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

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 AP 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.