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Biomechanical Impact of Pathogenic MYBPC3 Truncation Variant Revealed by Dynamically Tuning In Vitro Afterload
Abhinay Ramachandran1, Carissa E Livingston1, Alexia Vite2
1Perelman School of Medicine, University of Pennsylvania, Smilow Center for Translational Research, 3400 Civic Center Boulevard, 11-101, Philadelphia, PA, 19104, USA.
Journal of Cardiovascular Translational Research
|March 6, 2023
Summary
Engineered heart tissues with a myosin binding protein C (MYBPC3) mutation show increased contractility under higher afterload. This suggests external forces may worsen hypertrophic cardiomyopathy caused by this genetic variant.
Area of Science:
- Cardiovascular Biology
- Biomedical Engineering
- Stem Cell Therapy
Background:
- Hypertrophic cardiomyopathy (HCM) is a genetic heart disease often caused by mutations in sarcomeric proteins.
- Myosin binding protein C (MYBPC3) mutations are a common cause of HCM.
- Understanding how genetic predisposition interacts with mechanical forces is crucial for disease progression insights.
Purpose of the Study:
- To investigate the impact of in vitro afterload on cardiac microtissues engineered with a MYBPC3 mutation.
- To determine if extrinsic biomechanical challenges potentiate genetically-driven hypercontractility.
Main Methods:
- Fabrication of engineered cardiac microtissues using pluripotent stem cells harboring a MYBPC3 truncation variant (MYBPC3+/-).
- Utilizing iron-incorporated cantilevers for tunable in vitro afterload manipulation via magnets.
- Comparison of contractility (force, work, power) between MYBPC3+/- and isogenic control (MYBPC3+/+ (ed)) microtissues under varying afterloads.
Main Results:
- MYBPC3+/- microtissues exhibited augmented force, work, and power with increased in vitro afterload compared to controls.
- Conversely, MYBPC3+/- microtissues showed weaker contractility at lower in vitro afterloads.
- Both acute and sustained increases in afterload enhanced contractility in mature MYBPC3+/- microtissues.
Conclusions:
- Extrinsic biomechanical challenges can potentiate intrinsic contractility increases driven by MYBPC3 variants.
- These findings suggest a mechanism by which mechanical stress may contribute to disease progression in HCM patients with hypercontractile MYBPC3 variants.
