Electrophysiologic substrate of torsade de pointes: dispersion of repolarization or early afterdepolarizations?

Krannert Institute of Cardiology, Department of Medicine, Indiana University School of Medicine, Indianapolis 46202.

Recent experimental and clinical studies suggest that torsade de pointes may be precipitated by early afterdepolarizations in the Purkinje or ventricular muscle fibers. This hypothesis offers an alternative to the earlier one that attributes torsade to the underlying dispersion of repolarization. This review lists the clinical conditions associated with torsade de pointes and examines the experimental background of the two proposed electrophysiologic substrates of torsade, namely, the dispersion of repolarization and the early afterdepolarizations. The strengths and weaknesses of the two hypotheses are compared in relation to the following characteristics of torsade de pointes: facilitation by slow heart rate, suppression by pacing, R on T phenomenon, difficulty of induction by programmed stimulation, aggravation by hypokalemia, manifestation of an idiosyncratic reaction to class IA antiarrhythmic drugs, spontaneous termination, suppression by magnesium salts and isoproterenol and induction by such drugs as sotalol, bepridil and prenylamine. It appears that most clinical observations can be explained by either mechanism, but in some cases difficulties are encountered for the afterdepolarization hypothesis.

This article has been cited by other articles:

				M. Chinushi, D. Izumi, K. Iijima, S. Ahara, S. Komura, H. Furushima, Y. Hosaka, and Y. Aizawa Antiarrhythmic vs. pro-arrhythmic effects depending on the intensity of adrenergic stimulation in a canine anthopleurin-A model of type-3 long QT syndrome Europace, February 1, 2008; 10(2): 249 - 255. [Abstract] [Full Text] [PDF]

				B. London, L. C. Baker, P. Petkova-Kirova, J. M. Nerbonne, B.-R. Choi, and G. Salama Dispersion of repolarization and refractoriness are determinants of arrhythmia phenotype in transgenic mice with long QT J. Physiol., January 1, 2007; 578(1): 115 - 129. [Abstract] [Full Text] [PDF]

				N. Ueda, D. P. Zipes, and J. Wu Coronary occlusion and reperfusion promote early afterdepolarizations and ventricular tachycardia in a canine tissue model of type 3 long QT syndrome Am J Physiol Heart Circ Physiol, February 1, 2006; 290(2): H607 - H612. [Abstract] [Full Text] [PDF]

				N. Ueda, D. P Zipes, and J. Wu Prior ischemia enhances arrhythmogenicity in isolated canine ventricular wedge model of long QT 3 Cardiovasc Res, July 1, 2004; 63(1): 69 - 76. [Abstract] [Full Text] [PDF]

				J. He, M. E. Kargacin, G. J. Kargacin, and C. A. Ward Tamoxifen inhibits Na+ and K+ currents in rat ventricular myocytes Am J Physiol Heart Circ Physiol, July 11, 2003; 285(2): H661 - H668. [Abstract] [Full Text] [PDF]

				N. lost, L. Virag, A. Varro, and J. Gy. Papp Comparison of the Effect of Class IA Antiarrhythmic Drugs on Transmembrane Potassium Currents in Rabbit Ventricular Myocytes Journal of Cardiovascular Pharmacology and Therapeutics, March 1, 2003; 8(1): 31 - 41. [Abstract] [PDF]

				M. Viitasalo, L. Oikarinen, H. Swan, H. Vaananen, K. Glatter, P. J. Laitinen, K. Kontula, H. V. Barron, L. Toivonen, and M. M. Scheinman Ambulatory Electrocardiographic Evidence of Transmural Dispersion of Repolarization in Patients With Long-QT Syndrome Type 1 and 2 Circulation, November 5, 2002; 106(19): 2473 - 2478. [Abstract] [Full Text] [PDF]

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

				T. V. Pham and M. R. Rosen Sex, hormones, and repolarization Cardiovasc Res, February 15, 2002; 53(3): 740 - 751. [Abstract] [Full Text] [PDF]

				J. Wu, J. Wu, and D. P. Zipes Early Afterdepolarizations, U Waves, and Torsades de Pointes Circulation, February 12, 2002; 105(6): 675 - 676. [Full Text] [PDF]

				J. M. van Opstal, M. Schoenmakers, S. C. Verduyn, S.H. M. de Groot, J. D.M. Leunissen, F. F. van der Hulst, M. M.C. Molenschot, H. J.J. Wellens, and M. A. Vos Chronic Amiodarone Evokes No Torsade de Pointes Arrhythmias Despite QT Lengthening in an Animal Model of Acquired Long-QT Syndrome Circulation, November 27, 2001; 104(22): 2722 - 2727. [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]

				J. A. Sánchez-Chapula, E. Salinas-Stefanon, J. Torres-Jácome, D. E. Benavides-Haro, and R. A. Navarro-Polanco Blockade of Currents by the Antimalarial Drug Chloroquine in Feline Ventricular Myocytes J. Pharmacol. Exp. Ther., April 1, 2001; 297(1): 437 - 445. [Abstract] [Full Text]

				H. Tikiz, T. Terzi, Y. Balbay, A. D. Demir, M. Soylu, T. Keles, and E. Kutuk QT Dispersion in Single Coronary Artery Disease: Is There a Relation Between QT Dispersion and Diseased Coronary Artery or Lesion Localization? Angiology, January 1, 2001; 52(1): 43 - 51. [Abstract] [PDF]

				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]

				A.J. Camm, M.J. Janse, D.M. Roden, M.R. Rosen, J. Cinca, and S.M. Cobbe Congenital and acquired long QT syndrome Eur. Heart J., August 1, 2000; 21(15): 1232 - 1237. [PDF]

