|
|
||||||||
Cardiac Bioelectricity and Arrhythmia Center, Washington University in St. Louis, St. Louis, Missouri
Submitted 10 December 2006 ; accepted in final form 26 January 2007
Alternans of cardiac repolarization is associated with arrhythmias and sudden death. At the cellular level, alternans involves beat-to-beat oscillation of the action potential (AP) and possibly Ca2+ transient (CaT). Because of experimental difficulty in independently controlling the Ca2+ and electrical subsystems, mathematical modeling provides additional insights into mechanisms and causality. Pacing protocols were conducted in a canine ventricular myocyte model with the following results: 1) CaT alternans results from refractoriness of the sarcoplasmic reticulum Ca2+ release system; alternation of the L-type calcium current has a negligible effect; 2) CaT-AP coupling during late AP occurs through the sodium-calcium exchanger and underlies AP duration (APD) alternans; 3) increased Ca2+/calmodulin-dependent protein kinase II (CaMKII) activity extends the range of CaT and APD alternans to slower frequencies and increases alternans magnitude; its decrease suppresses CaT and APD alternans, exerting an antiarrhythmic effect; and 4) increase of the rapid delayed rectifier current (IKr) also suppresses APD alternans but without suppressing CaT alternans. Thus CaMKII inhibition eliminates APD alternans by eliminating its cause (CaT alternans) while IKr enhancement does so by weakening CaT-APD coupling. The simulations identify combined CaMKII inhibition and IKr enhancement as a possible antiarrhythmic intervention.
arrhythmia; calcium; sudden death; electrophysiology; calcium/calmodulin-dependent protein kinase II
This article has been cited by other articles:
![]() |
J. T. Koivumaki, J. Takalo, T. Korhonen, P. Tavi, and M. Weckstrom Modelling sarcoplasmic reticulum calcium ATPase and its regulation in cardiac myocytes Phil Trans R Soc A, June 13, 2009; 367(1896): 2181 - 2202. [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] |
||||
![]() |
K. F. Decker, J. Heijman, J. R. Silva, T. J. Hund, and Y. Rudy Properties and ionic mechanisms of action potential adaptation, restitution, and accommodation in canine epicardium Am J Physiol Heart Circ Physiol, April 1, 2009; 296(4): H1017 - H1026. [Abstract] [Full Text] [PDF] |
||||
![]() |
S. M. Narayan, J. D. Bayer, G. Lalani, and N. A. Trayanova Action Potential Dynamics Explain Arrhythmic Vulnerability in Human Heart Failure A Clinical and Modeling Study Implicating Abnormal Calcium Handling. J. Am. Coll. Cardiol., November 25, 2008; 52(22): 1782 - 1792. [Abstract] [Full Text] [PDF] |
||||
![]() |
Y. Rudy, M. J. Ackerman, D. M. Bers, C. E. Clancy, S. R. Houser, B. London, A. D. McCulloch, D. A. Przywara, R. L. Rasmusson, R. J. Solaro, et al. Systems Approach to Understanding Electromechanical Activity in the Human Heart: A National Heart, Lung, and Blood Institute Workshop Summary Circulation, September 9, 2008; 118(11): 1202 - 1211. [Abstract] [Full Text] [PDF] |
||||
![]() |
P. J. Hunter, E. J. Crampin, and P. M. F. Nielsen Bioinformatics, multiscale modeling and the IUPS Physiome Project Brief Bioinform, July 1, 2008; 9(4): 333 - 343. [Abstract] [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] |
||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Visit Other APS Journals Online |