Intracellular na+ modulates pacemaking activity in murine sinoatrial node myocytes: An in silico analysis

Stefano Morotti, Haibo Ni, Colin H. Peters, Christian Rickert, Ameneh Asgari-Targhi, Daisuke Sato, Alexey V. Glukhov, Catherine Proenza, Eleonora Grandi

Research output: Contribution to journalArticlepeer-review

Abstract

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. Car-diomyocyte [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 gen-erates 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.

Original languageEnglish (US)
Article number5645
JournalInternational journal of molecular sciences
Volume22
Issue number11
DOIs
StatePublished - Jun 1 2021

Keywords

  • Bistability
  • Cardiac arrhythmia
  • Cardiac pacemaking
  • Cardiomyocyte
  • Coupled-clock system
  • Sick sinus syndrome
  • Sinoatrial node
  • Sodium homeostasis
  • Sodium/calcium exchanger
  • Sodium/potassium pump

ASJC Scopus subject areas

  • Catalysis
  • Molecular Biology
  • Spectroscopy
  • Computer Science Applications
  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Inorganic Chemistry

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