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Updated: Aug 6, 2025
Automated Contraction Analysis of Human Engineered Heart Tissue for Cardiac Drug Safety Screening
Published on: April 15, 2017
Engineered cardiac tissue model of restrictive cardiomyopathy for drug discovery
Bryan Z Wang1, Trevor R Nash1, Xiaokan Zhang2
1Department of Biomedical Engineering, Columbia University, New York, NY 10032, USA.
Insights
Researchers identified a genetic cause of restrictive cardiomyopathy (RCM) and developed an engineered cardiac tissue model. Trequinsin, a PDE3 inhibitor, shows promise for treating RCM by improving cardiomyocyte relaxation.
Area of Science:
- Cardiology
- Genetics
- Stem Cell Biology
Background:
- Restrictive cardiomyopathy (RCM) is characterized by myocardial stiffness and impaired diastolic relaxation.
- Filamin C (FLNC) gene variants are associated with various cardiomyopathies.
Purpose of the Study:
- Investigate the functional impact of an FLNC in-frame deletion (p.Glu2472_Asn2473delinAsp) in a patient with RCM.
- Develop and validate an engineered cardiac tissue (ECT) model for RCM.
- Identify potential therapeutic targets for RCM.
Main Methods:
- Generated induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) with the FLNC variant.
- Utilized CRISPR-Cas9 for isogenic correction.
- Created mutant and control ECTs for functional assessment.
- Performed high-throughput small-molecule screening.
Main Results:
- iPSC-CMs with the FLNC variant exhibited impaired relaxation and altered calcium kinetics.
- Mutant ECTs showed increased passive tension and reduced relaxation velocity compared to controls.
- Phosphodiesterase 3 (PDE3) inhibition via trequinsin improved cardiomyocyte relaxation in the RCM model.
Conclusions:
- The study presents a novel ECT model for RCM.
- FLNC variants contribute to RCM pathophysiology.
- PDE3 inhibition represents a potential precision medicine therapeutic strategy for RCM.
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.
