Synchronization of pacemaker cell firing underlies autonomic modulation of beating intervals and their variability in a numerical model of heterogeneous SA node tissue.

Abstract

The normal heart beats regularly but not metronomically. It is initiated by pacemaker cells within the sinoatrial node (SAN), an extremely heterogeneous cellular network. The functional role of SAN cell heterogeneity remains unknown. Here we investigated the problem in a SAN tissue model comprised of 2025 single cell models. Each cell model features a coupled operation of the Ca and membrane clocks. We modeled tissue heterogeneity by varying the ICaL conductance (gCaL) and SR Ca pumping (Pup). In our simulations heterogeneous cells interacted in tissue and acquired new properties: while cells in isolation had all rhythmic or no firing, cells firing irregular APs emerged in local cell communities with similar properties. The heart rate is naturally increased via β-adrenergic receptors (βAR) and decreased via cholinergic receptors (ChR) in the SAN. βAR stimulation increased the rate and synchronization of AP firing of individual cell models within the SAN tissue, whereas ChR stimulation decreased the rate and synchronization of AP firing. The number of firing cells increased in βAR stimulation to 99% from 80%, and the average cycle length of the SAN decreased by ∼20%. Meanwhile the standard deviation of the cycle length decreased by a multiple of 25, reflecting a much higher level of synchronization. During ChR stimulation, the number of firing cells remained almost unchanged, but the average AP cycle length increased by almost 20%. The standard deviation also increased by a multiple of 2, demonstrating the higher level of desynchronization. The number of cells with emergent irregular APs firing was substantially greater under ChR stimulation than BAR stimulation, indicating importance of these cells as an intrinsic source of heart rate variability at various conditions.