Characterisation of novel methodologies for in-vitro prediction of human drug-induced cardiotoxicity

Abstract

Detrimental effects upon the cardiac system are a major cause of drug attrition. Current in-vitro methodologies for identification of drug-induced structural and functional cardiotoxicity and their underlying mechanism are sub-optimal and have limited utility for longer-term analyses and clinical translation. The emergence of innovative technologies combined with human stem-cell-derived cardiomyocytes has revolutionised preclinical identification of drug-induced cardiotoxicity. However, major limitations to these approaches include their complexity, specialised culture conditions, high cost and incomplete ability to fully detect drug-induced cardiotoxicity. A supplementary option is the use of immortalised cardiac cell lines, with capability for continuous growth and screening approaches. However, the limitations of these models for detecting both structural and functional cardiotoxicity are unknown. In this study, pathophysiological responsiveness of current cardiac cell lines to both structural and functional cardiotoxicants were evaluated using two-dimensional real-time impedance-based methodologies (xCELLigence) and three-dimensional spheroid systems. Specifically, using these cardiac cell models, the study evaluated effects of the histone deacetylase inhibitor (HDACi) sub-classes of drugs. The AC10 cell-line, although non-contractile, was able to detect HDACi-induced structural changes. The HL-1 cell-line exhibited a contractile phenotype in vitro, albeit non-uniformly and time-limited, and also detected drug-induced structural cardiotoxicity. In terms of HDACi, the occurrence of structural changes in both AC10 cells and HL-1 cells in response to sub-pharmacologically active concentrations of the drugs was observed, implicating their potential for clinical cardiotoxicity. In summary, this study supports the inclusion of cardiac cell-lines alongside primary cells and stem-cell-derived cardiomyocytes in preclinical evaluation of drug-induced cardiotoxicity.