on February 4, 2002
Published online before print February 4, 2002, doi: 10.1161/hc0902.104711
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Submitted on October 31, 2001
From the Cardiology Division, Department of Medicine, State University of New York Health Science Center and Veterans Affairs, NY Harbor Health Care System, Brooklyn, NY. * To whom correspondence should be addressed. E-mail: nelsherif{at}aol.com.
Background—Cardiac hypertrophy is associated with increased incidence of sudden death and susceptibility to proarrhythmic effects of antiarrhythmic agents. However, the in vivo electrophysiologic mechanism of the arrhythmias has not been investigated in detail. Methods and Results—Dose-dependent susceptibility to Torsade de Pointes (TdP) by class III drug dofetilide, 3, 10, and 30 µg/kg, was compared in 6 control dogs (C) and in 5 dogs 6 to 8 weeks after induction of complete atrioventricular block (AVB) that resulted in ventricular hypertrophy (H). Tridimensional ventricular activation and repolarization (R) patterns were simultaneously analyzed from unipolar extracellular electrograms, and local R was measured from activation recovery intervals. Both R and transmural dispersion of R (TDR) were significantly greater in dogs with H compared with C. Dofetilide resulted in cycle length--dependent and dose-dependent prolongation of R, which was more marked in left ventricular endocardium/midmyocardium compared with epicardium, resulting in significant increase of TDR. These changes were more accentuated in dogs with H compared with C. All 5 dogs with H developed TdP at a dose of 3 to 10 µg/kg, whereas only 1 of 6 C dogs developed TdP at 30 µg/kg. TdP was initiated by subendocardial focal activity that infringed on TDR, resulting in functional conduction block and reentrant excitation. Conclusions—Enhanced susceptibility of hypertrophied heart to class III drugs is attributable to baseline increased TDR and greater dose-related accentuation of TDR compared with nonhypertrophied heart. This provides the electrophysiologic substrate for drug-induced TdP.
Revised on December 19, 2001
Accepted on December 21, 2001
Electrophysiological
Mechanism of Enhanced Susceptibility of Hypertrophied Heart to
Acquired Torsade de Pointes Arrhythmias. Tridimensional Mapping of Activation and
Recovery Patterns
Dmitry O. Kozhevnikov MD,
Key words: hypertrophy • torsade de pointes • long-QT syndrome • antiarrhythmia agents
This article has been cited by other articles:
 |
|
 |
|
  M. B. Thomsen, A. Oros, M. Schoenmakers, J. M. van Opstal, J. N. Maas, J. D.M. Beekman, and M. A. Vos Proarrhythmic electrical remodelling is associated with increased beat-to-beat variability of repolarisation Cardiovasc Res, February 1, 2007; 73(3): 521 - 530. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Stengl, C. Ramakers, D. W. Donker, A. Nabar, A. V. Rybin, R. L.H.M.G. Spatjens, T. van der Nagel, W. K.W.H. Wodzig, K. R. Sipido, G. Antoons, et al. Temporal patterns of electrical remodeling in canine ventricular hypertrophy: Focus on IKs downregulation and blunted {beta}-adrenergic activation Cardiovasc Res, October 1, 2006; 72(1): 90 - 100. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Kijtawornrat, Y. Nishijima, B. M. Roche, B. W. Keene, and R. L. Hamlin Use of a Failing Rabbit Heart as a Model to Predict Torsadogenicity Toxicol. Sci., September 1, 2006; 93(1): 205 - 212. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. J. Kang Cardiac Hypertrophy: A Risk Factor for QT-Prolongation and Cardiac Sudden Death Toxicol Pathol, January 1, 2006; 34(1): 58 - 66. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Salles, S. Leocadio, K. Bloch, A. R. Nogueira, and E. Muxfeldt Combined QT Interval and Voltage Criteria Improve Left Ventricular Hypertrophy Detection in Resistant Hypertension Hypertension, November 1, 2005; 46(5): 1207 - 1212. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. D. Schreiner, K. Kelemen, J. Zehelein, R. Becker, J. C. Senges, A. Bauer, F. Voss, P. Kraft, H. A. Katus, and W. Schoels Biventricular hypertrophy in dogs with chronic AV block: effects of cyclosporin A on morphology and electrophysiology Am J Physiol Heart Circ Physiol, December 1, 2004; 287(6): H2891 - H2898. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Antzelevitch, L. Belardinelli, A. C. Zygmunt, A. Burashnikov, J. M. Di Diego, J. M. Fish, J. M. Cordeiro, and G. Thomas Electrophysiological Effects of Ranolazine, a Novel Antianginal Agent With Antiarrhythmic Properties Circulation, August 24, 2004; 110(8): 904 - 910. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Oikarinen, M. S. Nieminen, M. Viitasalo, L. Toivonen, S. Jern, B. Dahlof, R. B. Devereux, P. M. Okin, and for the LIFE Study Investigators QRS Duration and QT Interval Predict Mortality in Hypertensive Patients With Left Ventricular Hypertrophy: The Losartan Intervention for Endpoint Reduction in Hypertension Study Hypertension, May 1, 2004; 43(5): 1029 - 1034. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. M. Di Diego, L. Belardinelli, and C. Antzelevitch Cisapride-Induced Transmural Dispersion of Repolarization and Torsade de Pointes in the Canine Left Ventricular Wedge Preparation During Epicardial Stimulation Circulation, August 26, 2003; 108(8): 1027 - 1033. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. M. Russo, G. E. Hafley, K. L. Lee, N. J. Stamato, M. H. Lehmann, R. L. Page, T. Kus, and A. E. Buxton Racial Differences in Outcome in the Multicenter UnSustained Tachycardia Trial (MUSTT): A Comparison of Whites Versus Blacks Circulation, July 8, 2003; 108(1): 67 - 72. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Tsuji, T. Opthof, K. Yasui, Y. Inden, H. Takemura, N. Niwa, Z. Lu, J.-K. Lee, H. Honjo, K. Kamiya, et al. Ionic Mechanisms of Acquired QT Prolongation and Torsades de Pointes in Rabbits With Chronic Complete Atrioventricular Block Circulation, October 8, 2002; 106(15): 2012 - 2018. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Antzelevitch Sympathetic modulation of the long QT syndrome Eur. Heart J., August 2, 2002; 23(16): 1246 - 1252. [PDF]
|
|