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.