ Physiol, March 1, 2001; 280(3): H1075 - H1080. [Abstract] [Full Text] [PDF]
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J. M. Lupoglazoff, I. Denjoy, M. Berthet, N. Neyroud, L. Demay, P. Richard, B. Hainque, G. Vaksmann, D. Klug, A. Leenhardt, et al. Notched T Waves on Holter Recordings Enhance Detection of Patients With LQT2 (HERG) Mutations Circulation, February 27, 2001; 103(8): 1095 - 1101. [Abstract] [Full Text] [PDF]
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C. R Bezzina, M. B Rook, and A. A.M Wilde Cardiac sodium channel and inherited arrhythmia syndromes Cardiovasc Res, February 1, 2001; 49(2): 257 - 271. [Full Text] [PDF]
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C.-M. Chang, T.-J. Wu, S. Zhou, R. N. Doshi, M.-H. Lee, T. Ohara, M. C. Fishbein, H. S. Karagueuzian, P.-S. Chen, and L. S. Chen Nerve Sprouting and Sympathetic Hyperinnervation in a Canine Model of Atrial Fibrillation Produced by Prolonged Right Atrial Pacing Circulation, January 2, 2001; 103(1): 22 - 25. [Abstract] [Full Text] [PDF]
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P. J. Schwartz, S. G. Priori, C. Spazzolini, A. J. Moss, G. M. Vincent, C. Napolitano, I. Denjoy, P. Guicheney, G. Breithardt, M. T. Keating, et al. Genotype-Phenotype Correlation in the Long-QT Syndrome : Gene-Specific Triggers for Life-Threatening Arrhythmias Circulation, January 2, 2001; 103(1): 89 - 95. [Abstract] [Full Text] [PDF]
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S. G. Priori, R. Bloise, and L. Crotti The long QT syndrome Europace, January 1, 2001; 3(1): 16 - 27. [PDF]
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L. Zhang, K. W. Timothy, G. M. Vincent, M. H. Lehmann, J. Fox, L. C. Giuli, J. Shen, I. Splawski, S. G. Priori, S. J. Compton, et al. Spectrum of ST-T-Wave Patterns and Repolarization Parameters in Congenital Long-QT Syndrome : ECG Findings Identify Genotypes Circulation, December 5, 2000; 102(23): 2849 - 2855. [Abstract] [Full Text] [PDF]
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C. Antzelevitch Electrical Heterogeneity, Cardiac Arrhythmias, and the Sodium Channel Circ. Res., November 24, 2000; 87(11): 964 - 965. [Full Text] [PDF]
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J. Merot, V. Probst, M. Debailleul, U. Gerlach, N. S. Moise, H. Le Marec, and F. Charpentier Electropharmacological characterization of cardiac repolarization in German shepherd dogs with an inherited syndrome of sudden death: abnormal response to potassium channel blockers J. Am. Coll. Cardiol., September 1, 2000; 36(3): 939 - 947. [Abstract] [Full Text] [PDF]
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W. Shimizu and C. Antzelevitch Effects of a K+ Channel Opener to Reduce Transmural Dispersion of Repolarization and Prevent Torsade de Pointes in LQT1, LQT2, and LQT3 Models of the Long-QT Syndrome Circulation, August 8, 2000; 102(6): 706 - 712. [Abstract] [Full Text] [PDF]
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W Haverkamp, G Breithardt, A.J Camm, M.J Janse, M.R Rosen, C Antzelevitch, D Escande, M Franz, M Malik, A Moss, et al. The potential for QT prolongation and proarrhythmia by non-antiarrhythmic drugs: clinical and regulatory implications. Report on a Policy Conference of the European Society of Cardiology Eur. Heart J., August 1, 2000; 21(15): 1216 - 1231. [PDF]
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W. Haverkamp, G. Breithardt, A.J. Camm, M. J Janse, M. R Rosen, C. Antzelevitch, D. Escande, M. Franz, M. Malik, A. Moss, et al. The potential for QT prolongation and pro-arrhythmia by non-anti-arrhythmic drugs: Clinical and regulatory implications: Report on a Policy Conference of the European Society of Cardiology Cardiovasc Res, August 1, 2000; 47(2): 219 - 233. [Full Text] [PDF]
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C.-E. Chiang and D. M. Roden The long QT syndromes: genetic basis and clinical implications J. Am. Coll. Cardiol., July 1, 2000; 36(1): 1 - 12. [Abstract] [Full Text] [PDF]
