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Representation of multiple cellular phenotypes within tissue-level simulations of cardiac electrophysiology (2018)
Journal Article
Bowler, L. A., Gavaghan, D. J., Mirams, G. R., & Whiteley, J. P. (2018). Representation of multiple cellular phenotypes within tissue-level simulations of cardiac electrophysiology. Bulletin of Mathematical Biology, doi:10.1007/s11538-018-0516-1

Distinct electrophysiological phenotypes are exhibited 1 by biological cells that have differentiated into particular cell types. The usual approach when simulating the cardiac electrophysiology of tissue that includes different cell types is to mode... Read More

Assessment of an in silico mechanistic model for proarrhythmia risk prediction under the CiPA initiative (2018)
Journal Article
Li, Z., Wu, W. W., Sheng, J., Tran, P. N., Wu, M., Ranolph, A., …Strauss, D. G. (2019). Assessment of an in silico mechanistic model for proarrhythmia risk prediction under the CiPA initiative. Clinical Pharmacology and Therapeutics, 105(2), 466-475. doi:10.1002/cpt.1184

International Council on Harmonization S7B and E14 regulatory guidelines are sensitive but not specific for predicting which drugs are proarrhythmic. In response, the Comprehensive In Vitro Proarrhythmia Assay (CiPA) was proposed that integrates mult... Read More

Reproducible model development in the Cardiac Electrophysiology Web Lab (2018)
Journal Article
Daly, A. C., Clerx, M., Beattie, K. A., Cooper, J., Gavaghan, D. J., & Mirams, G. R. (in press). Reproducible model development in the Cardiac Electrophysiology Web Lab. Progress in Biophysics and Molecular Biology, doi:10.1016/j.pbiomolbio.2018.05.011

The modelling of the electrophysiology of cardiac cells is one of the most mature areas of systems biology. This extended concentration of research effort brings with it new challenges, foremost among which is that of choosing which of these models i... Read More

Sinusoidal voltage protocols for rapid characterisation of ion channel kinetics (2018)
Journal Article
Beattie, K., Hill, A. P., Bardenet, R., Cui, Y., Vandenberg, J. I., Gavaghan, D. J., …Mirams, G. R. (2018). Sinusoidal voltage protocols for rapid characterisation of ion channel kinetics. Journal of Physiology, 596(10), doi:10.1113/JP275733

Understanding the roles of ion currents is crucial to predict the action of pharmaceuticals and mutations in different scenarios, and thereby to guide clinical interventions in the heart, brain and other electrophysiological systems. Our ability to p... Read More

Tailoring mathematical models to stem-cell derived cardiomyocyte lines can improve predictions of drug-induced changes to their electrophysiology (2017)
Journal Article
Lei, C., Wang, K., Clerx, M., Johnstone, R. H., Hortigon-Vinagre, M. P., Zamora, V., …Polonchuk, L. (2017). Tailoring mathematical models to stem-cell derived cardiomyocyte lines can improve predictions of drug-induced changes to their electrophysiology. Frontiers in Physiology, 8, doi:10.3389/fphys.2017.00986

Human induced pluripotent stem cell derived cardiomyocytes (iPSC-CMs) have applications in disease modeling, cell therapy, drug screening and personalized medicine. Computational models can be used to interpret experimental findings in iPSC-CMs, prov... Read More

Uncertainty quantification reveals the importance of data variability and experimental design considerations for in silico proarrhythmia risk assessment (2017)
Journal Article
Chang, K., Dutta, S., Mirams, G. R., Beattie, K., Sheng, J., Tran, P. N., …Li, Z. (2017). Uncertainty quantification reveals the importance of data variability and experimental design considerations for in silico proarrhythmia risk assessment. Frontiers in Physiology, 8, doi:10.3389/fphys.2017.00917

The Comprehensive in vitro Proarrhythmia Assay (CiPA) is a global initiative intended to improve drug proarrhythmia risk assessment using a new paradigm of mechanistic assays. Under the CiPA paradigm, the relative risk of drug-induced Torsade de Poin... Read More

Nonclinical cardiovascular safety of pitolisant: comparing International Conference on Harmonization S7B and Comprehensive in vitro Pro-arrhythmia Assay initiative studies (2017)
Journal Article
Ligneau, X., Shah, R. R., Berrebi-Bertrand, I., Mirams, G. R., Robert, P., Landais, L., …Schwartz, J. (2017). Nonclinical cardiovascular safety of pitolisant: comparing International Conference on Harmonization S7B and Comprehensive in vitro Pro-arrhythmia Assay initiative studies. British Journal of Pharmacology, 174, doi:10.1111/bph.14047

