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Different Effects of Species-dependent Funny Channel Current on Engineered Biological Pacemaking Activity

It has been verified that biological pacemaker could be produced based on ventricular myocytes (VMs) by overexpressing HCN gene which codes the expression of hyperpolarization-activated current (If). Clinically, xenograft is in common use by which one specie' stem cell is infected with another specie's HCN gene so that the stem cell could transfer into cardiac pacemaker cell. The difference of HCN gene between species affects If properties, but how the If properties influence pacemaker creation is not easy to be qualified in biological experiments. In this study, we build an engineered biological pacemaker model based on a ventricular myocyte model by incorporating If formulation and simulated the membrane potential of biological pacemaker. The If of different species is simulated by modifying average half-maximal activation voltage (V1/2) of If activation gate and If conductance (Gf). Based on the modified pacemaker model, the effect of If properties on pacemaking stability and frequency is evaluated. Simulation results indicate that pacemaking ability is influenced dramatically by If properties. In addition, the spontaneous pacemaking mechanism showed both membrane-clock and Ca2+-clock and its deep reason is analyzed in this paper. This study may provide a subcellular perspective for the clinical use of biological pacemaker.