scholarly journals Mathematical model of the neonatal mouse ventricular action potential

2008 ◽  
Vol 294 (6) ◽  
pp. H2565-H2575 ◽  
Author(s):  
Linda J. Wang ◽  
Eric A. Sobie
Keyword(s):  
Experimental Data ◽  
Mathematical Model ◽  
Action Potential ◽  
Cell Function ◽  
Cell Model ◽  
Delayed Rectifier ◽  
Heart Cell ◽  
New Model ◽  
Adult Cell ◽  
Quantitative Understanding

Therapies for heart disease are based largely on our understanding of the adult myocardium. The dramatic differences in action potential (AP) shape between neonatal and adult cardiac myocytes, however, indicate that a different set of molecular interactions in neonatal myocytes necessitates different treatment for newborns. Computational modeling is useful for synthesizing data to determine how interactions between components lead to systems-level behavior, but this technique has not been used extensively to study neonatal heart cell function. We created a mathematical model of the neonatal ( day 1) mouse myocyte by modifying, on the basis of experimental data, the densities and/or formulations of ion transport mechanisms in an adult cell model. The new model reproduces the characteristic AP shape of neonatal cells, with a brief plateau phase and longer duration than the adult (action potential duration at 80% repolarization = 60.1 vs. 12.6 ms). The simulation results are consistent with experimental data, including 1) decreased density and altered inactivation of transient outward K+ currents, 2) increased delayed rectifier K+ currents, 3) Ca2+ entry through T-type as well as L-type Ca2+ channels, 4) increased Ca2+ influx through Na+/Ca2+ exchange, and 5) Ca2+ transients resulting from transmembrane Ca2+ entry rather than release from the sarcoplasmic reticulum (SR). Simulations performed with the model generated novel predictions, including increased SR Ca2+ leak and elevated intracellular Na+ concentration in neonatal compared with adult myocytes. This new model can therefore be used for testing hypotheses and obtaining a better quantitative understanding of differences between neonatal and adult physiology.

Exploring parameter space in detailed single neuron models: simulations of the mitral and granule cells of the olfactory bulb

1993 ◽  
Vol 69 (6) ◽  
pp. 1948-1965 ◽  
Author(s):  
U. S. Bhalla ◽  
J. M. Bower
Keyword(s):  
Experimental Data ◽  
Olfactory Bulb ◽  
Parameter Space ◽  
Potassium Current ◽  
Granule Cells ◽  
Cell Model ◽  
Mitral Cell ◽  
Delayed Rectifier ◽  
Model Output ◽  
Parameter Variations

1. Detailed compartmental computer simulations of single mitral and granule cells of the vertebrate olfactory bulb were constructed using previously published geometric data. Electrophysiological properties were determined by comparing model output to previously published experimental data, mainly current-clamp recordings. 2. The passive electrical properties of each model were explored by comparing model output with intracellular potential data from hyperpolarizing current injection experiments. The results suggest that membrane resistivity in both cells is nonuniform, with somatas having a substantially lower resistivity than the dendrites. 3. The active properties of these cells were explored by incorporating active ion channels into modeled compartments. On the basis of evidence from the literature, the mitral cell model included six channel types: fast sodium, fast delayed rectifier (Kfast), slow delayed rectifier (K), transient outward potassium current (KA), voltage- and calcium-dependent potassium current (KCa), and L-type calcium current. The granule cell model included four channel types: rat brain sodium, K, KA, and the non-inactivating muscarinic potassium current (KM). Modeled channels were based on the Hodgkin-Huxley formalism. 4. Representative kinetics for each of the channel classes above were obtained from the literature. The experimentally unknown spatial distributions of each included channel were obtained by systematic parameter searches. These were conducted in two ways: large-scale simulation series, in which each parameter was varied in turn, and an adaptation of a multidimensional conjugate gradient method. In each case, the simulated results were compared wtih experimental data using a curve-matching function evaluating mean squared differences of several aspects of the simulated and experimental voltage waveforms. 5. Systematic parameter variations revealed a single distinct region of parameter space in which the mitral cell model best fit the data. This region of parameter space was also very robust to parameter variations. Specifically, optimum performance was obtained when calcium and slow K channels were concentrated in the glomeruli, with a lower density in the soma and proximal secondary dendrites. The distribution of sodium and fast potassium channels, on the other hand, was highest at the soma and axon, with a much lighter distribution throughout the secondary dendrites. The KA and KCa channels were also concentrated near the soma. 6. The parameter search of the granule cell model was much less restrained by experimental data. Several parameter regimes were found that gave a good match to the data.(ABSTRACT TRUNCATED AT 400 WORDS)

