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

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

doi:10.3390/ijms22115645

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. 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.

Highlights

Introduction iationsIn a healthy individual, each cardiac beat is initiated by the periodic activation of the sinoatrial node (SAN), the primary pacemaker of the heart [1]
We demonstrated that individual blocks of Na+ /K+ ATPase (NKA) and Na+ /Ca2+ exchanger (NCX) could impair SAM automaticity
We previously described the key role of ICaL in the generation of SAM Action potential (AP), and the deleterious consequences of increasing Ca2+ -dependent inactivation (CDI) (Figures 5 and 6)

Summary

Introduction

Each cardiac beat is initiated by the periodic activation of the sinoatrial node (SAN), the primary pacemaker of the heart [1]. The first subsystem, called “membrane clock”, encompasses sarcolemmal ion channels and transporters that exhibit voltage- and time-dependent properties and interact nonlinearly to shape AP characteristics. Those include the hyperpolarization-activated cyclic nucleotide-gated channels The mechanisms underlying dysfunction in the sinoatrial node (SAN), the heart’s primary pacemaker, are incompletely understood. 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).

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