Establishing a context of use for three-dimensional cardiac tissue derived from human-induced pluripotent stem cell-derived cardiomyocytes using inotropes.

Abstract

Safety attrition due to drug-induced inotropic changes remains a significant risk factor for drug development. Mitigating these events during early screening remains challenging. Several in vitro predictive models have been developed to address these issues, with varying success in detecting drug-induced inotropic changes. In this study, we compared traditional two-dimensional human-induced pluripotent stem cell-derived cardiomyocytes (2D hiPSC-CMs) with three-dimensional engineered cardiac tissues (3D ECTs) to assess their ability to detect drug-induced inotropic changes in 17 drugs with known mechanisms of action. The models were exposed to various test compounds, and their responses were evaluated by measuring either the active force or maximum contraction speed. The 3D ECTs successfully detected all the tested positive inotropes, whereas the 2D hiPSC-CMs failed to detect the 2 compounds. Both models demonstrated high predictability for negative inotropy and showed similar results for detecting non-active compounds, except for higher concentrations of phentolamine, zimelidine, and tamsulosin. Irregular beating was less likely to occur in the 3D ECTs, suggesting that 3D ECTs provided superior detection of contractility compared to 2D hiPSC-CMs. Genetic analysis revealed a more mature phenotype for the 3D ECTs compared to the 2D hiPSC-CMs, and the compound-related target expression was comparable to that in the adult human heart tissues. The 3D ECTs captured inotropic changes more accurately and thus represented a more translatable model than the 2D hiPSC-CMs. Overall, contractility assessment using the 3D ECTs could be advantageous for profiling candidate compounds and mechanistic investigations of hemodynamic changes during in vivo or clinical studies.