Optical mapping of drug-induced polymorphic arrhythmias and torsade de pointes in the isolated rabbit heart

Department of Pharmacology, State University of New York Health Science Center, Syracuse 13210, USA.

OBJECTIVES: This study sought to 1) test the hypothesis that in the setting of bradycardia and drug-induced action potential prolongation, multiple foci of early afterdepolarizations (EADs) result in beat to beat changes in the origin and direction of the excitation wave front and are responsible for polymorphic arrhythmias; and 2) determine whether EADs may initiate nonstationary reentry, giving rise to the typical torsade de pointes (TDP) pattern. BACKGROUND: In the past, it has been difficult to associate EADs or reentry with the undulating electrocardiographic (ECG) patterns of TDP. METHODS: A voltage-sensitive dye was used for high resolution video imaging of electrical waves on the epicardial and endocardial surface of the Langendorff-perfused rabbit heart. ECG and monophasic action potentials from the right septal region were also recorded. Bradycardia was induced by ablation of the atrioventricular node. RESULTS: Perfusion of low potassium chloride Tyrode solution plus quinidine led to prolongation of the action potential and the QT interval. Eventually, EADs and triggered activity ensued, giving rise to intermittent episodes of polymorphic arrhythmia. In one experiment, triggered activity was followed by a long episode of vortex-like reentry with an ECG pattern characteristic of TDP. However, in most experiments, focal activity of varying origins and propagation patterns was observed. Triggered responses also showed varying degrees of local block. Similar results were obtained with E-4031. Burst pacing both at control conditions and in the presence of quinidine consistently led to vortex-like reentry whose ECG pattern resembled TDP. However, the cycle length of the arrhythmia with quinidine was longer than that for control ([mean +/- SEM] 194 +/- 12 vs. 132 +/- 8 ms, p < 0.03). CONCLUSIONS: Drug-induced polymorphic ventricular arrhythmias may result from beat to beat changes in wave propagation patterns initiated by EADs or EAD-induced nonstationary reentrant activity. In contrast, burst pacing-induced polymorphic tachycardia in the presence or absence of drugs is the result of nonstationary reentrant activity.

This article has been cited by other articles:

				M. Boulaksil, J. G. Jungschleger, G. Antoons, M. J. C. Houtman, T. P. de Boer, R. Wilders, J. D. Beekman, J. G. Maessen, F. F. van der Hulst, M. A. G. van der Heyden, et al. Drug-Induced Torsade de Pointes Arrhythmias in the Chronic AV Block Dog Are Perpetuated by Focal Activity Circ Arrhythm Electrophysiol, August 1, 2011; 4(4): 566 - 576. [Abstract] [Full Text] [PDF]

				M. S. Link, D. L. Atkins, R. S. Passman, H. R. Halperin, R. A. Samson, R. D. White, M. T. Cudnik, M. D. Berg, P. J. Kudenchuk, and R. E. Kerber Part 6: Electrical Therapies: Automated External Defibrillators, Defibrillation, Cardioversion, and Pacing * 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Circulation, November 2, 2010; 122(18_suppl_3): S706 - S719. [Full Text] [PDF]

				P. Stewart, O. V. Aslanidi, D. Noble, P. J. Noble, M. R. Boyett, and H. Zhang Mathematical models of the electrical action potential of Purkinje fibre cells Phil Trans R Soc A, June 13, 2009; 367(1896): 2225 - 2255. [Abstract] [Full Text] [PDF]

				D. Sato, L.-H. Xie, A. A. Sovari, D. X. Tran, N. Morita, F. Xie, H. Karagueuzian, A. Garfinkel, J. N. Weiss, and Z. Qu Synchronization of chaotic early afterdepolarizations in the genesis of cardiac arrhythmias PNAS, March 3, 2009; 106(9): 2983 - 2988. [Abstract] [Full Text] [PDF]

				E. B. Caref, M. Boutjdir, H. D. Himel, and N. El-Sherif Role of subendocardial Purkinje network in triggering torsade de pointes arrhythmia in experimental long QT syndrome Europace, October 1, 2008; 10(10): 1218 - 1223. [Abstract] [Full Text] [PDF]

				A. Matiukas, B. G. Mitrea, A. M. Pertsov, J. P. Wuskell, M.-d. Wei, J. Watras, A. C. Millard, and L. M. Loew New near-infrared optical probes of cardiac electrical activity Am J Physiol Heart Circ Physiol, June 1, 2006; 290(6): H2633 - H2643. [Abstract] [Full Text] [PDF]

				A. N. Katchman, J. Koerner, T. Tosaka, R. L. Woosley, and S. N. Ebert Comparative Evaluation of HERG Currents and QT Intervals following Challenge with Suspected Torsadogenic and Nontorsadogenic Drugs J. Pharmacol. Exp. Ther., March 1, 2006; 316(3): 1098 - 1106. [Abstract] [Full Text] [PDF]

