Engineering stable pacemaking at physiological rate in virtual ventricular myocytes

We evaluate the down-regulation of the time independent inward rectifying current (I_K1) and insertion of the hyperpolarisation-activated funny current (If) as methods to genetically engineer pacemaking in ventricular cells. The membrane systems (i.e., ionic concentrations clamped) of the Luo-Rudy dynamic cell model (LRd00) and a human ventricular cell model (HVM) are analysed using continuation algorithms with the maximum conductance (g) of I_K1 and I_f as bifurcation parameters. Autorhythmicity can be induced in both virtual ventricular models, either via Hopfor homoclinic bifurcations, by (1) reducing g macr_K1, (2) insertion of g macr_f, or (3) a combination of both. In the g macr_f-g macr_K1 parameter space of LRd00 membrane, unstable pacemaking activities clustered along the Hopf bifurcation boundary and with g macr_K1 ap 0 mS muF^-1. However, stable pacemaking with physiological rates can be induced by a combination of I_K1 down-regulation and insertion of I_f.