Coupling and heterogeneity modulate pacemaking capability in healthy and diseased two-dimensional sinoatrial node...

Area of Science:

• Cardiovascular Physiology
• Computational Biology
• Cardiac Electrophysiology

Background:

• The sinoatrial node (SAN) is crucial for initiating the heartbeat, but the mechanisms ensuring its robust electrical activity remain incompletely understood.
• Previous research has explored factors influencing SAN function, yet key questions regarding cellular heterogeneity and intercellular coupling persist.

Purpose of the Study:

• To investigate the roles of intercellular coupling and cellular heterogeneity in synchronization and pacemaking within the human and rabbit SAN using mathematical modeling.
• To understand how these factors contribute to SAN function in both healthy and diseased states.

Main Methods:

• Development of a multicellular computational model simulating a monolayer of human or rabbit SAN cells.
• Analysis of synchronization and pacemaking under varying degrees of cellular heterogeneity and intercellular coupling.
• Simulation of pathological conditions involving perturbed ionic currents and reduced cellular excitability.

Main Results:

• Heterogeneous SAN cells synchronize to a unique rhythm across a broad range of coupling and heterogeneity.
• An intermediate range of intercellular coupling (900-4000 MΩ) was found to be beneficial for SAN automaticity under pathological conditions.
• This intermediate coupling allowed a small tissue area to drive propagation, preventing failure seen at lower or higher resistances.

Conclusions:

• Intercellular coupling and cellular heterogeneity confer remarkable resilience to the SAN, preserving spontaneous beating despite perturbations.
• Specific degrees of gap junctional coupling protect the SAN from ionic disturbances caused by drugs or genetic mutations.
• The computational model provides insights into the mechanisms maintaining SAN function and highlights the importance of coupling in cardiac health.