Ziman, B. D. | Search bioRxiv

bioRxiv2020

Local calcium signals in pacemaker cells heart rate and body mass are self-similar from mice to humans

BackgroundTranslation of knowledge of sinoatrial nodal "SAN" automaticity gleaned from animal studies to human dysrhythmias, e.g. "Sick Sinus" Syndrome (SSS) requiring electronic pacemaker insertion has been sub-optimal, largely because heart rate (HR) varies widely across species. ObjectivesTo discover regulatory universal mechanisms of normal automaticity in SAN pacemaker cells that are self-similar across species. MethodSub-cellular Ca2+ releases, whole cell AP-induced Ca2+ transients and APs were recorded in isolated mouse, guinea-pig, rabbit and human SAN cells. Parametric Ca2+ and Vm Kinetic Transitions (PCVKT) during phases of AP cycles from their ignition to recovery were quantified. ResultsAlthough both action potential cycle lengths (APCL) and PCVKT during AP cycles differed across species by ten-fold, trans-species scaling of PCVKT during AP cycles and scaling, of PCVKT to APCL in cells in vitro, EKG RR intervals in vivo, and BM were self-similar (obeyed power laws) across species. Thus, APCL in vitro, HR in vivo, and BM of any species can be predicted by PCVKT during AP cycles in SAN cells measured in any single species in vitro. ConclusionsIn designing optimal HR to match widely different BM and energy requirements from mice to humans, nature did not "reinvent pacemaker cell wheels", but differentially scaled kinetics of gears that regulate the rates at which the "wheels spin". This discovery will facilitate the development of novel pharmalogic therapies and biologic pacemakers featuring a normal, wide-range rate regulation in animal models and the translation of these to humans to target recalcitrant human SSS. Condensed AbstractStudies in animal models are an important facet of cardiac arrhythmia research. Because HR differs by over ten-fold between some animals and humans, translation of knowledge about regulatory mechanisms of SAN normal automaticity gleaned from studies in animal models to target human SSS has been sub-optimal. Our findings demonstrating that trans-species self-similarity of sub-cellular and cellular mechanisms that couple Ca2+ to Vm during AP cycles can predict heart rate in vivo from mice to humans will inform on the design of novel studies in animal models and facilitate translation of this knowledge to target human disease.

physiology↗

bioRxiv2020

Self-similar action potential cycle-to-cycle variability of Ca2+ and current oscillators in cardiac pacemaker cells

Ca2+ and Vm transitions occurring throughout AP cycles in sinoatrial nodal (SAN) cells are cues that: (1) not only regulate activation states of molecules operating within criticality (Ca2+ domain) and limit-cycle (Vm domain) mechanisms of a coupled-clock system that underlies SAN cell automaticity; (2) but are also regulated by the activation states of the clock molecules they regulate. In other terms, these cues are both causes and effects of clock molecular activation (recursion). Recently, we demonstrated that Ca2+ and Vm transitions during AP cycles in single SAN cells isolated from mice, guinea pigs, rabbits and humans are self-similar (obey a power law) and are also self-similar to trans-species AP firing intervals of these cells in vitro, to heart rate in vivo, and to body mass. Neurotransmitter stimulation of {beta} adrenergic receptor or cholinergic receptor initiated signaling in SAN cells modulates their AP firing rate and rhythm by impacting on the degree to which SAN clocks couple to each other, creating the broad physiologic range of SAN cell mean AP firing intervals and firing interval variabilities. Here we show that Ca2+ and Vm domain kinetic transitions (time to AP ignition in diastole and 90% AP recovery) occurring within given AP, the mean AP firing intervals, and AP firing interval variabilities within time-series of APs in 230 individual SAN cells are self-similar (obey power laws). In other terms, these long-range correlations inform on self-similar distributions of order among SAN cells across the entire broad physiologic range of SAN AP firing intervals, regardless of whether autonomic receptors of these cells are stimulated or not, and regardless of the type (adrenergic or cholinergic) of autonomic receptor stimulation. These long-range correlations among distributions of Ca2+ and Vm kinetic functions that regulate SAN cell clock coupling during each AP cycle in different individual, isolated SAN cells not in contact with each other. Our numerical model simulations further extended our perspectives to the molecular scale and demonstrated that many ion currents also behave self-similar across autonomic states. Thus, to ensure rapid flexibility of AP firing rates in response to different types and degrees of autonomic input, nature "did not reinvent molecular wheels within the coupled-clock system of pacemaker cells", but differentially engaged or scaled the kinetics of gears that regulate the rate and rhythm at which the "wheels spin" in a given autonomic input context.

biophysics↗