Dataset Information

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 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.

SUBMITTER: Tagirova Sirenko S

PROVIDER: S-EPMC10089231 | biostudies-literature | 2021 Nov

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Tagirova Sirenko Syevda S Tsutsui Kenta K Tarasov Kirill V KV Yang Dongmei D Wirth Ashley N AN Maltsev Victor A VA Ziman Bruce D BD Yaniv Yael Y Lakatta Edward G EG

JACC. Clinical electrophysiology 20210428 11

<h4>Objectives</h4>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.<h4>Background</h4>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.<h4>Methods</h4>Subcellular Ca<sup>2+ ...[more]

PMID: 33933406

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Project description:Ca2+ and V m transitions occurring throughout action potential (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 (V m 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 V m 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 (APFIs) of these cells in vitro, to heart rate in vivo, and to body mass. Neurotransmitter stimulation of β-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 APFIs and firing interval variabilities. Here we show that Ca2+ and V m domain kinetic transitions (time to AP ignition in diastole and 90% AP recovery) occurring within given AP, the mean APFIs, and APFI variabilities within the 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 APFIs, 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 V m 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.

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Dataset Information

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

Objectives

Background

Methods

Results

Conclusions

Publications

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

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