(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
This article has been cited by other articles:
 |
|
 |
|
  J. J. Goldberger, M. E. Cain, S. H. Hohnloser, A. H. Kadish, B. P. Knight, M. S. Lauer, B. J. Maron, R. L. Page, R. S. Passman, D. Siscovick, et al. American Heart Association/American College of Cardiology Foundation/Heart Rhythm Society Scientific Statement on Noninvasive Risk Stratification Techniques for Identifying Patients at Risk for Sudden Cardiac Death: A Scientific Statement From the American Heart Association Council on Clinical Cardiology Committee on Electrocardiography and Arrhythmias and Council on Epidemiology and Prevention Circulation, September 30, 2008; 118(14): 1497 - 1518. [Full Text] [PDF]
|
|
|
|
 |
|
 D. Guo, L. Young, C. Patel, Z. Jiao, Y. Wu, T. Liu, P. R. Kowey, and G.-X. Yan Calcium-activated chloride current contributes to action potential alternations in left ventricular hypertrophy rabbit Am J Physiol Heart Circ Physiol, July 1, 2008; 295(1): H97 - H104. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Mironov, J. Jalife, and E. G. Tolkacheva Role of Conduction Velocity Restitution and Short-Term Memory in the Development of Action Potential Duration Alternans in Isolated Rabbit Hearts Circulation, July 1, 2008; 118(1): 17 - 25. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. de Diego, R. K. Pai, A. S. Dave, A. Lynch, M. Thu, F. Chen, L.-H. Xie, J. N. Weiss, and M. Valderrabano Spatially discordant alternans in cardiomyocyte monolayers Am J Physiol Heart Circ Physiol, March 1, 2008; 294(3): H1417 - H1425. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Mahajan, D. Sato, Y. Shiferaw, A. Baher, L.-H. Xie, R. Peralta, R. Olcese, A. Garfinkel, Z. Qu, and J. N. Weiss Modifying L-Type Calcium Current Kinetics: Consequences for Cardiac Excitation and Arrhythmia Dynamics Biophys. J., January 15, 2008; 94(2): 411 - 423. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. B. Harvey and J. W. Buchanan Characterization of T Wave Alternans With Ambulatory Electrocardiography Biol Res Nurs, January 1, 2008; 9(3): 223 - 230. [Abstract] [PDF]
|
|
|
|
|
|
W. T. Clusin Mechanisms of calcium transient and action potential alternans in cardiac cells and tissues Am J Physiol Heart Circ Physiol, January 1, 2008; 294(1): H1 - H10. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. L. Wit and H. S. Duffy Drug development for treatment of cardiac arrhythmias: targeting the gap junctions Am J Physiol Heart Circ Physiol, January 1, 2008; 294(1): H16 - H18. [Full Text] [PDF]
|
|
|
|
|
|
A. L. Kjolbye, M. Dikshteyn, B. C. Eloff, I. Deschenes, and D. S. Rosenbaum Maintenance of intercellular coupling by the antiarrhythmic peptide rotigaptide suppresses arrhythmogenic discordant alternans Am J Physiol Heart Circ Physiol, January 1, 2008; 294(1): H41 - H49. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. de Diego, F. Chen, L.-H. Xie, A. S. Dave, M. Thu, C. Rongey, J. N. Weiss, and M. Valderrabano Cardiac alternans in embryonic mouse ventricles Am J Physiol Heart Circ Physiol, January 1, 2008; 294(1): H433 - H440. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. C. Myles, C. E. Jackson, I. Tsorlalis, M. C. Petrie, J. J. V. McMurray, and S. M. Cobbe Is Microvolt T-Wave Alternans the Answer to Risk Stratification in Heart Failure? Circulation, December 18, 2007; 116(25): 2984 - 2991. [Full Text] [PDF]
|
|
|
|
|
|
