scholarly journals Functional heterogeneity of cell populations increases robustness of pacemaker function in a numerical model of the sinoatrial node tissue

2021 ◽  
Author(s):  
Alexander V Maltsev ◽  
Michael D Stern ◽  
Edward G Lakatta ◽  
Victor A Maltsev
Keyword(s):  
Sinoatrial Node ◽  
Cardiac Pacemaker ◽  
System Stability ◽  
Cell Populations ◽  
Model Parameters ◽  
Functional Heterogeneity ◽  
Pumping Rate ◽  
Dormant Cells ◽  
Pacemaker Function ◽  
Heterogeneity Of Cell Populations

Each heartbeat is initiated by specialized pacemaker cells operating within the sinoatrial node (SAN). While individual cells within SAN tissue exhibit substantial heterogeneity of their electrophysiological parameters and Ca cycling, the role of this heterogeneity for cardiac pacemaker function remains mainly unknown. Here we investigated the problem numerically in a 25x25 square grid of coupled-clock Maltsev-Lakatta cell models and tested the hypothesis that functional heterogeneity of cell populations increases robustness of SAN function. The tissue models were populated by cells with different degree of heterogeneity of the two key model parameters of the coupled-clock system, maximum L-type Ca current conductance (gCaL) and sarcoplasmic reticulum Ca pumping rate (Pup). Our simulations showed that in the areas of Pup-gCaL parametric space at the edge of the system stability where action potential (AP) firing was absent or dysrhythmic in tissues populated by identical cells, rhythmic AP generation was rescued in tissues populated by cells with uniformly random distributions of gCaL or Pup (but keeping the same average values). This effect to increase robust AP generation was synergistic with respect to heterogeneity in both gCaL and Pup and was further strengthened by clustering of cells with higher gCaL or Pup. The effect of functional heterogeneity was not due to a simple summation of activity of intrinsically firing cells naturally present in SAN; rather AP firing cells locally and critically interacted with non-firing/dormant cells. When firing cells prevailed, they recruited many dormant cells to fire, strongly enhancing overall SAN function. And vice versa, prevailing dormant cells suppressed AP firing in cells with intrinsic automaticity and halted SAN automaticity.

scholarly journals CaMKII-dependent phosphorylation regulates basal cardiac pacemaker function via modulation of local Ca2+ releases

2016 ◽  
Vol 311 (3) ◽  
pp. H532-H544 ◽  
Author(s):  
Yue Li ◽  
Syevda Sirenko ◽  
Daniel R. Riordon ◽  
Dongmei Yang ◽  
Harold Spurgeon ◽  
...  
Keyword(s):  
Protein Phosphorylation ◽  
Sinoatrial Node ◽  
Ventricular Myocytes ◽  
Ryanodine Receptors ◽  
Cardiac Pacemaker ◽  
Gradual Change ◽  
Pacemaker Function ◽  
Dependent Protein ◽  
Highly Correlated ◽  
Camkii Activation

Spontaneous beating of the heart pacemaker, the sinoatrial node, is generated by sinoatrial node cells (SANC) due to gradual change of the membrane potential called diastolic depolarization (DD). Spontaneous, submembrane local Ca2+ releases (LCR) from ryanodine receptors (RyR) occur during late DD and activate an inward Na+/Ca2+exchange current to boost the DD rate and fire an action potential (AP). Here we studied the extent of basal Ca2+/calmodulin-dependent protein kinase II (CaMKII) activation and the role of basal CaMKII-dependent protein phosphorylation in generation of LCRs and regulation of normal automaticity of intact rabbit SANC. The basal level of activated (autophosphorylated) CaMKII in rabbit SANC surpassed that in ventricular myocytes (VM) by approximately twofold, and this was accompanied by high basal level of protein phosphorylation. Specifically, phosphorylation of phospholamban (PLB) at the CaMKII-dependent Thr17 site was approximately threefold greater in SANC compared with VM, and RyR phosphorylation at CaMKII-dependent Ser2815 site was ∼10-fold greater in the SA node, compared with that in ventricle. CaMKII inhibition reduced phosphorylation of PLB and RyR, decreased LCR size, increased LCR periods (time from AP-induced Ca2+ transient to subsequent LCR), and suppressed spontaneous SANC firing. Graded changes in CaMKII-dependent phosphorylation (indexed by PLB phosphorylation at the Thr17site) produced by CaMKII inhibition, β-AR stimulation or phosphodiesterase inhibition were highly correlated with changes in SR Ca2+ replenishment times and LCR periods and concomitant changes in spontaneous SANC cycle lengths ( R2 = 0.96). Thus high basal CaMKII activation modifies the phosphorylation state of Ca2+ cycling proteins PLB, RyR, L-type Ca2+ channels (and likely others), adjusting LCR period and characteristics, and ultimately regulates both normal and reserve cardiac pacemaker function.

