A Population of In Silico Models to Face the Variability of Human Induced Pluripotent Stem Cell-derived Cardiomyocytes: the hERG Block Case Study

Michelangelo Paci, Elisa Passini, Stefano Severi, Jari Hyttinen, Blanca Rodriguez

    Research output: Chapter in Book/Report/Conference proceedingConference contributionScientificpeer-review

    7 Citations (Scopus)

    Abstract

    Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are characterized by an extreme variability, which cannot be reproduced by a single in silico model. Here we present a population of hiPSC-CM models, calibrated using six different experimental datasets. By sampling the maximum conductances of 11 ionic currents, 10000 parameter sets were obtained. The experimental data-based calibration selected 1355 in silico models to be included in the final population. Such population reproduces the experimental data variability and it is used to assess the different responses to a 90% IKr block. Three different profiles emerged: models still normally beating (562), action potentials with EADs (336) and repolarization failures (457). The models still beating after 800 s since IKr block showed a mean APD90 of 723±12 ms. We observed significant differences among these three classes in the maximum conductances of ICaL, IKr, IKs, IK1, INaCa and INaK, supporting the idea that hiPSC-CM belonging to the same control population can however show dramatically different responses to an external perturbation, due to the physiological variability. This has to be taken in proper consideration in the perspective of using hiPSC-CMs for safety pharmacology assays.
    Original languageEnglish
    Title of host publicationComputing in Cardiology
    Pages1189-1192
    Number of pages4
    ISBN (Electronic)9781509008964
    Publication statusPublished - 2016
    Publication typeA4 Article in conference proceedings
    EventComputing in cardiology conference -
    Duration: 1 Jan 1900 → …

    Publication series

    NameComputing in cardiology
    Volume43
    ISSN (Print)2325-8861
    ISSN (Electronic)2325-887X

    Conference

    ConferenceComputing in cardiology conference
    Period1/01/00 → …

    Publication forum classification

    • Publication forum level 1

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