				C. W. Zemlin, S. Mironov, and A. M. Pertsov Near-threshold field stimulation: Intramural versus surface activation Cardiovasc Res, January 1, 2006; 69(1): 98 - 106. [Abstract] [Full Text] [PDF]

				R. P. Katra and K. R. Laurita Cellular Mechanism of Calcium-Mediated Triggered Activity in the Heart Circ. Res., March 18, 2005; 96(5): 535 - 542. [Abstract] [Full Text] [PDF]

				W. Han, L. Zhang, G. Schram, and S. Nattel Properties of potassium currents in Purkinje cells of failing human hearts Am J Physiol Heart Circ Physiol, December 1, 2002; 283(6): H2495 - H2503. [Abstract] [Full Text] [PDF]

				W. Han, W. Bao, Z. Wang, and S. Nattel Comparison of Ion-Channel Subunit Expression in Canine Cardiac Purkinje Fibers and Ventricular Muscle Circ. Res., November 1, 2002; 91(9): 790 - 797. [Abstract] [Full Text] [PDF]

				C. Antzelevitch Sympathetic modulation of the long QT syndrome Eur. Heart J., August 2, 2002; 23(16): 1246 - 1252. [PDF]

				G. Schram, M. Pourrier, P. Melnyk, and S. Nattel Differential Distribution of Cardiac Ion Channel Expression as a Basis for Regional Specialization in Electrical Function Circ. Res., May 17, 2002; 90(9): 939 - 950. [Abstract] [Full Text] [PDF]

				G.-X. Yan, S. J. Rials, Y. Wu, T. Liu, X. Xu, R. A. Marinchak, and P. R. Kowey Ventricular hypertrophy amplifies transmural repolarization dispersion and induces early afterdepolarization Am J Physiol Heart Circ Physiol, November 1, 2001; 281(5): H1968 - H1975. [Abstract] [Full Text] [PDF]

				C. Antzelevitch Heterogeneity of cellular repolarization in LQTS: the role of M cells Eur. Heart J. Suppl., September 1, 2001; 3(suppl_K): K2 - K16. [Abstract] [PDF]

				A. W. Cates, W. M. Smith, R. E. Ideker, and A. E. Pollard Purkinje and ventricular contributions to endocardial activation sequence in perfused rabbit right ventricle Am J Physiol Heart Circ Physiol, August 1, 2001; 281(2): H490 - H505. [Abstract] [Full Text] [PDF]

				F. G. Akar, B. J. Roth, and D. S. Rosenbaum Optical measurement of cell-to-cell coupling in intact heart using subthreshold electrical stimulation Am J Physiol Heart Circ Physiol, August 1, 2001; 281(2): H533 - H542. [Abstract] [Full Text] [PDF]

				J. F. Spear and E. N. Moore Modulation of arrhythmias by isoproterenol in a rabbit heart model of d-sotalol-induced long Q-T intervals Am J Physiol Heart Circ Physiol, July 1, 2000; 279(1): H15 - H25. [Abstract] [Full Text] [PDF]

				D. Vaidya, G. E. Morley, F. H. Samie, and J. Jalife Reentry and Fibrillation in the Mouse Heart : A Challenge to the Critical Mass Hypothesis Circ. Res., July 23, 1999; 85(2): 174 - 181. [Abstract] [Full Text] [PDF]

				D. Lacroix, F. Extramiana, P. Delfaut, M. Adamantidis, D. Grandmougin, D. Klug, S. Kacet, and B. Dupuis Factors affecting epicardial dispersion of repolarization: a mapping study in the isolated porcine heart Cardiovasc Res, March 1, 1999; 41(3): 563 - 574. [Abstract] [Full Text] [PDF]

				L. Eckardt, W. Haverkamp, M. Borggrefe, and G. Breithardt Experimental models of torsade de pointes Cardiovasc Res, July 1, 1998; 39(1): 178 - 193. [Abstract] [Full Text] [PDF]

				O. Berenfeld and J. Jalife Purkinje-Muscle Reentry as a Mechanism of Polymorphic Ventricular Arrhythmias in a 3-Dimensional Model of the Ventricles Circ. Res., June 1, 1998; 82(10): 1063 - 1077. [Abstract] [Full Text] [PDF]

				J. F. Spear and E. N. Moore Modulation of quinidine-induced arrhythmias by temperature in perfused rabbit heart Am J Physiol Heart Circ Physiol, March 1, 1998; 274(3): H817 - H828. [Abstract] [Full Text] [PDF]

				S. Nattel Experimental evidence for proarrhythmic mechanisms of antiarrhythmic drugs Cardiovasc Res, March 1, 1998; 37(3): 567 - 577. [Abstract] [Full Text] [PDF]