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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.

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