An Engineering-Optimized Cardiac Pacemaker by Manipulating Na+/Ca2+ Exchange Current and Na+/K+ Pumping Current

摘要

Biological pacemaker is a possible therapy for arrhythmias but there are several problems when creating single pacemaker cells based on ventricular myocytes by inhibiting inward rectifier current (IK1) and combining hyperpolarization-activated funny channel current (If), such as the change of intracellular concentration equilibrium and un-physiological pacing frequency. Previous biological studies suggested that Na^{+-Ca2+ exchange current (INaCa) -related gene increased 4-fold in pacemaker cells than normal cardiac myocytes. In addition, the accumulation of intracellular Na+ was observed due to the combination of If and prompting feedback mechanism of Na+/K+ pumping may accelerate pumping out excessive Na+ in pacemaker cells. In this study, we construct a pacemaker model based on a ventricular myocyte model by manipulating IK1 and If and optimize this pacemaker model by augmenting INaCa and INaK. Simulating results showed that overexpressing INaCa and INaK balanced the equilibrium of intracellular ionic concentrations effectively and enhanced the pacemaking ability. And the most optimized cooperation between INaCa and INaK was defined in this study. The action of If in pacemaker even changed in optimized model and the deep reason is illustrated in detailed. This study might guide the clinical research of biological pacemaker.}