Objective

Detrimental effects upon the cardiac system are a major cause of drug attrition. Current in vitro methodologies for assessment of drug-induced cardiotoxicity involve sub-optimal screens of non-cardiac cell lines engineered to express cardiac ion channels, or primary tissue with limited utility for clinical translation. The advent of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM), with the ability to synchronously beat (contract) in vitro, opened up opportunities for improved identification of cardiotoxicity. However, these cells are costly, time-limited, and require complex maintenance techniques, posing constraints in terms of widespread use. One resolution is the use of immortalised cardiac cell lines, with capability for continuous growth and clinical translation. However, the limitations of these models for detecting both structural and functional cardiotoxicity are unknown. In this study we assess the predictive value of an immortalised non-contractile human cardiac cell line (AC10) and functionally-responsive hiPSC-CM to determine toxicity of the histone deacetylase inhibitor (HDACi) class of drug, thus highlighting the advantages of each type of cell model in relation to structural and functional cardiotoxicity. This not only supports the value of comprehensive cellular screening models, but offers a predictive tool to assess cardiotoxicity that would allow development of efficacious and safer drugs in this class.