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

Journal Article · · Toxicological Sciences
 [1];  [2];  [3];  [4];  [5]
  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

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.

Sponsoring Organization:
USDOE
OSTI ID:
1603386
Journal Information:
Toxicological Sciences, Journal Name: Toxicological Sciences; ISSN 1096-6080
Publisher:
Oxford University PressCopyright Statement
Country of Publication:
United States
Language:
English
Citation Metrics:
Cited by: 8 works
Citation information provided by
Web of Science

References (23)

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
Effects of the chromanol 293B, a selective blocker of the slow, component of the delayed rectifier K+ current, on repolarization in human and guinea pig ventricular myocytes journal May 1998
Drug Screening Using a Library of Human Induced Pluripotent Stem Cell–Derived Cardiomyocytes Reveals Disease-Specific Patterns of Cardiotoxicity journal April 2013
Rate dependence of the effect of antiarrhythmic drugs delaying cardiac repolarization: an overview journal October 2000
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
Structural and Functional Maturation of Cardiomyocytes Derived from Human Pluripotent Stem Cells journal July 2013
Thorough QT/QTc in a Dish: An In Vitro Human Model That Accurately Predicts Clinical Concentration‐QTc Relationships journal December 2018
Assessment of Proarrhythmic Potential of Drugs in Optogenetically Paced Induced Pluripotent Stem Cell-Derived Cardiomyocytes journal March 2019
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
Reverse rate-dependent changes are determined by baseline action potential duration in mammalian and human ventricular preparations journal February 2010
International Multisite Study of Human-Induced Pluripotent Stem Cell-Derived Cardiomyocytes for Drug Proarrhythmic Potential Assessment journal September 2018
Cross-Site Reliability of Human Induced Pluripotent stem cell-derived Cardiomyocyte Based Safety Assays Using Microelectrode Arrays: Results from a Blinded CiPA Pilot Study journal April 2018
Frequency-Dependent Multi-Well Cardiotoxicity Screening Enabled by Optogenetic Stimulation journal December 2017
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
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
Mechanism-Based Facilitated Maturation of Human Pluripotent Stem Cell–Derived Cardiomyocytes journal February 2013
Recapitulation of Clinical Individual Susceptibility to Drug-Induced QT Prolongation in Healthy Subjects Using iPSC-Derived Cardiomyocytes journal February 2017