Self-similar synchronization of calcium and membrane potential transitions during AP cycles predict HR across species

Background Translation 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. Objectives To discover regulatory universal mechanisms of normal automaticity in SAN pacemaker cells that are self-similar across species. Method Sub-cellular Ca 2+ releases, whole cell AP-induced Ca 2+ transients and APs were recorded in isolated mouse, guinea-pig, rabbit and human SAN cells. Parametric Ca 2+ and Vm Kinetic Transitions (PCVKT) during phases of AP cycles from their ignition to recovery were quantified. Results Although 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 . Conclusions In 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 Abstract Studies 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 Ca 2+ 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.