Sinoatrial node cells and tissue operate via stochastic resonance.

Abstract

Sinoatrial node (SAN), the primary heart pacemaker, is a highly heterogeneous, complex cellular network. Recent imaging data indicate that synchronized action potentials (APs) that exit the SAN emerge from heterogeneous signals, including subthreshold, irregular signals. We tested the hypothesis that SAN cells and tissue operate via stochastic resonance, i.e. biological noise within and among SAN cells plays an important role in generation of cardiac impulses. We performed patch-clamp experiments in current-clamp mode in isolated single rabbit SAN cells. When uniformly random current noise of a few pA amplitude with a zero average was applied via the patch pipette, cells that had been firing APs rarely and irregularly began firing more frequently and rhythmically. Further, similar noise application to non-firing cells (dormant cells or artificially hyperpolarized cells) initiated AP firing. These results were supported by simulations of Maltsev-Lakatta numerical model of SAN cells. Further, simulations using a numerical model of heterogeneous SAN cellular network, in which the rate of Ca pumping and ICaL conductance varied, revealed that random current noise applied within cells also improved the tissue function. In scenarios at the edge of criticality, in which the cell network could not operate (99.84% of non-firing cells), almost all cells (97.12%) fired APs when noise was applied to cells within the network. Although artificial noise was applied in our experiments and simulations, similar noise is likely to be generated under physiological conditions by stochastic openings of ion channels (RyRs and L-type Ca-channels) within cells and by subthreshold signals from neighboring cells in SAN tissue. Our results support the idea that the SAN operates via stochastic resonance, thus shifting the paradigm of SAN operation from dictatorship and democracy theories, to a complex neuronal-type modus operandi, i.e. the SAN operates as “the heart's brain”.