Cardiac Pacemaker Cells Harness Stochastic Resonance to Avoid Sinus Arrest

BACKGROUND: The sinoatrial node (SAN) is the primary pacemaker of the heart. Recent high-resolution imaging showed that synchronized action potentials exiting the SAN emerge from heterogeneous signals, including subthreshold signals in nonfiring (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. In addition, 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 synchronized Ca transients, SAN tissue exhibited heterogeneous local Ca signals with different kinetics. Noise currents, mimicking the heterogeneous natural cellular environment, restored action potential firing in dormant cells and substantially improved the rate and rhythm of cells firing infrequently and irregularly. Performance followed a bell-shaped curve, peaking and then declining, demonstrating a hallmark of stochastic resonance. Rhythmic action potential 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 action potential generation at low noise levels. Adding noise currents to the cell and tissue numerical models allowed firing under conditions in which 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 may help avoid sinus arrest when the heart slows and biological noise increases, such as during parasympathetic stimulation, bradyarrhythmia, or aging.