Inter-individual variability and modeling of electrical activity: a possible new approach to explore cardiac safety?
Safety pharmacology aims to predict rare side effects of new drugs. We explored whether rare pro-arrhythmic effects could be linked to the variability of the effects of these drugs on ion currents and whether taking into consideration this variability in computational models could help to better det...
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Nature Publishing Group
2016
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| Online Access: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5128803/ |
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pubmed-51288032016-12-09 Inter-individual variability and modeling of electrical activity: a possible new approach to explore cardiac safety? Le Guennec, Jean-Yves Thireau, Jérôme Ouillé, Aude Roussel, Julien Roy, Jérôme Richard, Serge Richard, Sylvain Martel, Eric Champéroux, Pascal Article Safety pharmacology aims to predict rare side effects of new drugs. We explored whether rare pro-arrhythmic effects could be linked to the variability of the effects of these drugs on ion currents and whether taking into consideration this variability in computational models could help to better detect and predict cardiac side effects. For this purpose, we evaluated how intra- and inter-individual variability influences the effect of hERG inhibition on both the action potential duration and the occurrence of arrhythmias. Using two computer simulation models of human action potentials (endocardial and Purkinje cells), we analyzed the contribution of two biological parameters on the pro-arrhythmic effects of several hERG channel blockers: (i) spermine concentration, which varies with metabolic status, and (ii) L-type calcium conductance, which varies due to single nucleotide polymorphisms or mutations. By varying these parameters, we were able to induce arrhythmias in 1 out of 16 simulations although conventional modeling methods to detect pro-arrhythmic molecules failed. On the basis of our results, taking into consideration only 2 parameters subjected to intra- and inter-individual variability, we propose that in silico computer modeling may help to better define the risks of new drug candidates at early stages of pre-clinical development. Nature Publishing Group 2016-11-30 /pmc/articles/PMC5128803/ /pubmed/27901061 http://dx.doi.org/10.1038/srep37948 Text en Copyright © 2016, The Author(s) http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ |
| repository_type |
Open Access Journal |
| institution_category |
Foreign Institution |
| institution |
US National Center for Biotechnology Information |
| building |
NCBI PubMed |
| collection |
Online Access |
| language |
English |
| format |
Online |
| author |
Le Guennec, Jean-Yves Thireau, Jérôme Ouillé, Aude Roussel, Julien Roy, Jérôme Richard, Serge Richard, Sylvain Martel, Eric Champéroux, Pascal |
| spellingShingle |
Le Guennec, Jean-Yves Thireau, Jérôme Ouillé, Aude Roussel, Julien Roy, Jérôme Richard, Serge Richard, Sylvain Martel, Eric Champéroux, Pascal Inter-individual variability and modeling of electrical activity: a possible new approach to explore cardiac safety? |
| author_facet |
Le Guennec, Jean-Yves Thireau, Jérôme Ouillé, Aude Roussel, Julien Roy, Jérôme Richard, Serge Richard, Sylvain Martel, Eric Champéroux, Pascal |
| author_sort |
Le Guennec, Jean-Yves |
| title |
Inter-individual variability and modeling of electrical activity: a possible new approach to explore cardiac safety? |
| title_short |
Inter-individual variability and modeling of electrical activity: a possible new approach to explore cardiac safety? |
| title_full |
Inter-individual variability and modeling of electrical activity: a possible new approach to explore cardiac safety? |
| title_fullStr |
Inter-individual variability and modeling of electrical activity: a possible new approach to explore cardiac safety? |
| title_full_unstemmed |
Inter-individual variability and modeling of electrical activity: a possible new approach to explore cardiac safety? |
| title_sort |
inter-individual variability and modeling of electrical activity: a possible new approach to explore cardiac safety? |
| description |
Safety pharmacology aims to predict rare side effects of new drugs. We explored whether rare pro-arrhythmic effects could be linked to the variability of the effects of these drugs on ion currents and whether taking into consideration this variability in computational models could help to better detect and predict cardiac side effects. For this purpose, we evaluated how intra- and inter-individual variability influences the effect of hERG inhibition on both the action potential duration and the occurrence of arrhythmias. Using two computer simulation models of human action potentials (endocardial and Purkinje cells), we analyzed the contribution of two biological parameters on the pro-arrhythmic effects of several hERG channel blockers: (i) spermine concentration, which varies with metabolic status, and (ii) L-type calcium conductance, which varies due to single nucleotide polymorphisms or mutations. By varying these parameters, we were able to induce arrhythmias in 1 out of 16 simulations although conventional modeling methods to detect pro-arrhythmic molecules failed. On the basis of our results, taking into consideration only 2 parameters subjected to intra- and inter-individual variability, we propose that in silico computer modeling may help to better define the risks of new drug candidates at early stages of pre-clinical development. |
| publisher |
Nature Publishing Group |
| publishDate |
2016 |
| url |
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5128803/ |
| _version_ |
1613746941798121472 |