Screening drug-induced arrhythmia events using human induced pluripotent stem cell-derived cardiomyocytes and low-impedance microelectrode arrays

Enrique G. Navarrete, Ping Liang, Feng Lan, Verónica Sanchez-Freire, Chelsey Simmons, Tingyu Gong, Arun Sharma, Paul W. Burridge, Bhagat Patlolla, Andrew S. Lee, Haodi Wu, Ramin E. Beygui, Sean M. Wu, Robert C. Robbins, Donald M Bers, Joseph C. Wu

Research output: Contribution to journalArticle

175 Citations (Scopus)

Abstract

BACKGROUND - Drug-induced arrhythmia is one of the most common causes of drug development failure and withdrawal from market. This study tested whether human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) combined with a low-impedance microelectrode array (MEA) system could improve on industry-standard preclinical cardiotoxicity screening methods, identify the effects of well-characterized drugs, and elucidate underlying risk factors for drug-induced arrhythmia. hiPSC-CMs may be advantageous over immortalized cell lines because they possess similar functional characteristics as primary human cardiomyocytes and can be generated in unlimited quantities. METHODS AND RESULTS - Pharmacological responses of beating embryoid bodies exposed to a comprehensive panel of drugs at 65 to 95 days postinduction were determined. Responses of hiPSC-CMs to drugs were qualitatively and quantitatively consistent with the reported drug effects in literature. Torsadogenic hERG blockers, such as sotalol and quinidine, produced statistically and physiologically significant effects, consistent with patch-clamp studies, on human embryonic stem cell-derived cardiomyocytes hESC-CMs. False-negative and false-positive hERG blockers were identified accurately. Consistent with published studies using animal models, early afterdepolarizations and ectopic beats were observed in 33% and 40% of embryoid bodies treated with sotalol and quinidine, respectively, compared with negligible early afterdepolarizations and ectopic beats in untreated controls. CONCLUSIONS - We found that drug-induced arrhythmias can be recapitulated in hiPSC-CMs and documented with low impedance MEA. Our data indicate that the MEA/hiPSC-CM assay is a sensitive, robust, and efficient platform for testing drug effectiveness and for arrhythmia screening. This system may hold great potential for reducing drug development costs and may provide significant advantages over current industry standard assays that use immortalized cell lines or animal models.

Original languageEnglish (US)
JournalCirculation
Volume128
Issue numberSUPPL.1
DOIs
StatePublished - Sep 10 2013

Fingerprint

Induced Pluripotent Stem Cells
Preclinical Drug Evaluations
Microelectrodes
Electric Impedance
Cardiac Myocytes
Cardiac Arrhythmias
Pharmaceutical Preparations
Embryoid Bodies
Sotalol
Quinidine
Industry
Animal Models
Product Recalls and Withdrawals
Cell Line
Drug Costs
Pharmacology

Keywords

  • Arrhythmias cardiac
  • Genomics
  • Myocytes cardiac
  • Pharmacogenetics
  • Pharmacology
  • Stem cells

ASJC Scopus subject areas

  • Physiology (medical)
  • Cardiology and Cardiovascular Medicine

Cite this

Screening drug-induced arrhythmia events using human induced pluripotent stem cell-derived cardiomyocytes and low-impedance microelectrode arrays. / Navarrete, Enrique G.; Liang, Ping; Lan, Feng; Sanchez-Freire, Verónica; Simmons, Chelsey; Gong, Tingyu; Sharma, Arun; Burridge, Paul W.; Patlolla, Bhagat; Lee, Andrew S.; Wu, Haodi; Beygui, Ramin E.; Wu, Sean M.; Robbins, Robert C.; Bers, Donald M; Wu, Joseph C.

In: Circulation, Vol. 128, No. SUPPL.1, 10.09.2013.

