(Circulation. 1999;99:2466-2474.)
© 1999 American Heart Association, Inc.
Basic Science Reports |
Effects of IKr and IKs Heterogeneity on Action Potential Duration and Its Rate Dependence
A Simulation Study
Presented in part at the 69th Scientific Sessions of the American Heart Association, New Orleans, La, November 10–13, 1996, and published in abstract form (Circulation. 1996;94[suppl I]:I-712 and Biophys J. 1997;72:MP131–MP131).
From the Cardiac Bioelectricity Research and Training Center, Department of Physiology and Biophysics (P.C.V., Y.R.) and Department of Biomedical Engineering (R.M.S., Y.R.), Case Western Reserve University, Cleveland, Ohio.
Correspondence to Dr Yoram Rudy, Director, Cardiac Bioelectricity Research and Training Center, 505, Wickenden Bldg, Case Western Reserve University, Cleveland, OH 44106-7207. E-mail yxr{at}po.cwru.edu
Background—A growing body of evidence suggests that heterogeneity of ion channel expression and electrophysiological characteristics is an important property of the ventricular myocardium. The 2 components of the delayed rectifier potassium current, IKr (rapid) and IKs (slow), play a dominant role in the repolarization of the action potential and are important determinants of its duration.
Methods and Results—In this report, the effects of heterogeneities of IKr and IKs on action potential duration (APD) and its rate dependence (adaptation) are studied with the use of the LRd model of a mammalian ventricular cell. Results demonstrate the importance of IKs density variations in heterogeneity of repolarization. Cells with reduced IKs (eg, mid-myocardial M cells) display long APD and steep dependence of APD on rate. Mechanistically, accumulation of IKs activation and increased sodium calcium exchange current, INaCa, secondary to Na+ accumulation at a fast rate underlie the steep APD-rate relation of these cells. When cells are electrotonically coupled in a multicellular fiber through resistive gap junction, APD differences are reduced. The results demonstrate strong dependence of APD heterogeneity on the degree of intercellular coupling even in the normal physiological range. Highly reduced coupling maximizes APD heterogeneity.
Conclusions—Heterogeneity of IKs:IKr density strongly influences APD and its rate dependence. However, in the intact myocardium, the degree of gap-junction coupling may be an important factor that determines the manifestation of APD heterogeneity and dispersion of repolarization. The clinical significance of this study is in the context of repolarization abnormalities and associated arrhythmias (eg, long QT syndrome and torsade de pointes).
Key Words: arrhythmia • action potentials • conduction • potassium • calcium channels
This article has been cited by other articles:
 |
|
 |
|
  R. J. Sung, Y.-H. Wu, N. H.-J. Lai, C.-H. Teng, C.-H. Luo, H.-C. Tien, C.-P. Lo, and S.-N. Wu {beta}-Adrenergic modulation of arrhythmogenesis and identification of targeted sites of antiarrhythmic therapy in Timothy (LQT8) syndrome: a theoretical study Am J Physiol Heart Circ Physiol, January 1, 2010; 298(1): H33 - H44. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. G. Chang, Y. Zhang, C. Y. Chang, L. Xu, R. Emokpae, L. Tung, E. Marban, and M. R. Abraham Spiral Waves and Reentry Dynamics in an In Vitro Model of the Healed Infarct Border Zone Circ. Res., November 20, 2009; 105(11): 1062 - 1071. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. C. Ahrens-Nicklas, C. E. Clancy, and D. J. Christini Re-evaluating the efficacy of {beta}-adrenergic agonists and antagonists in long QT-3 syndrome through computational modelling Cardiovasc Res, June 1, 2009; 82(3): 439 - 447. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. P. Nickerson and M. L. Buist A physiome standards-based model publication paradigm Phil Trans R Soc A, May 28, 2009; 367(1895): 1823 - 1844. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. A. Niederer, H. E. D. J. ter Keurs, and N. P. Smith Modelling and measuring electromechanical coupling in the rat heart Exp Physiol, May 1, 2009; 94(5): 529 - 540. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. P. Imredy, J. R. Penniman, S. J. Dech, W. D. Irving, and J. J. Salata Modeling of the adrenergic response of the human IKs current (hKCNQ1/hKCNE1) stably expressed in HEK-293 cells Am J Physiol Heart Circ Physiol, November 1, 2008; 295(5): H1867 - H1881. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. G Campbell, S. N Flaim, C. H Leem, and A. D McCulloch Mechanisms of transmurally varying myocyte electromechanics in an integrated computational model Phil Trans R Soc A, September 28, 2008; 366(1879): 3361 - 3380. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Bebarova, T. O'Hara, J. L. M. C. Geelen, R. J. Jongbloed, C. Timmermans, Y. H. Arens, L.