Accéder directement au contenu Accéder directement à la navigation
Article dans une revue

Inter-individual variability and modeling of electrical activity: a possible new approach to explore cardiac safety?

Abstract : 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.
Type de document :
Article dans une revue
Liste complète des métadonnées

https://hal.umontpellier.fr/hal-01784408
Contributeur : Dominique Mornet <>
Soumis le : mardi 24 mars 2020 - 13:35:03
Dernière modification le : mercredi 14 octobre 2020 - 04:15:26

Fichier

2016 Le guennec et al., Inter ...
Fichiers produits par l'(les) auteur(s)

Licence


Distributed under a Creative Commons Paternité 4.0 International License

Identifiants

Citation

Jean-Yves Le Guennec, J Thireau, Aude Ouillé, Julien Roussel, Jérôme Roy, et al.. Inter-individual variability and modeling of electrical activity: a possible new approach to explore cardiac safety?. Scientific Reports, Nature Publishing Group, 2016, 6 (1), pp.37948. ⟨10.1038/srep37948⟩. ⟨hal-01784408⟩

Partager

Métriques

Consultations de la notice

377

Téléchargements de fichiers

648