Effects of pacemaker currents on creation and modulation of human ventricular pacemaker: theoretical study with application to biological pacemaker engineering

A 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). We theoretically investigated the effects of incorporating 1(h), T-type Ca2+ current (I-Ca,I-T), sustained inward current (I-st), and/or low-voltage-activated L-type Ca2+ channel current (I-Ca,I-LD) on 1) creation of BP cells, 2) robustness of BP activity to electrotonic loads of nonpacemaking (NP) cells, and 3) BP cell ability to drive NP cells. We used a single-cell model for human ventricular myocytes (HVMs) and also coupled-cell models composed of BP and NP cells. Bifurcation structures of the model cells were explored during changes in conductance of the currents and gap junction. Incorporating the pacemaker currents did not yield BP activity in HVM with normal IK1 but increased the critical IK1 conductance for BP activity to emerge. Expressing Ih appeared to be most helpful in facilitating creation of BP cells via IK1 suppression. In the coupled-cell model, Ist significantly enlarged the gap conductance (GC) region where stable BP cell pacemaking and NP cell driving occur, reducing the number of BP cells required for robust pacemaking and driving. In contrast, Ih enlarged the GC region of pacemaking and driving only when IK1 of the NP cell was relatively low. ICa, T or ICa, LD exerted effects similar to those of Ist but caused shrinkage or irregularity of BP oscillations. These findings suggest that expressing Ist most effectively improves the structural stability of BPs to electrotonic loads and the BP ability to drive the ventricle.