(Circulation. 1999;99:1385-1394.)
© 1999 American Heart Association, Inc.
Basic Science Reports |
Mechanism Linking T-Wave Alternans to the Genesis of Cardiac Fibrillation
Presented in part at the 18th annual scientific sessions of the North American Society of Pacing and Electrophysiology, New Orleans, La, 1997.
From the Departments of Medicine and Biomedical Engineering and the Cardiac Bioelectricity Research and Training Center, Case Western Reserve University, and the Veterans Affairs Medical Center, Cleveland, Ohio.
Correspondence to David S. Rosenbaum, MD, Case Western Reserve University, Department of Biomedical Engineering, Wickenden Building, Room 504, Cleveland, OH 44106-7207. E-mail dsr{at}pace.cwru.edu
Background—Although T-wave alternans has been closely associated with vulnerability to ventricular arrhythmias, the cellular processes underlying T-wave alternans and their role, if any, in the mechanism of reentry remain unclear.
Methods and Results—T-wave alternans on the surface ECG was elicited in 8 Langendorff-perfused guinea pig hearts during fixed-rate pacing while action potentials were recorded simultaneously from 128 epicardial sites with voltage-sensitive dyes. Alternans of the repolarization phase of the action potential was observed above a critical threshold heart rate (HR) (209±46 bpm) that was significantly lower (by 57±36 bpm) than the HR threshold for alternation of action potential depolarization. The magnitude (range, 2.7 to 47.0 mV) and HR threshold (range, 171 to 272 bpm) of repolarization alternans varied substantially between cells across the epicardial surface. T-wave alternans on the surface ECG was explained primarily by beat-to-beat alternation in the time course of cellular repolarization. Above a critical HR, membrane repolarization alternated with the opposite phase between neighboring cells (ie, discordant alternans), creating large spatial gradients of repolarization. In the presence of discordant alternans, a small acceleration of pacing cycle length produced a characteristic sequence of events: (1) unidirectional block of an impulse propagating against steep gradients of repolarization, (2) reentrant propagation, and (3) the initiation of ventricular fibrillation.
Conclusions—Repolarization alternans at the level of the single cell accounts for T-wave alternans on the surface ECG. Discordant alternans produces spatial gradients of repolarization of sufficient magnitude to cause unidirectional block and reentrant ventricular fibrillation. These data establish a mechanism linking T-wave alternans of the ECG to the pathogenesis of sudden cardiac death.
Key Words: mapping • repolarization • fibrillation • electrical alternans • reentry • electrocardiogram
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J. Kockskamper and L. A Blatter Subcellular Ca2+ alternans represents a novel mechanism for the generation of arrhythmogenic Ca2+ waves in cat atrial myocytes J. Physiol., November 15, 2002; 545(1): 65 - 79. [Abstract] [Full Text] [PDF]
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S. M. Narayan, F. Bode, P. L. Karasik, and M. R. Franz Alternans of Atrial Action Potentials During Atrial Flutter as a Precursor to Atrial Fibrillation Circulation, October 8, 2002; 106(15): 1968 - 1973. [Abstract] [Full Text] [PDF]
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B. Pieske and J. Kockskamper Alternans Goes Subcellular: A "Disease" of the Ryanodine Receptor? Circ. Res., October 4, 2002; 91(7): 553 - 555. [Full Text] [PDF]
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A. A. Armoundas, G. F. Tomaselli, and H. D. Esperer Pathophysiological basis and clinical application of T-wave alternans J. Am. Coll. Cardiol., July 17, 2002; 40(2): 207 - 217. [Abstract] [Full Text] [PDF]
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H. Kitamura, Y. Ohnishi, K. Okajima, A. Ishida, E. Galeano, K. Adachi, and M. Yokoyama Onset heart rate of microvolt-level T-wave alternans provides clinical and prognostic value in nonischemic dilated cardiomyopathy J. Am. Coll. Cardiol., January 16, 2002; 39(2): 295 - 300. [Abstract] [Full Text] [PDF]