-M. Rodriguez, Y. Rudy, and P. G. A. Volders Subepicardial phase 0 block and discontinuous transmural conduction underlie right precordial ST-segment elevation by a SCN5A loss-of-function mutation Am J Physiol Heart Circ Physiol, July 1, 2008; 295(1): H48 - H58. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Colli Franzone, L. F. Pavarino, S. Scacchi, and B. Taccardi Monophasic action potentials generated by bidomain modeling as a tool for detecting cardiac repolarization times Am J Physiol Heart Circ Physiol, November 1, 2007; 293(5): H2771 - H2785. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Antzelevitch Role of spatial dispersion of repolarization in inherited and acquired sudden cardiac death syndromes Am J Physiol Heart Circ Physiol, October 1, 2007; 293(4): H2024 - H2038. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Tsujimae, S. Suzuki, S. Murakami, and Y. Kurachi Frequency-dependent effects of various IKr blockers on cardiac action potential duration in a human atrial model Am J Physiol Heart Circ Physiol, July 1, 2007; 293(1): H660 - H669. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. B. Huffaker, J. N. Weiss, and B. Kogan Effects of early afterdepolarizations on reentry in cardiac tissue: a simulation study Am J Physiol Heart Circ Physiol, June 1, 2007; 292(6): H3089 - H3102. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. J. Sung, S.-N. Wu, J.-S. Wu, H.-D. Chang, and C.-H. Luo Electrophysiological mechanisms of ventricular arrhythmias in relation to Andersen-Tawil syndrome under conditions of reduced IK1: a simulation study Am J Physiol Heart Circ Physiol, December 1, 2006; 291(6): H2597 - H2605. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Fink, W. R Giles, and D. Noble Contributions of inwardly rectifying K+ currents to repolarization assessed using mathematical models of human ventricular myocytes Phil Trans R Soc A, May 15, 2006; 364(1842): 1207 - 1222. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. N. Subbiah, M. Kondo, T. J. Campbell, and J. I. Vandenberg Tryptophan scanning mutagenesis of the HERG K+ channel: the S4 domain is loosely packed and likely to be lipid exposed J. Physiol., December 1, 2005; 569(2): 367 - 379. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Liu, T. Yang, P. C. Viswanathan, and D. M. Roden New Mechanism Contributing to Drug-Induced Arrhythmia: Rescue of a Misprocessed LQT3 Mutant Circulation, November 22, 2005; 112(21): 3239 - 3246. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Silva and Y. Rudy Subunit Interaction Determines IKs Participation in Cardiac Repolarization and Repolarization Reserve Circulation, September 6, 2005; 112(10): 1384 - 1391. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. J. Sampson and C. S. Henriquez Electrotonic influences on action potential duration dispersion in small hearts: a simulation study Am J Physiol Heart Circ Physiol, July 1, 2005; 289(1): H350 - H360. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Terrenoire, C. E. Clancy, J. W. Cormier, K. J. Sampson, and R. S. Kass Autonomic Control of Cardiac Action Potentials: Role of Potassium Channel Kinetics in Response to Sympathetic Stimulation Circ. Res., March 18, 2005; 96(5): e25 - e34. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Ashihara and N. A. Trayanova Cell and tissue responses to electric shocks Europace, January 1, 2005; 7(s2): S155 - S165. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Melnyk, J. R. Ehrlich, M. Pourrier, L. Villeneuve, T.-J. Cha, and S. Nattel Comparison of ion channel distribution and expression in cardiomyocytes of canine pulmonary veins versus left atrium Cardiovasc Res, January 1, 2005; 65(1): 104 - 116. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Ueda, D. P. Zipes, and J. Wu Functional and transmural modulation of M cell behavior in canine ventricular wall Am J Physiol Heart Circ Physiol, December 1, 2004; 287(6): H2569 - H2575. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. J. Hund and Y. Rudy Rate Dependence and Regulation of Action Potential and Calcium Transient in a Canine Cardiac Ventricular Cell Model Circulation, November 16, 2004; 110(20): 3168 - 3174. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Vanoli, S. Bacchini, S. Panigada, F. Pentimalli, and P. B Adamson Experimental models of heart failure Eur. Heart J. Suppl., November 1, 2004; 6(suppl_F): F7 - F15. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Poelzing and D. S. Rosenbaum Altered connexin43 expression produces arrhythmia substrate in heart failure Am J Physiol Heart Circ Physiol, October 1, 2004; 287(4): H1762 - H1770. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. N. Subbiah, C. E. Clarke, D. J. Smith, J. Zhao, T. J. Campbell, and J. I. Vandenberg Molecular basis of slow activation of the human ether-a-go-go related gene potassium channel J. Physiol., July 15, 2004; 558(2): 417 - 431. