© 2003 by European Society of Cardiology
Copyright © 2003, European Society of Cardiology
Repolarization alternans: implications for the mechanism and prevention of sudden cardiac death
The Heart and Vascular Research Center, MetroHealth Campus, Case Western Reserve University, 2500 MetroHealth Drive, Hamman 322, Cleveland, OH 44109-1998, USA
drosenbaum{at}metrohealth.org
* Corresponding author. Tel.: +1-216-778-2005; fax: +1-216-778-4924.
For nearly 100 years, beat to beat alternation of T wave amplitude, termed T wave alternans (TWA), has been closely linked to electrical instability in the heart. TWA is now established among the strongest markers of susceptibility to sudden cardiac death. Since computer technology allows for detection of very subtle yet clinically significant TWA during standard exercise testing, TWA has been used increasingly as a noninvasive clinical tool for identifying and treating patients at risk for sudden cardiac death. The observation of TWA hastening ventricular tachyarrhythmias in an extraordinary variety of clinical and experimental conditions suggest potential universality of TWA in the pathophysiological mechanism of sudden death. High resolution optical mapping studies have shown that TWA arises from alternans of repolarization at the level of the ventricular myocyte. Cellular alternans is likely due to the actions of one or more ionic currents and is closely related to, if not directly dependent on, the kinetics of intracellular calcium cycling. Impairment in calcium cycling at the cellular and sub-cellular levels has been implicated in the mechanism of cellulcar alternans. Importantly, spatially discordant alternans between cells is most likely a consequence of heterogeneities of electrophysiological properties between cells which span the ventricular wall, serving to amplify spatial heterogeneities of repolarization, and forming a substrate for reentrant excitation. Through this mechanism, TWA is linked directly and mechanistically to the pathogenesis of arrhythmias. Although available data would suggest that TWA is certainly closely related to a mechanism of arrhythmogenesis, and is a strong marker of clinical risk, the precise sequence of events which triggers sudden cardiac death, and the potential role of TWA in this process remains elusive.
KEYWORDS Arrhythmia (mechanisms); ECG; Sudden death; Ventricular arrhythmias
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  J. A. Wasserstrom, R. Sharma, M. J. O'Toole, J. Zheng, J. E. Kelly, J. Shryock, L. Belardinelli, and G. L. Aistrup Ranolazine Antagonizes the Effects of Increased Late Sodium Current on Intracellular Calcium Cycling in Rat Isolated Intact Heart J. Pharmacol. Exp. Ther., November 1, 2009; 331(2): 382 - 391. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. A. Brown and W. E. Cascio 'Leaky' ryanodine receptors and sudden cardiac death Cardiovasc Res, October 28, 2009; (2009) cvp330v2. [Full Text] [PDF]
|
|
|
|
|
|
A. E. Belevych, D. Terentyev, S. Viatchenko-Karpinski, R. Terentyeva, A. Sridhar, Y. Nishijima, L. D. Wilson, A. J. Cardounel, K. R. Laurita, C. A. Carnes, et al. Redox modification of ryanodine receptors underlies calcium alternans in a canine model of sudden cardiac death Cardiovasc Res, August 14, 2009; (2009) cvp246v2. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. A. Wasserstrom, R. Sharma, S. Kapur, J. E. Kelly, A. H. Kadish, C. W. Balke, and G. L. Aistrup Multiple Defects in Intracellular Calcium Cycling in Whole Failing Rat Heart Circ Heart Fail, May 1, 2009; 2(3): 223 - 232. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 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 J. Am. Coll. Cardiol., September 30, 2008; 52(14): 1179 - 1199. [Full Text] [PDF]
|
|
|
|
 |
|
 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]
|
|
|
|
 |
|
