Bridging Functional and Structural Cardiotoxicity Assays Using Human Embryonic Stem Cell-Derived Cardiomyocytes for a More Comprehensive Risk Assessment

Abstract

More relevant and reliable preclinical cardiotoxicity tests are required to improve drug safety and reduce the cost of drug development. Current in vitro testing strategies predominantly take the form of functional assays to predict the potential for drug-induced ECG abnormalities in vivo. Cardiotoxicity can also be structural in nature, so a full and efficient assessment of cardiac liabilities for new chemical entities should account for both these phenomena. As well as providing a more appropriate nonclinical model for in vitro cardiotoxicity testing, human stem cell-derived cardiomyocytes offer an integrated system to study drug impact on cardiomyocyte structure as well as function. Employing human embryonic stem cell-derived cardiacmyocytes (hESC-CMs) on 3 assay platforms with complementary insights into cardiac biology (multielectrode array assay, electrophysiology; impedance assay, cell movement/beating; and high content analysis assay, subcellular structure) we profiled a panel of 13 drugs with well characterized cardiac liabilities (Amiodarone, Aspirin, Astemizole, Axitinib, AZT, Bepridil, Doxorubicin, E-4031, Mexiletine, Rosiglitazone, Sunitinib, Sibutramine, and Verapamil). Our data show good correlations with previous studies and reported clinical observations. Using multiparameter phenotypic profiling techniques we demonstrate the dynamic relationship that exists between functional and structural toxicity, and the benefits of this more holistic approach to risk assessment. We conclude by showing for the first time how the advent of transparent MEA plate technology enables functional and structural cardiotoxic responses to be recorded from the same cell population. This approach more directly links changes in morphology of the hESC-CMs with recorded electrophysiology signatures, offering even greater insight into the wide range of potential drug impacts on cardiac physiology, with a throughput that is more amenable to early drug discovery.

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

“…In our study, doxorubicin caused delayed effects on the contractile properties of hiPS-CMs at 1 μM (free C max ), whereas higher concentrations displayed acute and more severe effects resulting in cessation of beating arrest and myocardial injury. These findings are in accordance with previously reported doxorubicin-induced effects on human stem cell-derived cardiomyocytes using impedance-based technologies (Nguemo et al, 2012;Clements et al, 2015). Furthermore, patient-specific hiPSC-CMs can replicate the predilection to doxorubicin-induced cardiotoxicity of individual patients at the cellular level (Burridge et al, 2016).…”

On-chip, multisite extracellular and intracellular recordings from primary cultured skeletal myotubes

“…In contrast to the extensive use of substrate integrated planar multielectrode arrays (MEA) to characterize the electrophysiological properties of cultured neuron and cardiac muscles networks7891011121314 the vast community of skeletal muscle researchers do not make use of MEA. One plausible reason why MEA technology has not been adopted for skeletal muscle research and diagnostics is because progress in the culturing technologies of skeletal myotubes and NMJ from rodents and human is relatively recent151617181920.…”

Salvianolic Acid A, as a Novel ETA Receptor Antagonist, Shows Inhibitory Effects on Tumor in Vitro

“…The xCelligence RTCA cardio system has been a useful tool used to monitor the cardio-toxicity effect on hiPS-CMs in the short and long term [25,26]. In this study, the effect of Sal A on available commercial hiPS-CMs was evaluated.…”

“…Additionally, the sensitive label-free assay made it possible to detect the regular beating pattern of cardiomyocytes under normal physiological conditions [42,43,44]. As mentioned [26], the loss of cell index reflected the loss of mitochondria and cell viability induced by Adriamycin. Amiodarone lengthens the cardiac action potential to induce acute cardiac myocyte dysfunction [45].…”