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. C. Hao, D. J. Christini, K. M. Stein, P. N. Jordan, S. Iwai, O. Bramwell, S. M. Markowitz, S. Mittal, and B. B. Lerman Effect of {beta}-adrenergic blockade on dynamic electrical restitution in vivo Am J Physiol Heart Circ Physiol, July 1, 2004; 287(1): H390 - H394. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Poelzing, F. G. Akar, E. Baron, and D. S. Rosenbaum Heterogeneous connexin43 expression produces electrophysiological heterogeneities across ventricular wall Am J Physiol Heart Circ Physiol, May 1, 2004; 286(5): H2001 - H2009. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. J. Severs, S. R. Coppen, E. Dupont, H.-I Yeh, Y.-S. Ko, and T. Matsushita Gap junction alterations in human cardiac disease Cardiovasc Res, May 1, 2004; 62(2): 368 - 377. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. E Conrath, R. Wilders, R. Coronel, J. M.T de Bakker, P. Taggart, J. R de Groot, and T. Opthof Intercellular coupling through gap junctions masks M cells in the human heart Cardiovasc Res, May 1, 2004; 62(2): 407 - 414. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Oikarinen, M. S. Nieminen, M. Viitasalo, L. Toivonen, S. Jern, B. Dahlof, R. B. Devereux, P. M. Okin, and for the LIFE Study Investigators QRS Duration and QT Interval Predict Mortality in Hypertensive Patients With Left Ventricular Hypertrophy: The Losartan Intervention for Endpoint Reduction in Hypertension Study Hypertension, May 1, 2004; 43(5): 1029 - 1034. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Rosati and D. McKinnon Regulation of Ion Channel Expression Circ. Res., April 16, 2004; 94(7): 874 - 883. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Smetana, V. N. Batchvarov, K. Hnatkova, A. J. Camm, and M. Malik Ventricular gradient and nondipolar repolarization components increase at higher heart rate Am J Physiol Heart Circ Physiol, January 1, 2004; 286(1): H131 - H136. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. C. Eloff, E. Gilat, X. Wan, and D. S. Rosenbaum Pharmacological Modulation of Cardiac Gap Junctions to Enhance Cardiac Conduction: Evidence Supporting a Novel Target for Antiarrhythmic Therapy Circulation, December 23, 2003; 108(25): 3157 - 3163. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. P. Thomas, J. P. Kucera, L. Bircher-Lehmann, Y. Rudy, J. E. Saffitz, and A. G. Kleber Impulse Propagation in Synthetic Strands of Neonatal Cardiac Myocytes With Genetically Reduced Levels of Connexin43 Circ. Res., June 13, 2003; 92(11): 1209 - 1216. [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]
|
|
|
|
 |
|
 J. Kurokawa, L. Chen, and R. S. Kass Requirement of subunit expression for cAMP-mediated regulation of a heart potassium channel PNAS, February 18, 2003; 100(4): 2122 - 2127. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. H. W. J. Ten Tusscher and A. V. Panfilov Reentry in heterogeneous cardiac tissue described by the Luo-Rudy ventricular action potential model Am J Physiol Heart Circ Physiol, February 1, 2003; 284(2): H542 - H548. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Chiello Tracy, C. Cabo, J. Coromilas, J. Kurokawa, R. S. Kass, and A. L. Wit Electrophysiological consequences of human IKs channel expression in adult murine heart Am J Physiol Heart Circ Physiol, January 1, 2003; 284(1): H168 - H175. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Ohara, Z. Qu, M.-H. Lee, K. Ohara, C. Omichi, W. J. Mandel, P.-S. Chen, and H. S. Karagueuzian Increased vulnerability to inducible atrial fibrillation caused by partial cellular uncoupling with heptanol Am J Physiol Heart Circ Physiol, September 1, 2002; 283(3): H1116 - H1122. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Gima and Y. Rudy Ionic Current Basis of Electrocardiographic Waveforms: A Model Study Circ. Res., May 3, 2002; 90(8): 889 - 896. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Ishihara, D.-H. Yan, S. Yamamoto, and T. Ehara Inward rectifier K+ current under physiological cytoplasmic conditions in guinea-pig cardiac ventricular cells J. Physiol., May 1, 2002; 540(3): 831 - 841. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Ohya, K. Asakura, K. Muraki, M. Watanabe, and Y. Imaizumi Molecular and functional characterization of ERG, KCNQ, and KCNE subtypes in rat stomach smooth muscle Am J Physiol Gastrointest Liver Physiol, February 1, 2002; 282(2): G277 - G287. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. W. Wang, P. C. Viswanathan, J. R. Balser, A. L. George Jr, and D. W. Benson Clinical, Genetic, and Biophysical Characterization of SCN5A Mutations Associated With Atrioventricular Conduction Block Circulation, January 22, 2002; 105(3): 341 - 346. