Endogenous subthreshold noise and PIP 2 tune diastolic coherence across the intact sinoatrial node through stochastic resonance

The heartbeat originates in the sinoatrial (SA) node, where spontaneously firing pacemaker myocytes interact to generate a coherent rhythm. The classical entrainment account is deterministic: the fastest cells entrain the rest, and variability is an error term that coupling suppresses. We proposed previously that the node instead exploits its own noise through stochastic resonance, with rhythm quality peaking at intermediate fluctuation amplitude, and since mapped a metabolic gradient capable of supplying it. Two-photon imaging of the voltage sensor ASAP5 in the intact mouse node resolved the subthreshold regime that tissue-scale mapping averages away. Diastolic coherence followed an inverted-U against endogenous noise amplitude in both poles, with optima 3.5-fold apart, and each pole operated near its own. β-adrenergic stimulation raised noise in both poles to a common level. The inferior pole, which began below its optimum, gained coherence, while the superior pole, already at its optimum, lost interval regularity. Blocking HCN-mediated I f with ivabradine lowered superior coherence without changing superior noise, and lowered inferior noise without lowering inferior coherence, dissociating the two coordinates. Thus, coherence is a surface defined by noise and coupled-clock drive. Phosphoinositide 4,5-bisphosphate (PIP 2 ), an ATP-dependent lipid cofactor for HCN channels, increased firing rate and noise in both poles but improved coherence only in the energy-poor inferior node. Prior I f block abolished that rescue. Pacemaking is therefore graded by a bioenergetic supply chain that sets the noise, not by entrainment alone. Noise, long treated as a nuisance to be averaged away, is an active ingredient of the pacemaker. Key points summary The sinoatrial node contains pacemaker cells with different firing patterns and metabolic states, but how this heterogeneity produces a coherent heartbeat is not fully understood. Biological noise is usually viewed as something that disrupts coordination. Using two-photon voltage imaging in the intact mouse sinoatrial node, we found that subthreshold voltage fluctuations are structured, regionally graded and larger in the energy-poor inferior node. Coherence of SA node pacemaker cells was highest at an intermediate level of noise, demonstrating that endogenous noise can strengthen rhythm through stochastic resonance rather than simply impair pacemaking. Changing sympathetic drive, blocking the HCN pacemaker current and supplying phosphatidylinositol 4,5-bisphosphate (PIP 2 ) showed that coherence depends jointly on noise amplitude and pacemaker drive, linking cellular energy supply to electrical coordination. These findings identify cardiac pacemaking as a bioenergetically tuned, noise-assisted process in which regional energy supply shapes subthreshold fluctuations and, together with pacemaker drive, determines coordination across the SA node.