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P. G.A. Volders, M. A. Vos, B. Szabo, K. R. Sipido, S.H.M. de Groot, A. P.M. Gorgels, H. J.J. Wellens, and R. Lazzara Progress in the understanding of cardiac early afterdepolarizations and torsades de pointes: time to revise current concepts Cardiovasc Res, June 1, 2000; 46(3): 376 - 392. [Full Text] [PDF]
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P. C. Viswanathan and Y. Rudy Cellular Arrhythmogenic Effects of Congenital and Acquired Long-QT Syndrome in the Heterogeneous Myocardium Circulation, March 14, 2000; 101(10): 1192 - 1198. [Abstract] [Full Text] [PDF]
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L. C. Baker, B. London, B.-R. Choi, G. Koren, and G. Salama Enhanced Dispersion of Repolarization and Refractoriness in Transgenic Mouse Hearts Promotes Reentrant Ventricular Tachycardia Circ. Res., March 3, 2000; 86(4): 396 - 407. [Abstract] [Full Text] [PDF]
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W. Shimizu and C. Antzelevitch Differential effects of beta-adrenergic agonists and antagonists in LQT1, LQT2 and LQT3 models of the long QT syndrome J. Am. Coll. Cardiol., March 1, 2000; 35(3): 778 - 786. [Abstract] [Full Text] [PDF]
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A. Varro, B. Balati, N. Iost, J. Takacs, L. Virag, D. A Lathrop, L. Csaba, L. Talosi, and J. G. Papp The role of the delayed rectifier component IKs in dog ventricular muscle and Purkinje fibre repolarization J. Physiol., February 15, 2000; 523(1): 67 - 81. [Abstract] [Full Text] [PDF]
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P. G. A. Volders, K. R. Sipido, M. A. Vos, R. L. H. M. G. Spatjens, J. D. M. Leunissen, E. Carmeliet, and H. J. J. Wellens Downregulation of Delayed Rectifier K+ Currents in Dogs With Chronic Complete Atrioventricular Block and Acquired Torsades de Pointes Circulation, December 14, 1999; 100(24): 2455 - 2461. [Abstract] [Full Text] [PDF]
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A. Bauer, R. Becker, K. D. Freigang, J. C. Senges, F. Voss, A. Hansen, M. Muller, H. J. Lang, U. Gerlach, A. Busch, et al. Rate- and Site-Dependent Effects of Propafenone, Dofetilide, and the New IKs-Blocking Agent Chromanol 293b on Individual Muscle Layers of the Intact Canine Heart Circulation, November 23, 1999; 100(21): 2184 - 2190. [Abstract] [Full Text] [PDF]
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J. J. Lynch Jr, M. S. Houle, G. L. Stump, A. A. Wallace, D. B. Gilberto, H. Jahansouz, G. R. Smith, A. J. Tebben, N. J. Liverton, H. G. Selnick, et al. Antiarrhythmic Efficacy of Selective Blockade of the Cardiac Slowly Activating Delayed Rectifier Current, IKs, in Canine Models of Malignant Ischemic Ventricular Arrhythmia Circulation, November 2, 1999; 100(18): 1917 - 1922. [Abstract] [Full Text] [PDF]
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N. S. Moise, C. Antzelevitch, and W. Shimizu As Americans, We Should Get This Right • Response Circulation, September 28, 1999; 100(13): 1462 - 1462. [Full Text] [PDF]
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Gene-specific lethality of arrhythmic events in the long QT syndrome? A message from the International Registry Eur. Heart J., August 2, 1999; 20(16): 1137 - 1139. [PDF]
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A. Busjahn, H. Knoblauch, H.-D. Faulhaber, T. Boeckel, M. Rosenthal, R. Uhlmann, M. Hoehe, H. Schuster, and F. C. Luft QT Interval Is Linked to 2 Long-QT Syndrome Loci in Normal Subjects Circulation, June 22, 1999; 99(24): 3161 - 3164. [Abstract] [Full Text] [PDF]
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W. Shimizu and C. Antzelevitch Cellular and Ionic Basis for T-Wave Alternans Under Long-QT Conditions Circulation, March 23, 1999; 99(11): 1499 - 1507. [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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