Z. I. Zhu and C. E. Clancy L-type Ca2+ channel mutations and T-wave alternans: a model study Am J Physiol Heart Circ Physiol, December 1, 2007; 293(6): H3480 - H3489. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. D. Wilson and D. S. Rosenbaum Mechanisms of arrythmogenic cardiac alternans Europace, November 1, 2007; 9(suppl_6): vi77 - vi82. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Pruvot, F. Jousset, P. Ruchat, J.-M. Vesin, Y. Prudat, T. Zerm, and M. Fromer Propagation velocity kinetics and repolarization alternans in a free-behaving sheep model of pacing-induced atrial fibrillation Europace, November 1, 2007; 9(suppl_6): vi83 - vi88. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Nieminen, T. Lehtimaki, J. Viik, R. Lehtinen, K. Nikus, T. Koobi, K. Niemela, V. Turjanmaa, W. Kaiser, H. Huhtala, et al. T-wave alternans predicts mortality in a population undergoing a clinically indicated exercise test Eur. Heart J., October 1, 2007; 28(19): 2332 - 2337. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Z. Qu and J. N. Weiss The chicken or the egg? Voltage and calcium dynamics in the heart Am J Physiol Heart Circ Physiol, October 1, 2007; 293(4): H2054 - H2055. [Full Text] [PDF]
|
|
|
|
|
|
J. F. Huizar, M. D. Warren, A. G. Shvedko, J. Kalifa, J. Moreno, S. Mironov, J. Jalife, and A. V. Zaitsev Three distinct phases of VF during global ischemia in the isolated blood-perfused pig heart Am J Physiol Heart Circ Physiol, September 1, 2007; 293(3): H1617 - H1628. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M.-J. Yang, D. X. Tran, J. N. Weiss, A. Garfinkel, and Z. Qu The pinwheel experiment revisited: effects of cellular electrophysiological properties on vulnerability to cardiac reentry Am J Physiol Heart Circ Physiol, September 1, 2007; 293(3): H1781 - H1790. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. E. Bondarenko and R. L. Rasmusson Simulations of propagated mouse ventricular action potentials: effects of molecular heterogeneity Am J Physiol Heart Circ Physiol, September 1, 2007; 293(3): H1816 - H1832. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Y. Kim, S.-J. Woo, S.-m. Hwang, J. H. Hong, and K. J. Lee Cardiac beat-to-beat alternations driven by unusual spiral waves PNAS, July 10, 2007; 104(28): 11639 - 11642. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. M. Livshitz and Y. Rudy Regulation of Ca2+ and electrical alternans in cardiac myocytes: role of CAMKII and repolarizing currents Am J Physiol Heart Circ Physiol, June 1, 2007; 292(6): H2854 - H2866. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. E. D. J. ter Keurs and P. A. Boyden Calcium and Arrhythmogenesis Physiol Rev, April 1, 2007; 87(2): 457 - 506. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Sato, Y. Shiferaw, Z. Qu, A. Garfinkel, J. N. Weiss, and A. Karma Inferring the Cellular Origin of Voltage and Calcium Alternans from the Spatial Scales of Phase Reversal during Discordant Alternans Biophys. J., February 15, 2007; 92(4): L33 - L35. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Krogh-Madsen and D. J. Christini Action Potential Duration Dispersion and Alternans in Simulated Heterogeneous Cardiac Tissue with a Structural Barrier Biophys. J., February 15, 2007; 92(4): 1138 - 1149. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Hayashi, Y. Shiferaw, D. Sato, M. Nihei, S.-F. Lin, P.-S. Chen, A. Garfinkel, J. N. Weiss, and Z. Qu Dynamic Origin of Spatially Discordant Alternans in Cardiac Tissue Biophys. J., January 15, 2007; 92(2): 448 - 460. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. L. Aistrup, J. E. Kelly, S. Kapur, M. Kowalczyk, I. Sysman-Wolpin, A. H. Kadish, and J. A. Wasserstrom Pacing-induced Heterogeneities in Intracellular Ca2+ Signaling, Cardiac Alternans, and Ventricular Arrhythmias in Intact Rat Heart Circ. Res., September 29, 2006; 99(7): E65 - E73. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Sato, Y. Shiferaw, A. Garfinkel, J. N. Weiss, Z. Qu, and A. Karma Spatially Discordant Alternans in Cardiac Tissue: Role of Calcium Cycling Circ. Res., September 1, 2006; 99(5): 520 - 527. