A novel conceptual model of heart rate autonomic modulation based on a small-world modular structure of the sinoatrial node

Frontiers in Physiology, Journal Year: 2023, Volume and Issue: 14

Published: Dec. 11, 2023

The present view on heartbeat initiation is that a primary pacemaker cell or group of cells in the sinoatrial node (SAN) center paces rest SAN and atria. However, recent high-resolution imaging studies show more complex paradigm function emerges from heterogeneous signaling, mimicking brain cytoarchitecture function. Here, we developed tested new conceptual numerical model organized similarly to networks featuring modular structure with small-world topology. In our model, lower rate module leads action potential (AP) firing basal state during parasympathetic stimulation, whereas higher β-adrenergic stimulation. Such system reproduces respective shift leading site observed experimentally wide range modulation robust while conserving energy. Since experimental found functional modules at different scales, few up highest scale superior inferior SAN, appears feature hierarchical modularity, i.e., within each module, there set sub-modules, like brain, exhibiting greater robustness, adaptivity, evolvability network this perspective, offers mainframe for interpreting data signaling providing insights into cardiac SAN-related arrhythmias aging disease.

Language: Английский

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The virtual sinoatrial node: What did computational models tell us about cardiac pacemaking?

Progress in Biophysics and Molecular Biology, Journal Year: 2022, Volume and Issue: 177, P. 55 - 79

Published: Oct. 29, 2022

Language: Английский

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Tongyang Huoxue decoction (TYHX) ameliorating hypoxia/reoxygenation-induced disequilibrium of calcium homeostasis via regulating β-tubulin in rabbit sinoatrial node cells

Journal of Ethnopharmacology, Journal Year: 2023, Volume and Issue: 318, P. 117006 - 117006

Published: Aug. 6, 2023

Language: Английский

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The paradigm shift: Heartbeat initiation without “the pacemaker cell”

Frontiers in Physiology, Journal Year: 2022, Volume and Issue: 13

Published: Dec. 9, 2022

The current dogma about the heartbeat origin is based on “the pacemaker cell,” a specialized cell residing in sinoatrial node (SAN) that exhibits spontaneous diastolic depolarization triggering rhythmic action potentials (APs). Recent high-resolution imaging, however, demonstrated Ca signals and APs SAN are heterogeneous, with many cells generating of different rates rhythms or even remaining non-firing (dormant cells), i.e., only subthreshold signals. Here we numerically tested hypothesis community dormant can generate normal automaticity, cell” not required to initiate cardiac impulses. Our model includes 1) non-excitable oscillatory local releases 2) an excitable lacking automaticity. While each isolation was cell”, system generated APs: were transformed into respective membrane potential oscillations via electrogenic Na/Ca exchange further transferred integrated (computed) by reach its AP threshold, pacemaking. Cardiac impulse emergent property cellular network be initiated intrinsic Cell heterogeneity, weak coupling, signals, their summation critical properties new mechanism, operate signaling process basically similar “temporal summation” happening neuron input from multiple presynaptic cells. does refute classical cell-based mechanism: both mechanisms co-exist interact within tissue.

Language: Английский

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Meaningful local signalling in sinoatrial node identified by random matrix theory and PCA

Journal of Physics Complexity, Journal Year: 2022, Volume and Issue: 4(1), P. 015003 - 015003

Published: Dec. 21, 2022

Abstract The sinoatrial node (SAN) is the pacemaker of heart. Recently calcium signals, believed to be crucially important in rhythm generation, have been imaged intact SAN and shown heterogeneous various regions with a lot analysis relying on visual inspection rather than mathematical tools. Here we apply methods random matrix theory (RMT) developed for financial data biological sets including β -cell collectives electroencephalograms (EEG) analyse correlations signals using eigenvalues eigenvectors correlation matrix. We use principal component locate signalling modules corresponding localization properties high eigenvalues. find that top eigenvector captures global behaviour i.e. action potential (AP) induced transient. In some cases, second highest eigenvalue yields region whose predict AP. Furthermore, new analytic methods, study relationship between covariance coefficients distance, even inside central zone, there are non-trivial long range correlations, indicating intercellular interactions most cases. Lastly, perform an nearest-neighbour distances it coincides universal Wigner surmise under all available experimental conditions, while number variance, which sensitive conditions. Thus RMT application allows remove noise effects AP-induced transient thereby isolate local meaningful signalling.

