Mutation-specific Hypertrophic Cardiomyopathy and Mavacamten: a Mechano-energetic In Silico Study

Mohamadamin Forouzandehmehr, Michelangelo Paci, Jussi T. Koivumäki, Jari Hyttinen

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

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    Abstract

    Mavacamten is the first drug with proven efficacy for hypertrophic cardiomyopathy (HCM), the most prevalent genetic cardiac disorder. Our goal is to investigate the pathophysiology of the R403Q HCM mutation and the capability of Mavacamten to ameliorate the impaired cellular mechano-energetics. We incorporated a reparametrized metabolic-sensitive contractile element (CE) into our model of human induced pluripotent stem cell derived cardiomyocyte (hiPSC-CMs) electromechanics relating the effects of MgATP, MgADP, inorganic phosphate, and ATP hydrolysis-derived proton to the tension development. Our results suggest that the prolonged contractile relaxation duration, observed in vitro, due to R403Q mutation (33%) is captured by a variant of the metabolic-sensitive CE without assuming additional fluxes to the thin filaments. Further, our HCM model could correctly predict the unaltered ATPase activity and 40% increase in fractional shortening (FS) in R403Q mode. In R403Q mode, our model simulates the improved FS, contractile relaxation, and ATPase rate due to 0.5 μM Mavacamten: 14.6%, 21%, and 19.3%, respectively, consistent with the experiments. This work is a step toward robust computational models of cardiac electro-mechano-energetic coupling for pharmacological investigations on sarcomeric cardiomyopathies.

    Original languageEnglish
    Title of host publication2022 Computing in Cardiology (CinC)
    PublisherIEEE
    Pages1-4
    ISBN (Electronic)9798350300970
    DOIs
    Publication statusPublished - 2022
    Publication typeA4 Article in conference proceedings
    EventComputing in Cardiology - Tampere Hall, Tampere, Finland
    Duration: 4 Sept 20227 Sept 2022
    Conference number: 49
    https://events.tuni.fi/cinc2022/

    Publication series

    NameComputing in Cardiology
    Volume2022-September
    ISSN (Print)2325-8861
    ISSN (Electronic)2325-887X

    Conference

    ConferenceComputing in Cardiology
    Abbreviated titleCinC 2022
    Country/TerritoryFinland
    CityTampere
    Period4/09/227/09/22
    Internet address

    Publication forum classification

    • Publication forum level 1

    ASJC Scopus subject areas

    • General Computer Science
    • Cardiology and Cardiovascular Medicine

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