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This Article Full Text Full Text (PDF) Supplemental Material All Versions of this Article: 296/4/H1017    most recent 01216.2008v1 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 Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Decker, K. F. Articles by Rudy, Y. Search for Related Content PubMed PubMed Citation Articles by Decker, K. F. Articles by Rudy, Y.

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

¹Cardiac Bioelectricity and Arrhythmia Center, Department of Biomedical Engineering, Washington University in St. Louis; St. Louis, Missouri; ²Departments of Cardiology and Mathematics, Maastricht University, Maastricht, The Netherlands; ³Department of Pediatrics, University of Chicago, Pritzker School of Medicine; Chicago, Illinois; and ⁴Department 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 Ca²⁺ 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 Ca²⁺ 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. Ca²⁺ entry via I_Ca,L at fast rate drives increased Na⁺-Ca²⁺ exchanger Ca²⁺ 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