scholarly journals In silico assessment of Y1795C and Y1795H SCN5A mutations: implication for inherited arrhythmogenic syndromes

2007 ◽  
Vol 292 (1) ◽  
pp. H56-H65 ◽  
Author(s):  
Stefania Vecchietti ◽  
Eleonora Grandi ◽  
Stefano Severi ◽  
Ilaria Rivolta ◽  
Carlo Napolitano ◽  
...  
Keyword(s):  
Action Potential ◽  
Cell Model ◽  
Sodium Current ◽  
Outward Current ◽  
Delayed Rectifier ◽  
Transient Outward Current ◽  
Dependent Manner ◽  
St Segment Elevation ◽  
Rate Dependent ◽  
Surface Ecg

The effects of two SCN5A mutations (Y1795C, Y1795H), previously identified in one Long QT syndrome type 3 (LQT3) and one Brugada syndrome (BrS) families, were investigated by means of numerical modeling of ventricular action potential (AP). A Markov model capable of reproducing a wild-type as well as a mutant sodium current ( INa) was identified and was included into the Luo-Rudy ventricular cell model for action potential (AP) simulation. The characteristics of endocardial, midmyocardial, and epicardial cells were reproduced by differentiating the transient outward current ( ITO) and the ratio of slow delayed rectifier potassium ( IKs) to rapid delayed rectifier current ( IKr). Administration of flecainide and mexiletine was simulated by appropriately modifying INa, calcium current ( ICa), ITO, and IKr. Y1795C prolonged AP in a rate-dependent manner, and early afterdepolarizations (EADs) appeared during bradycardia in epicardial and midmyocardial cells; flecainide and mexiletine shortened AP and abolished EADs. Y1795H resulted in minimal changes in the APs; flecainide but not mexiletine induced APs heterogeneity across the ventricular wall that accounts for the ST segment elevation induced by flecainide in Y1795H carriers. The AP abnormalities induced by Y1795H and Y1795C can explain the clinically observed surface ECG phenotype. For the first time by modeling the effects of flecainide and mexiletine, we are able to gather mechanistic insights on the response to drugs administration observed in affected patients.

Ionic mechanisms underlying human atrial action potential properties: insights from a mathematical model

1998 ◽  
Vol 275 (1) ◽  
pp. H301-H321 ◽  
Author(s):  
Marc Courtemanche ◽  
Rafael J. Ramirez ◽  
Stanley Nattel
Keyword(s):  
Mathematical Model ◽  
Action Potential ◽  
Important Determinant ◽  
Outward Current ◽  
Delayed Rectifier ◽  
Transient Outward Current ◽  
Rate Dependent ◽  
Delayed Rectifier Current ◽  
Recovery From Inactivation ◽  
Ionic Mechanisms

The mechanisms underlying many important properties of the human atrial action potential (AP) are poorly understood. Using specific formulations of the K+, Na+, and Ca2+ currents based on data recorded from human atrial myocytes, along with representations of pump, exchange, and background currents, we developed a mathematical model of the AP. The model AP resembles APs recorded from human atrial samples and responds to rate changes, L-type Ca2+ current blockade, Na+/Ca2+ exchanger inhibition, and variations in transient outward current amplitude in a fashion similar to experimental recordings. Rate-dependent adaptation of AP duration, an important determinant of susceptibility to atrial fibrillation, was attributable to incomplete L-type Ca2+ current recovery from inactivation and incomplete delayed rectifier current deactivation at rapid rates. Experimental observations of variable AP morphology could be accounted for by changes in transient outward current density, as suggested experimentally. We conclude that this mathematical model of the human atrial AP reproduces a variety of observed AP behaviors and provides insights into the mechanisms of clinically important AP properties.