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T. Klingenheben, G. Gronefeld, Y.-G. Li, and S. H. Hohnloser Effect of metoprolol and d,l-sotalol on microvolt-level T-wave alternans: Results of a prospective, double-blind, randomized study J. Am. Coll. Cardiol., December 1, 2001; 38(7): 2013 - 2019. [Abstract] [Full Text] [PDF]
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K. J. Sampson and C. S. Henriquez Simulation and prediction of functional block in the presence of structural and ionic heterogeneity Am J Physiol Heart Circ Physiol, December 1, 2001; 281(6): H2597 - H2603. [Abstract] [Full Text] [PDF]
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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]
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J. A. Kovach, B. D. Nearing, and R. L. Verrier Angerlike behavioral state potentiates myocardial ischemia-induced T-wave alternans in canines J. Am. Coll. Cardiol., May 1, 2001; 37(6): 1719 - 1725. [Abstract] [Full Text] [PDF]
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K. R. Laurita and A. Singal Mapping action potentials and calcium transients simultaneously from the intact heart Am J Physiol Heart Circ Physiol, May 1, 2001; 280(5): H2053 - H2060. [Abstract] [Full Text] [PDF]
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D. J. Christini, K. M. Stein, S. M. Markowitz, S. Mittal, D. J. Slotwiner, M. A. Scheiner, S. Iwai, and B. B. Lerman Nonlinear-dynamical arrhythmia control in humans PNAS, April 18, 2001; (2001) 91553398. [Abstract] [Full Text]
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F. L Burton and S. M Cobbe Dispersion of ventricular repolarization and refractory period Cardiovasc Res, April 1, 2001; 50(1): 10 - 23. [Full Text] [PDF]
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R. D. Berger Repolarization Alternans : Toward a Unifying Theory of Reentrant Arrhythmia Induction Circ. Res., December 8, 2000; 87(12): 1083 - 1084. [Full Text] [PDF]
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J. N. Weiss, P.-S. Chen, Z. Qu, H. S. Karagueuzian, and A. Garfinkel Ventricular Fibrillation : How Do We Stop the Waves From Breaking? Circ. Res., December 8, 2000; 87(12): 1103 - 1107. [Abstract] [Full Text] [PDF]
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J. M. Pastore and D. S. Rosenbaum Role of Structural Barriers in the Mechanism of Alternans-Induced Reentry Circ. Res., December 8, 2000; 87(12): 1157 - 1163. [Abstract] [Full Text] [PDF]
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M. L. Koller, M. L. Riccio, and R. F. Gilmour Jr Effects of [K+]o on electrical restitution and activation dynamics during ventricular fibrillation Am J Physiol Heart Circ Physiol, December 1, 2000; 279(6): H2665 - H2672. [Abstract] [Full Text] [PDF]
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B.-R. Choi and G. Salama Simultaneous maps of optical action potentials and calcium transients in guinea-pig hearts: mechanisms underlying concordant alternans J. Physiol., November 15, 2000; 529(1): 171 - 188. [Abstract] [Full Text] [PDF]
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K. R. Laurita and D. S. Rosenbaum Interdependence of Modulated Dispersion and Tissue Structure in the Mechanism of Unidirectional Block Circ. Res., November 10, 2000; 87(10): 922 - 928. [Abstract] [Full Text] [PDF]
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Z. Qu, A. Garfinkel, P.-S. Chen, and J. N. Weiss Mechanisms of Discordant Alternans and Induction of Reentry in Simulated Cardiac Tissue Circulation, October 3, 2000; 102(14): 1664 - 1670. [Abstract] [Full Text] [PDF]
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 P M I Sutton, P Taggart, T Opthof, R Coronel, R Trimlett, W Pugsley, and P Kallis Repolarisation and refractoriness during early ischaemia in humans Heart, October 1, 2000; 84(4): 365 - 369. [Abstract] [Full Text]
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O. Voroshilovsky, Z. Qu, M.-H. Lee, T. Ohara, G. A. Fishbein, H.-L. A. Huang, C. D. Swerdlow, S.-F. Lin, A. Garfinkel, J. N. Weiss, et al. Mechanisms of Ventricular Fibrillation Induction by 60-Hz Alternating Current in Isolated Swine Right Ventricle Circulation, September 26, 2000; 102(13): 1569 - 1574. [Abstract] [Full Text] [PDF]
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