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 language | English |
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Title of host publication | 2022 Computing in Cardiology (CinC) |
Publisher | IEEE |
Pages | 1-4 |
ISBN (Electronic) | 9798350300970 |
DOIs | |
Publication status | Published - 2022 |
Publication type | A4 Article in conference proceedings |
Event | Computing in Cardiology - Tampere Hall, Tampere, Finland Duration: 4 Sept 2022 → 7 Sept 2022 Conference number: 49 https://events.tuni.fi/cinc2022/ |
Publication series
Name | Computing in Cardiology |
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Volume | 2022-September |
ISSN (Print) | 2325-8861 |
ISSN (Electronic) | 2325-887X |
Conference
Conference | Computing in Cardiology |
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Abbreviated title | CinC 2022 |
Country/Territory | Finland |
City | Tampere |
Period | 4/09/22 → 7/09/22 |
Internet address |
Publication forum classification
- Publication forum level 1
ASJC Scopus subject areas
- General Computer Science
- Cardiology and Cardiovascular Medicine