Derivative-based Inference for Cell and Channel Electrophysiology Models

Clerx, Michael; Augustin, David; Dale-Evans, Alister R.; Mirams, Gary R.

doi:10.22489/CinC.2022.287

Optimising experimental designs for model selection of ion channel drug binding mechanisms (2024)
Preprint / Working Paper
Patten-Elliott, F., Lei, C. L., Preston, S. P., Wilkinson, R. D., & Mirams, G. R. Optimising experimental designs for model selection of ion channel drug binding mechanisms

The rapid delayed rectifier current carried by the human Ether-à-go-go-Related Gene (hERG) channel is susceptible to drug-induced reduction which can lead to an increased risk of cardiac arrhythmia. Establishing the mechanism by which a specific drug... Read More about Optimising experimental designs for model selection of ion channel drug binding mechanisms.

Evaluating the predictive accuracy of ion channel models using data from multiple experimental designs (2024)
Preprint / Working Paper
Shuttleworth, J. G., Lei, C. L., Windley, M. J., Hill, A. P., Preston, S. P., & Mirams, G. R. Evaluating the predictive accuracy of ion channel models using data from multiple experimental designs

Mathematical models are increasingly being relied upon to provide quantitatively accurate predictions of cardiac electrophysiology. Many such models concern the behaviour of particular subcellular components (namely, ion channels) which, together, al... Read More about Evaluating the predictive accuracy of ion channel models using data from multiple experimental designs.

A range of voltage-clamp protocol designs for rapid capture of hERG kinetics (2024)
Preprint / Working Paper
Lei, C. L., Whittaker, D. G., Windley, M. J., Perry, M. D., Hill, A. P., & Mirams, G. R. A range of voltage-clamp protocol designs for rapid capture of hERG kinetics

We provide details of a series of short voltage-clamp protocols designed for gathering a large amount of information on hERG (Kv11.1) ion channel gating. The protocols have a limited number of steps and consist only of steps and ramps, making them ea... Read More about A range of voltage-clamp protocol designs for rapid capture of hERG kinetics.

Resolving artefacts in voltage-clamp experiments with computational modelling: an application to fast sodium current recordings (2024)
Preprint / Working Paper
Lei, C. L., Clark, A. P., Clerx, M., Wei, S., Bloothooft, M., de Boer, T. P., Christini, D. J., Krogh-Madsen, T., & Mirams, G. R. Resolving artefacts in voltage-clamp experiments with computational modelling: an application to fast sodium current recordings

Cellular electrophysiology is the foundation of many fields, from basic science in neurology, cardiology, oncology to safety critical applications for drug safety testing, clinical phenotyping, etc. Patch-clamp voltage clamp is the gold standard tech... Read More about Resolving artefacts in voltage-clamp experiments with computational modelling: an application to fast sodium current recordings.

Optimal experimental designs for characterising ion channel gating by filling the phase-voltage space of model dynamics (2024)
Journal Article
Mirams, G. R., Clerx, M., Whittaker, D. G., & Lei, C. L. (2024). Optimal experimental designs for characterising ion channel gating by filling the phase-voltage space of model dynamics. Mathematics in Medical and Life Sciences, 1(1), Article 2375494. https://doi.org/10.1080/29937574.2024.2375494

Voltage-clamp waveforms are imposed in the patch-clamp electrophysiology technique to provoke ion currents, the particular waveform that is used is known as the “voltage-clamp protocol”. Designing protocols to probe and quantify how gating for a part... Read More about Optimal experimental designs for characterising ion channel gating by filling the phase-voltage space of model dynamics.

Optimal experimental designs for characterising ion channel gating by filling the phase-voltage space of model dynamics (2024)
Journal Article
Mirams, G. R., Clerx, M., Whittaker, D. G., & Lei, C. L. (2024). Optimal experimental designs for characterising ion channel gating by filling the phase-voltage space of model dynamics. Mathematics in Medical and Life Sciences, 2024(1), Article 2375494. https://doi.org/10.1080/29937574.2024.2375494

Voltage-clamp waveforms are imposed in the patch-clamp electrophysiology technique to provoke ion currents, the particular waveform that is used is known as the “voltage-clamp protocol”. Designing protocols to probe and quantify how gating for a part... Read More about Optimal experimental designs for characterising ion channel gating by filling the phase-voltage space of model dynamics.

