Biomechanical Impact of Pathogenic MYBPC3 Truncation Variant Revealed by Dynamically Tuning In Vitro Afterload

Abhinay Ramachandran; Carissa E Livingston; Alexia Vite; Elise A Corbin; Alexander I Bennett; Kevin T Turner; Benjamin W Lee; Chi Keung Lam; Joseph C Wu; Kenneth B Margulies

doi:10.1007/s12265-022-10348-4

Biomechanical Impact of Pathogenic MYBPC3 Truncation Variant Revealed by Dynamically Tuning In Vitro Afterload

J Cardiovasc Transl Res. 2023 Aug;16(4):828-841. doi: 10.1007/s12265-022-10348-4. Epub 2023 Mar 6.

Authors

Abhinay Ramachandran¹, Carissa E Livingston¹, Alexia Vite², Elise A Corbin^{3

4

5}, Alexander I Bennett⁶, Kevin T Turner⁶, Benjamin W Lee², Chi Keung Lam^{7

8}, Joseph C Wu⁷, Kenneth B Margulies^{9

10}

Affiliations

¹ Perelman School of Medicine, University of Pennsylvania, Smilow Center for Translational Research, 3400 Civic Center Boulevard, 11-101, Philadelphia, PA, 19104, USA.
² Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
³ Department of Biomedical Engineering, University of Delaware, Newark, DE, 19716, USA.
⁴ Department of Materials Science and Engineering, University of Delaware, Newark, DE, 19716, USA.
⁵ Nemours/Alfred I. duPont Hospital for Children, Wilmington, DE, 19803, USA.
⁶ Department of Mechanical Engineering and Applied Mechanics, School of Engineering and Applied Sciences, University of Pennsylvania, Philadelphia, PA, 19104, USA.
⁷ Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, 94305, USA.
⁸ Department of Biological Sciences, University of Delaware, Newark, DE, 19716, USA.
⁹ Perelman School of Medicine, University of Pennsylvania, Smilow Center for Translational Research, 3400 Civic Center Boulevard, 11-101, Philadelphia, PA, 19104, USA. kenb@upenn.edu.
¹⁰ Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA. kenb@upenn.edu.

Abstract

Engineered cardiac microtissues were fabricated using pluripotent stem cells with a hypertrophic cardiomyopathy associated c. 2827 C>T; p.R943x truncation variant in myosin binding protein C (MYBPC3^+/-). Microtissues were mounted on iron-incorporated cantilevers, allowing manipulations of cantilever stiffness using magnets, enabling examination of how in vitro afterload affects contractility. MYPBC3^+/- microtissues developed augmented force, work, and power when cultured with increased in vitro afterload when compared with isogenic controls in which the MYBPC3 mutation had been corrected (MYPBC3^+/+(ed)), but weaker contractility when cultured with lower in vitro afterload. After initial tissue maturation, MYPBC3^+/- CMTs exhibited increased force, work, and power in response to both acute and sustained increases of in vitro afterload. Together, these studies demonstrate that extrinsic biomechanical challenges potentiate genetically-driven intrinsic increases in contractility that may contribute to clinical disease progression in patients with HCM due to hypercontractile MYBPC3 variants.

Keywords: Afterload; Cardiac microtissues; Contractility; Hypertrophic cardiomyopathy; MYBPC3.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Cardiomyopathy, Hypertrophic* / genetics
Cardiomyopathy, Hypertrophic* / metabolism
Heart
Humans
Mutation
Pluripotent Stem Cells* / metabolism

Abstract

Publication types

MeSH terms

Grants and funding