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Z. Qu, A. Garfinkel, and J. N. Weiss Vulnerable Window for Conduction Block in a One-Dimensional Cable of Cardiac Cells, 1: Single Extrasystoles Biophys. J., August 1, 2006; 91(3): 793 - 804. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Z. Qu, A. Garfinkel, and J. N. Weiss Vulnerable Window for Conduction Block in a One-Dimensional Cable of Cardiac Cells, 2: Multiple Extrasystoles Biophys. J., August 1, 2006; 91(3): 805 - 815. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Wisialowski, K. Crimin, J. Engtrakul, J. O'Donnell, B. Fermini, and A. A. Fossa Differentiation of Arrhythmia Risk of the Antibacterials Moxifloxacin, Erythromycin, and Telithromycin Based on Analysis of Monophasic Action Potential Duration Alternans and Cardiac Instability J. Pharmacol. Exp. Ther., July 1, 2006; 318(1): 352 - 359. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. Shusterman, A. Goldberg, and B. London Upsurge in T-Wave Alternans and Nonalternating Repolarization Instability Precedes Spontaneous Initiation of Ventricular Tachyarrhythmias in Humans Circulation, June 27, 2006; 113(25): 2880 - 2887. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. N. Weiss, A. Karma, Y. Shiferaw, P.-S. Chen, A. Garfinkel, and Z. Qu From Pulsus to Pulseless: The Saga of Cardiac Alternans Circ. Res., May 26, 2006; 98(10): 1244 - 1253. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. G. Chang, L. Tung, R. B. Sekar, C. Y. Chang, J. Cysyk, P. Dong, E. Marban, and M. R. Abraham Proarrhythmic Potential of Mesenchymal Stem Cell Transplantation Revealed in an In Vitro Coculture Model Circulation, April 18, 2006; 113(15): 1832 - 1841. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Shiferaw and A. Karma Turing instability mediated by voltage and calcium diffusion in paced cardiac cells PNAS, April 11, 2006; 103(15): 5670 - 5675. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Bien, L. Yin, and E. Entcheva Calcium Instabilities in Mammalian Cardiomyocyte Networks Biophys. J., April 1, 2006; 90(7): 2628 - 2640. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. M. Scheinman and E. Keung The Year in Clinical Electrophysiology J. Am. Coll. Cardiol., March 21, 2006; 47(6): 1207 - 1213. [Full Text] [PDF]
|
|
|
|
|
|
W. Bian and L. Tung Structure-Related Initiation of Reentry by Rapid Pacing in Monolayers of Cardiac Cells Circ. Res., March 3, 2006; 98(4): e29 - e38. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. P. Nash, C. P. Bradley, P. M. Sutton, R. H. Clayton, P. Kallis, M. P. Hayward, D. J. Paterson, and P. Taggart Whole heart action potential duration restitution properties in cardiac patients: a combined clinical and modelling study Exp Physiol, March 1, 2006; 91(2): 339 - 354. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. M. Narayan T-Wave Alternans and the Susceptibility to Ventricular Arrhythmias J. Am. Coll. Cardiol., January 17, 2006; 47(2): 269 - 281. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. N. Jordan and D. J. Christini Action Potential Morphology Influences Intracellular Calcium Handling Stability and the Occurrence of Alternans Biophys. J., January 15, 2006; 90(2): 672 - 680. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Poelzing, B. J. Roth, and D. S. Rosenbaum Optical measurements reveal nature of intercellular coupling across ventricular wall Am J Physiol Heart Circ Physiol, October 1, 2005; 289(4): H1428 - H1435. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Z. Qu and J. N. Weiss Effects of Na+ and K+ channel blockade on vulnerability to and termination of fibrillation in simulated normal cardiac tissue Am J Physiol Heart Circ Physiol, October 1, 2005; 289(4): H1692 - H1701. