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Circulation. 1998;98:2314-2322

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(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

Wataru Shimizu, MD, PhD; ; Charles Antzelevitch, PhD

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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P. Chevalier, C. Rodriguez, L. Bontemps, M. Miquel, G. Kirkorian, R. Rousson, F. Potet, J.-J. Schott, I. Baro, and P. Touboul
Non-invasive testing of acquired long QT syndrome: Evidence for multiple arrhythmogenic substrates
Cardiovasc Res, May 1, 2001; 50(2): 386 - 398.
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P.-S. Chen, L. S Chen, J.-M. Cao, B. Sharifi, H. S Karagueuzian, and M. C Fishbein
Sympathetic nerve sprouting, electrical remodeling and the mechanisms of sudden cardiac death
Cardiovasc Res, May 1, 2001; 50(2): 409 - 416.
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J Am Coll CardiolHome page
Y. Tanabe, M. Inagaki, T. Kurita, N. Nagaya, A. Taguchi, K. Suyama, N. Aihara, S. Kamakura, K. Sunagawa, K. Nakamura, et al.
Sympathetic stimulation produces a greater increase in both transmural and spatial dispersion of repolarization in LQT1 than LQT2 forms of congenital long QT syndrome
J. Am. Coll. Cardiol., March 1, 2001; 37(3): 911 - 919.
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Toxicol SciHome page
K. Yamamoto, T. Tamura, R. Imai, and M. Yamamoto
Acute Canine Model for Drug-Induced Torsades de Pointes in Drug Safety Evaluation--Influences of Anesthesia and Validation with Quinidine and Astemizole
Toxicol. Sci., March 1, 2001; 60(1): 165 - 176.
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Am. J. Physiol. Heart Circ. Physiol.Home page
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.
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CirculationHome page
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.
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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.
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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.
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CirculationHome page
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.
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EuropaceHome page
S. G. Priori, R. Bloise, and L. Crotti
The long QT syndrome
Europace, January 1, 2001; 3(1): 16 - 27.
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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.
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C. Antzelevitch
Electrical Heterogeneity, Cardiac Arrhythmias, and the Sodium Channel
Circ. Res., November 24, 2000; 87(11): 964 - 965.
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J Am Coll CardiolHome page
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.
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CirculationHome page
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.
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Eur Heart JHome page
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.
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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.
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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.
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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.
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CirculationHome page
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.
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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.
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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.
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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.
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CirculationHome page
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.
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CirculationHome page
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.
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CirculationHome page
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.
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CirculationHome page
N. S. Moise, C. Antzelevitch, and W. Shimizu
As Americans, We Should Get This Right • Response
Circulation, September 28, 1999; 100(13): 1462 - 1462.
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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.
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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.
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CirculationHome page
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.
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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.
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