This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: 110/20/3168    most recent 01.CIR.0000147231.69595.D3v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Hund, T. J. Articles by Rudy, Y. Search for Related Content PubMed PubMed Citation Articles by Hund, T. J. Articles by Rudy, Y. Related Collections Contractile function Arrythmias-basic studies Quantitative modeling

(Circulation. 2004;110:3168-3174.)
© 2004 American Heart Association, Inc.

Arrhythmia/Electrophysiology

Rate Dependence and Regulation of Action Potential and Calcium Transient in a Canine Cardiac Ventricular Cell Model

From the Departments of Biomedical Engineering (T.J.H., Y.R.) and Pathology (T.J.H.), Washington University, St. Louis, Mo.

Correspondence to Yoram Rudy, Department of Biomedical Engineering, Washington University, Campus Box 1097, One Brookings Dr, St. Louis, MO 63130-4899. E-mail rudy{at}wustl.edu

Received January 29, 2004; de novo received April 19, 2004; accepted June 7, 2004.

Background— Computational biology is a powerful tool for elucidating arrhythmogenic mechanisms at the cellular level, where complex interactions between ionic processes determine behavior. A novel theoretical model of the canine ventricular epicardial action potential and calcium cycling was developed and used to investigate ionic mechanisms underlying Ca²⁺ transient (CaT) and action potential duration (APD) rate dependence.

Methods and Results— The Ca²⁺/calmodulin-dependent protein kinase (CaMKII) regulatory pathway was integrated into the model, which included a novel Ca²⁺-release formulation, Ca²⁺ subspace, dynamic chloride handling, and formulations for major ion currents based on canine ventricular data. Decreasing pacing cycle length from 8000 to 300 ms shortened APD primarily because of I_Ca(L) reduction, with additional contributions from I_to1, I_NaK, and late I_Na. CaT amplitude increased as cycle length decreased from 8000 to 500 ms. This positive rate–dependent property depended on CaMKII activity.

Conclusions— CaMKII is an important determinant of the rate dependence of CaT but not of APD, which depends on ion-channel kinetics. The model of CaMKII regulation may serve as a paradigm for modeling effects of other regulatory pathways on cell function.

Key Words: electrophysiology • action potentials • calcium • ion channels

This article has been cited by other articles:

				A. Mahajan, Y. Shiferaw, D. Sato, A. Baher, R. Olcese, L.-H. Xie, M.-J. Yang, P.-S. Chen, J. G. Restrepo, A. Karma, et al. A Rabbit Ventricular Action Potential Model Replicating Cardiac Dynamics at Rapid Heart Rates Biophys. J., January 15, 2008; 94(2): 392 - 410. [Abstract] [Full Text] [PDF]

				E. Grandi, J. L. Puglisi, S. Wagner, L. S. Maier, S. Severi, and D. M. Bers Simulation of Ca-Calmodulin-Dependent Protein Kinase II on Rabbit Ventricular Myocyte Ion Currents and Action Potentials Biophys. J., December 1, 2007; 93(11): 3835 - 3847. [Abstract] [Full Text] [PDF]

				J. M. Cordeiro, J. E. Malone, J. M. Di Diego, F. S. Scornik, G. L. Aistrup, C. Antzelevitch, and J. A. Wasserstrom Cellular and subcellular alternans in the canine left ventricle Am J Physiol Heart Circ Physiol, December 1, 2007; 293(6): H3506 - H3516. [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]

				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]

				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]

				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]

				N. P. Smith, E. J. Crampin, S. A. Niederer, J. B. Bassingthwaighte, and D. A. Beard Computational biology of cardiac myocytes: proposed standards for the physiome J. Exp. Biol., May 1, 2007; 210(9): 1576 - 1583. [Abstract] [Full Text] [PDF]

				G. M. Faber, J. Silva, L. Livshitz, and Y. Rudy Kinetic Properties of the Cardiac L-Type Ca2+ Channel and Its Role in Myocyte Electrophysiology: A Theoretical Investigation Biophys. J., March 1, 2007; 92(5): 1522 - 1543. [Abstract] [Full Text] [PDF]

				C. Lengyel, L. Virag, T. Biro, N. Jost, J. Magyar, P. Biliczki, E. Kocsis, R. Skoumal, P. P. Nanasi, M. Toth, et al. Diabetes mellitus attenuates the repolarization reserve in mammalian heart Cardiovasc Res, February 1, 2007; 73(3): 512 - 520. [Abstract] [Full Text] [PDF]

				K. H. W. J. ten Tusscher and A. V. Panfilov Alternans and spiral breakup in a human ventricular tissue model Am J Physiol Heart Circ Physiol, September 1, 2006; 291(3): H1088 - H1100. [Abstract] [Full Text] [PDF]

				M. Dong, X. Sun, A. A. Prinz, and H.-S. Wang Effect of simulated Ito on guinea pig and canine ventricular action potential morphology Am J Physiol Heart Circ Physiol, August 1, 2006; 291(2): H631 - H637. [Abstract] [Full Text] [PDF]

				J. L. Greenstein, R. Hinch, and R. L. Winslow Mechanisms of Excitation-Contraction Coupling in an Integrative Model of the Cardiac Ventricular Myocyte Biophys. J., January 1, 2006; 90(1): 77 - 91. [Abstract] [Full Text] [PDF]

				Z. Qu Critical mass hypothesis revisited: role of dynamical wave stability in spontaneous termination of cardiac fibrillation Am J Physiol Heart Circ Physiol, January 1, 2006; 290(1): H255 - H263. [Abstract] [Full Text] [PDF]

				M. Shah, F. G. Akar, and G. F. Tomaselli Molecular Basis of Arrhythmias Circulation, October 18, 2005; 112(16): 2517 - 2529. [Abstract] [Full Text] [PDF]

				N. Jost, L. Virag, M. Bitay, J. Takacs, C. Lengyel, P. Biliczki, Z. Nagy, G. Bogats, D. A. Lathrop, J. G. Papp, et al. Restricting Excessive Cardiac Action Potential and QT Prolongation: A Vital Role for IKs in Human Ventricular Muscle Circulation, September 6, 2005; 112(10): 1392 - 1399. [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]

				J.M. Cordeiro, R. Brugada, Y.S. Wu, K. Hong, and R. Dumaine Modulation of IKr inactivation by mutation N588K in KCNH2: A link to arrhythmogenesis in short QT syndrome Cardiovasc Res, August 15, 2005; 67(3): 498 - 509. [Abstract] [Full Text] [PDF]