Electrophysiological characterization of drug response in hSC-derived cardiomyocytes using voltage-sensitive optical platforms

Pfeiffer-Kaushik, E. R. et al. (2019) Electrophysiological characterization of drug response in hSC-derived cardiomyocytes using voltage-sensitive optical platforms. Journal of Pharmacological and Toxicological Methods, 99, 106612. (doi: 10.1016/j.vascn.2019.106612) (PMID:31319140)

Abstract

Introduction: Voltage-sensitive optical (VSO) sensors offer a minimally invasive method to study the time course of repolarization of the cardiac action potential (AP). This Comprehensive in vitro Proarrhythmia Assay (CiPA) cross-platform study investigates protocol design and measurement variability of VSO sensors for preclinical cardiac electrophysiology assays. Methods: Three commercial and one academic laboratory completed a limited study of the effects of 8 blinded compounds on the electrophysiology of 2 commercial lines of human induced pluripotent stem-cell derived cardiomyocytes (hSC-CMs). Acquisition technologies included CMOS camera and photometry; fluorescent voltage sensors included di-4-ANEPPS, FluoVolt and genetically encoded QuasAr2. The experimental protocol was standardized with respect to cell lines, plating and maintenance media, blinded compounds, and action potential parameters measured. Serum-free media was used to study the action of drugs, but the exact composition and the protocols for cell preparation and drug additions varied among sites. Results: Baseline AP waveforms differed across platforms and between cell types. Despite these differences, the relative responses to four selective ion channel blockers (E-4031, nifedipine, mexiletine, and JNJ 303 blocking IKr, ICaL, INa, and IKs, respectively) were similar across all platforms and cell lines although the absolute changes differed. Similarly, four mixed ion channel blockers (flecainide, moxifloxacin, quinidine, and ranolazine) had comparable effects in all platforms. Differences in repolarisation time course and response to drugs could be attributed to cell type and experimental method differences such as composition of the assay media, stimulated versus spontaneous activity, and single versus cumulative compound addition. Discussion: In conclusion, VSOs represent a powerful and appropriate method to assess the electrophysiological effects of drugs on iPSC-CMs for the evaluation of proarrhythmic risk. Protocol considerations and recommendations are provided toward standardizing conditions to reduce variability of baseline AP waveform characteristics and drug responses.

• Item Type: Articles
• Additional Information: This project was funded in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract no. HHSN261200800001E and R24 HL117756.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Zamora Rodriguez, Dr Victor and Smith, Professor Godfrey and Hortigon, Dr Maria
• Authors: Pfeiffer-Kaushik, E. R., Smith, G. L., Cai, B., Dempsey, G. T., Hortigon-Vinagre, M. P., Zamora, V., Feng, S., Ingermanson, R., Zhu, R., Hariharan, V., Nguyen, C., Pierson, J., Gintant, G. A., and Tung, L.
• College/School: College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health
• Journal Name: Journal of Pharmacological and Toxicological Methods
• Publisher: Elsevier
• ISSN: 1056-8719
• ISSN (Online): 1873-488X
• Published Online: 15 July 2019
• Copyright Holders: Copyright © 2019 Elsevier Inc.
• First Published: First published in Journal of Pharmacological and Toxicological Methods 99:106612
• Publisher Policy: Reproduced in accordance with the publisher copyright policy