AUTHOR=Maltsev Alexander V. , Stern Michael D. , Lakatta Edward G. , Maltsev Victor A. TITLE=Functional Heterogeneity of Cell Populations Increases Robustness of Pacemaker Function in a Numerical Model of the Sinoatrial Node Tissue JOURNAL=Frontiers in Physiology VOLUME=13 YEAR=2022 URL=https://www.frontiersin.org/journals/physiology/articles/10.3389/fphys.2022.845634 DOI=10.3389/fphys.2022.845634 ISSN=1664-042X ABSTRACT=

Each heartbeat is initiated by specialized pacemaker cells operating within the sinoatrial node (SAN). While individual cells within SAN tissue exhibit substantial heterogeneity of their electrophysiological parameters and Ca cycling, the role of this heterogeneity for cardiac pacemaker function remains mainly unknown. Here we investigated the problem numerically in a 25 × 25 square grid of connected coupled-clock Maltsev-Lakatta cell models. The tissue models were populated by cells with different degree of heterogeneity of the two key model parameters, maximum L-type Ca current conductance (gCaL) and sarcoplasmic reticulum Ca pumping rate (Pup). Our simulations showed that in the areas of Pup-gCaL parametric space at the edge of the system stability, where action potential (AP) firing is absent or dysrhythmic in SAN tissue models populated with identical cells, rhythmic AP firing can be rescued by populating the tissues with heterogeneous cells. This robust SAN function is synergistic with respect to heterogeneity in gCaL and Pup and can be further strengthened by clustering of cells with similar properties. The effect of cell heterogeneity is not due to a simple summation of activity of intrinsically firing cells naturally present in heterogeneous SAN; rather AP firing cells locally and critically interact with non-firing/dormant cells. When firing cells prevail, they recruit many dormant cells to fire, strongly enhancing overall SAN function; and vice versa, prevailing dormant cells suppress AP firing in cells with intrinsic automaticity and halt SAN function. The transitions between firing and non-firing states of the system are sharp, resembling phase transitions in statistical physics. Furthermore, robust function of heterogeneous SAN tissue requires weak cell coupling, a known property of the central area of SAN where cardiac impulse emerges; stronger cell coupling reduces AP firing rate and ultimately halts SAN automaticity at the edge of stability.