Objective

Functional cardiotoxicity assessment using 3D cardiac microtissue

 

Priyanka Narasimhan¹, Ana Teixeira² , Matthew Burnham¹

 

1-Mechanistic Biology and Profiling, Discovery Sciences, IMED Biotech Unit, AstraZeneca, Alderley Park, UK 2- AstraZeneca, Science and Enabling Units, IT, Granta Park, Cambridge, United Kingdom

 

 

Introduction: Cardiotoxicity due to functional changes in cardiomyocytes is a common reason for attrition in drug development. Identifying cardiotoxicity early on in drug discovery enables development of safer drugs and lowers safety related drug attrition in clinical development.

 

Objective: To develope a label free, 3D cardiomyocyte contractility assay to predict drug induced changes in cardiomyocyte function.

 

Material & Methods: 3D cardiac microtissue used in the assay were co-cultures of hiPSC derived cardiomyocytes and human cardiac fibroblasts. For assay validation, 35 compounds with known in vivo effects (inotropes or non-inotropes) and diverse mechanisms of action were tested. Compounds were dosed on day 7 after seeding in a 6 point, 0.5 log-spaced concentration range cumulative-dosing format. Compound effects on cardiac contractility were detected using beat rate and beat amplitude metric on CardioExcyte96 platform (Nanion Technologies).

 

Results: Using the beat rate metric, assay predicted functional cardiotoxic compounds with 68% sensitivity, 87% specificity. The assay had Z’> 0.6 and generated reproducible IC50s with minimum detectable difference of 0.5.

 

Conclusion: We have developed a label-free, 3D assay that can detect drug induced changes in cardaic contractility. The assay thoughput is suitable for integration in SAR screening cascades early in drug discovery to detect cardiac liabilities.