Background and purpose: We evaluated the concordance of results from two sets of nonclinical cardiovascular safety studies on pitolisant. Experimental approach: Nonclinical studies envisaged both in the ICH S7B guideline and Comprehensive in vitro P... Read More

Early afterdepolarisation tendency as a simulated pro-arrhythmic risk indicator (2017)
Journal Article
McMillan, B., Gavaghan, D. J., & Mirams, G. R. (2017). Early afterdepolarisation tendency as a simulated pro-arrhythmic risk indicator. Toxicology Research, 6, doi:10.1039/C7TX00141J

Drug-induced Torsades de Pointes (TdP) arrhythmia is of major interest in predictive toxicology. Drugs which cause TdP block the hERG cardiac potassium channel. However, not all drugs that block hERG cause TdP. As such, further understanding of the m... Read More

Systems toxicology: real world applications and opportunities (2017)
Journal Article
Hartung, T., FitzGerald, R. E., Jennings, P., Mirams, G. R., Peitsch, M. C., Rostami-Hodjegan, A., …Sturla, S. J. (in press). Systems toxicology: real world applications and opportunities. Chemical Research in Toxicology, 30(4), doi:10.1021/acs.chemrestox.7b00003

Systems Toxicology aims to change the basis of how adverse biological effects of xenobiotics are characterized from empirical end points to describing modes of action as adverse outcome pathways and perturbed networks. Toward this aim, Systems Toxico... Read More

Hierarchical Bayesian inference for ion channel screening dose-response data (2017)
Journal Article
Johnstone, R. H., Bardenet, R., Gavaghan, D. J., & Mirams, G. R. (2017). Hierarchical Bayesian inference for ion channel screening dose-response data. Wellcome Open Research, 1, doi:10.12688/wellcomeopenres.9945.2

Dose-response (or 'concentration-effect') relationships commonly occur in biological and pharmacological systems and are well characterised by Hill curves. These curves are described by an equation with two parameters: the inhibitory concentration 50... Read More

High resolution structural evidence suggests the Sarcoplasmic Reticulum forms microdomains with acidic stores (lysosomes) in the heart (2017)
Journal Article
Aston, D., Capel, R. A., Ford, K. L., Christian, H. C., Mirams, G. R., Rog-Zielinska, E. A., …Terrar, D. A. (2017). High resolution structural evidence suggests the Sarcoplasmic Reticulum forms microdomains with acidic stores (lysosomes) in the heart. Scientific Reports, 7, doi:10.1038/srep40620

Nicotinic Acid Adenine Dinucleotide Phosphate (NAADP) stimulates calcium release from acidic stores such as lysosomes and is a highly potent calcium-mobilising second messenger. NAADP plays an important role in calcium signalling in the heart under b... Read More

Connexin43 contributes to electrotonic conduction across scar tissue in the intact heart (2016)
Journal Article
Mahoney, V., Mezzano, V., Mirams, G., Maass, K., Li, Z., Cerrone, M., …Morley, G. (2016). Connexin43 contributes to electrotonic conduction across scar tissue in the intact heart. Scientific Reports, 6, doi:10.1038/srep26744

Studies have demonstrated non-myocytes, including fibroblasts, can electrically couple to myocytes in culture. However, evidence demonstrating current can passively spread across scar tissue in the intact heart remains elusive. We hypothesize electro... Read More

The Cardiac Electrophysiology Web Lab (2016)
Journal Article
Mirams, G., Cooper, J., & Scharm, M. (2016). The Cardiac Electrophysiology Web Lab. Biophysical Journal, 110(2), 292-300. doi:10.1016/j.bpj.2015.12.012

Uncertainty and variability in models of the cardiac action potential: Can we build trustworthy models? (2015)
Journal Article
Johnstone, R. H., Chang, E. T., Bardenet, R., de Boer, T. P., Gavaghan, D. J., Pathmanathan, P., …Mirams, G. R. (2016). Uncertainty and variability in models of the cardiac action potential: Can we build trustworthy models?. Journal of Molecular and Cellular Cardiology, 96, 49-62. doi:10.1016/j.yjmcc.2015.11.018

Cardiac electrophysiology models have been developed for over 50 years, and now include detailed descriptions of individual ion currents and sub-cellular calcium handling. It is commonly accepted that there are many uncertainties in these systems, wi... Read More