Please use this identifier to cite or link to this item: http://hdl.handle.net/10662/24296
Title: Application of optical action potentials in human induced pluripotent stem cells-derived cardiomyocytes to predict drug-induced cardiac arrhythmias
Authors: Lu, Hua Rong
Hortigón Vinagre, Maria Pura
Zamora Rodríguez, Víctor
Kopljar, Ivan
De Bondt, A.
Gallacher, David J.
Smith, Godfrey L.
Keywords: Cardiomiocitos humanos derivados de células madre inducidas pluripotentes;Arritmias cardíacas;Potencial de acción;Human induced pluripotent stem cells derived cardiomyocytes;Cardiac arrhythmias;Action potential;Potencial de acción óptica;Optical action potential;Prolongación del intervalo QT;QT-prolongation;Acortamiento del intervalo QT;QT shortening
Issue Date: 2017
Publisher: Elsevier
Abstract: INTRODUCTION: Human induced pluripotent stem cell-derived cardiomyocytes (hiPS-CMs) are emerging as new and human-relevant source in vitro model for cardiac safety assessment that allow us to investigate a set of 20 reference drugs for predicting cardiac arrhythmogenic liability using optical action potential (oAP) assay. METHODS: Here, we describe our examination of the oAP measurement using a voltage sensitive dye (Di-4-ANEPPS) to predict adverse compound effects using hiPS-CMs and 20 cardioactive reference compounds. Fluorescence signals were digitized at 10 kHz and the records subsequently analyzed off-line. Cells were exposed to 30 min incubation to vehicle or compound (n = 5/dose, 4 doses/compound) that were blinded to the investigating laboratory. Action potential parameters were measured, including rise time (Trise) of the optical action potential duration (oAPD). RESULTS: Significant effects on oAPD were sensitively detected with 11 QT-prolonging drugs, while oAPD shortening was observed with ICa-antagonists, IKr-activator or ATP-sensitive K+ channel (KATP)-opener. Additionally, the assay detected varied effects induced by 6 different sodium channel blockers. The detection threshold for these drug effects was at or below the published values of free effective therapeutic plasma levels or effective concentrations by other studies. DISCUSSION: The results of this blinded study indicate that OAP is a sensitive method to accurately detect drug-induced effects (i.e., duration/QT-prolongation, shortening, beat rate, and incidence of early after depolarizations) in hiPS-CMs; therefore, this technique will potentially be useful in predicting drug-induced arrhythmogenic liabilities in early de-risking within the drug discovery phase.
Description: Publicado en: Journal of Pharmacological and Toxicological Methods, Volume 87, September 2017, Pages 53-67. https://doi.org/10.1016/j.vascn.2017.05.001
URI: http://hdl.handle.net/10662/24296
ISSN: 1056-8719
DOI: 10.1016/j.vascn.2017.05.001
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