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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., …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.

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.

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.

Modelling the Effect of Intracellular Calcium in the Rundown of L-Type Calcium Current (2022)
Presentation / Conference Contribution
Agrawal, A., Clerx, M., Wang, K., Polonchuk, L., Gavaghan, D. J., & Mirams, G. R. (2022). Modelling the Effect of Intracellular Calcium in the Rundown of L-Type Calcium Current. In 2022 Computing in Cardiology (CinC). https://doi.org/10.22489/CinC.2022.051

The L-type calcium current (ICaL) is a key current of the heart playing an important role in the contraction of the cardiomyocyte. Patch-clamp recordings of ionic currents can be associated with a reduction of the current magnitude with time (termed... Read More about Modelling the Effect of Intracellular Calcium in the Rundown of L-Type Calcium Current.

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.

Nuanced Interactions between AKAP79 and STIM1 with Orai1 Ca 2+ Channels at Endoplasmic Reticulum-Plasma Membrane Junctions Sustain NFAT Activation (2022)
Journal Article
Lin, Y.-P., Scappini, E., Landaverde, C., Parekh-Glitsch, F., Tucker, C. J., Mirams, G. R., & Parekh, A. B. (2022). Nuanced Interactions between AKAP79 and STIM1 with Orai1 Ca 2+ Channels at Endoplasmic Reticulum-Plasma Membrane Junctions Sustain NFAT Activation. Molecular and Cellular Biology, 42(11), Article e00175-22. https://doi.org/10.1128/mcb.00175-22

A-kinase anchoring protein 79 (AKAP79) is a human scaffolding protein that organizes Ca2+/calmodulin-dependent protein phosphatase calcineurin, calmodulin, cAMP-dependent protein kinase, protein kinase C, and the transcription factor nuclear factor o... Read More about Nuanced Interactions between AKAP79 and STIM1 with Orai1 Ca 2+ Channels at Endoplasmic Reticulum-Plasma Membrane Junctions Sustain NFAT Activation.

A Parameter Representing Missing Charge Should Be Considered when Calibrating Action Potential Models (2022)
Journal Article
Barral, Y. H. M., Shuttleworth, J., Clerx, M., Whittaker, D. G., Wang, K., Polonchuk, L., …Mirams, G. R. (2022). A Parameter Representing Missing Charge Should Be Considered when Calibrating Action Potential Models. Frontiers in Physiology, 13, Article 879035. https://doi.org/10.3389/fphys.2022.879035

Computational models of the electrical potential across a cell membrane are longstanding and vital tools in electrophysiology research and applications. These models describe how ionic currents, internal fluxes, and buffering interact to determine me... Read More about A Parameter Representing Missing Charge Should Be Considered when Calibrating Action Potential Models.

A Quantitative Systems Pharmacology Perspective on the Importance of Parameter Identifiability (2022)
Journal Article
Sher, A., Niederer, S. A., Mirams, G. R., Kirpichnikova, A., Allen, R., Pathmanathan, P., …Noble, D. (2022). A Quantitative Systems Pharmacology Perspective on the Importance of Parameter Identifiability. Bulletin of Mathematical Biology, 84(3), Article 39. https://doi.org/10.1007/s11538-021-00982-5

There is an inherent tension in Quantitative Systems Pharmacology (QSP) between the need to incorporate mathematical descriptions of complex physiology and drug targets with the necessity of developing robust, predictive and well-constrained models.... Read More about A Quantitative Systems Pharmacology Perspective on the Importance of Parameter Identifiability.

Neural Network Differential Equations For Ion Channel Modelling (2021)
Journal Article
Lei, C. L., & Mirams, G. R. (2021). Neural Network Differential Equations For Ion Channel Modelling. Frontiers in Physiology, 12, Article 708944. https://doi.org/10.3389/fphys.2021.708944

Mathematical models of cardiac ion channels have been widely used to study and predict the behaviour of ion currents. Typically models are built using biophysically-based mechanistic principles such as Hodgkin-Huxley or Markov state transitions. Thes... Read More about Neural Network Differential Equations For Ion Channel Modelling.

Immediate and Delayed Response of Simulated Human Atrial Myocytes to Clinically-Relevant Hypokalemia (2021)
Journal Article
Clerx, M., Mirams, G. R., Rogers, A. J., Narayan, S. M., & Giles, W. R. (2021). Immediate and Delayed Response of Simulated Human Atrial Myocytes to Clinically-Relevant Hypokalemia. Frontiers in Physiology, 12, Article 651162. https://doi.org/10.3389/fphys.2021.651162

Although plasma electrolyte levels are quickly and precisely regulated in the mammalian cardiovascular system, even small transient changes in K+, Na+, Ca2+, and/or Mg2+ can significantly alter physiological responses in the heart, blood vessels, and... Read More about Immediate and Delayed Response of Simulated Human Atrial Myocytes to Clinically-Relevant Hypokalemia.

Development, Implementation and Testing of a Multicellular Dynamic Action Potential Clamp Simulator for Drug Cardiac Safety Assessment (2020)
Presentation / Conference Contribution
Camporesi, M., Bartolucci, C., Lei, C. L., Mirams, G. R., De Boer, T. P., & Severi, S. (2020). Development, Implementation and Testing of a Multicellular Dynamic Action Potential Clamp Simulator for Drug Cardiac Safety Assessment. . https://doi.org/10.22489/CinC.2020.416

© 2020 Creative Commons; the authors hold their copyright. As drugs can be multichannel blockers it is important to assess their cardiac safety taking into account multiple currents. In silico action potential (AP) models have been proposed for being... Read More about Development, Implementation and Testing of a Multicellular Dynamic Action Potential Clamp Simulator for Drug Cardiac Safety Assessment.

Use of Patient Health Records to Quantify Drug-Related Pro-arrhythmic Risk (2020)
Journal Article
Davies, M. R., Martinec, M., Walls, R., Schwarz, R., Mirams, G. R., Wang, K., …Polonchuk, L. (2020). Use of Patient Health Records to Quantify Drug-Related Pro-arrhythmic Risk. Cell Reports Medicine, 1(5), Article 100076. https://doi.org/10.1016/j.xcrm.2020.100076

There is an increasing expectation that computational approaches may supplement existing human decision-making. Frontloading of models for cardiac safety prediction is no exception to this trend, and ongoing regulatory initiatives propose use of high... Read More about Use of Patient Health Records to Quantify Drug-Related Pro-arrhythmic Risk.

A nonlinear and time-dependent leak current in the presence of calcium fluoride patch-clamp seal enhancer [version 1; peer review: 2 approved with reservations] (2020)
Journal Article
Lei, C. L., Fabbri, A., Whittaker, D. G., Clerx, M., Windley, M. J., Hill, A. P., …de Boer, T. P. (2020). A nonlinear and time-dependent leak current in the presence of calcium fluoride patch-clamp seal enhancer [version 1; peer review: 2 approved with reservations]. Wellcome Open Research, 5, Article 152. https://doi.org/10.12688/wellcomeopenres.15968.1

Automated patch-clamp platforms are widely used and vital tools in both academia and industry to enable high-throughput studies such as drug screening. A leak current to ground occurs whenever the seal between a pipette and cell (or internal solution... Read More about A nonlinear and time-dependent leak current in the presence of calcium fluoride patch-clamp seal enhancer [version 1; peer review: 2 approved with reservations].