Roles of sarcoplasmic reticulum Ca2+ cycling and Na+/Ca2+ exchanger in sinoatrial node pacemaking: Insights from bifurcation analysis of mathematical models

2012 ◽  
Vol 302 (11) ◽  
pp. H2285-H2300 ◽  
Author(s):  
Yasutaka Kurata ◽  
Ichiro Hisatome ◽  
Toshishige Shibamoto
Keyword(s):  
Sarcoplasmic Reticulum ◽  
Numerical Simulations ◽  
Sinoatrial Node ◽  
Oscillatory System ◽  
Model Parameters ◽  
Full System ◽  
Pumping Rate ◽  
Model Cell ◽  
System Robustness ◽  
The Stability

To elucidate the roles of sarcoplasmic reticulum (SR) Ca2+ cycling and Na+/Ca2+ exchanger (NCX) in sinoatrial node (SAN) pacemaking, we have applied stability and bifurcation analyses to a coupled-clock system model developed by Maltsev and Lakatta ( Am J Physiol Heart Circ Physiol 296: H594-H615, 2009). Equilibrium point (EP) at which the system is stationary (i.e., the oscillatory system fails to function), periodic orbit (limit cycle), and their stability were determined as functions of model parameters. The stability analysis to detect bifurcation points confirmed crucial importance of SR Ca2+ pumping rate constant ( Pup), NCX density ( kNCX), and L-type Ca2+ channel conductance for the system function reported in previous parameter-dependent numerical simulations. We showed, however, that the model cell does not exhibit self-sustained automaticity of SR Ca2+ release at any clamped voltage and therefore needs further tuning to reproduce oscillatory local Ca2+ release and net membrane current reported experimentally at −10 mV. Our further extended bifurcation analyses revealed important novel features of the pacemaker system that go beyond prior numerical simulations in relation to the roles of SR Ca2+ cycling and NCX in SAN pacemaking. Specifically, we found that 1) NCX contributes to EP instability and enhancement of robustness in the full system during normal spontaneous action potential firings, while stabilizing EPs to prevent sustained Ca2+ oscillations under voltage clamping; 2) SR requires relatively large kNCX and subsarcolemmal Ca2+ diffusion barrier (i.e., subspace) to contribute to EP destabilization and enhancement of robustness; and 3) decrementing Pup or kNCX decreased the full system robustness against hyperpolarizing loads because EP stabilization and cessation of pacemaking were observed at the lower critical amplitude of hyperpolarizing bias currents, suggesting that SR Ca2+ cycling contributes to enhancement of the full system robustness by modulating NCX currents and promoting EP destabilization.

scholarly journals CaMKII-Dependent Phosphorylation Modulates Ca2+ Cycling in Sinoatrial Node Cells to Regulate Cardiac Pacemaker Function

2013 ◽  
Vol 104 (2) ◽  
pp. 361a-362a
Author(s):  
Tatiana M. Vinogradova ◽  
Syevda Sirenko ◽  
Yue Li ◽  
Dongmei Yang ◽  
Harold Spurgeon ◽  
...  
Keyword(s):  
Sinoatrial Node ◽  
Cardiac Pacemaker ◽  
Pacemaker Function ◽  
Sinoatrial Node Cells

scholarly journals Assembly of the Cardiac Pacemaking Complex: Electrogenic Principles of Sinoatrial Node Morphogenesis

