Related Experiment Video
Updated: Jul 1, 2025
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Assessment of Myofilament Ca2+ Sensitivity Underlying Cardiac Excitation-contraction Coupling
Published on: August 1, 2016
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Translating myosin-binding protein C and titin abnormalities to whole-heart function using a novel
Theo Arts1, Aurore Lyon1, Tammo Delhaas1
1Department of Biomedical Engineering, Cardiovascular Research Center Maastricht (CARIM), Maastricht University, 6200MD Maastricht, the Netherlands.
Journal of Molecular and Cellular Cardiology
|March 10, 2024
Summary
Computer models reveal how mutations in cardiac myosin-binding protein C (cMyBP-C) and titin cause heart conditions. This research links cellular changes to hypertrophic (HCM) and dilated (DCM) cardiomyopathies, improving our understanding of heart disease mechanisms.
Area of Science:
- Cardiovascular Physiology
- Computational Biology
- Molecular Cardiology
Background:
- Mutations in cardiac myosin-binding protein C (cMyBP-C) and titin are linked to hypertrophic (HCM) and dilated (DCM) cardiomyopathies, respectively.
- The precise mechanisms translating cellular dysfunction to whole-heart and systemic effects in these cardiomyopathies remain incompletely understood.
Purpose of the Study:
- To develop and validate a novel computer model of calcium-contraction coupling that incorporates the functions of cMyBP-C and titin.
- To investigate how cMyBP-C and titin abnormalities influence cardiac mechanics and hemodynamics at both cellular and whole-heart levels.
- To elucidate the potential mechanisms by which cMyBP-C and titin mutations lead to HCM and DCM phenotypes.
Main Methods:
- Developed a novel computational model of calcium-contraction coupling based on key assumptions regarding the mechanochemical regulation of cross-bridge attachment by cMyBP-C and titin tension.
- Validated the cellular model against experimental data for stationary calcium-tension curves, isotonic and isometric contractions, and quick release experiments.
- Integrated the validated cellular model into the CircAdapt whole-heart and circulation model to simulate cardiac and circulatory function.
Main Results:
- The model accurately reproduced experimental data, predicting that loss of cMyBP-C function decreases calcium-tension curve steepness.
- The model predicted that increased titin compliance reduces passive and active tension and its dependence on sarcomere length.
- Simulations showed that cMyBP-C loss resulted in HCM-like hemodynamics (higher LV end-diastolic pressure, smaller volumes), while increased titin compliance led to DCM-like hemodynamics (higher diastolic pressures, ventricular dilation).
Conclusions:
- The novel computational model successfully integrates the roles of cMyBP-C and titin in calcium-contraction coupling.
- Coupling the cellular model to whole-heart mechanics effectively translates cellular changes into alterations in cardiac pump and circulatory function.
- This modeling platform provides insights into the distinct mechanisms underlying HCM and DCM phenotypes caused by cMyBP-C and titin abnormalities, aiding in the identification of distinct mechanisms in clinical cardiac diseases.
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