Development, calibration, and validation of a novel human ventricular myocyte model in health, disease, and drug block

Human-based modelling and simulations are becoming ubiquitous in biomedical science due to their ability to augment experimental and clinical investigations. Cardiac electrophysiology is one of the most advanced areas, with cardiac modelling and simulation being considered for virtual testing of pharmacological therapies and medical devices. Current models present inconsistencies with experimental data, which limit further progress. In this study, we present the design, development, calibration and independent validation of a human-based ventricular model (ToR-ORd) for simulations of electrophysiology and excitation-contraction coupling, from ionic to whole-organ dynamics, including the electrocardiogram. Validation based on substantial multiscale simulations supports the credibility of the ToR-ORd model under healthy and key disease conditions, as well as drug blockade. In addition, the process uncovers new theoretical insights into the biophysical properties of the L-type calcium current, which are critical for sodium and calcium dynamics. These insights enable the reformulation of L-type calcium current, as well as replacement of the hERG current model.

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Computer Simulation of the Responses of Human Motoneurons to Composite 1A EPSPS: Effects of Background Firing Rate

Journal of Neurophysiology ◽

10.1152/jn.1997.77.1.405 ◽

1997 ◽

Vol 77 (1) ◽

pp. 405-420 ◽

Cited By ~ 36

Author(s):

Kelvin E. Jones ◽

Parveen Bawa

Keyword(s):

Computer Simulation ◽

Firing Rate ◽

Time Course ◽

Current Model ◽

Response Probability ◽

Muscle Spindles ◽

Excitatory Postsynaptic Potential ◽

Biophysical Properties ◽

Rhythmic Firing ◽

The Relationship

Jones, Kelvin E. and Parveen Bawa. Computer simulation of the responses of human motoneurons to composite 1A EPSPS: effects of background firing rate. J. Neurophysiol. 77: 405–420, 1997. Two compartmental models of spinal alpha motoneurons were constructed to explore the relationship between background firing rate and response to an excitatory input. The results of these simulations were compared with previous results obtained from human motoneurons and discussed in relation to the current model for repetitively firing human motoneurons. The morphologies and cable parameters of the models were based on two type-identified cat motoneurons previously reported in the literature. Each model included five voltage-dependent channels that were modeled using Hodgkin-Huxley formalism. These included fast Na+ and K+ channels in the initial segment and fast Na+ and K+ channels as well as a slow K+ channel in the soma compartment. The density and rate factors for the slow K+ channel were varied until the models could reproduce single spike AHP parameters for type-identified motoneurons in the cat. Excitatory synaptic conductances were distributed along the equivalent dendrites with the same density described for la synapses from muscle spindles to type-identified cat motoneurons. Simultaneous activation of all synapses on the dendrite resulted in a large compound excitatory postsynaptic potential (EPSP). Brief depolarizing pulses injected into a compartment of the equivalent dendrite resulted in pulse potentials (PPs), which resembled the compound EPSPs. The effects of compound EPSPs and PPs on firing probability of the two motoneuron models were examined during rhythmic firing. Peristimulus time histograms, constructed between the stimulus and the spikes of the model motoneuron, showed excitatory peaks whose integrated time course approximated the time course of the underlying EPSP or PP as has been shown in cat motoneurons. The excitatory peaks were quantified in terms of response probability, and the relationship between background firing rate and response probability was explored. As in real human motoneurons, the models exhibited an inverse relationship between response probability and background firing rate. The biophysical properties responsible for the relationship between response probability and firing rate included the shapes of the membrane voltage trajectories between spikes and nonlinear changes in PP amplitude during the interspike interval at different firing rates. The results from these simulations suggest that the relationship between response probability and background firing rate is an intrinsic feature of motoneurons. The similarity of the results from the models, which were based on the properties of cat motoneurons, and those from human motoneurons suggests that the biophysical properties governing rhythmic firing in human motoneurons are similar to those of the cat.

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Models of the cardiac L-type calcium current: a quantitative comparison

10.1101/2021.10.04.462988 ◽

2021 ◽

Author(s):

Aditi Agrawal ◽

Ken Wang ◽

Liudmila Polonchuk ◽

Jonathan Cooper ◽

Gary R Mirams ◽

...

