Properties and ionic mechanisms of action potential adaptation, restitution, and accommodation in canine epicardium.
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.
Decker
Keith F
KF
Cardiac Bioelectricity and Arrhythmia Center, Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, Missouri, USA.
Heijman
Jordi
J
Silva
Jonathan R
JR
Hund
Thomas J
TJ
Rudy
Yoram
Y
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
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