Published online before print October 25, 2004, doi: 10.1161/01.CIR.0000147231.69595.D3
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(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 ICa(L) reduction, with additional contributions from Ito1, INaK, and late INa. 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
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