Keyword(s):

Calcium Current ◽

Cardiac Electrophysiology ◽

Critical Role ◽

Data Driven ◽

Consensus Model ◽

Simulation Code ◽

Large Variability ◽

Critical Comparison ◽

Mathematical Equations ◽

Major Data

The L-type calcium current (ICaL) plays a critical role in cardiac electrophysiology, and models of ICaL are vital tools to predict arrhythmogenicity of drugs and mutations. Five decades of measuring and modelling ICaL have resulted in several competing theories (encoded in mathematical equations). However, the introduction of new models has not typically been accompanied by a data-driven critical comparison with previous work, so that it is unclear where predictions overlap or conflict, or which model is best suited for any particular application. We gathered 71 mammalian ICaL models, compared their structure, and reproduced simulated experiments to show that there is a large variability in their predictions, which was not substantially diminished when grouping by species or other categories. By highlighting the differences in these competing theories, listing major data sources, and providing simulation code, we have laid strong foundations for the development of a consensus model of ICaL.

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Utility of hERG Assays as Surrogate Markers of Delayed Cardiac Repolarization and QT Safety

Toxicologic Pathology ◽

10.1080/01926230500431376 ◽

2006 ◽

Vol 34 (1) ◽

pp. 81-90 ◽

Cited By ~ 62

Author(s):

Gary A. Gintant ◽

Zhi Su ◽

Ruth L. Martin ◽

Bryan F. Cox

Keyword(s):

Cardiac Electrophysiology ◽

Critical Role ◽

Drug Effects ◽

Torsades De Pointes ◽

Cardiac Repolarization ◽

Surrogate Markers ◽

Related Gene ◽

Drug Induced ◽

Herg Current

HERG (human-ether-a-go-go-related gene) encodes for a cardiac potassium channel that plays a critical role in defining ventricular repolarization. Noncardiovascular drugs associated with a rare but potentially lethal ventricular arrhythmia (Torsades de Pointes) have been linked to delayed cardiac repolarization and block of hERG current. This brief overview will discuss the role of hERG current in cardiac electrophysiology, its involvement in drug-induced delayed repolarization, and approaches used to define drug effects on hERG current. In addition, examples of hERG blocking drugs acting differently (i.e., overt and covert hERG blockade due to multichannel block) together with the utility and limitations of hERG assays as tools to predict the risk of delayed repolarization and proarrhythmia are discussed.

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An audit of uncertainty in multi-scale cardiac electrophysiology models

Philosophical Transactions of The Royal Society A Mathematical Physical and Engineering Sciences ◽

10.1098/rsta.2019.0335 ◽

2020 ◽

Vol 378 (2173) ◽

pp. 20190335 ◽

Cited By ~ 4

Author(s):

Richard H. Clayton ◽

Yasser Aboelkassem ◽

Chris D. Cantwell ◽

Cesare Corrado ◽

Tammo Delhaas ◽

...

Keyword(s):

Cardiac Electrophysiology ◽

Spatial Scales ◽

Cardiac Cells ◽

Multi Scale ◽

Clinical Procedures ◽

Influence Model ◽

Open Questions ◽

Cardiac Modelling ◽

Model Predictions ◽

Quantitative Understanding

Models of electrical activation and recovery in cardiac cells and tissue have become valuable research tools, and are beginning to be used in safety-critical applications including guidance for clinical procedures and for drug safety assessment. As a consequence, there is an urgent need for a more detailed and quantitative understanding of the ways that uncertainty and variability influence model predictions. In this paper, we review the sources of uncertainty in these models at different spatial scales, discuss how uncertainties are communicated across scales, and begin to assess their relative importance. We conclude by highlighting important challenges that continue to face the cardiac modelling community, identifying open questions, and making recommendations for future studies. This article is part of the theme issue ‘Uncertainty quantification in cardiac and cardiovascular modelling and simulation’.

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Computationally efficient model of myocardial electromechanics for multiscale simulations

PLoS ONE ◽

10.1371/journal.pone.0255027 ◽

2021 ◽

Vol 16 (7) ◽

pp. e0255027

Author(s):

Fyodor Syomin ◽

Anna Osepyan ◽

Andrey Tsaturyan

Keyword(s):

