Self-Similar Synchronization of Calcium and Membrane Potential Transitions During Action Potential Cycles Predict Heart Rate Across Species.

Abstract Objectives The purpose of this study was to discover regulatory universal mechanisms of normal automaticity in sinoatrial nodal (SAN) pacemaker cells that are self-similar across species. Background Translation of knowledge of SAN automaticity gleaned from animal studies to human dysrhythmias (e.g., “sick sinus” syndrome [SSS]) requiring electronic pacemaker insertion has been suboptimal, largely because heart rate varies widely across species. Methods Subcellular Ca2+ releases, whole cell action potential (AP)–induced Ca2+ transients, and APs were recorded in isolated mouse, guinea pig, rabbit, and human SAN cells. Ca2+-Vm kinetic parameters during phases of AP cycles from their ignition to recovery were quantified. Results Although both action potential cycle lengths (APCLs) and Ca2+-Vm kinetic parameters during AP cycles differed across species by 10-fold, trans-species scaling of these during AP cycles and scaling of these to APCL in cells in vitro, electrocardiogram RR intervals in vivo, and body mass (BM) were self-similar (obeyed power laws) across species. Thus, APCL in vitro, heart rate in vivo, and BM of any species can be predicted by Ca2+-Vm kinetics during AP cycles in SAN cells measured in any single species in vitro. Conclusions In designing optimal heart rate 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 pharmacological and biological pacemakers featuring a normal, wide-range rate regulation in animal models and the translation of these to humans to target recalcitrant human SSS.