Properties and ionic mechanisms of action potential adaptation, restitution, and accommodation in canine epicardium

1 Cardiac Bioelectricity and Arrhythmia Center, Department of Biomedical Engineering, Washington University in St. Louis; St. Louis, Missouri; 2 Departments of Cardiology and Mathematics, Maastricht University, Maastricht, The Netherlands; 3 Department of Pediatrics, University of Chicago, Pritzker School of Medicine; Chicago, Illinois; and 4 Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, Iowa Submitted 18 November 2008 ; accepted in final form 16 January 2009 Computational models of cardiac myocytes are important tools for understanding ionic mechanisms of arrhythmia. This work presents a new model of the canine epicardial myocyte that reproduces a wide range of experimentally observed rate-dependent behaviors in cardiac cell and tissue, including action potential (AP) duration (APD) adaptation, restitution, and accommodation. Model behavior depends on updated formulations for the 4-aminopyridine-sensitive transient outward current ( I to1 ), the slow component of the delayed rectifier K + current ( I Ks ), the L-type Ca 2+ channel current ( I Ca,L ), and the Na + -K + pump current ( I NaK ) fit to data from canine ventricular myocytes. We found that I to1 plays a limited role in potentiating peak I Ca,L and sarcoplasmic reticulum Ca 2+ release for propagated APs but modulates the time course of APD restitution. I Ks plays an important role in APD shortening at short diastolic intervals, despite a limited role in AP repolarization at longer cycle lengths. In addition, we found that I Ca,L plays a critical role in APD accommodation and rate dependence of APD restitution. Ca 2+ entry via I Ca,L at fast rate drives increased Na + -Ca 2+ exchanger Ca 2+ extrusion and Na + entry, which in turn increases Na + extrusion via outward I NaK . APD accommodation results from this increased outward I NaK . Our simulation results provide valuable insight into the mechanistic basis of rate-dependent phenomena important for determining the heart's response to rapid and irregular pacing rates (e.g., arrhythmia). Accurate simulation of rate-dependent phenomena and increased understanding of their mechanistic basis will lead to more realistic multicellular simulations of arrhythmia and identification of molecular therapeutic targets. arrhythmia; cardiac electrophysiology; mathematical modeling; ion channels Address for reprint requests and other correspondence: Y. Rudy, Campus Box 1097, Whitaker Hall Rm. 290, Washington Univ. in S