Cardiac Pacemaker Cells Harness Stochastic Resonance to Ensure Fail-Safe Operation at Low Rates Bordering on Sinus Arrest

ABSTRACT BACKGROUND The sinoatrial node (SAN) is the primary pacemaker of the heart. Recent high-resolution imaging showed that synchronized action potentials (APs) exiting the SAN emerge from heterogeneous signals, including subthreshold signals in non-firing (dormant) cells. This raises a new question in cardiac biology: how do these signals contribute to heartbeat generation? Here, we tested the hypothesis that pacemaker cells harness stochastic resonance to ensure fail-safe operation, especially at low rates bordering on sinus arrest. METHODS Membrane potential and Ca signals were measured using perforated-patch recordings in rabbit SAN cells exposed to sine-wave or white-noise currents. Additionally, we imaged Ca signals in intact mouse SAN tissue and performed multiscale model simulations at the subcellular, cellular, and tissue levels. RESULTS In addition to classical synchronized Ca transients, SAN tissue exhibited heterogeneous local Ca signals of different kinetics. Noise currents, mimicking the heterogeneous natural cell environment, restored AP firing in dormant cells and substantially improved the rate and rhythm of those firing infrequently and irregularly. The benefit followed a bell-shaped curve: the performance improved but then declined, demonstrating a hallmark of stochastic resonance. Rhythmic AP generation in response to sine-wave currents of different frequencies defined a resonance spectrum in SAN cells, reflecting their ability to respond via stochastic resonance to specific frequency components embedded in noise. Cholinergic stimulation shifted the resonance spectrum and responses to noise toward lower frequencies across all amplitudes tested, rendering cells unresponsive to higher-frequency signals while enabling more effective processing of slower signals. Both the numerical models and simultaneous recordings of membrane potential and Ca dynamics demonstrated that stochastic resonance is amplified by coupled electrical and Ca signaling, enhancing AP generation at low noise levels. Adding noise currents to the cell and tissue models allowed firing under conditions where they otherwise would have stopped. CONCLUSIONS SAN cells harness stochastic resonance amplified by coupled membrane-Ca signaling to ensure rhythmic heartbeat initiation, especially at low rates. This new signaling mechanism could help avoid sinus arrest when heart slows but noise increases, such as during parasympathetic stimulation, bradyarrhythmia, or aging.