Chronic drug‐induced effects on contractile motion properties and cardiac biomarkers in human induced pluripotent stem cell‐derived cardiomyocytes

Abstract

BACKGROUND AND PURPOSEIn the pharmaceutical industry risk assessments of chronic cardiac safety liabilities are mostly performed during late stages of preclinical drug development using in vivo animal models. Here, we explored the potential of human induced pluripotent stem cell-derived cardiomyocytes (hiPS-CMs) to detect chronic cardiac risks such as drug-induced cardiomyocyte toxicity. EXPERIMENTAL APPROACHVideo microscopy-based motion field imaging was applied to evaluate the chronic effect (over 72 h) of cardiotoxic drugs on the contractile motion of hiPS-CMs. In parallel, the release of cardiac troponin I (cTnI), heart fatty acid binding protein (FABP3) and N-terminal pro-brain natriuretic peptide (NT-proBNP) was analysed from cell medium, and transcriptional profiling of hiPS-CMs was done at the end of the experiment. KEY RESULTSDifferent cardiotoxic drugs altered the contractile motion properties of hiPS-CMs together with increasing the release of cardiac biomarkers. FABP3 and cTnI were shown to be potential surrogates to predict cardiotoxicity in hiPS-CMs, whereas NT-proBNP seemed to be a less valuable biomarker. Furthermore, drug-induced cardiotoxicity produced by chronic exposure of hiPS-CMs to arsenic trioxide, doxorubicin or panobinostat was associated with different profiles of changes in contractile parameters, biomarker release and transcriptional expression. CONCLUSION AND IMPLICATIONSWe have shown that a parallel assessment of motion field imaging-derived contractile properties, release of biomarkers and transcriptional changes can detect diverse mechanisms of chronic drug-induced cardiac liabilities in hiPS-CMs. Hence, hiPS-CMs could potentially improve and accelerate cardiovascular de-risking of compounds at earlier stages of drug discovery.

Conduction and contraction properties of human iPS cell-derived cardiomyocytes: analysis by motion field imaging compared with the guinea-pig isolated heart model

“…These features mean that the contraction property and the conduction property can be simultaneously measured in the same cells at a moderate to high through-put, which supports the potential that MFI has to allow us to use hiPS-CMs in an integrated cardiac safety assessment. Recent studies demonstrated that the cardiac proarrhythmic potential, alterations in contractility, and chronic cardiotoxicity can be evaluated by analyzing the contractile motion obtained by MFI (Kopljar et al, 2017;Hayakawa et al, 2014). However, the conduction property remains to be characterized and used to evaluate cardiac toxicities.…”

Personalized medicine in cardio-oncology: the role of induced pluripotent stem cell

“…iPSC-CMs have been used to show decreased contractility, contraction velocity, and beating rates in response to DOX. They have also been used to document stress release biomarkers such as N-terminal pro-brain natriuretic peptide (NT-proBNP), cTnI, and heart-type fatty acid binding protein (hFABP), 75 as well as to identify novel biomarkers such as growth differentiation factor 15 (GDF15). 76 Tissue engineering technologies are also taking the platform beyond the traditional two-dimensional monolayer culture methods towards more physiologic three-dimensional (3D) approaches, allowing the integration of other cardiac cell types into the model.…”

hiPSCs in cardio-oncology: deciphering the genomics

“…Hsu et al 75 used four independent hiPSC-CM lines to examine the mechanism of increased DIC in the presence of lapatinib. Other studies have used single hiPSC-CM lines to characterize CAEs caused by doxorubicin, 58,[76][77][78][79][80][81][82][83][84] trastuzumab, 58,85,86 etoposide, 87 arsenic trioxide, 84,88,89 TKIs, [90][91][92][93][94][95][96] and histone deacetylase inhibitors. 84,97,98…”

“…The concentration of troponin in cell culture media following chemotherapeutic exposure can also be quantified as a surrogate for CM damage. 84,92 This again relies on membrane permeabilization and thus is a measure of late-stage cell damage caused by either apoptosis or necrosis.…”