 Y. G. Wang, A. V. Zima, X. Ji, R. Pabbidi, L. A. Blatter, and S. L. Lipsius Ginsenoside Re suppresses electromechanical alternans in cat and human cardiomyocytes Am J Physiol Heart Circ Physiol, August 1, 2008; 295(2): H851 - H859. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Santoro, E. Mancini, G. London, L. Mercadal, H. Fessy, B. Perrone, L. Cagnoli, E. Grandi, S. Severi, and S. Cavalcanti Patients with complex arrhythmias during and after haemodialysis suffer from different regimens of potassium removal Nephrol. Dial. Transplant., April 1, 2008; 23(4): 1415 - 1421. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Jiang, W. Chen, R. Wang, L. Zhang, and S. R. W. Chen Loss of luminal Ca2+ activation in the cardiac ryanodine receptor is associated with ventricular fibrillation and sudden death PNAS, November 13, 2007; 104(46): 18309 - 18314. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. A. Fossa, T. Wisialowski, J. N. Duncan, S. Deng, and M. Dunne Azithromycin/Chloroquine Combination Does Not Increase Cardiac Instability despite an Increase in Monophasic Action Potential Duration in the Anesthetized Guinea Pig Am J Trop Med Hyg, November 1, 2007; 77(5): 929 - 938. [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]
|
|
|
|
|
|
P. N. Jordan and D. J. Christini Characterizing the contribution of voltage- and calcium-dependent coupling to action potential stability: implications for repolarization alternans Am J Physiol Heart Circ Physiol, October 1, 2007; 293(4): H2109 - H2118. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Iravanian and D. J. Christini Optical mapping system with real-time control capability Am J Physiol Heart Circ Physiol, October 1, 2007; 293(4): H2605 - H2611. [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]
|
|
|
|
|
|
N. Ono, H. Hayashi, A. Kawase, S.-F. Lin, H. Li, J. N. Weiss, P.-S. Chen, and H. S. Karagueuzian Spontaneous atrial fibrillation initiated by triggered activity near the pulmonary veins in aged rats subjected to glycolytic inhibition Am J Physiol Heart Circ Physiol, January 1, 2007; 292(1): H639 - H648. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Picht, J. DeSantiago, L. A. Blatter, and D. M. Bers Cardiac Alternans Do Not Rely on Diastolic Sarcoplasmic Reticulum Calcium Content Fluctuations Circ. Res., September 29, 2006; 99(7): 740 - 748. [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]
|
|
|
|
|
|
H. Morita, D. P. Zipes, J. Lopshire, S. T. Morita, and J. Wu T wave alternans in an in vitro canine tissue model of Brugada syndrome Am J Physiol Heart Circ Physiol, July 1, 2006; 291(1): H421 - H428. [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]
|
|
|
|
|
|
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]
|
|
|
|
|
|
A. A. Fossa, T. Wisialowski, A. Magnano, E. Wolfgang, R. Winslow, W. Gorczyca, K. Crimin, and D. L. Raunig Dynamic Beat-to-Beat Modeling of the QT-RR Interval Relationship: Analysis of QT Prolongation during Alterations of Autonomic State versus Human Ether a-go-go-Related Gene Inhibition J. Pharmacol. Exp. Ther., January 1, 2005; 312(1): 1 - 11. [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]
|
|
|
|
|
|
M. B. Thomsen, S. C. Verduyn, M. Stengl, J. D.M. Beekman, G. de Pater, J. van Opstal, P. G.A. Volders, and M. A. Vos Increased Short-Term Variability of Repolarization Predicts d-Sotalol-Induced Torsades de Pointes in Dogs Circulation, October 19, 2004; 110(16): 2453 - 2459. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. R. Sipido Understanding Cardiac Alternans: The Answer Lies in the Ca2+ Store Circ. Res., March 19, 2004; 94(5): 570 - 572. [Full Text] [PDF]
|
|
|
|
|
|
M. E. Diaz, S. C. O'Neill, and D. A. Eisner Sarcoplasmic Reticulum Calcium Content Fluctuation Is the Key to Cardiac Alternans Circ. Res., March 19, 2004; 94(5): 650 - 656. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. L. Walker, X. Wan, G. E. Kirsch, and D. S. Rosenbaum Hysteresis Effect Implicates Calcium Cycling as a Mechanism of Repolarization Alternans Circulation, November 25, 2003; 108(21): 2704 - 2709. [Abstract] [Full Text] [PDF]
|
|