The Periodicity of a Ca2+ Clock Intrinsic to Individual Cardiac Sinoatrial Nodal Pacemaker Cells Universally Scales to Body Mass from Mice to Humans

Abstract

Prior studies showed allometric scaling relationships between body mass (BM) and EKG of mammal's heart, including heart rate (HR), atrioventricular conduction (PR interval),etc., as a ¼-power of BM. But can ¼-power scaling that regulates HR in vivo relate to BM when downscaled to the subcellular level? Our prior studies revealed that coupling of spontaneous local intracellular calcium releases (LCRs), generated by a Ca2+ clock (sarcoplasmic reticulum-SR) to a membrane clock sarcolemmal electrogenic molecules regulates spontaneous sinoatrial nodal cell (SANC) action potential cycle length (APCL) via activating NCX inward current, the larger amplitude and early occurrence (period) of the spontaneous LCR Ca2+ signal, the earlier and larger NCX, the faster AP (shorter APCL). Relationships among LCR periods and APCL conforms to a unique linear function. We hypothesized that the LCR periods, generated within SANC from hearts of different species that vary in BM and HR scale non-linearly as ¼-power of BM of the donor species. Methods: Confocal-line-scan microscopy was used to record AP-induced-Ca2+ transients and spontaneous LCRs in spontaneously beating, single SANC, isolated from mouse-(M), guinea-pig-(GP), rabbit-(R) and human-(H) hearts. The APCL and other LCR characteristics and variations of BM across species were analyzed via double-logarithmic plots. Results: Species with larger BM exhibited longer APCL and LCR period, and more LCR events per cycle versus that in species with smaller BM. The average APCL and LCR period linearly scaled with BM with scaling exponent close to ¼. Conclusions: LCR period and APCL in single spontaneously beating SANC obey the universal law for allometric scaling for BM as does in vivo HR, therefore species differences in LCR characteristics of subcellular LCRs predict species differences in EKG parameters in vivo.