Paper Info
Title
Reciprocal Interaction Between I-K1 And I-F In Biological Pacemakers: A Simulation Study
Abstract
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 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 (I-K1) or by overexpressing hyperpolarization-activated cyclic nucleotide gated channel genes responsible for the "funny" current (I-f). 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. In this study, the possible mechanism (s) responsible for VMs to generate spontaneous pacemaking activity by regulating I-K1 and I-f density were investigated by a computational approach. Our results showed that there was a reciprocal interaction between I-K1 and I-f in ventricular pacemaker model. The effect of I-K1 depression on generating ventricular pacemaker was mono-phasic while that of I-f augmentation was bi-phasic. A moderate increase of I-f promoted pacemaking activity but excessive increase of I-f resulted in a slowdown in the pacemaking rate and even an unstable pacemaking state. The dedicated interplay between I-K1 and I-f in generating stable pacemaking and dysrhythmias was evaluated. Finally, a theoretical analysis in the I-K1/I-f 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 I-K1 and I-f, which may be helpful in designing engineered biological pacemakers for application purposes.Author summaryPacemaking dysfunction has become one of the most severe cardiac diseases, which may result in arrhythmia and even death. The treatment of pacemaking dysfunction by electronic pacemaker has saved millions of people in the past fifty years. But not every patient can benefit from it because of possible limitations, such as surgical implication and lack of response to the autonomic stimulus. The development of biological pacemaker based on gene engineering technology provides a promising alternative to the electronic pacemaker by manipulating the gene expression of cardiac cells. However, it is still unclear how a stable and robust biological pacemaker can be generated in this way. The present study aims to elucidate possible mechanisms responsible for a bio-engineered pacemaker using a computational electrophysiological model by modifying ionic channel properties of I-K1 and incorporating I-f in a human ventricular cell model. Simulation results indicated that the reciprocal interaction between I-K1 and I-f decided the stability and ability of biological pacemaker. This study provides new insight into the understanding of the initiation of pacemaking behaviours in non-rhythmic cardiac myocytes, providing a theoretical basis for experimental designing of biological pacemakers.
Year
DOI
Venue
2021
10.1371/journal.pcbi.1008177
PLOS COMPUTATIONAL BIOLOGY
DocType
Volume
Issue
Journal
17
3
ISSN
Citations 
PageRank 
1553-734X
0
0.34
References 
Authors
0
5
Name
Order
Citations
PageRank
Yacong Li105.07
Kuanquan Wang21617141.11
Qince Li379.91
Jules C Hancox400.34
Henggui Zhang510551.88