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Lu, M. P Mahaut-Smith, A. Varghese, C. L-H Huang, P. R Kemp, and J. I Vandenberg Effects of premature stimulation on HERG K+ channels J. Physiol., December 15, 2001; 537(3): 843 - 851. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Members of the Sicilian Gambit New Approaches to Antiarrhythmic Therapy, Part I: Emerging Therapeutic Applications of the Cell Biology of Cardiac Arrhythmias Circulation, December 4, 2001; 104(23): 2865 - 2873. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Members of the Sicilian Gambit New approaches to antiarrhythmic therapy; emerging therapeutic applications of the cell biology of cardiac arrhythmias Eur. Heart J., December 1, 2001; 22(23): 2148 - 2163. [Abstract] [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]
|
|
|
|
|
|
Members of the Sicilian Gambit New approaches to antiarrhythmic therapy: emerging therapeutic applications of the cell biology of cardiac arrhythmias Cardiovasc Res, December 1, 2001; 52(3): 345 - 360. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G.-X. Yan, S. J. Rials, Y. Wu, T. Liu, X. Xu, R. A. Marinchak, and P. R. Kowey Ventricular hypertrophy amplifies transmural repolarization dispersion and induces early afterdepolarization Am J Physiol Heart Circ Physiol, November 1, 2001; 281(5): H1968 - H1975. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Taggart, P. M.I Sutton, T. Opthof, R. Coronel, R. Trimlett, W. Pugsley, and P. Kallis Transmural repolarisation in the left ventricle in humans during normoxia and ischaemia Cardiovasc Res, June 1, 2001; 50(3): 454 - 462. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. B. Adamson and E. Vanoli Early autonomic and repolarization abnormalities contribute to lethal arrhythmias in chronic ischemic heart failure: Characteristics of a novel heart failure model in dogs with postmyocardial infarction left ventricular dysfunction J. Am. Coll. Cardiol., May 1, 2001; 37(6): 1741 - 1748. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. E. Clancy and Y. Rudy Cellular consequences of HERG mutations in the long QT syndrome: precursors to sudden cardiac death Cardiovasc Res, May 1, 2001; 50(2): 301 - 313. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. M. Hondeghem, L. Carlsson, and G. Duker Instability and Triangulation of the Action Potential Predict Serious Proarrhythmia, but Action Potential Duration Prolongation Is Antiarrhythmic Circulation, April 17, 2001; 103(15): 2004 - 2013. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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]
|
|
|
|
|
|
D. E. Gutstein, G. E. Morley, H. Tamaddon, D. Vaidya, M. D. Schneider, J. Chen, K. R. Chien, H. Stuhlmann, and G. I. Fishman Conduction Slowing and Sudden Arrhythmic Death in Mice With Cardiac-Restricted Inactivation of Connexin43 Circ. Res., February 16, 2001; 88(3): 333 - 339. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. S. Kass and C. Cabo Channel structure and drug-induced cardiac arrhythmias PNAS, October 24, 2000; 97(22): 11683 - 11684. [Full Text] [PDF]
|
|
|
|
|
|
T. J. Hund, N. F. Otani, and Y. Rudy Dynamics of action potential head-tail interaction during reentry in cardiac tissue: ionic mechanisms Am J Physiol Heart Circ Physiol, October 1, 2000; 279(4): H1869 - H1879. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X. H. T. Wehrens, H. Abriel, C. Cabo, J. Benhorin, and R. S. Kass Arrhythmogenic Mechanism of an LQT-3 Mutation of the Human Heart Na+ Channel {alpha}-Subunit : A Computational Analysis Circulation, August 1, 2000; 102(5): 584 - 590. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Wang and Y. Rudy Action potential propagation in inhomogeneous cardiac tissue: safety factor considerations and ionic mechanism Am J Physiol Heart Circ Physiol, April 1, 2000; 278(4): H1019 - H1029. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. C. Viswanathan and Y. Rudy Cellular Arrhythmogenic Effects of Congenital and Acquired Long-QT Syndrome in the Heterogeneous Myocardium Circulation, March 14, 2000; 101(10): 1192 - 1198. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Stankovicova, M. Szilard, I De Scheerder, and K. R Sipido M cells and transmural heterogeneity of action potential configuration in myocytes from the left ventricular wall of the pig heart Cardiovasc Res, March 1, 2000; 45(4): 952 - 960. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. E. Clancy and Y. Rudy Na+ Channel Mutation That Causes Both Brugada and Long-QT Syndrome Phenotypes: A Simulation Study of Mechanism Circulation, March 12, 2002; 105(10): 1208 - 1213. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Gima and Y. Rudy Ionic Current Basis of Electrocardiographic Waveforms: A Model Study Circ. Res., May 3, 2002; 90(8): 889 - 896. [Abstract] [Full Text] [PDF]
|
|