One major cause of attrition in drug discovery and development is cardiotoxicity, which can be a consequence of structural (morphological) and/or functional (e.g., arrhythmias, reduced contractility) effects.
Our research has focused on developing in vitro screens for detecting different mechanisms of cardiac liability – namely cardiac hypertrophy, cardiac cytotoxicity (structural effects) and calcium flux (functional effect).
Cardiac left ventricular hypertrophy resulting from an increase in cardiomyocyte mass is a major risk factor for heart failure, with detection in preclinical species being often poor. Two different in vitro 3D cell‑based models were selected to evaluate hypertrophy – a monoculture spheroid model using human iPSC-derived cardiomyocytes and a tri‑culture model using human iPSC-derived cardiomyocytes, human cardiac endothelial cells and human cardiac fibroblasts. Interestingly, only the monoculture model could predict the hypertrophic effects but both models could detect general structural toxic mechanisms such as mitochondrial function and ATP content.
Alterations in calcium flux in cardiomyocytes are associated with functional cardiotoxic effects. A calcium‑sensitive indicator dye was used in combination with a cell imager (Cytation 3 Multimode Reader) to detect transient calcium flux. Monoculture spheroids formed from human iPSC-derived cardiomyocytes were used for the research. Cell imaging technology monitored the spontaneous contractions and a regular beat pattern exhibited by the spheroids. Furthermore, the technology identified increased contractility by the positive inotropic compound isoproterenol and a corresponding decrease by the negative inotropic compound propranolol.
The study illustrated that 3D spheroids consisting of human iPSC-derived cardiomyocytes can reliably detect both structural and functional cardiotoxic effects. This format is amenable to early stage screening to identify human cardiac liabilities and reduce late stage drug development failure.
The research was presented at SOT in San Antonio, Texas from March 11-15, 2018.