An experimental investigation of rundown of the L-type calcium current [version 1; peer review: awaiting peer review] (2024)
Preprint / Working Paper
Agrawal, A., Clerx, M., Wang, K., Gissinger, E., J. Gavaghan, D., Polonchuk, L., & R. Mirams, G. An experimental investigation of rundown of the L-type calcium current [version 1; peer review: awaiting peer review]

Background

L-type calcium channels (LCCs) are multi-protein macro-molecular ion channel complexes that are involved in several critical functions in cardiac, skeletal, neuronal, smooth muscle, and endocrine cells. Like other ion channels, LCCs can... Read More about An experimental investigation of rundown of the L-type calcium current [version 1; peer review: awaiting peer review].

Variability in reported midpoints of (in)activation of cardiac INa (2024)
Preprint / Working Paper
Clerx, M., G.A. Volders, P., & R. Mirams, G. Variability in reported midpoints of (in)activation of cardiac INa

Electrically active cells like cardiomyocytes show variability in their size, shape, and electrical activity. But should we expect variability in the properties of their ionic currents? In this brief review we gather and visualise measurements of two... Read More about Variability in reported midpoints of (in)activation of cardiac INa.

Neural network emulation of the human ventricular cardiomyocyte action potential for more efficient computations in pharmacological studies (2024)
Journal Article
Grandits, T., Augustin, C. M., Haase, G., Jost, N., Mirams, G. R., Niederer, S. A., …Jung, A. (2024). Neural network emulation of the human ventricular cardiomyocyte action potential for more efficient computations in pharmacological studies. eLife, 12, Article RP91911. https://doi.org/10.7554/elife.91911.3

Computer models of the human ventricular cardiomyocyte action potential (AP) have reached a level of detail and maturity that has led to an increasing number of applications in the pharmaceutical sector. However, interfacing the models with experimen... Read More about Neural network emulation of the human ventricular cardiomyocyte action potential for more efficient computations in pharmacological studies.

Compartmentalization proteomics revealed endolysosomal protein network changes in a goat model of atrial fibrillation (2024)
Journal Article
Ayagama, T., Charles, P. D., Bose, S. J., Boland, B., Priestman, D. A., Aston, D., …Burton, R. A. (2024). Compartmentalization proteomics revealed endolysosomal protein network changes in a goat model of atrial fibrillation. iScience, 27(6), Article 109609. https://doi.org/10.1016/j.isci.2024.109609

Endolysosomes (EL) are known for their role in regulating both intracellular trafficking and proteostasis. EL facilitate the elimination of damaged membranes, protein aggregates, membranous organelles and play an important role in calcium signaling.... Read More about Compartmentalization proteomics revealed endolysosomal protein network changes in a goat model of atrial fibrillation.

Understanding the impact of numerical solvers on inference for differential equation models (2024)
Journal Article
Creswell, R., Shepherd, K. M., Lambert, B., Mirams, G. R., Lei, C. L., Tavener, S., Robinson, M., & Gavaghan, D. J. (2024). Understanding the impact of numerical solvers on inference for differential equation models. Journal of the Royal Society, Interface, 21(212), Article 20230369. https://doi.org/10.1098/rsif.2023.0369

Most ordinary differential equation (ODE) models used to describe biological or physical systems must be solved approximately using numerical methods. Perniciously, even those solvers that seem sufficiently accurate for the forward problem, i.e. for... Read More about Understanding the impact of numerical solvers on inference for differential equation models.

Strengthening cardiac therapy pipelines using human pluripotent stem cell-derived cardiomyocytes (2024)
Journal Article
Raniga, K., Nasir, A., Vo, N. T., Vaidyanathan, R., Dickerson, S., Hilcove, S., Mosqueira, D., Mirams, G. R., Clements, P., Hicks, R., Pointon, A., Stebbeds, W., Francis, J., & Denning, C. (2024). Strengthening cardiac therapy pipelines using human pluripotent stem cell-derived cardiomyocytes. Cell Stem Cell, 31(3), 292-311. https://doi.org/10.1016/j.stem.2024.01.007

Advances in hiPSC isolation and reprogramming and hPSC-CM differentiation have prompted their therapeutic application and utilization for evaluating potential cardiovascular safety liabilities. In this perspective, we showcase key efforts toward the... Read More about Strengthening cardiac therapy pipelines using human pluripotent stem cell-derived cardiomyocytes.

The impact of uncertainty in hERG binding mechanism on in silico predictions of drug-induced proarrhythmic risk (2023)
Journal Article
Lei, C. L., Whittaker, D. G., & Mirams, G. R. (2024). The impact of uncertainty in hERG binding mechanism on in silico predictions of drug-induced proarrhythmic risk. British Journal of Pharmacology, 181(7), 987-1004. https://doi.org/10.1111/bph.16250

Background and Purpose
Drug-induced reduction of the rapid delayed rectifier potassium current carried by the human Ether-à-go-go-Related Gene (hERG) channel is associated with increased risk of arrhythmias. Recent updates to drug safety regulatory... Read More about The impact of uncertainty in hERG binding mechanism on in silico predictions of drug-induced proarrhythmic risk.

