Multicellular automaticity of cardiac cell monolayers: effects of density and spatial distribution of pacemaker cells

Abstract

The biological pacemaker approach is an alternative to cardiac electronic pacemakers. Its main objective is to create pacemaking activity from added or modified distribution of spontaneous cells in the myocardium. This paper aims to assess how automaticity strength of pacemaker cells (i.e. their ability to maintain robust spontaneous activity with fast rate and to drive neighboring quiescent cells) and structural linear anisotropy, combined with density and spatial distribution of pacemaker cells, may affect the macroscopic behavior of the biological pacemaker. A stochastic algorithm was used to randomly distribute pacemaker cells, with various densities and spatial distributions, in a semi-continuous mathematical model. Simulations of the model showed that stronger automaticity allows onset of spontaneous activity for lower densities and more homogeneous spatial distributions, displayed more central foci, less variability in cycle lengths and synchronization of electrical activation for similar spatial patterns, but more variability in those same variables for dissimilar spatial patterns. Compared to their isotropic counterparts, in silico anisotropic monolayers had less central foci and displayed more variability in cycle lengths and synchronization of electrical activation for both similar and dissimilar spatial patterns. The present study established a link between microscopic structure and macroscopic behavior of the biological pacemaker, and may provide crucial information for optimized biological pacemaker therapies.

In silico study of multicellular automaticity of heterogeneous cardiac cell monolayers: Effects of automaticity strength and structural linear anisotropy

“… and N cluster as a function of D aut and displayed remarkable similarities with our previous study [ 14 ], despite different model structure and different number of neighbors. In fact, average of the maximum PM cluster size monotonically increased with D aut , with a transition around D aut = 0.5 ( Fig 5 ).…”

“…Our previous study [ 14 ] demonstrated that not only the density but also the spatial distribution of PM cells may induce important intrinsic variability in the BP dynamical behavior. The study focused on a simple continuous and isotropic 2D substrate with a single period of activity for the autonomous cells.…”

“…Higher values of D aut and p thr correlate with higher percentage and more homogeneous spatial distribution of PM cells respectively. A previously described stochastic algorithm [ 14 ] was modified and implemented to randomly attribute positions to PM cells in the isotropic and anisotropic networks. Aggregation occurred when a PM cell was placed in the immediate neighborhood of another PM cell.…”

“…These concepts are limited by the lack of control on the spatial distribution and phenotype of pacemaker (PM) cells within the resting but excitable cellular network of the myocardium. We have shown that density and spatial distribution of PM cells can alter significantly the emergence and characteristics of multicellular spontaneous activity [ 14 ]. In fact, density and spatial distribution of PM cells, a priori unknown in BPs, may lead to a non-negligible intrinsic variability in the spontaneous activity of the overall network.…”

Acetylation mediates Cx43 reduction caused by electrical stimulation

“…In fact, spontaneous activity in cultured cells starts at one specific point on the periphery of the cell monolayer and propagates through gap junctions like a 2-dimensional wave (Supplementary Fig. 1) [48,49]. Conversely, field stimulation induces an almost instantaneous excitation across the cell monolayer and, consequently, pulse propagation does not occur.…”