Effect of rectified gap junctional electrical coupling and spatial distribution of biologically engineered pacemaking cells on ventricular excitation

Abstract

AimBiologically engineered pacemaker, or bio-pacemaker, is a promising replacement for electronic pacemakers for treating cardiac dysfunction. Previous animal experimental studies, however, have not been able to accurately demonstrate the stability and efficiency of the bio-pacemaker yet. This study aimed to elucidate the underlying factors that affect bio-pacemakers performance and to discover possible optimising solutions to enable the potential use of bio-pacemaker therapy. Methods and resultsThe human ventricular myocytes model in this study followed the ten Tussuchers model in 2006, and the bio-pacemaker single cell model was modified based on it as what has been expatiated in our previous work. In tissue model, two factors were primarily evaluated for their effects on bio-pacemakers to pace and drive surrounding cardiac tissue: gap junction between bio-pacemaker cells (PMs) and adjacent ventricular myocytes (VMs) and the spatial distribution of bio-pacemakers. A suppressed gap junctional electrical coupling between and heterotypic gap junctions were simulated and a combination of them led to the best performance of the bio-pacemaker. Then, the pacemaking behaviours of three kinds of idealised PM-VM slices were simulated, in which an electrically isolated distribution of bio-pacemaker showed optimal drive capacities. Finally, a real human ventricular slice model was used to verified the conclusions in idealized tissues. ConclusionThis study develops a theory that weak-rectified electrical coupling and electrically isolated distribution can enhance the pacemaking efficiency of bio-pacemakers, which lays the groundwork for future research into therapeutic applications of bio-pacemakers. Author summaryBiologically engineered pacemakers are expected to be a substitute for electronic pacemakers because of their physiological superiority, but how to transform them for practical application remains challenging. In this paper, we presented a theoretical perspective on optimising biological pacemaking capability based on a computational simulation approach. By manipulating the gap junctional electrical coupling among bio-pacemaking cells and between the pacemaker and their surrounding cells, and controlling spatial distribution of bio-pacemaker, we demonstrated that an enhanced capacity of a bio-pacemaker can be achieved. The results of this study may provide a theoretical basis for the further clinical development of bio-pacemakers.