Role of I_f Density on Electrical Action Potential of Bio-engineered Cardiac Pacemaker: A Simulation Study

Due to the inevitable drawbacks of the implantable electrical pacemaker, the biological pacemaker was believed to be an alternative therapy for heart failure. Previous experimental studies have shown that biological pacemaker could be produced by genetically manipulating non-pacemaking cardiac cells by suppressing the inward rectifier potassium current (I_K1) and expressing the hyperpolarization- activated current (I_f). However, the role of I_f in such bio-engineered pacemaker is not clear. In this study, we simulated the action potential of biological pacemaker cells by manipulating I_f-I_K1 parameters (i.e., inhibiting I_K1 as well as incorporating I_f) to analyze possible mechanisms by which different I_f densities control pacemaking action potentials. Our simulation results showed different pacing mechanism between the bioengineered pacemaking cells with and without I_f. In addition, it was shown that a greater I_f density might result in a slower pacing frequency, and excessive of it might produce an early-afterdepolarizations-like action potential due to a sudden release of calcium from sarcoplasmic reticulum into the cytoplasm. This study indicated that when I_K1 was significantly suppressed, incorporating I_f may not enhance the pacing ability of biological pacemaker, but lead to abnormal dynamics of intracellular ionic concentration, increasing risks of dysrhythmia in the heart.