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. L. Koller, S. K.G. Maier, A. R. Gelzer, W. R. Bauer, M. Meesmann, and R. F. Gilmour Jr Altered Dynamics of Action Potential Restitution and Alternans in Humans With Structural Heart Disease Circulation, September 13, 2005; 112(11): 1542 - 1548. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. N. Weiss, Z. Qu, P.-S. Chen, S.-F. Lin, H. S. Karagueuzian, H. Hayashi, A. Garfinkel, and A. Karma The Dynamics of Cardiac Fibrillation Circulation, August 23, 2005; 112(8): 1232 - 1240. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. K. Gehi, R. H. Stein, L. D. Metz, and J. A. Gomes Microvolt T-Wave Alternans for the Risk Stratification of Ventricular Tachyarrhythmic Events: A Meta-Analysis J. Am. Coll. Cardiol., July 5, 2005; 46(1): 75 - 82. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
O. Bernus, C. W. Zemlin, R. M. Zaritsky, S. F. Mironov, and A. M. Pertsov Alternating conduction in the ischaemic border zone as precursor of reentrant arrhythmias: A simulation study Europace, January 1, 2005; 7(s2): S93 - S104. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. Lakireddy, P. Baweja, A. Syed, G. Bub, M. Boutjdir, and N. El-Sherif Contrasting effects of ischemia on the kinetics of membrane voltage and intracellular calcium transient underlie electrical alternans Am J Physiol Heart Circ Physiol, January 1, 2005; 288(1): H400 - H407. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Z. Qu Dynamical effects of diffusive cell coupling on cardiac excitation and propagation: a simulation study Am J Physiol Heart Circ Physiol, December 1, 2004; 287(6): H2803 - H2812. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Huang, X. Zhou, W. M. Smith, and R. E. Ideker Restitution Properties During Ventricular Fibrillation in the In Situ Swine Heart Circulation, November 16, 2004; 110(20): 3161 - 3167. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Bursac, F. Aguel, and L. Tung Multiarm spirals in a two-dimensional cardiac substrate PNAS, October 26, 2004; 101(43): 15530 - 15534. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. R. Efimov, V. P. Nikolski, and G. Salama Optical Imaging of the Heart Circ. Res., July 9, 2004; 95(1): 21 - 33. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. M. Cherry and F. H. Fenton Suppression of alternans and conduction blocks despite steep APD restitution: electrotonic, memory, and conduction velocity restitution effects Am J Physiol Heart Circ Physiol, June 1, 2004; 286(6): H2332 - H2341. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Hua, D. C. Johns, and R. F. Gilmour Jr. Suppression of electrical alternans by overexpression of HERG in canine ventricular myocytes Am J Physiol Heart Circ Physiol, June 1, 2004; 286(6): H2342 - H2351. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Omichi, S. T. Lamp, S.-F. Lin, J. Yang, A. Baher, S. Zhou, M. Attin, M.-H. Lee, H. S. Karagueuzian, B. Kogan, et al. Intracellular Ca dynamics in ventricular fibrillation Am J Physiol Heart Circ Physiol, May 1, 2004; 286(5): H1836 - H1844. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. Libbus, X. Wan, and D. S. Rosenbaum Electrotonic load triggers remodeling of repolarizing current Ito in ventricle Am J Physiol Heart Circ Physiol, May 1, 2004; 286(5): H1901 - H1909. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. J. Pruvot, R. P. Katra, D. S. Rosenbaum, and K. R. Laurita Role of Calcium Cycling Versus Restitution in the Mechanism of Repolarization Alternans Circ. Res., April 30, 2004; 94(8): 1083 - 1090. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Z. Qu, H. S. Karagueuzian, A. Garfinkel, and J. N. Weiss Effects of Na+ channel and cell coupling abnormalities on vulnerability to reentry: a simulation study Am J Physiol Heart Circ Physiol, April 1, 2004; 286(4): H1310 - H1321. [Abstract] [Full Text] [PDF]
|
|