Language: Английский

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Structure-Function Relationship of the Ryanodine Receptor Cluster Network in Sinoatrial Node Cells

Cells, Journal Year: 2024, Volume and Issue: 13(22), P. 1885 - 1885

Published: Nov. 14, 2024

The rate of spontaneous action potentials (APs) generated by sinoatrial node cells (SANC) is regulated local Ca2+ release (LCR) from the sarcoplasmic reticulum via channels (ryanodine receptors, RyRs). LCR events propagate and self-organize within network RyR clusters (Ca units, CRUs) Ca-induced-Ca-release (CICR) that depends on CRU sizes locations: While larger CRUs generate stronger signals, network’s topology governs signal diffusion propagation. This study used super-resolution structured illumination microscopy to image 3D in rabbit SANC. peripheral formed a spatial mesh, reflecting cell surface geometry. Two distinct subpopulations were identified each cell, with size distributions conforming two-component Gamma mixture model. Furthermore, neighboring exhibited repulsive behavior. Functional properties further examined novel numerical SANC model developed using our experimental data. Model simulations revealed heterogeneities both locations facilitate CICR increase AP firing cooperative manner. However, these reduce effect β-adrenergic stimulation terms its relative change rate. presence allows reach higher absolute rates during stimulation. Thus, facilitation regulates optimizes cardiac pacemaker operation under various physiological conditions. Dysfunction this optimization could be key factor heart reserve decline aging disease.

Language: Английский

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Cardiac Pacemaker Cells Harness Stochastic Resonance to Ensure Fail-Safe Operation at Low Rates Bordering on Sinus Arrest

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 20, 2024

ABSTRACT BACKGROUND The sinoatrial node (SAN) is primary pacemaker of the heart. Recent high-resolution imaging showed that synchronized action potentials (APs) exit SAN emerge from heterogeneous signals, including subthreshold signals in non-firing (dormant) cells. This sets up a new problem cardiac biology how these contribute to heartbeat generation. Here we tested hypothesis cells harness stochastic resonance ensure their fail-safe operation, especially at low rates bordering on sinus arrest. METHODS We measured membrane potential and Ca isolated rabbit hearts response external currents form sine waves or white noise. Protocols were applied via perforated patch while either basal state presence cholinergic receptor stimulation. Additionally, performed multiscale model simulations respective sub-cellular, cellular, tissue levels. RESULTS Noise awakened dormant fire APs substantially improved rate rhythm firing infrequent, dysrhythmic APs. Rhythmic AP generation applications wave different frequencies outlined spectrum cells: capability responding, resonance, specific frequency components embedded Cholinergic stimulation shifted towards lower frequencies, i.e. responded but could not process higher signals. added single cell– tissue-models expanded parametric space beyond bifurcation line where failed operate without Both numerical models our simultaneous recordings dynamics also demonstrated amplified by coupled electrical signaling, enhancing noise CONCLUSIONS membrane-Ca signaling rhythmic initiation rates, providing last-resort mechanism avoid arrest when signal synchronization decreases increases, such as during strong parasympathetic stimulation, disease aging heart slows high-frequency wanes.

