Engineered cardiac tissue model of restrictive cardiomyopathy for drug discovery

Bryan Z Wang; Trevor R Nash; Xiaokan Zhang; Jenny Rao; Laura Abriola; Youngbin Kim; Sergey Zakharov; Michael Kim; Lori J Luo; Margaretha Morsink; Bohao Liu; Roberta I Lock; Sharon Fleischer; Manuel A Tamargo; Michael Bohnen; Carrie L Welch; Wendy K Chung; Steven O Marx; Yulia V Surovtseva; Gordana Vunjak-Novakovic; Barry M Fine

doi:10.1016/j.xcrm.2023.100976

Engineered cardiac tissue model of restrictive cardiomyopathy for drug discovery

Cell Rep Med. 2023 Mar 21;4(3):100976. doi: 10.1016/j.xcrm.2023.100976. Epub 2023 Mar 14.

Authors

Bryan Z Wang¹, Trevor R Nash¹, Xiaokan Zhang², Jenny Rao², Laura Abriola³, Youngbin Kim¹, Sergey Zakharov², Michael Kim², Lori J Luo¹, Margaretha Morsink¹, Bohao Liu¹, Roberta I Lock¹, Sharon Fleischer¹, Manuel A Tamargo¹, Michael Bohnen², Carrie L Welch⁴, Wendy K Chung⁴, Steven O Marx², Yulia V Surovtseva³, Gordana Vunjak-Novakovic⁵, Barry M Fine⁶

Affiliations

¹ Department of Biomedical Engineering, Columbia University, New York, NY 10032, USA.
² Department of Medicine, Division of Cardiology, Columbia University Medical Center, New York, NY 10032, USA.
³ Yale Center for Molecular Discovery, Yale University, New Haven, CT 06520, USA.
⁴ Department of Pediatrics, Columbia University, New York, NY 10032, USA.
⁵ Department of Biomedical Engineering, Columbia University, New York, NY 10032, USA; Department of Medicine, Division of Cardiology, Columbia University Medical Center, New York, NY 10032, USA; College of Dental Medicine, Columbia University, New York, NY 10032, USA.
⁶ Department of Medicine, Division of Cardiology, Columbia University Medical Center, New York, NY 10032, USA. Electronic address: barry.fine@columbia.edu.

Abstract

Restrictive cardiomyopathy (RCM) is defined as increased myocardial stiffness and impaired diastolic relaxation leading to elevated ventricular filling pressures. Human variants in filamin C (FLNC) are linked to a variety of cardiomyopathies, and in this study, we investigate an in-frame deletion (c.7416_7418delGAA, p.Glu2472_Asn2473delinAsp) in a patient with RCM. Induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) with this variant display impaired relaxation and reduced calcium kinetics in 2D culture when compared with a CRISPR-Cas9-corrected isogenic control line. Similarly, mutant engineered cardiac tissues (ECTs) demonstrate increased passive tension and impaired relaxation velocity compared with isogenic controls. High-throughput small-molecule screening identifies phosphodiesterase 3 (PDE3) inhibition by trequinsin as a potential therapy to improve cardiomyocyte relaxation in this genotype. Together, these data demonstrate an engineered cardiac tissue model of RCM and establish the translational potential of this precision medicine approach to identify therapeutics targeting myocardial relaxation.

Keywords: FLNC; high throughput drug screen; induced pluripotent stem cell; restrictive cardiomyopathy; tissue engineering.

Publication types

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

MeSH terms

Cardiomyopathy, Restrictive* / genetics
Drug Discovery
Humans
Myocardium
Myocytes, Cardiac
Tissue Engineering

Abstract

Publication types

MeSH terms

Grants and funding