Role of I_f (Funny Current) on Biological Pacemaker - Insight from A Ventricular Model

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 ([Ca²⁺]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.