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

BACKGROUNDThe sinoatrial node (SAN) is primary pacemaker of the heart. Recent high-resolution imaging showed that synchronized action potentials (APs) that exit the SAN emerge from heterogeneous signals, including subthreshold signals in non-firing (dormant) cells. This sets up a new problem in cardiac biology of how these signals contribute to heartbeat generation. Here we tested a hypothesis that pacemaker cells harness stochastic resonance to ensure their fail-safe operation, especially at low rates bordering on sinus arrest. METHODSWe measured membrane potential and Ca signals in SAN cells isolated from rabbit hearts in response to external currents in the form of sine waves or white noise. Protocols were applied via a perforated patch while cells were either in the basal state or in the presence of cholinergic receptor stimulation. Additionally, we performed multiscale model simulations at respective sub-cellular, cellular, and tissue levels. RESULTSNoise currents awakened dormant cells to fire APs and substantially improved the rate and rhythm of cells firing infrequent, dysrhythmic APs. Rhythmic AP generation in response to applications of sine wave currents of different frequencies outlined a resonance spectrum in SAN cells: their capability of responding, via stochastic resonance, to specific frequency components embedded in the noise. Cholinergic stimulation shifted the resonance spectrum towards lower frequencies, i.e. cells responded to lower frequency signals but could not process higher frequency signals. Noise currents added to SAN single cell- and tissue-models substantially expanded the parametric space of AP firing beyond the bifurcation line where cells failed to operate without noise. Both the numerical models and our simultaneous recordings of membrane potential and Ca dynamics also demonstrated that stochastic resonance in SAN cells is amplified by coupled electrical and Ca signaling, enhancing AP generation at low noise levels. CONCLUSIONSSAN cells harness stochastic resonance amplified by coupled membrane-Ca signaling to ensure rhythmic heartbeat initiation especially at low rates, providing a last-resort signaling mechanism to avoid sinus arrest when signal synchronization decreases but noise substantially increases, such as during strong parasympathetic stimulation, disease or aging when the heart slows and high-frequency signaling wanes.