(Circulation. 2000;102:1664.)
© 2000 American Heart Association, Inc.
Clinical Investigation and Reports |
Mechanisms of Discordant Alternans and Induction of Reentry in Simulated Cardiac Tissue
From the Cardiovascular Research Laboratory and the Departments of Medicine (Cardiology), Physiology, and Physiological Science, UCLA, and Cedars-Sinai Medical Center, Los Angeles, Calif.
Correspondence to Zhilin Qu, PhD, Cardiovascular Research Laboratory, MRL 3645, UCLA School of Medicine, 675 Charles E. Young Dr South, Las Angeles, CA 90095-1760. E-mail zqu{at}ucla.edu
Background—T-wave alternans, which is associated with the genesis of cardiac fibrillation, has recently been related to discordant action potential duration (APD) alternans. However, the cellular electrophysiological mechanisms responsible for discordant alternans are poorly understood.
Methods and Results—We simulated a 2D sheet of cardiac tissue using phase 1 of the Luo-Rudy cardiac action potential model. A steep (slope >1) APD restitution curve promoted concordant APD alternans and T-wave alternans without QRS alternans. When pacing was from a single site, discordant APD alternans occurred only when the pacing rate was fast enough to engage conduction velocity (CV) restitution, producing both QRS and T-wave alternans. Tissue heterogeneity was not required for this effect. Discordant alternans markedly increases dispersion of refractoriness and increases the ability of a premature stimulus to cause localized wavebreak and induce reentry. In the absence of steep APD restitution and of CV restitution, sustained discordant alternans did not occur, but reentry could be induced if there was marked electrophysiological heterogeneity. Both discordant APD alternans and preexisting APD heterogeneity facilitate reentry by causing the waveback to propagate slowly.
Conclusion—Discordant alternans arises dynamically from APD and CV restitution properties and markedly increases dispersion of refractoriness. Preexisting and dynamically induced (via restitution) dispersion of refractoriness independently increase vulnerability to reentrant arrhythmias. Reduction of dynamically induced dispersion by appropriate alteration of electrical restitution has promise as an antiarrhythmic strategy.
Key Words: alternans • arrhythmias • reentry • action potentials
This article has been cited by other articles:
 |
|
 |
|
  A. R.M. Gelzer, M. L. Koller, N. F. Otani, J. J. Fox, M. W. Enyeart, G. J. Hooker, M. L. Riccio, C. R. Bartoli, and R. F. Gilmour Jr Dynamic Mechanism for Initiation of Ventricular Fibrillation In Vivo Circulation, September 9, 2008; 118(11): 1123 - 1129. [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]
|
|
|
|
|
|
R. H. Keldermann, K. H. W. J. ten Tusscher, M. P. Nash, R. Hren, P. Taggart, and A. V. Panfilov Effect of heterogeneous APD restitution on VF organization in a model of the human ventricles Am J Physiol Heart Circ Physiol, February 1, 2008; 294(2): H764 - H774. [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]
|
|
|
|
|
|
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]
|
|
|
|
|
|
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]
|
|
|
|
|
|
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]
|
|
|
|
|
|
Y. Gong, F. Xie, K. M. Stein, A. Garfinkel, C. A. Culianu, B. B. Lerman, and D. J. Christini Mechanism Underlying Initiation of Paroxysmal Atrial Flutter/Atrial Fibrillation by Ectopic Foci: A Simulation Study Circulation, April 24, 2007; 115(16): 2094 - 2102. [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]
|
|
|
|
 |
|
 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]
|
|
|
|
|
|
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]
|
|
|
|
|
|
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]
|
|
|
|
|
|
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]
|
|
|
|
|
|
V. S. Chauhan, E. Downar, K. Nanthakumar, J. D. Parker, H. J. Ross, W. Chan, and P. Picton Increased ventricular repolarization heterogeneity in patients with ventricular arrhythmia vulnerability and cardiomyopathy: a human in vivo study Am J Physiol Heart Circ Physiol, January 1, 2006; 290(1): H79 - H86. [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]
