Intracellular Na + Modulates Pacemaking Activity in Murine Sinoatrial Node Myocytes: An In Silico Analysis.

Background : The mechanisms underlying dysfunction in the sinoatrial node (SAN), the heart's primary pacemaker, are incompletely understood. Electrical and Ca ²⁺ -handling remodeling have been implicated in SAN dysfunction associated with heart failure, aging, and diabetes. Cardiomyocyte [Na ⁺ ] _i is also elevated in these diseases, where it contributes to arrhythmogenesis. Here, we sought to investigate the largely unexplored role of Na ⁺ homeostasis in SAN pacemaking and test whether [Na ⁺ ] _i dysregulation may contribute to SAN dysfunction. Methods : We developed a dataset-specific computational model of the murine SAN myocyte and simulated alterations in the major processes of Na ⁺ entry (Na ⁺ /Ca ²⁺ exchanger, NCX) and removal (Na ⁺ /K ⁺ ATPase, NKA). Results : We found that changes in intracellular Na ⁺ homeostatic processes dynamically regulate SAN electrophysiology. Mild reductions in NKA and NCX function increase myocyte firing rate, whereas a stronger reduction causes bursting activity and loss of automaticity. These pathologic phenotypes mimic those observed experimentally in NCX- and ankyrin-B-deficient mice due to altered feedback between the Ca ²⁺ and membrane potential clocks underlying SAN firing. Conclusions : Our study generates new testable predictions and insight linking Na ⁺ homeostasis to Ca ²⁺ handling and membrane potential dynamics in SAN myocytes that may advance our understanding of SAN (dys)function.