UC Davis

Background: The mechanisms underlying dysfunction in the sinoatrial node (SAN), the heart's primary pacemaker, are incompletely understood. Electrical and Ca²⁺-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⁺/Ca²⁺ 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 Ca²⁺ and membrane potential clocks underlying SAN firing. Conclusions: Our study generates new testable predictions and insight linking Na⁺ homeostasis to Ca²⁺ handling and membrane potential dynamics in SAN myocytes that may advance our understanding of SAN (dys)function.