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

Emily R. Pfeiffer-Kaushik, Godfrey L. Smith, Beibei Cai, Graham T. Dempsey, Maria P. Hortigon-Vinagre, Victor Zamora, Shuyun Feng, Randall Ingermanson, Renjun Zhu, Venkatesh Hariharan, C. Nguyen, Jennifer Pierson, Gary A. Gintant, Leslie Tung

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Article number106612
JournalJournal of Pharmacological and Toxicological Methods
DOIs
StateAccepted/In press - Jan 1 2019

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Cardiac Myocytes
Action Potentials
Electric potential
Assays
Ion Channels
Pharmaceutical Preparations
Optical sensors
Cardiac Electrophysiology
Mexiletine
Flecainide
Photometry
Cell Line
Induced Pluripotent Stem Cells
Drug Compounding
Quinidine
Cells
Electrophysiology
Serum-Free Culture Media
Nifedipine
Stem cells

Keywords

  • Action potential
  • Cardiac electrophysiology
  • Comprehensive in vitro proarrhythmia assay (CiPA)
  • hERG
  • ICH S7B
  • Methods
  • Safety pharmacology
  • Stem cell-derived cardiomyocyte
  • Torsades de pointes (TdP) arrhythmia
  • Voltage-sensitive optical sensors

ASJC Scopus subject areas

  • Toxicology
  • Pharmacology

Cite this

Electrophysiological characterization of drug response in hSC-derived cardiomyocytes using voltage-sensitive optical platforms. / Pfeiffer-Kaushik, Emily R.; Smith, Godfrey L.; Cai, Beibei; Dempsey, Graham T.; Hortigon-Vinagre, Maria P.; Zamora, Victor; Feng, Shuyun; Ingermanson, Randall; Zhu, Renjun; Hariharan, Venkatesh; Nguyen, C.; Pierson, Jennifer; Gintant, Gary A.; Tung, Leslie.

In: Journal of Pharmacological and Toxicological Methods, 01.01.2019.

Research output: Contribution to journalArticle

Pfeiffer-Kaushik, ER, Smith, GL, Cai, B, Dempsey, GT, Hortigon-Vinagre, MP, Zamora, V, Feng, S, Ingermanson, R, Zhu, R, Hariharan, V, Nguyen, C, Pierson, J, Gintant, GA & Tung, L 2019, 'Electrophysiological characterization of drug response in hSC-derived cardiomyocytes using voltage-sensitive optical platforms', Journal of Pharmacological and Toxicological Methods. https://doi.org/10.1016/j.vascn.2019.106612
Pfeiffer-Kaushik, Emily R. ; Smith, Godfrey L. ; Cai, Beibei ; Dempsey, Graham T. ; Hortigon-Vinagre, Maria P. ; Zamora, Victor ; Feng, Shuyun ; Ingermanson, Randall ; Zhu, Renjun ; Hariharan, Venkatesh ; Nguyen, C. ; Pierson, Jennifer ; Gintant, Gary A. ; Tung, Leslie. / Electrophysiological characterization of drug response in hSC-derived cardiomyocytes using voltage-sensitive optical platforms. In: Journal of Pharmacological and Toxicological Methods. 2019.
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AU - Dempsey, Graham T.

AU - Hortigon-Vinagre, Maria P.

AU - Zamora, Victor

AU - Feng, Shuyun

AU - Ingermanson, Randall

AU - Zhu, Renjun

AU - Hariharan, Venkatesh

AU - Nguyen, C.

AU - Pierson, Jennifer

AU - Gintant, Gary A.

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N2 - 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.

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