The use of voltage sensitive dye di-4-ANEPPS and video-based contractility measurements to assess drug effects on excitation-contraction coupling in human induced pluripotent stem cell-derived cardiomyocytes

Hortigon-Vinagre, M.P., Zamora, V., Burton, F. L. and Smith, G. L. (2021) The use of voltage sensitive dye di-4-ANEPPS and video-based contractility measurements to assess drug effects on excitation-contraction coupling in human induced pluripotent stem cell-derived cardiomyocytes. Journal of Cardiovascular Pharmacology, 77(3), pp. 280-290. (doi: 10.1097/FJC.0000000000000937) (PMID:33109927)

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Publisher's URL: https://journals.lww.com/cardiovascularpharm/Abstract/9000/The_use_of_voltage_sensitive_dye_di_4_ANEPPS_and.98331.aspx

Abstract

Since cardiotoxicity is one of the leading causes of drug failure and attrition, the design of new protocols and technologies to assess pro-arrhythmic risks on cardiac cells is in continuous development by different laboratories. Current methodologies use electrical, intracellular Ca2+ or contractility assays to evaluate cardiotoxicity. Increasingly, the human induced pluripotent stem cells derived cardiomyocytes (hiPSC-CMs) are the in vitro tissue model used in commercial assays because it is thought to recapitulate many aspects of human cardiac physiology. In this work, we demonstrate that the combination of a contractility and voltage measurements, using video-based imaging and fluorescence microscopy, on hiPSC-CMs allows the investigation of mechanistic links between electrical and mechanical effects in an assay design that can address medium throughput scales necessary for drug screening, offering a view of the mechanisms underlying drug toxicity. To assess the accuracy of this novel technique, 10 commercially available inotropic drugs were tested (5 positive and 5 negative). Included were drugs with a simple and specific mechanisms such as nifedipine, Bay K8644 and blebbistatin, and others with a more complex action like isoproterenol, pimobendan, digoxin and amrinone, among others. In addition, the results provide a mechanism for the toxicity of itraconazole in a human model, a drug with reported side effects on the heart. The data demonstrates a strong negative inotropic effect due to the blockade of L-type Ca2+ channels and additional action on the cardiac myofilaments. We can conclude that the combination of contractility and AP measurements can provide wider mechanistic knowledge of drug cardiotoxicity for pre-clinical assays.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Burton, Dr Francis and Smith, Professor Godfrey
Authors: Hortigon-Vinagre, M.P., Zamora, V., Burton, F. L., and Smith, G. L.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
Journal Name:Journal of Cardiovascular Pharmacology
Publisher:Lippincott, Williams & Wilkins
ISSN:0160-2446
ISSN (Online):1533-4023
Published Online:23 October 2020
Copyright Holders:Copyright © 2020 Wolters Kluwer Health, Inc.
First Published:First published in Journal of Cardiovascular Pharmacology 2020
Publisher Policy:Reproduced in accordance with the copyright policy of the publisher

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