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

Area of Science:

• Cardiovascular Physiology
• Computational Biology
• Cardiac Electrophysiology

Background:

• Sinoatrial node (SAN) dysfunction mechanisms are not fully understood.
• Electrical and calcium (Ca2+) remodeling contribute to SAN dysfunction in diseases like heart failure, aging, and diabetes.
• Elevated intracellular sodium ([Na+]i) in cardiomyocytes is linked to arrhythmogenesis.

Purpose of the Study:

• Investigate the role of sodium (Na+) homeostasis in SAN pacemaking.
• Determine if [Na+]i dysregulation contributes to SAN dysfunction.

Main Methods:

• Developed a computational model of murine SAN myocytes.
• Simulated alterations in Na+/Ca2+ exchanger (NCX) and Na+/K+ ATPase (NKA) function.

Main Results:

• Altered intracellular Na+ homeostasis dynamically regulates SAN electrophysiology.
• Reduced NKA and NCX function increased myocyte firing rate.
• Severe reductions in NKA/NCX function led to bursting activity and loss of automaticity, mimicking experimental findings in deficient mice.

Conclusions:

• Na+ homeostasis is intrinsically linked to Ca2+ handling and membrane potential dynamics in SAN myocytes.
• Findings provide new insights into the mechanisms of SAN dysfunction.
• Generated testable predictions for future research on cardiac pacemaking and disease.