Evaluation of cardiac drugs through 3D-engineered heart tissue from stem cells
2020
innoVitro GmbH, Juelich, Germany
Stem cell-derived cardiomyocytes (SC-CM) offer a great opportunity for the development of new in vitro models for the assessment of cardiac contractility and thus for the development of therapeutics for cardiovascular diseases. However, the immature phenotype of SC-CM is a recognised limitation in the assessment of inotropy, particularly with regard to the lack of or reduced positive inotropic response to β-adrenergic agonists. The recent development of 3D engineered cardiac tissues (ECTs) using human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM) in the BiowireTM II platform has demonstrated improved maturation. To assess their suitability for detecting drug-induced changes in cardiac contractility, positive inotropic agents with different mechanisms, including β-adrenergic agonists, PDE3 inhibitors, Ca2+ sensitizers, myosin and troponin activators and an apelin receptor agonist, were blindly tested. In total, the compounds tested were dobutamine, milrinone, pimobendan, levosimendan, omecamtiv mecarbil, AMG1, AMG2 and pyr-apelin-13. Contractility was assessed by analysing the amplitude, speed and duration of contraction and relaxation. All agents tested, except for pyr-apelin-13, increased contractility by raising the amplitude and speed of contraction. In addition, myosin and troponin activators prolonged the duration of contraction. These results suggest that ECTs generated with the BiowireTM II platform can identify inotropic agents with different mechanisms and provide a human-based in vitro model for the evaluation of potential therapeutics.
Integration of mechanical conditioning into a high throughput contractility assay for cardiac safety assessment
Matthias Goßmann
Added on: 09-12-2023
[1] https://www.sciencedirect.com/science/article/abs/pii/S1056871920302215?via%3Dihub
