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Title: Effects of Electrical Stimulation on hiPSC-CM Responses to Classic Ion Channel Blockers

Abstract

Abstract Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) hold great potential for personalized cardiac safety prediction, particularly for that of drug-induced proarrhythmia. However, hiPSC-CMs fire spontaneously and the variable beat rates of cardiomyocytes can be a confounding factor that interferes with data interpretation. Controlling beat rates with pacing may reduce batch and assay variations, enable evaluation of rate-dependent drug effects, and facilitate the comparison of results obtained from hiPSC-CMs with those from adult human cardiomyocytes. As electrical stimulation (E-pacing) of hiPSC-CMs has not been validated with high-throughput assays, herein, we compared the responses of hiPSC-CMs exposed with classic cardiac ion channel blockers under spontaneous beating and E-pacing conditions utilizing microelectrode array technology. We found that compared with spontaneously beating hiPSC-CMs, E-pacing: (1) reduced overall assay variabilities, (2) showed limited changes of field potential duration to pacemaker channel block, (3) revealed reverse rate dependence of multiple ion channel blockers on field potential duration, and (4) eliminated the effects of sodium channel block on depolarization spike amplitude and spike slope due to a software error in acquiring depolarization spike at cardiac pacing mode. Microelectrode array optogenetic pacing and current clamp recordings at various stimulation frequencies demonstrated rate-dependent block of sodium channels inmore » hiPSC-CMs as reported in adult cardiomyocytes. In conclusion, pacing enabled more accurate rate- and concentration-dependent drug effect evaluations. Analyzing responses of hiPSC-CMs under both spontaneously beating and rate-controlled conditions may help better assess the effects of test compounds on cardiac electrophysiology and evaluate the value of the hiPSC-CM model.« less

Authors:
 [1];  [2];  [3];  [4];  [5]
+ Show Author Affiliations
  1. Division of Systems Biology, National Center for Toxicological Research, Food and Drug Administration, Jefferson, Arkansas 72079, Department of Structural Heart Disease, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi 710061, China
  2. IonsGate Preclinical Services Inc, Vancouver, British Columbia, Canada V6T 1Z3
  3. Division of Applied and Regulatory Science, Office of Clinical Pharmacology, Office of Translational Science, Center for Drug Evaluation and Research
  4. Division of Cardiovascular and Renal Products, Office of New Drugs I, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, Maryland 20993
  5. Division of Systems Biology, National Center for Toxicological Research, Food and Drug Administration, Jefferson, Arkansas 72079
Publication Date:
Sponsoring Org.:
USDOE
OSTI Identifier:
1603386
Resource Type:
Publisher's Accepted Manuscript
Journal Name:
Toxicological Sciences
Additional Journal Information:
Journal Name: Toxicological Sciences; Journal ID: ISSN 1096-6080
Publisher:
Oxford University Press
Country of Publication:
United States
Language:
English

Citation Formats

Wei, Feng, Pourrier, Marc, Strauss, David G., Stockbridge, Norman, and Pang, Li. Effects of Electrical Stimulation on hiPSC-CM Responses to Classic Ion Channel Blockers. United States: N. p., 2020. Web. https://doi.org/10.1093/toxsci/kfaa010.
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Wei, Feng, Pourrier, Marc, Strauss, David G., Stockbridge, Norman, & Pang, Li. Effects of Electrical Stimulation on hiPSC-CM Responses to Classic Ion Channel Blockers. United States. https://doi.org/10.1093/toxsci/kfaa010
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Wei, Feng, Pourrier, Marc, Strauss, David G., Stockbridge, Norman, and Pang, Li. Mon . "Effects of Electrical Stimulation on hiPSC-CM Responses to Classic Ion Channel Blockers". United States. https://doi.org/10.1093/toxsci/kfaa010.
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@article{osti_1603386,
title = {Effects of Electrical Stimulation on hiPSC-CM Responses to Classic Ion Channel Blockers},
author = {Wei, Feng and Pourrier, Marc and Strauss, David G. and Stockbridge, Norman and Pang, Li},
abstractNote = {Abstract Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) hold great potential for personalized cardiac safety prediction, particularly for that of drug-induced proarrhythmia. However, hiPSC-CMs fire spontaneously and the variable beat rates of cardiomyocytes can be a confounding factor that interferes with data interpretation. Controlling beat rates with pacing may reduce batch and assay variations, enable evaluation of rate-dependent drug effects, and facilitate the comparison of results obtained from hiPSC-CMs with those from adult human cardiomyocytes. As electrical stimulation (E-pacing) of hiPSC-CMs has not been validated with high-throughput assays, herein, we compared the responses of hiPSC-CMs exposed with classic cardiac ion channel blockers under spontaneous beating and E-pacing conditions utilizing microelectrode array technology. We found that compared with spontaneously beating hiPSC-CMs, E-pacing: (1) reduced overall assay variabilities, (2) showed limited changes of field potential duration to pacemaker channel block, (3) revealed reverse rate dependence of multiple ion channel blockers on field potential duration, and (4) eliminated the effects of sodium channel block on depolarization spike amplitude and spike slope due to a software error in acquiring depolarization spike at cardiac pacing mode. Microelectrode array optogenetic pacing and current clamp recordings at various stimulation frequencies demonstrated rate-dependent block of sodium channels in hiPSC-CMs as reported in adult cardiomyocytes. In conclusion, pacing enabled more accurate rate- and concentration-dependent drug effect evaluations. Analyzing responses of hiPSC-CMs under both spontaneously beating and rate-controlled conditions may help better assess the effects of test compounds on cardiac electrophysiology and evaluate the value of the hiPSC-CM model.},
doi = {10.1093/toxsci/kfaa010},
journal = {Toxicological Sciences},
number = ,
volume = ,
place = {United States},
year = {2020},
month = {2}
}
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https://doi.org/10.1093/toxsci/kfaa010
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