Research ArticleCardiovascular Disease

Dynamic loading of human engineered heart tissue enhances contractile function and drives a desmosome-linked disease phenotype

See allHide authors and affiliations

Science Translational Medicine  21 Jul 2021:
Vol. 13, Issue 603, eabd1817
DOI: 10.1126/scitranslmed.abd1817

You are currently viewing the abstract.

View Full Text

Log in to view the full text

Log in through your institution

Log in through your institution

Enhancing EHT platforms

Although several engineered heart tissue (EHT) systems have been developed, most are not able to incorporate physiologic loads and cannot model resultant changes in heart structure. Here, Bliley and colleagues developed and tested a dynamic EHT platform that models both preload and afterload to recapitulate the effects of hemodynamic loading on heart muscle. Dynamic loading of EHT derived from a patient with arrhythmogenic cardiomyopathy revealed reduced desmosome numbers, decreased contractile force, and impaired contractile shortening, resulting in decreased contractile work and power, unlike standard EHT approaches. Dynamic loading of EHTs could recapitulate disease phenotypes, suggesting that this platform may be useful in studying other heart diseases.

Abstract

The role that mechanical forces play in shaping the structure and function of the heart is critical to understanding heart formation and the etiology of disease but is challenging to study in patients. Engineered heart tissues (EHTs) incorporating human induced pluripotent stem cell (hiPSC)–derived cardiomyocytes have the potential to provide insight into these adaptive and maladaptive changes. However, most EHT systems cannot model both preload (stretch during chamber filling) and afterload (pressure the heart must work against to eject blood). Here, we have developed a new dynamic EHT (dyn-EHT) model that enables us to tune preload and have unconstrained contractile shortening of >10%. To do this, three-dimensional (3D) EHTs were integrated with an elastic polydimethylsiloxane strip providing mechanical preload and afterload in addition to enabling contractile force measurements based on strip bending. Our results demonstrated that dynamic loading improves the function of wild-type EHTs on the basis of the magnitude of the applied force, leading to improved alignment, conduction velocity, and contractility. For disease modeling, we used hiPSC-derived cardiomyocytes from a patient with arrhythmogenic cardiomyopathy due to mutations in the desmoplakin gene. We demonstrated that manifestation of this desmosome-linked disease state required dyn-EHT conditioning and that it could not be induced using 2D or standard 3D EHT approaches. Thus, a dynamic loading strategy is necessary to provoke the disease phenotype of diastolic lengthening, reduction of desmosome counts, and reduced contractility, which are related to primary end points of clinical disease, such as chamber thinning and reduced cardiac output.

View Full Text

Stay Connected to Science Translational Medicine