Ionic mechanisms of action potential rate dependence, conduction and block in normal epicardium and in remodeled epicardium post-infarction

In this work, detailed computational models are used to study the electrophysiology of normal epicardium and the arrhythmogenic effects of epicardial cell remodeling post-infarction. The canine epicardial myocyte model described here reproduces a wide range of experimentally observed rate dependent phenomena in cell and tissue. Model behavior depends on updated formulations for the 4-AP sensitive transient outward current (Ito1), the slow component of the delayed rectifier potassium current (IKs), the L-type Ca2+ channel (ICa,L) and the sodium-potassium pump (INaK) fit to data from canine ventricular myocytes. The model shows that Ito1 plays a limited role in potentiating peak ICa,L and Ca2+ release for propagated action potentials (APs), but modulates the time course of action potential duration (APD) restitution. IKs plays an important role in APD shortening at short diastolic intervals but a limited role in AP repolarization at longer cycle lengths. In addition, simulations demonstrate that ICa,L, INaK and [Na+]i play critical roles in APD accommodation and the rate dependence of APD restitution. Starting from the ionic model of a normal epicardial cell described above, an epicardial border zone (EBZ) model was developed based on available remodeling data. Ionic models of normal zone (NZ) and EBZ myocytes were incorporated into one-dimensional models of propagation to gain mechanistic insight into how ion channel remodeling affects APD and refractoriness, vulnerability to conduction block and conduction safety post-infarction. Simulations of EBZ APD restitution show that remodeled INa and ICaL promote increased effective refractory period (ERP) and prolonged APD at short diastolic interval (DI). Heterogeneous tissue simulations show that increased post-repolarization refractoriness and altered restitution lead to a large rate dependent vulnerable window for conduction block. In simulations of conduction post-infarction, EBZ IK1 remodeling partially offsets the reduction in conduction safety due to altered INa, while Ito1 and ICaL have a negligible effect on conduction. Further simulations show that injection of skeletal muscle sodium channel SkM1-INa, a recently proposed anti-arrhythmic therapy, has several desirable effects including normalization of EBZ ERP and APD restitution, elimination of vulnerability to conduction block and normalization of conduction in uncoupled tissue.