skip to main content
DOE PAGES title logo U.S. Department of Energy
Office of Scientific and Technical Information

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. doi:10.1093/toxsci/kfaa010.
Copy to clipboard
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. doi:10.1093/toxsci/kfaa010.
Copy to clipboard
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. doi:10.1093/toxsci/kfaa010.
Copy to clipboard
@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}
}
Copy to clipboard
Journal Article:
Free Publicly Available Full Text
Accepted Manuscript (Publisher)
Publisher's Version of Record
DOI: 10.1093/toxsci/kfaa010
Copyright Statement
Other availability
Search WorldCat Search WorldCat to find libraries that may hold this journal
Save / Share:
Export Metadata
Save to My Library
You must Sign In or Create an Account in order to save documents to your library.

Works referenced in this record:

Electrophysiological aspects of changes in heart rate
journal, October 1998

Modeling susceptibility to drug-induced long QT with a panel of subject-specific induced pluripotent stem cells
journal, January 2017

Mechanism of Reverse Rate-Dependent Action of Cardioactive Agents
journal, August 2011

I K1 -enhanced human-induced pluripotent stem cell-derived cardiomyocytes: an improved cardiomyocyte model to investigate inherited arrhythmia syndromes
journal, June 2016

  • Vaidyanathan, Ravi; Markandeya, Yogananda S.; Kamp, Timothy J.
  • American Journal of Physiology-Heart and Circulatory Physiology, Vol. 310, Issue 11
  • DOI: 10.1152/ajpheart.00481.2015

Structural and Functional Maturation of Cardiomyocytes Derived from Human Pluripotent Stem Cells
journal, July 2013

  • Lundy, Scott D.; Zhu, Wei-Zhong; Regnier, Michael
  • Stem Cells and Development, Vol. 22, Issue 14
  • DOI: 10.1089/scd.2012.0490

Thorough QT/QTc in a Dish: An In Vitro Human Model That Accurately Predicts Clinical Concentration‐QTc Relationships
journal, December 2018

  • Blanchette, Alexander D.; Grimm, Fabian A.; Dalaijamts, Chimedullam
  • Clinical Pharmacology & Therapeutics, Vol. 105, Issue 5
  • DOI: 10.1002/cpt.1259

Assessment of Proarrhythmic Potential of Drugs in Optogenetically Paced Induced Pluripotent Stem Cell-Derived Cardiomyocytes
journal, March 2019

  • Patel, Dakshesh; Stohlman, Jayna; Dang, Qianyu
  • Toxicological Sciences, Vol. 170, Issue 1
  • DOI: 10.1093/toxsci/kfz076

Restricting Excessive Cardiac Action Potential and QT Prolongation: A Vital Role for I Ks in Human Ventricular Muscle
journal, September 2005

Genome Editing of Induced Pluripotent Stem Cells to Decipher Cardiac Channelopathy Variant
journal, July 2018

  • Garg, Priyanka; Oikonomopoulos, Angelos; Chen, Haodong
  • Journal of the American College of Cardiology, Vol. 72, Issue 1
  • DOI: 10.1016/j.jacc.2018.04.041

Reverse rate-dependent changes are determined by baseline action potential duration in mammalian and human ventricular preparations
journal, February 2010

  • Bárándi, László; Virág, László; Jost, Norbert
  • Basic Research in Cardiology, Vol. 105, Issue 3
  • DOI: 10.1007/s00395-009-0082-7

International Multisite Study of Human-Induced Pluripotent Stem Cell-Derived Cardiomyocytes for Drug Proarrhythmic Potential Assessment
journal, September 2018

Frequency-Dependent Multi-Well Cardiotoxicity Screening Enabled by Optogenetic Stimulation
journal, December 2017

  • Rehnelt, Susanne; Malan, Daniela; Juhasz, Krisztina
  • International Journal of Molecular Sciences, Vol. 18, Issue 12
  • DOI: 10.3390/ijms18122634

Response of human induced pluripotent stem cell-derived cardiomyocytes to several pharmacological agents when intrinsic syncytial pacing is overcome by acute external stimulation
journal, May 2018

  • Zeng, Haoyu; Balasubramanian, Bharathi; Lagrutta, Armando
  • Journal of Pharmacological and Toxicological Methods, Vol. 91
  • DOI: 10.1016/j.vascn.2017.12.004

Frequency-dependent drug screening using optogenetic stimulation of human iPSC-derived cardiomyocytes
journal, August 2017

High-throughput screening of tyrosine kinase inhibitor cardiotoxicity with human induced pluripotent stem cells
journal, February 2017

Proarrhythmia Risk Assessment in Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes Using the Maestro MEA Platform
journal, June 2015

Clinical Trial in a Dish: Personalized Stem Cell–Derived Cardiomyocyte Assay Compared With Clinical Trial Results for Two QT ‐Prolonging Drugs
journal, August 2019

  • Blinova, Ksenia; Schocken, Derek; Patel, Dakshesh
  • Clinical and Translational Science, Vol. 12, Issue 6
  • DOI: 10.1111/cts.12674

Mechanism-Based Facilitated Maturation of Human Pluripotent Stem Cell–Derived Cardiomyocytes
journal, February 2013

  • Lieu, Deborah K.; Fu, Ji-Dong; Chiamvimonvat, Nipavan
  • Circulation: Arrhythmia and Electrophysiology, Vol. 6, Issue 1
  • DOI: 10.1161/CIRCEP.111.973420

Recapitulation of Clinical Individual Susceptibility to Drug-Induced QT Prolongation in Healthy Subjects Using iPSC-Derived Cardiomyocytes
journal, February 2017

    [ × clear filter / sort ]

    Similar Records in DOE PAGES and OSTI.GOV collections: