There are three primary pathways by which drug-induced cardiovascular toxicities can manifest:
- Functional toxicity – electrophysiological impairments such QT prolongation, which can lead to potentially fatal disorders like Torsade de Pointes (TdP).
- Structural toxicity – morphological damage, such as vascular loss, fibrosis, necrosis and hypertrophy.
- Indirect toxicity – systemic effects like elevated blood pressure, oedema or thrombosis which can lead to damage to the heart.
One significant threat from structural toxicities is left ventricular hypertrophy due to increased cardiomyocyte mass, which poses a serious risk of heart failure. To assess structural liabilities such as hypertrophy, we have developed an assay that uses 3D cardiac microtissues and confocal high content imaging.
In this assay, microtissues formed using iPSC-derived cardiomyocytes were exposed to seven compounds known to induce hypertrophy and seven compounds with other structural cardiotoxic effects over both acute (72 hours) and chronic (14 days) time courses. Brightfield imaging makes the detection of structural damage like hypertrophy possible because its non-invasive nature allows for repeat imaging of a plate. Gross structural cardiotoxic effects were assessed using HCS on day 14 using calcium, mitochondrial and DNA probes in combination with cellular ATP measurement.
The research demonstrates how time course hypertrophy monitoring of 3D microtissues combined with multiparametric HCS and cytotoxicity assessment presents a valuable in vitro screening approach for the accurate detection of drug-induced hypertrophic and non-hypertrophic structural cardiotoxicity early in drug development.
This research was presented at ISSX 2016 in Busan, South Korea.