The paradigm shift: Heartbeat initiation without "the pacemaker cell".

Area of Science:

• Cardiac Electrophysiology
• Computational Biology
• Cellular Cardiology

Background:

• The traditional view identifies specialized sinoatrial node (SAN) pacemaker cells as the sole initiators of cardiac rhythm via spontaneous action potentials (APs).
• Recent imaging reveals heterogeneity within the SAN, with many cells exhibiting dormant behavior (subthreshold signals) rather than firing APs.

Purpose of the Study:

• To numerically test the hypothesis that a community of dormant cells, not individual pacemaker cells, can generate normal cardiac automaticity.
• To investigate if rhythmic cardiac impulses can be initiated without relying on intrinsically automatic cells.

Main Methods:

• Developed a computational model comprising non-excitable cells with oscillatory calcium (Ca) releases and an excitable cell lacking automaticity.
• Simulated signal transformation via electrogenic Na/Ca exchange and integration within the excitable cell to reach AP threshold.

Main Results:

• The coupled cell system, where individual cells were not automatic, generated rhythmic APs.
• Subthreshold Ca signals from non-excitable cells were converted to membrane potential oscillations and integrated by the excitable cell to initiate pacemaking.
• Cardiac impulse generation was identified as an emergent property of the SAN network, driven by cell heterogeneity, weak coupling, and signal summation.

Conclusions:

• Cardiac pacemaking can be initiated by cells lacking intrinsic automaticity, challenging the dogma of the sole pacemaker cell.
• A novel mechanism for cardiac impulse initiation involves the integration of subthreshold signals, akin to neuronal temporal summation.
• Both the classical pacemaker cell mechanism and this emergent network mechanism can coexist and interact within the SAN.