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

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 (I<inf>K1</inf>) and combining hyperpolarization-activated funny channel current (I<inf>f</inf>), such as the change of intracellular concentration equilibrium and un-physiological pacing frequency. Previous biological studies suggested that Na<sup>+</sup>-Ca<sup>2+</sup> exchange current (I<inf>NaCa</inf>) -related gene increased 4-fold in pacemaker cells than normal cardiac myocytes. In addition, the accumulation of intracellular Na<sup>+</sup> was observed due to the combination of I<inf>f</inf> and prompting feedback mechanism of Na<sup>+</sup>/K<sup>+</sup> pumping may accelerate pumping out excessive Na<sup>+</sup> in pacemaker cells. In this study, we construct a pacemaker model based on a ventricular myocyte model by manipulating I<inf>K1</inf> and I<inf>f</inf> and optimize this pacemaker model by augmenting I<inf>NaCa</inf> and I<inf>NaK</inf>. Simulating results showed that overexpressing I<inf>NaCa</inf> and I<inf>NaK</inf> balanced the equilibrium of intracellular ionic concentrations effectively and enhanced the pacemaking ability. And the most optimized cooperation between I<inf>NaCa</inf> and I<inf>NaK</inf> was defined in this study. The action of I<inf>f</inf> 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.

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