School of Computer Science and Technology, Harbin Institute of Technology, Harbin, China.
Peng Cheng Laboratory, Shenzhen, China.
PLoS Comput Biol. 2021 Mar 10;17(3):e1008177. doi: 10.1371/journal.pcbi.1008177. eCollection 2021 Mar.
Pacemaking dysfunction (PD) may result in heart rhythm disorders, syncope or even death. Current treatment of PD using implanted electronic pacemakers 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 and computationally, it has been shown that bio-engineered pacemaker cells can be generated from non-rhythmic ventricular myocytes (VMs) by knocking out genes related to the inward rectifier potassium channel current (IK1) or by overexpressing hyperpolarization-activated cyclic nucleotide gated channel genes responsible for the "funny" current (If). However, it is unclear if a bio-engineered pacemaker based on the modification of IK1- and If-related channels simultaneously would enhance the ability and stability of bio-engineered pacemaking action potentials. In this study, the possible mechanism(s) responsible for VMs to generate spontaneous pacemaking activity by regulating IK1 and If density were investigated by a computational approach. Our results showed that there was a reciprocal interaction between IK1 and If in ventricular pacemaker model. The effect of IK1 depression on generating ventricular pacemaker was mono-phasic while that of If augmentation was bi-phasic. A moderate increase of If promoted pacemaking activity but excessive increase of If resulted in a slowdown in the pacemaking rate and even an unstable pacemaking state. The dedicated interplay between IK1 and If in generating stable pacemaking and dysrhythmias was evaluated. Finally, a theoretical analysis in the IK1/If parameter space for generating pacemaking action potentials in different states was provided. In conclusion, to the best of our knowledge, this study provides a wide theoretical insight into understandings for generating stable and robust pacemaker cells from non-pacemaking VMs by the interplay of IK1 and If, which may be helpful in designing engineered biological pacemakers for application purposes.
起博功能障碍（PD）可能导致心律失常、晕厥甚至死亡。目前，使用植入式电子起搏器治疗 PD 存在一些局限性，例如电池寿命有限和重复手术的风险。因此，生物起搏器已被提议作为电子起搏器治疗 PD 的潜在替代方案。实验和计算表明，可以通过敲除与内向整流钾通道电流（IK1）相关的基因，或过表达负责“有趣”电流（If）的超极化激活环核苷酸门控通道基因，从非节律性心室肌细胞（VM）中产生生物工程起搏细胞。然而，目前尚不清楚基于同时修饰 IK1 和 If 相关通道的生物起搏器是否会增强生物起搏器动作电位的能力和稳定性。在这项研究中，通过计算方法研究了通过调节 IK1 和 If 密度使 VM 产生自发性起搏活动的可能机制。我们的结果表明，在心室起搏模型中，IK1 和 If 之间存在相互作用。IK1 抑制对产生心室起搏的影响是单相位的，而 If 增强的影响是双相位的。适度增加 If 会促进起搏活动，但过度增加 If 会导致起搏率减慢，甚至起搏状态不稳定。评估了 IK1 和 If 之间在产生稳定起搏和心律失常中的专门相互作用。最后，在 IK1/If 参数空间中提供了用于在不同状态下产生起搏动作电位的理论分析。总之，据我们所知，这项研究为理解 IK1 和 If 的相互作用如何从非起搏 VM 中产生稳定和强大的起搏细胞提供了广泛的理论见解，这可能有助于设计用于应用目的的工程生物起搏器。
