Effects of Pacemaker Currents on Creation and Modulation of Pacemaker Activity in Human Ventricular Myocytes: a theoretical study with applications to engineering of biological pacemaker

Abstract

The cardiac biological pacemaker (BP) has been created by suppression of the inward-rectifier K⁺ current (I_K1) or overexpression of the hyperpolarization-activated current (I_h) in ventricular (Purkinje) or atrial myocytes, suggesting possible development of the functional BP as a therapeutic alternative to the electronic pacemaker. In this study, we investigated the effects of incorporating regulatory inward currents (pacemaker currents) such as I_h, sustained inward current (I_st), and low voltage-activated L-type Ca²⁺ channel current (I_Ca,LD) on 1) creation of BP cells, 2) robustness of BP activity to electrotonic loads of adjacent non-pacemaker cells, and 3) BP cell ability to drive the surrounding non-pacemaker cells. Bifurcation structures of single BP cell and coupled-cell models for human ventricular myocytes (HVMs) were explored during changes in conductance of I_K1, the regulatory inward currents, and gap junction. Our findings suggest that 1) incorporating I_h and I_st (or I_h and I_Ca,LD) facilitates BP generation during I_K1 suppression, although it does not lead to BP oscillation without I_K1 inhibition, and that 2) incorporating I_st or I_Ca,LD significantly improve the structural stability of BP cells to electrotonic loads and BP cell ability to drive adjacent HVMs. [J Physiol Sci. 2006;56 Suppl:S129]