Language: Английский

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Structure-Function Relationship of the Ryanodine Receptor Cluster Network in Sinoatrial Node Cells

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Oct. 13, 2024

ABSTRACT The rate of spontaneous action potentials (APs) generated by sinoatrial node cells (SANC) is regulated local Ca 2+ release (LCR) from the sarcoplasmic reticulum via channels (ryanodine receptors, RyRs). LCR events propagate and self-organize within network RyR clusters (Ca units, CRUs) Ca-induced-Ca-release (CICR) that depends on CRU sizes locations: while larger CRUs generate stronger signals, network’s topology governs signal diffusion propagation. This study used super-resolution structured illumination microscopy to image 3D in rabbit SANC. peripheral formed a spatial mesh, reflecting cell surface geometry. Two distinct subpopulations were identified each cell, with size distributions conforming two component Gamma mixture model. Furthermore, neighboring exhibited repulsive behavior. Functional properties further examined novel numerical SANC model developed using our experimental data. Model simulations revealed heterogeneities both locations facilitate CICR increase AP firing cooperative manner. However, these reduce effect β-adrenergic stimulation terms its relative change rate. presence allows reach higher absolute rates during stimulation. Thus, facilitation regulates optimizes cardiac pacemaker operation under various physiological conditions. Dysfunction this optimization could be key factor heart reserve decline aging disease.

Language: Английский

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A novel conceptual model of heart rate autonomic modulation based on a small-world modular structure and heterogeneous innervation of the sinoatrial node

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: Aug. 7, 2023

Abstract The current theory of cardiac pacemaker rate modulation by the autonomic nervous system is based on concept that a primary cell or group cells in center sinoatrial node (SAN) can change its AP firing within broad range, driving respective myocardium contractions to commensurate body demands. Experimental data show, however, are extremely heterogeneous, with different areas SAN clusters specializing drive APs at specific rates. Thus, higher heart rates under stress mainly driven superior SAN, whereas low inferior basal state generated somewhere middle node. Cells feature intrinsic electrophysiological and Ca cycling properties, sympathetic parasympathetic innervation, vasculature, thereby supporting effective shift an optimal (under given conditions) accompanied shifts leading site. popular single-cell-based does not capture this complex emerging paradigm function tissue revealed recent experimental studies. Here we propose more realistic, conceptual model these Our new (the ‘gear model’) simulates as brain-like structure featuring small world loosely connected (functional modules) tightly coupled cells, modeled Maltsev-Lakatta coupled-clock system. One module chronotropic gear) generates β-adrenergic stimulation, but activity strongly suppressed stimulation. other lower has sensitivity Such modular, gear-like reproduces site observed experimentally features wide range robust whilst conserving energy. In perspective, future refinement application mechanism will provide better understanding function, deterioration aging disease, ultimately creation therapies treat sick sinus syndrome function-related arrythmias.

Language: Английский

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The paradigm shift: heartbeat initiation without “the pacemaker cell”

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2022, Volume and Issue: unknown

Published: Nov. 5, 2022

Abstract The current dogma about the heartbeat origin is based on “the pacemaker cell”, a specialized cell residing in sinoatrial node (SAN) that exhibits spontaneous diastolic depolarization triggering rhythmic action potentials (APs). Recent high-resolution imaging, however, demonstrated Ca signals and APs SAN are heterogeneous, with many cells generating of different rates rhythms or even remaining non-firing (dormant cells), i.e. only subthreshold signals. Here we numerically tested hypothesis community dormant can generate normal automaticity, cell” not required to initiate cardiac impulses. Our model includes (i) non-excitable oscillatory local releases (ii) an excitable lacking automaticity. While each isolation was system generated APs: were transformed into respective membrane potential oscillations via electrogenic Na/Ca exchange further transferred integrated (computed) by reach its AP threshold, pacemaking. Conclusions: Cardiac impulse emergent property cellular network be initiated intrinsic Cell heterogeneity, weak coupling, signals, their summation critical properties new mechanism, i.e operate signaling process basically similar “temporal summation” happening neuron input from multiple presynaptic cells. does refute classical cell-based mechanism: both mechanisms co-exist interact within tissue.

Language: Английский

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