Towards an engineered biopacemaker therapy: Understanding multicellular spontaneous activity by mathematical modeling and experiments.

The sinus node is the most important entity behind the rhythmic beating of the heart, with the spontaneous activity being regulated by the interplay of ion channels and regulating signaling pathways. Abnormal sinus rhythm or malfunction of the conduction system need therapeutic interventions often in the form of an implanted electronic pacemaker. A new therapy has been put forward where a new structure of spontaneously beating cells, the biological pacemaker, is created to replace the malfunctioning structure. The proposed approaches to develop biological pacemakers to date are composed of heterogeneous derived cardiac cells with resting and spontaneously beating phenotypes. However, the combined interaction between characteristics, density and spatial distribution of the pacemaker cells on spontaneous activity is unknown. Simulations show that spontaneous activity is dependent on the pacemaker cell characteristics with weaker pacemaker cells needing higher density and larger clusters to sustain multicellular activity. Moreover, stronger pacemaker cells had a decrease sensitivity to the voltage noise which also favored spontaneous activity at a lower density, and decreased the temporal variation in periods of activity. Although voltage noise in simulations induces temporal variation similar to experimental data, spatial effects on focal sites seen in experiments cannot be reproduced. Control on intercellular electrical coupling and pacemaker cell characteristics is thus central for optimization of an engineered biological pacemaker. More accurate mathematical representations of the derived cardiomyocytes including pacemaker cells remain much needed.