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 I(h), T-type Ca(2+) current (I(Ca,T)), sustained inward current (I(st)), and/or low-voltage-activated L-type Ca(2+) channel current (I(Ca,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 I(K1) but increased the critical I(K1) conductance for BP activity to emerge. Expressing I(h) appeared to be most helpful in facilitating creation of BP cells via I(K1) suppression. In the coupled-cell model, I(st) significantly enlarged the gap conductance (G(C)) 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, I(h) enlarged the G(C) region of pacemaking and driving only when I(K1) of the NP cell was relatively low. I(Ca,T) or I(Ca,LD) exerted effects similar to those of I(st) but caused shrinkage or irregularity of BP oscillations. These findings suggest that expressing I(st) most effectively improves the structural stability of BPs to electrotonic loads and the BP ability to drive the ventricle.