title: From the Cover: High-Throughput Imaging of Cardiac Microtissues for the Assessment of Cardiac Contraction during Drug Discovery.
abstract: Cardiotoxicity is a common cause of attrition in preclinical and clinical drug development. Current in vitro approaches have two main limitations, they either are limited to low throughput methods not amendable to drug discovery or lack the physiological responses to allow an integrated risk assessment. A human 3D cardiac microtissue containing human-induced pluripotent stem cell-derived cardiomyocytes (hiPS-CMs), cardiac endothelial cells and cardiac fibroblast were used to assess their suitability to detect drug induced changes in cardiomyocyte contraction. These cardiac microtissues, have a uniform size, spontaneously beat, lack a hypoxic core, and contain key markers of each cell type. Application of field stimulation and measurement of cardiac contraction confirm cardiac microtissues to be a suitable model to investigate drug-induced changes in cardiomyocyte contractility. Using a bespoke image acquisition work flow and optical flow analysis method to test 29 inotroptic and 13 non-inotroptic compounds in vivo We report that cardiac microtissues provide a high-throughput experimental model that is both able to detect changes in cardiac contraction with a sensitivity and specificity of 80 and 91%, respectively, and provide insight into the direction of the inotropic response. Allowing improved in vitro cardiac contractility risk assessment. Moreover, our data provide evidence of the detection of this liability at therapeutically relevant concentrations with a throughput amenable to drug discovery.
authors.affiliation: Safety and ADME Translational Sciences, Drug Safety and Metabolism; amy.pointon@astrazeneca.com.
authors.forename: Amy
authors.initials: A
authors.lastname: Pointon
authors.affiliation: Discovery Sciences, Innovative Medicines and Early Development, AstraZeneca R&D, Cambridge CB4 0WG, UK.
authors.forename: James
authors.initials: J
authors.lastname: Pilling
authors.affiliation: Discovery Sciences, Innovative Medicines and Early Development, AstraZeneca R&D, Cambridge CB4 0WG, UK.
authors.forename: Thierry
authors.initials: T
authors.lastname: Dorval
authors.affiliation: Discovery Sciences, Innovative Medicines and Early Development, AstraZeneca R&D, Cambridge CB4 0WG, UK.
authors.forename: Yinhai
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Safety and ADME Translational Sciences, Drug Safety and Metabolism.
authors.forename: Caroline
authors.initials: C
authors.lastname: Archer
authors.affiliation: Safety and ADME Translational Sciences, Drug Safety and Metabolism.
authors.forename: Christopher
authors.initials: C
authors.lastname: Pollard
mesh_terms: D002478:Cells, Cultured; D055808:Drug Discovery; D015870:Gene Expression; D057166:High-Throughput Screening Assays / Q000379:methods*; D006801:Humans; D009200:Myocardial Contraction / Q000187:drug effects*; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000648:ultrastructure*
keywords: cardiotoxicity; drug discovery and development.; hiPS-CMs