				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]

				H Yamanari, K Nakayama, H Morita, K Miyazi, K Fukushima, H Matsubara, T Emori, and T Ohe Effects of cardiac sympathetic innervation on regional wall motion abnormality in patients with long QT syndrome Heart, March 1, 2000; 83(3): 295 - 300. [Abstract] [Full Text]

				J. B. Moubarak, P. E. Karasik, R. D. Fletcher, and M. R. Franz High dispersion of ventricular repolarization after an implantable defibrillator shock predicts induction of ventricular fibrillation as well as unsuccessful defibrillation J. Am. Coll. Cardiol., February 1, 2000; 35(2): 422 - 427. [Abstract] [Full Text] [PDF]

				J. Merot, F. Charpentier, J.-M. Poirier, G. Coutris, and J. Weissenburger Effects of chronic treatment by amiodarone on transmural heterogeneity of canine ventricular repolarization in vivo: interactions with acute sotalol Cardiovasc Res, November 1, 1999; 44(2): 303 - 314. [Abstract] [Full Text] [PDF]

				P. C. Viswanathan, R. M. Shaw, and Y. Rudy Effects of IKr and IKs Heterogeneity on Action Potential Duration and Its Rate Dependence : A Simulation Study Circulation, May 11, 1999; 99(18): 2466 - 2474. [Abstract] [Full Text] [PDF]

				P. C Viswanathan and Y. Rudy Pause induced early afterdepolarizations in the long QT syndrome: a simulation study Cardiovasc Res, May 1, 1999; 42(2): 530 - 542. [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]

				E. Robert, A. G. M. Aya, J. E. de la Coussaye, P. Peray, J.-M. Juan, J. Brugada, J.-M. Davy, and J.-J. Eledjam Dispersion-based reentry: mechanism of initiation of ventricular tachycardia in isolated rabbit hearts Am J Physiol Heart Circ Physiol, February 1, 1999; 276(2): H413 - H423. [Abstract] [Full Text] [PDF]

				M. T. Speakman and E. Ostrzega Primary Hyperparathyroidism and Polymorphic Ventricular Tachycardia Journal of Cardiovascular Pharmacology and Therapeutics, January 1, 1999; 4(4): 269 - 271. [Abstract] [PDF]

				K Nakayama, H Yamanari, F Otsuka, K Fukushima, H Saito, Y Fujimoto, T Emori, H Matsubara, S Uchida, and T Ohe Dispersion of regional wall motion abnormality in patients with long QT syndrome Heart, September 1, 1998; 80(3): 245 - 250. [Abstract] [Full Text]

				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]

				K. Derakhchan, R. Cardinal, S. Brunet, D. Klug, C. Pharand, T. Kus, and B. I. Sasyniuk Polymorphic ventricular tachycardias induced by D-sotalol and phenylephrine in canine preparations of atrioventricular block: initiation in the conduction system followed by spatially unstable re-entry Cardiovasc Res, June 1, 1998; 38(3): 617 - 630. [Abstract] [Full Text] [PDF]

				G. Cui, P. T. Sager, B. N. Singh, and L. Sen Different Effects of Amiodarone and Quinidine on the Homogeneity of Myocardial Refractoriness in Patients With Intraventricular Conduction Delay Journal of Cardiovascular Pharmacology and Therapeutics, January 1, 1998; 3(3): 201 - 207. [Abstract] [PDF]

				N. Takahashi, M. Ito, T. Saikawa, M. Arita, T. Fujino, H. Kagiyama, T. Fukumoto, and T. Sakata Clinical suppression of bradycardia dependent premature ventricular contractions by the potassium channel opener nicorandil Heart, January 1, 1998; 79(1): 64 - 68. [Abstract] [Full Text] [PDF]

				W. Shimizu and C. Antzelevitch 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 Circulation, September 16, 1997; 96(6): 2038 - 2047. [Abstract] [Full Text]

				S.C. Verduyn, M.A. Vos, J. van der Zande, F.F. van der Hulst, and H.J. Wellens Role of interventricular dispersion of repolarization in acquired torsade-de-pointes arrhythmias: reversal by magnesium Cardiovasc Res, June 1, 1997; 34(3): 453 - 463. [Abstract] [Full Text] [PDF]

				S. Sicouri, S. Moro, and M. V. Elizari d-Sotalol Induces Marked Action Potential Prolongation and Early Afterdepolarizations in M but Not Epicardial or Endocardial Cells of the Canine Ventricle Journal of Cardiovascular Pharmacology and Therapeutics, January 1, 1997; 2(1): 27 - 37. [Abstract] [PDF]

				N. El-Sherif, E. B. Caref, H. Yin, and M. Restivo The Electrophysiological Mechanism of Ventricular Arrhythmias in the Long QT Syndrome: Tridimensional Mapping of Activation and Recovery Patterns Circ. Res., September 1, 1996; 79(3): 474 - 492. [Abstract] [Full Text]

				A. A. Grace and K. R. Chien Congenital Long QT Syndromes : Toward Molecular Dissection of Arrhythmia Substrates Circulation, November 15, 1995; 92(10): 2786 - 2789. [Full Text]

				J. J. Salata, N. K. Jurkiewicz, A. A. Wallace, R. F. Stupienski III, P. J. Guinosso Jr, and J. J. Lynch Jr Cardiac Electrophysiological Actions of the Histamine H1-Receptor Antagonists Astemizole and Terfenadine Compared With Chlorpheniramine and Pyrilamine Circ. Res., January 1, 1995; 76(1): 110 - 119. [Abstract] [Full Text]