|
|
|
|
 |
|
 A. M. Yue, M. R. Franz, P. R. Roberts, and J. M. Morgan Global Endocardial Electrical Restitution in Human Right and Left Ventricles Determined by Noncontact Mapping J. Am. Coll. Cardiol., September 20, 2005; 46(6): 1067 - 1075. [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]
|
|
|
|
 |
|
 S.-m. Hwang, T. Y. Kim, and K. J. Lee From The Cover: Complex-periodic spiral waves in confluent cardiac cell cultures induced by localized inhomogeneities PNAS, July 19, 2005; 102(29): 10363 - 10368. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. G. Priori, S. V. Pandit, I. Rivolta, O. Berenfeld, E. Ronchetti, A. Dhamoon, C. Napolitano, J. Anumonwo, M. R. di Barletta, S. Gudapakkam, et al. A Novel Form of Short QT Syndrome (SQT3) Is Caused by a Mutation in the KCNJ2 Gene Circ. Res., April 15, 2005; 96(7): 800 - 807. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Comtois, J. Kneller, and S. Nattel Of circles and spirals: Bridging the gap between the leading circle and spiral wave concepts of cardiac reentry Europace, January 1, 2005; 7(s2): S10 - S20. [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]
|
|
|
|
|
|
D. A. Eisner, M. E. Diaz, Y. Li, S. C. O'Neill, and A. W. Trafford Stability and instability of regulation of intracellular calcium Exp Physiol, January 1, 2005; 90(1): 3 - 12. [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]
|
|
|
|
 |
|
 C. Bellocq, R. Wilders, J.-J. Schott, B. Louerat-Oriou, P. Boisseau, H. Le Marec, D. Escande, and I. Baro A Common Antitussive Drug, Clobutinol, Precipitates the Long QT Syndrome 2 Mol. Pharmacol., November 1, 2004; 66(5): 1093 - 1102. [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]
|
|
|
|
|
|
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]
|
|
|
|
|
|
R. Wu and A. Patwardhan Restitution of Action Potential Duration During Sequential Changes in Diastolic Intervals Shows Multimodal Behavior Circ. Res., March 19, 2004; 94(5): 634 - 641. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y.-W. Qian, R. J. Sung, S.-F. Lin, R. Province, and W. T. Clusin Spatial heterogeneity of action potential alternans during global ischemia in the rabbit heart Am J Physiol Heart Circ Physiol, December 1, 2003; 285(6): H2722 - H2733. [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]
|
|
|
|
|
|
R. Derksen, H. V.M. van Rijen, R. Wilders, S. Tasseron, R. N.W. Hauer, W. L.C. Rutten, and J. M.T. de Bakker Tissue Discontinuities Affect Conduction Velocity Restitution: A Mechanism by Which Structural Barriers May Promote Wave Break Circulation, August 19, 2003; 108(7): 882 - 888. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. L Walker and D. S Rosenbaum Repolarization alternans: implications for the mechanism and prevention of sudden cardiac death Cardiovasc Res, March 1, 2003; 57(3): 599 - 614. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Xie, Z. Qu, A. Garfinkel, and J. N. Weiss Electrical refractory period restitution and spiral wave reentry in simulated cardiac tissue Am J Physiol Heart Circ Physiol, July 1, 2002; 283(1): H448 - H460. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. J. Fox, M. L. Riccio, F. Hua, E. Bodenschatz, and R. F. Gilmour Jr Spatiotemporal Transition to Conduction Block in Canine Ventricle Circ. Res., February 22, 2002; 90(3): 289 - 296. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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]
|
|
|
|
|
|
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]
|
|
|
|
|
|
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]
|
|
|
|
|
|
M. Swissa, Z. Qu, T. Ohara, M.-H. Lee, S.-F. Lin, A. Garfinkel, H. S. Karagueuzian, J. N. Weiss, and P.-S. Chen Action potential duration restitution and ventricular fibrillation due to rapid focal excitation Am J Physiol Heart Circ Physiol, May 1, 2002; 282(5): H1915 - H1923. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. J. Fox, M. L. Riccio, F. Hua, E. Bodenschatz, and R. F. Gilmour Jr Spatiotemporal Transition to Conduction Block in Canine Ventricle Circ. Res., February 22, 2002; 90(3): 289 - 296. [Abstract] [Full Text] [PDF]
|
|