Role of If (Funny Current) on Biological Pacemaker - Insight From A Ventricular Model

Abstract

Biological pacemaker has been proposed as a promising alternative to electrical pacemaker for treating patients with impaired native cardiac pacemaker. It has been verified that overexpressing the hyperpolarization-activated funny channel current (funny current, $I_{f)}$ can induce automatic pacing activities in ventricular myocytes (VMs). In this study, possible roles of $I_{f}$ expression in generating automaticity in VMs are systematically investigated. We implemented a computational approach to study mechanism by which increase of $I_{f}$ induces automaticity in VMs. The TP06 model of the electrical action potential in the human VMs was modified by incorporating $I_{f}$ formulation. When the channel conductance of $I_{f}$ was greater than 0.09 nS/pF, the VMs showed spontaneous pacing activities. During the time course of spontaneous action potentials, incorporating $I_{f}$ induced changes in the intracellular ionic concentrations, leading to accumulation of intracellular calcium $([Ca^{2+}]_{i})$ as well as sodium concentration $([Na^{+}]_{i})$, but a decrease in the intracellular potassium concentration $([K^{+}]_{i})$. By clamping $[Na^{+}]_{i} \ \ and \ \ [K^{+}]_{i}$ to a constant level, a fast and stable spontaneous pacemaking activity was observed. This study helps to understand the mechanism of creating biological pacemakers using $I_{f}$ overexpression.