Coupling and Heterogeneity Modulate Pacemaking Capability in Healthy and Diseased Two-Dimensional Sinoatrial Node Tissue Models

ABSTRACT Both experimental and modeling studies have attempted to determine mechanisms by which a small anatomical region, such as the sinoatrial node (SAN), can robustly drive electrical conduction in the human heart. However, despite important advances from prior research, important questions remain unanswered. This study aimed to investigate, through mathematical modeling, the role of intercellular coupling and cellular heterogeneity in synchronization and pacemaking within the healthy and diseased SAN. In a multicellular computational model of a monolayer of either human or rabbit SAN cells, simulations revealed that heterogenous cells synchronize their discharge frequency into a unique beating rhythm across a wide range of cellular heterogeneity and intercellular coupling. However, an insightful and unanticipated behavior appears in pathological conditions precipitated by perturbations of certain ionic currents (g CaL = 0.5): an intermediate range of intercellular coupling (900-4000 MΩ) is beneficial to the human SAN automaticity, enabling a very small portion of tissue (3.4%) to drive propagation, which fails with both lower and higher resistances. This protective effect of intercellular coupling and heterogeneity, seen in both human and rabbit tissues, highlights the remarkable resilience of the SAN. Overall, the model here developed allowed insight into the mechanisms of automaticity of the human sinoatrial node. The simulations suggest that certain degrees of gap junctional expressions protect the SAN from ionic perturbations that might be caused by drugs or mutations.