Determinants of Heterogeneity, Excitation and Conduction in the Sinoatrial Node: A Model Study

The sinoatrial node (SAN) is a complex structure that exhibits anatomical and functional heterogeneity which may depend on: 1) The existence of distinct cell populations, 2) electrotonic influences of the surrounding atrium, 3) the presence of a high density of fibroblasts, and 4) atrial cells intermingled within the SAN. Our goal was to utilize a computer model to predict critical determinants and modulators of excitation and conduction in the SAN. We built a theoretical “non-uniform” model composed of distinct central and peripheral SAN cells and a “uniform” model containing only central cells connected to the atrium. We tested the effects of coupling strength between SAN cells in the models, as well as the effects of fibroblasts and interspersed atrial cells. Although we could simulate single cell experimental data supporting the “multiple cell type” hypothesis, 2D “non-uniform” models did not simulate expected tissue behavior, such as central pacemaking. When we considered the atrial effects alone in a simple homogeneous “uniform” model, central pacemaking initiation and impulse propagation in simulations were consistent with experiments. Introduction of fibroblasts in our simulated tissue resulted in various effects depending on the density, distribution, and fibroblast-myocyte coupling strength. Incorporation of atrial cells in our simulated SAN tissue had little effect on SAN electrophysiology. Our tissue model simulations suggest atrial electrotonic effects as plausible to account for SAN heterogeneity, sequence, and rate of propagation. Fibroblasts can act as obstacles, current sinks or shunts to conduction in the SAN depending on their orientation, density, and coupling.Author Summary: It is well known that a small structure in the atrium called the sinoatrial node (SAN) is the pacemaker for the heart. However, the complexity and heterogeneity intrinsic to this structure has made it difficult to determine some aspects of sinoatrial node function. Here we use a computational approach, based on experimental data, to tease out the individual contributions of cellular and tissue heterogeneities and the effect of fibroblasts and atrial cells on sinoatrial node function. The computational models suggest that the complex features of the intact sinoatrial node can be reconstructed with a relatively simple model. Our simulations also predict that the presence of non-cardiac cells in the node likely contribute to its function.