Leak current, even with gigaohm seals, can cause misinterpretation of stem cell-derived cardiomyocyte action potential recordings (2023)
Journal Article
Clark, A. P., Clerx, M., Wei, S., Lei, C. L., de Boer, T. P., Mirams, G. R., …Krogh-Madsen, T. (2023). Leak current, even with gigaohm seals, can cause misinterpretation of stem cell-derived cardiomyocyte action potential recordings. EP-Europace, 25(9), Article euad243. https://doi.org/10.1093/europace/euad243

Aims
Human-induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) have become an essential tool to study arrhythmia mechanisms. Much of the foundational work on these cells, as well as the computational models built from the resultant data,... Read More about Leak current, even with gigaohm seals, can cause misinterpretation of stem cell-derived cardiomyocyte action potential recordings.

Model-driven optimal experimental design for calibrating cardiac electrophysiology models (2023)
Journal Article
Lei, C. L., Clerx, M., Gavaghan, D. J., & Mirams, G. R. (2023). Model-driven optimal experimental design for calibrating cardiac electrophysiology models. Computer Methods and Programs in Biomedicine, 240, Article 107690. https://doi.org/10.1016/j.cmpb.2023.107690

Background and Objective: Models of the cardiomyocyte action potential have contributed immensely to the understanding of heart function, pathophysiology, and the origin of heart rhythm disturbances. However, action potential models are highly nonlin... Read More about Model-driven optimal experimental design for calibrating cardiac electrophysiology models.

Computational Cardiac Safety Testing (2023)
Book Chapter
Mirams, G. R. (2023). Computational Cardiac Safety Testing. In F. J. Hock, M. R. Gralinski, & M. K. Pugsley (Eds.), Drug Discovery and Evaluation: Safety and Pharmacokinetic Assays (1-33). Springer. https://doi.org/10.1007/978-3-030-73317-9_137-1

In recent years, computational cardiac electrophysiology simulations using mathematical models have begun to be used in industrial and regulatory assessment of the proarrhythmic risk of candidate drug compounds. The aim of this chapter is to equip th... Read More about Computational Cardiac Safety Testing.

Using many different voltage protocols to characterise discrepancy in mathematical ion channel models (2023)
Journal Article
Shuttleworth, J. G., Lok Lei, C., Windley, M., Hill, A. P., Perry, M. D., Preston, S., & Mirams, G. R. (2023). Using many different voltage protocols to characterise discrepancy in mathematical ion channel models. Biophysical Journal, 122(3, Suppl. 1), 242a. https://doi.org/10.1016/j.bpj.2022.11.1415

The Kv11.1 protein encoded by the hERG gene forms the primary subunit of a voltage-sensitive ion channel responsible for IKr in cardiomyocytes. Mathematical models of the macroscopic current are fitted to data from patch-clamp experiments - in which... Read More about Using many different voltage protocols to characterise discrepancy in mathematical ion channel models.

Normalisation of Action Potential Data Recorded with Sharp Electrodes Maximises Its Utility for Model Development (2022)
Presentation / Conference Contribution
Barral, Y. S. H., Polonchuk, L., R. Mirams, G., Clerx, M., Page, G., Sweat, K., …Gavaghan, D. J. (2022). Normalisation of Action Potential Data Recorded with Sharp Electrodes Maximises Its Utility for Model Development. In Computing in Cardiology 2022. https://doi.org/10.22489/cinc.2022.356

In silico models of cardiomyocyte electrophysiology describe the various ionic currents and fluxes that lead to the formation of action potentials (APs). Experimental data used to create such models can be recorded in adult human cardiac trabeculae u... Read More about Normalisation of Action Potential Data Recorded with Sharp Electrodes Maximises Its Utility for Model Development.

Derivative-based Inference for Cell and Channel Electrophysiology Models (2022)
Presentation / Conference Contribution
Clerx, M., Augustin, D., Dale-Evans, A. R., & Mirams, G. R. (2022, September). Derivative-based Inference for Cell and Channel Electrophysiology Models. Presented at 2022 Computing in Cardiology Conference, Tampere, Finland (online)

Models of ionic currents or of the cardiac action potential (AP) are frequently calibrated by defining an error function that quantifies the mismatch between simulations and data, and using numerical optimisation to find the parameter values that min... Read More about Derivative-based Inference for Cell and Channel Electrophysiology Models.

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