2021 ◽  
Vol 8 (4) ◽  
pp. 40
Author(s):  
Marietta Easterling ◽  
Simone Rossi ◽  
Anthony J Mazzella ◽  
Michael Bressan
Keyword(s):  
Cardiac Tissue ◽  
Sinoatrial Node ◽  
Cardiac Pacemaker ◽  
Tissue Level ◽  
Rhythmic Contraction ◽  
Entire Volume ◽  
Impulse Generation ◽  
Cardiac Pacemaking ◽  
Electrical Impulses ◽  
Sufficient Strength

Cardiac pacemaker cells located in the sinoatrial node initiate the electrical impulses that drive rhythmic contraction of the heart. The sinoatrial node accounts for only a small proportion of the total mass of the heart yet must produce a stimulus of sufficient strength to stimulate the entire volume of downstream cardiac tissue. This requires balancing a delicate set of electrical interactions both within the sinoatrial node and with the downstream working myocardium. Understanding the fundamental features of these interactions is critical for defining vulnerabilities that arise in human arrhythmic disease and may provide insight towards the design and implementation of the next generation of potential cellular-based cardiac therapeutics. Here, we discuss physiological conditions that influence electrical impulse generation and propagation in the sinoatrial node and describe developmental events that construct the tissue-level architecture that appears necessary for sinoatrial node function.

scholarly journals Synergism of coupled subsarcolemmal Ca2+ clocks and sarcolemmal voltage clocks confers robust and flexible pacemaker function in a novel pacemaker cell model

2009 ◽  
Vol 296 (3) ◽  
pp. H594-H615 ◽  
Author(s):  
Victor A. Maltsev ◽  
Edward G. Lakatta
Keyword(s):  
Cell Model ◽  
Numerical Models ◽  
Experimental Studies ◽  
Cardiac Pacemaker ◽  
Critical Dimension ◽  
Pacemaker Cell ◽  
Pumping Rate ◽  
Rate Modulation ◽  
Wide Scale ◽  
Fail Safe

Recent experimental studies have demonstrated that sinoatrial node cells (SANC) generate spontaneous, rhythmic, local subsarcolemmal Ca2+ releases (Ca2+ clock), which occur during late diastolic depolarization (DD) and interact with the classic sarcolemmal voltage oscillator (membrane clock) by activating Na+-Ca2+ exchanger current ( INCX). This and other interactions between clocks, however, are not captured by existing essentially membrane-delimited cardiac pacemaker cell numerical models. Using wide-scale parametric analysis of classic formulations of membrane clock and Ca2+ cycling, we have constructed and initially explored a prototype rabbit SANC model featuring both clocks. Our coupled oscillator system exhibits greater robustness and flexibility than membrane clock operating alone. Rhythmic spontaneous Ca2+ releases of sarcoplasmic reticulum (SR)-based Ca2+ clock ignite rhythmic action potentials via late DD INCX over much broader ranges of membrane clock parameters [e.g., L-type Ca2+ current ( ICaL) and/or hyperpolarization-activated (“funny”) current ( If) conductances]. The system Ca2+ clock includes SR and sarcolemmal Ca2+ fluxes, which optimize cell Ca2+ balance to increase amplitudes of both SR Ca2+ release and late DD INCX as SR Ca2+ pumping rate increases, resulting in a broad pacemaker rate modulation (1.8–4.6 Hz). In contrast, the rate modulation range via membrane clock parameters is substantially smaller when Ca2+ clock is unchanged or lacking. When Ca2+ clock is disabled, the system parametric space for fail-safe SANC operation considerably shrinks: without rhythmic late DD INCX ignition signals membrane clock substantially slows, becomes dysrhythmic, or halts. In conclusion, the Ca2+ clock is a new critical dimension in SANC function. A synergism of the coupled function of Ca2+ and membrane clocks confers fail-safe SANC operation at greatly varying rates.