Interstimulus Interval ◽

Cardiac Electrophysiology ◽

Multiscale Simulation ◽

Multiscale Simulations ◽

Muscle Strain ◽

Computationally Efficient ◽

Time Step ◽

Contraction Coupling ◽

The Impact ◽

High Stimulation Frequency

A model of myocardial electromechanics is suggested. It combines modified and simplified versions of previously published models of cardiac electrophysiology, excitation-contraction coupling, and mechanics. The mechano-calcium and mechano-electrical feedbacks, including the strain-dependence of the propagation velocity of the action potential, are also accounted for. The model reproduces changes in the twitch amplitude and Ca2+-transients upon changes in muscle strain including the slow response. The model also reproduces the Bowditch effect and changes in the twitch amplitude and duration upon changes in the interstimulus interval, including accelerated relaxation at high stimulation frequency. Special efforts were taken to reduce the stiffness of the differential equations of the model. As a result, the equations can be integrated numerically with a relatively high time step making the model suitable for multiscale simulation of the human heart and allowing one to study the impact of myocardial mechanics on arrhythmias.

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Comparative cardiovascular physiology and pathology in selected lineages of minipigs

Toxicology Research and Application ◽

10.1177/2397847317696367 ◽

2017 ◽

Vol 1 ◽

pp. 239784731769636

Author(s):

Alain Stricker-Krongrad ◽

Catherine Shoemake ◽

Derek Brocksmith ◽

Jason Liu ◽

Robert Hamlin ◽

...

Keyword(s):

Cardiac Electrophysiology ◽

Safety Evaluation ◽

Toxicity Testing ◽

Vessel Diameter ◽

Peripheral Vessel ◽

Drug Safety Evaluation ◽

Clinical Investigations ◽

Heart Blood ◽

Cardiovascular Systems ◽

And Control

The minipig has been increasingly recognized as a valid alternative to canines and nonhuman primates in regulatory toxicity. This article presents the results of cardiovascular assessments in the Yucatan, Hanford, Sinclair, and Göttingen minipigs conducted during nonclinical investigations and control toxicity testing. Cardiac electrophysiology was obtained using clinical electrocardiogram and surgical monitor units. Peripheral vessel diameter, velocity, and flow were obtained by Doppler ultrasonography, and cardiac vessel diameter was obtained postmortem. Anatomic parameters were obtained at necropsy. Histopathology assessments were conducted on heart, blood vessels, and kidneys. Collected data were compared to published cardiovascular measurements of adult humans to illustrate similarities and differences. Each lineage of minipigs was found to have specific anatomic and physiologic characteristics that may accurately reflect response of human cardiovascular systems in clinical investigations and toxicity testing. In conclusion, the interspecies similarities between the cardiovascular systems make these lineages of minipigs suitable as models for the human counterpart. In addition, these reported differences between lineages will aid investigators in selecting a relevant lineage of minipigs if specific cardiovascular parameters are required during drug safety evaluation.

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A Computerized System for Clinical Investigations in Cardiac Electrophysiology

Journal of Clinical Engineering ◽

10.1097/00004669-198911000-00008 ◽

1989 ◽

Vol 14 (6) ◽

pp. 493-504 ◽

Cited By ~ 2

Author(s):

COSIMO IMPERIALE

Keyword(s):

Cardiac Electrophysiology ◽

Clinical Investigations ◽

Computerized System

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Early ossicle growth in the regenerating disc of a brittle star

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100169559 ◽

1994 ◽

Vol 52 ◽

pp. 364-365

Author(s):

M. Shlepr ◽

R. L. Turner

Keyword(s):

Cell Membrane ◽

Light Microscopy ◽

De Novo ◽

Current Model ◽

Syncytium Formation ◽

Brittle Star ◽

Intracellular Location ◽

Limited Volume ◽

Tissue Calcification

Calcification in the echinoderms occurs within a limited-volume cavity enclosed by cytoplasmic extensions of the mineral depositing cells, the sclerocytes. The current model of this process maintains that the sheath formed from these cytoplasmic extensions is syncytial. Prior studies indicate that syncytium formation might be dependent on sclerocyte density and not required for calcification. This model further envisions that ossicles formed de novo nucleate and grow intracellularly until the ossicle effectively outgrows the vacuole. Continued ossicle growth occurs within the sheath but external to the cell membrane. The initial intracellular location has been confirmed only for elements of the echinoid tooth.The regenerating aboral disc integument of ophiophragmus filograneus was used to test the current echinoderm calcification model. This tissue is free of calcite fragments, thus avoiding questions of cellular engulfment, and ossicles are formed de novo. The tissue calcification pattern was followed by light microscopy in both living and fixed preparations.

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