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Intracellular Na<sup>+</sup> Modulates Pacemaking Activity in Murine Sinoatrial Node Myocytes: An <i>In Silico</i> Analysis
oleh: Stefano Morotti, Haibo Ni, Colin H. Peters, Christian Rickert, Ameneh Asgari-Targhi, Daisuke Sato, Alexey V. Glukhov, Catherine Proenza, Eleonora Grandi
Format: | Article |
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Diterbitkan: | MDPI AG 2021-05-01 |
Deskripsi
<i>Background</i>: The mechanisms underlying dysfunction in the sinoatrial node (SAN), the heart’s primary pacemaker, are incompletely understood. Electrical and Ca<sup>2+</sup>-handling remodeling have been implicated in SAN dysfunction associated with heart failure, aging, and diabetes. Cardiomyocyte [Na<sup>+</sup>]<sub>i</sub> is also elevated in these diseases, where it contributes to arrhythmogenesis. Here, we sought to investigate the largely unexplored role of Na<sup>+</sup> homeostasis in SAN pacemaking and test whether [Na<sup>+</sup>]<sub>i</sub> dysregulation may contribute to SAN dysfunction. <i>Methods</i>: We developed a dataset-specific computational model of the murine SAN myocyte and simulated alterations in the major processes of Na<sup>+</sup> entry (Na<sup>+</sup>/Ca<sup>2+</sup> exchanger, NCX) and removal (Na<sup>+</sup>/K<sup>+</sup> ATPase, NKA). <i>Results</i>: We found that changes in intracellular Na<sup>+</sup> 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<sup>2+</sup> and membrane potential clocks underlying SAN firing. <i>Conclusions</i>: Our study generates new testable predictions and insight linking Na<sup>+</sup> homeostasis to Ca<sup>2+</sup> handling and membrane potential dynamics in SAN myocytes that may advance our understanding of SAN (dys)function.