scholarly journals Methods for the Calculation of Thermoacoustic Stability Margins and Monte Carlo-Free Uncertainty Quantification

2017 ◽  
Author(s):  
Georg A. Mensah ◽  
Luca Magri ◽  
Jonas P. Moeck
Keyword(s):  
Monte Carlo ◽  
Factor Analysis ◽  
Risk Factor ◽  
Uncertainty Quantification ◽  
Frequency Domain ◽  
Gas Turbines ◽  
Network Models ◽  
System Stability ◽  
Risk Factor Analysis ◽  
Model Parameters

Thermoacoustic instabilities are a major threat for modern gas turbines. Frequency-domain based stability methods, such as network models and Helmholtz solvers, are common design tools because they are fast compared to compressible CFD computations. Frequency-domain approaches result in an eigenvalue problem, which is nonlinear with respect to the eigenvalue. Nonlinear functions of the frequency are, for example, the n–τ model, impedance boundary conditions, etc. Thus, the influence of the relevant parameters on mode stability is only given implicitly. Small changes in some model parameters, which are obtained by experiments with some uncertainty, may have a great impact on stability. The assessment of how parameter uncertainties propagate to system stability is therefore crucial for safe gas turbine operation. This question is addressed by uncertainty quantification. A common strategy for uncertainty quantification in thermoacoustics is risk factor analysis. It quantifies the uncertainty of a set of parameters in terms of the probability of a mode to become unstable. One general challenge regarding uncertainty quantification is the sheer number of uncertain parameter combinations to be quantified. For instance, uncertain parameters in an annular combustor might be the equivalence ratio, convection times, geometrical parameters, boundary impedances, flame response model parameters etc. Assessing also the influence of all possible combinations of these parameters on the risk factor is a numerically very costly task. A new and fast way to obtain algebraic parameter models in order to tackle the implicit nature of the eigenfrequency problem is using adjoint perturbation theory. Though adjoint perturbation methods were recently applied to accelerate the risk factor analysis, its potential to improve the theory has not yet been fully exploited. This paper aims to further utilize adjoint methods for the quantification of uncertainties. This analytical method avoids the usual random Monte Carlo simulations, making it particularly attractive for industrial purposes. Using network models and the open-source Helmholtz solver PyHoltz it is also discussed how to apply the method with standard modeling techniques. The theory is exemplified based on a simple ducted flame and a combustor of EM2C laboratory for which experimental validation is available.

Autonomic regulation of subsidiary atrial pacemakers during exercise

1991 ◽  
Vol 70 (3) ◽  
pp. 1175-1183 ◽  
Author(s):  
J. L. Ardell ◽  
W. C. Randall ◽  
G. Pomeroy ◽  
M. Lawton ◽  
T. Kim
Keyword(s):  
Right Atrium ◽  
Sinoatrial Node ◽  
Pacemaker Activity ◽  
Work Intensity ◽  
Heart Rates ◽  
Cardiac Responses ◽  
Pacemaker Function ◽  
Before And After ◽  
Autonomic Blockade ◽  
Marked Suppression

Cardiac responses to graded treadmill exercise were compared in conscious dogs before and after excision of the sinoatrial node (SAN) and adjacent tissue along the sulcus terminalis. The chronotropic and dromotropic responses to dynamic exercise were compared with and without selective muscarinic (atropine) and/or beta-adrenergic (timolol) blockade. With the SAN intact, cardiac acceleration was prompt during onset of exercise and in proportion to work intensity. Immediately after SAN excision (1-7 days), pacemaker activity exhibited marked instability in rate and pacemaker location, with rapid shifts between atrial and junctional foci. Soon thereafter (1-2 wk), subsidiary atrial pacemakers (SAPs) assumed the primary pacemaker function. Although the SAP foci demonstrated stable heart rates and atrioventricular (AV) intervals at rest and during exercise, heart rates at rest and during steady-state exercise were reduced 34% from corresponding levels in the SAN-intact state, both with and without selective autonomic blockade. For control of dromotropic function, animals with SAP foci showed pronounced shortening in AV interval in conjunction with exercise that was further exacerbated by pretreatment with atropine. Eight weeks after excision of the primary SAN pacemakers, direct electrophysiological mapping localized the SAP foci to either the inferior right atrium along the sulcus terminalis or the dorsal cranial right atrium (in or near Bachmann's bundle). Animals with SAPs localized to the inferior right atrium had a more marked suppression in heart rate with a corresponding greater decrease in AV interval during exercise than dogs with SAP foci identified within the dorsal cranial right atrium.