Dissipative Structures and Superplasticity

1990 ◽  
Vol 196 ◽  
Author(s):  
Hechun Chen ◽  
Reginald W. Smith ◽  
Jiwei Shi ◽  
Yang Zhengheng
Keyword(s):  
Experimental Data ◽  
Mathematical Model ◽  
Plastic Deformation ◽  
Thermodynamic Equilibrium ◽  
Dissipative Structures ◽  
Irreversible Thermodynamics ◽  
Dissipative Process ◽  
Deformation Mechanisms ◽  
New Model ◽  
Model Combining

ABSTRACTThe characteristics of superplasticity are discussed from the viewpoint of irreversible thermodynamics, in particular, system evolution and the formation of dissipative structures. A mathematical model combining determinism with indeterminism is used to analyze plastic deformation and superplasticity in metals. Since the plastic deformation of a metal is in essence a dissipative process occurring in a system far away from thermodynamic equilibrium, the instability of the system resulting from structure fluctuations (defects) and thermodynamic bifurcations (possible thermodynamic states) will result in many deformation mechanisms being available to provide the deformation observed in the system. Thus it is virtually impossible to describe all the possible models in conventional terms i.e. by the application of the method of determinism. A new model is proposed, and is shown to account for much of the experimental data reported.

scholarly journals Computational Model for Simulating Drug-Induced Arrhythmia Sensitivity of Human iPSC-derived Cardiomyocytes

2017 ◽  
Author(s):  
Xin Gao ◽  
Yue Yin ◽  
Neil Daily ◽  
Tyler Engel ◽  
Li Pang ◽  
...  
Keyword(s):  
Experimental Data ◽  
Mathematical Model ◽  
Membrane Potential ◽  
Action Potential ◽  
Induced Pluripotent Stem Cell ◽  
Patient Specific ◽  
Resting Membrane Potential ◽  
Gene Expressions ◽  
Drug Induced

AbstractA mathematical model describing the electrophysiology and ion handling of cardiomyocytes is a complement to experimental analysis predicting drug-induced proarrhythmic potential in humans as proposed by Comprehensive in vitro Proarrhythmia Assay (CiPA). While CiPA endorses the use of the O’Hara Rudy (ORd) model, which was developed to simulate electrophysiology of human adult ventricular cardiomyocytes (hAVCMs), to predict drug-induced proarrhythmias; the human induced pluripotent stem cell derived-cardiomyocytes (hiPSC-CMs) was proposed for experimental verifications. The hiPSC-CMs, especially cultured in 2D culture dishes, are inherently different from hAVCMs exhibiting different ion channel density and an immature sarcoplasmic reticulum function. To reconcile this mismatch, we have developed a mathematical electrophysiology model of an hiPSC-CM by incorporating differences in gene expressions of ion channels, pumps and receptors in hiPSC-CMs against those found in hAVCMs. This model can be used to model any hiPSC-CM cell line where expression data has been obtained and replaces the background currents for K+ and Na+ in the ORd model with the known ultra-rapid K+ channel and hyperpolarization activated K+/Na+ channel currents. With this new model, three batches each from two different hiPSC-CM cell lines are compared to experimental data of action potential duration. This mathematical model recapitulates a ventricular-like action potential morphology with a Phase 2 plateau lasting a few hundred milliseconds. However, the resting membrane potential is not as depolarized (−65 to −70 mV) as that of hAVCM (-80 mV). The elevated resting membrane potential matches experimental data previously and is thought to keep rapid sodium channels from triggering membrane depolarization instead being replaced by an overexpression of L-Type Ca2+ channel current. This model is a key step in identifying the variability between different hiPSC-CM lines and even batches of the same line, opening the door to realizing analysis of patient specific preparations in the future.

