title: Properties and ionic mechanisms of action potential adaptation, restitution, and accommodation in canine epicardium.
abstract: 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.
authors.affiliation: Cardiac Bioelectricity and Arrhythmia Center, Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, Missouri, USA.
authors.forename: Keith F
authors.initials: KF
authors.lastname: Decker
authors.forename: Jordi
authors.initials: J
authors.lastname: Heijman
authors.forename: Jonathan R
authors.initials: JR
authors.lastname: Silva
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Hund
authors.forename: Yoram
authors.initials: Y
authors.lastname: Rudy
mesh_terms: D015761:4-Aminopyridine / Q000378:metabolism; D000200:Action Potentials / Q000502:physiology*; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000503:physiopathology; D002118:Calcium / Q000378:metabolism; D020746:Calcium Channels, L-Type / Q000502:physiology; D003198:Computer Simulation; D051668:Delayed Rectifier Potassium Channels / Q000502:physiology; D004285:Dogs; D007473:Ion Channels / Q000502:physiology*; D023421:Models, Animal; D032383:Myocytes, Cardiac / Q000502:physiology*; D018408:Patch-Clamp Techniques; D010496:Pericardium / Q000166:cytology / Q000502:physiology*; D019831:Sodium-Calcium Exchanger / Q000502:physiology; D000254:Sodium-Potassium-Exchanging ATPase / Q000502:physiology
chemical_list: D020746:Calcium Channels, L-Type; D051668:Delayed Rectifier Potassium Channels; D007473:Ion Channels; D019831:Sodium-Calcium Exchanger; D015761:4-Aminopyridine; D000254:Sodium-Potassium-Exchanging ATPase; D002118:Calcium