Reciprocal interaction between IK1 and If in biological pacemakers: A simulation study

Pacemaking dysfunction (PD) may result in heart rhythm disorders, syncope or even death. Current treatment of PD using implanted electronic pacemaker has some limitations, such as finite battery life and the risk of repeated surgery. As such, the biological pacemaker has been proposed as a potential alternative to the electronic pacemaker for PD treatment. Experimentally it has been shown that bio-engineered pacemaker cells can be generated from non-rhythmic ventricular myocytes (VMs) by knocking down genes related to the inward rectifier potassium channel current (I K1 ) or by overexpressing hyperpolarization-activated cyclic nucleotide gated channel genes responsible for the “funny” current (I f ). Such approaches can turn the VM cells into rhythmic pacemaker cells. However, it is unclear if a bio-engineered pacemaker based on the modification of I K1 - and I f -related channels simultaneously would enhance the ability and stability of bio-engineered pacemaking action potentials (APs). This study aimed to investigate by a computational approach the combined effects of modifying I K1 and I f density on the initiation of pacemaking activity in human ventricular cell models. First, the possible mechanism(s) responsible for VMs to generate spontaneous pacemaking APs by changing the density of I K1 and I f were investigated. Then the integral action of targeting both I K1 and I f simultaneously on the pacemaking APs was analysed. Our results showed a reciprocal interaction between I K1 and I f on generating stable and robust pacemaking APs in VMs. In addition, we thoroughly investigated the dynamical behaviours of automatic rhythms in VMs in the I K1 and I f parameter space, providing optimal parameter ranges for a robust pacemaker cell. In conclusion, to the best of our knowledge, this study provides a novel theoretical basis for generating stable and robust pacemaker cells from non-pacemaking VMs, which may be helpful in designing engineered biological pacemakers for application purposes.