Insulin granule trafficking in β-cells: mathematical model of glucose-induced insulin secretion

2007 ◽  
Vol 293 (1) ◽  
pp. E396-E409 ◽  
Author(s):  
Alessandro Bertuzzi ◽  
Serenella Salinari ◽  
Geltrude Mingrone
Keyword(s):  
Experimental Data ◽  
Mathematical Model ◽  
Insulin Secretion ◽  
Cell Function ◽  
Model Parameters ◽  
Β Cells ◽  
Experimental Conditions ◽  
Pharmacological Agents ◽  
Hyperglycemic Clamp ◽  
Β Cell Function

A mathematical model that represents the dynamics of intracellular insulin granules in β-cells is proposed. Granule translocation and exocytosis are controlled by signals assumed to be essentially related to ATP-to-ADP ratio and cytosolic Ca2+ concentration. The model provides an interpretation of the roles of the triggering and amplifying pathways of glucose-stimulated insulin secretion. Values of most of the model parameters were inferred from available experimental data. The numerical simulations represent a variety of experimental conditions, such as the stimulation by high K+ and by different time courses of extracellular glucose, and the predicted responses agree with published experimental data. Model capacity to represent data measured in a hyperglycemic clamp was also tested. Model parameter changes that may reflect alterations of β-cell function present in type 2 diabetes are investigated, and the action of pharmacological agents that bind to sulfonylurea receptors is simulated.

Confocal imaging of calcium in intact ventricular muscle provides a new view of excitation-contraction coupling

1996 ◽  
Vol 54 ◽  
pp. 738-739
Author(s):  
W.G. Wier
Keyword(s):  
Local Control ◽  
Cardiac Tissue ◽  
Cell Function ◽  
Isolated Heart ◽  
Cardiac Cells ◽  
Confocal Imaging ◽  
Ion Concentration ◽  
Heart Cell ◽  
Free Calcium ◽  
Heart Cells

A fundamentally new understanding of cardiac excitation-contraction (E-C) coupling is being developed from recent experimental work using confocal microscopy of single isolated heart cells. In particular, the transient change in intracellular free calcium ion concentration ([Ca2+]i transient) that activates muscle contraction is now viewed as resulting from the spatial and temporal summation of small (∼ 8 μm3), subcellular, stereotyped ‘local [Ca2+]i-transients' or, as they have been called, ‘calcium sparks'. This new understanding may be called ‘local control of E-C coupling'. The relevance to normal heart cell function of ‘local control, theory and the recent confocal data on spontaneous Ca2+ ‘sparks', and on electrically evoked local [Ca2+]i-transients has been unknown however, because the previous studies were all conducted on slack, internally perfused, single, enzymatically dissociated cardiac cells, at room temperature, usually with Cs+ replacing K+, and often in the presence of Ca2-channel blockers. The present work was undertaken to establish whether or not the concepts derived from these studies are in fact relevant to normal cardiac tissue under physiological conditions, by attempting to record local [Ca2+]i-transients, sparks (and Ca2+ waves) in intact, multi-cellular cardiac tissue.

The substantiation of the formalized estimation of effectiveness of technological and production systems

2018 ◽  
Vol 15 (1) ◽  
pp. 169-181
Author(s):  
M. I. Sidorov ◽  
М. Е. Stavrovsky ◽  
V. V. Irogov ◽  
E. S. Yurtsev
Keyword(s):  
Experimental Data ◽  
Mathematical Model ◽  
Production Systems ◽  
Van Der Pol

Using the example of van der Pol developed a mathematical model of frictional self-oscillations in topochemically kinetics. Marked qualitative correspondence of the results of calculation performed using the experimental data of researchers.

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