Effect of Chest Wall Stimulation on Cardiac Pacemaker Function

1970 ◽  
Vol 260 (5) ◽  
pp. 285-298 ◽  
Author(s):  
P Samel ◽  
S Z Abbas ◽  
F J Hildner ◽  
R P Javier ◽  
B Befeler ◽  
...  
Keyword(s):  
Chest Wall ◽  
Cardiac Pacemaker ◽  
Pacemaker Function

scholarly journals Genetic regulation of homeostatic immune architecture in the lungs of Collaborative Cross mice

2021 ◽  
Author(s):  
Brea K Hampton ◽  
Kara L. Jensen ◽  
Alan C. Whitmore ◽  
Colton L. Linnertz ◽  
Paul Maurizio ◽  
...  
Keyword(s):  
Immune Cell ◽  
Genetic Regulation ◽  
Reference Population ◽  
Collaborative Cross ◽  
System Stability ◽  
Mouse Strains ◽  
Cell Populations ◽  
Immune Homeostasis ◽  
Heritable Variation ◽  
Organ Systems

Variation in immune homeostasis, immune system stability, in organ systems such as the lungs is likely to shape the host response to infection at these exposed tissues. We evaluated immune homeostasis in immune cell populations in the lungs of the Collaborative Cross (CC) mouse genetic reference population. We found vast heritable variation in leukocyte populations with the frequency of many of these cell types showing distinct patterns relative to classic inbred strains C57BL/6J and BALB/cJ. We identified 28 quantitative trait loci (QTL) associated with variation in baseline lung immune cell populations, including several loci that broadly regulate the abundance of immune populations from distinct developmental lineages, and found that many of these loci have predictive value for influenza disease outcomes, demonstrating that genetic determinants of homeostatic immunity in the lungs regulate susceptibility to virus-induced disease. All told, we highlight the need to assess diverse mouse strains in understanding immune homeostasis and resulting immune responses.

Combustion System Damping Augmentation With Helmholtz Resonators

1999 ◽  
Vol 122 (2) ◽  
pp. 269-274 ◽  
Author(s):  
D. L. Gysling ◽  
G. S. Copeland ◽  
D. C. McCormick ◽  
W. M. Proscia
Keyword(s):  
System Dynamics ◽  
Small Amplitude ◽  
Linear Instability ◽  
Side Branch ◽  
System Stability ◽  
Simplified Model ◽  
Model Parameters ◽  
Combustion System ◽  
Pressure Oscillations ◽  
Helmholtz Resonators

This paper describes an analytical and experimental investigation to enhance combustion system operability using side branch resonators. First, a simplified model of the combustion system dynamics is developed in which the large amplitude pressure oscillations encountered at the operability limit are viewed as limit cycle oscillations of an initially linear instability. Under this assumption, increasing the damping of the small amplitude combustion system dynamics will increase combustor operability. The model is then modified to include side branch resonators. The parameters describing the side branch resonators and their coupling to the combustion system are identified, and their influence on system stability is examined. The parameters of the side branch resonator are optimized to maximize damping augmentation and frequency robustness. Secondly, the model parameters for the combustor and side branch resonator dynamics are identified from experimental data. The analytical model predicts the observed trends in combustor operability as a function of the resonator parameters and is shown to be a useful guide in developing resonators to improve the operability of combustion systems. [S0742-4795(00)00602-5]

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