Research output: Contribution to journalArticle

Navarrete, EG, Liang, P, Lan, F, Sanchez-Freire, V, Simmons, C, Gong, T, Sharma, A, Burridge, PW, Patlolla, B, Lee, AS, Wu, H, Beygui, RE, Wu, SM, Robbins, RC, Bers, DM & Wu, JC 2013, 'Screening drug-induced arrhythmia events using human induced pluripotent stem cell-derived cardiomyocytes and low-impedance microelectrode arrays', Circulation, vol. 128, no. SUPPL.1. https://doi.org/10.1161/CIRCULATIONAHA.112.000570
Navarrete, Enrique G. ; Liang, Ping ; Lan, Feng ; Sanchez-Freire, Verónica ; Simmons, Chelsey ; Gong, Tingyu ; Sharma, Arun ; Burridge, Paul W. ; Patlolla, Bhagat ; Lee, Andrew S. ; Wu, Haodi ; Beygui, Ramin E. ; Wu, Sean M. ; Robbins, Robert C. ; Bers, Donald M ; Wu, Joseph C. / Screening drug-induced arrhythmia events using human induced pluripotent stem cell-derived cardiomyocytes and low-impedance microelectrode arrays. In: Circulation. 2013 ; Vol. 128, No. SUPPL.1.
@article{34c012a151294a14a848e4e16f09f485,
title = "Screening drug-induced arrhythmia events using human induced pluripotent stem cell-derived cardiomyocytes and low-impedance microelectrode arrays",
abstract = "BACKGROUND - Drug-induced arrhythmia is one of the most common causes of drug development failure and withdrawal from market. This study tested whether human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) combined with a low-impedance microelectrode array (MEA) system could improve on industry-standard preclinical cardiotoxicity screening methods, identify the effects of well-characterized drugs, and elucidate underlying risk factors for drug-induced arrhythmia. hiPSC-CMs may be advantageous over immortalized cell lines because they possess similar functional characteristics as primary human cardiomyocytes and can be generated in unlimited quantities. METHODS AND RESULTS - Pharmacological responses of beating embryoid bodies exposed to a comprehensive panel of drugs at 65 to 95 days postinduction were determined. Responses of hiPSC-CMs to drugs were qualitatively and quantitatively consistent with the reported drug effects in literature. Torsadogenic hERG blockers, such as sotalol and quinidine, produced statistically and physiologically significant effects, consistent with patch-clamp studies, on human embryonic stem cell-derived cardiomyocytes hESC-CMs. False-negative and false-positive hERG blockers were identified accurately. Consistent with published studies using animal models, early afterdepolarizations and ectopic beats were observed in 33{\%} and 40{\%} of embryoid bodies treated with sotalol and quinidine, respectively, compared with negligible early afterdepolarizations and ectopic beats in untreated controls. CONCLUSIONS - We found that drug-induced arrhythmias can be recapitulated in hiPSC-CMs and documented with low impedance MEA. Our data indicate that the MEA/hiPSC-CM assay is a sensitive, robust, and efficient platform for testing drug effectiveness and for arrhythmia screening. This system may hold great potential for reducing drug development costs and may provide significant advantages over current industry standard assays that use immortalized cell lines or animal models.",
keywords = "Arrhythmias cardiac, Genomics, Myocytes cardiac, Pharmacogenetics, Pharmacology, Stem cells",
author = "Navarrete, {Enrique G.} and Ping Liang and Feng Lan and Ver{\'o}nica Sanchez-Freire and Chelsey Simmons and Tingyu Gong and Arun Sharma and Burridge, {Paul W.} and Bhagat Patlolla and Lee, {Andrew S.} and Haodi Wu and Beygui, {Ramin E.} and Wu, {Sean M.} and Robbins, {Robert C.} and Bers, {Donald M} and Wu, {Joseph C.}",
year = "2013",
month = "9",
day = "10",
doi = "10.1161/CIRCULATIONAHA.112.000570",
language = "English (US)",
volume = "128",
journal = "Circulation",
issn = "0009-7322",
publisher = "Lippincott Williams and Wilkins",
number = "SUPPL.1",

}

TY - JOUR

T1 - Screening drug-induced arrhythmia events using human induced pluripotent stem cell-derived cardiomyocytes and low-impedance microelectrode arrays

AU - Navarrete, Enrique G.

AU - Liang, Ping

AU - Lan, Feng

AU - Sanchez-Freire, Verónica

AU - Simmons, Chelsey

AU - Gong, Tingyu

AU - Sharma, Arun

AU - Burridge, Paul W.

AU - Patlolla, Bhagat

AU - Lee, Andrew S.

AU - Wu, Haodi

AU - Beygui, Ramin E.

AU - Wu, Sean M.

AU - Robbins, Robert C.

AU - Bers, Donald M

AU - Wu, Joseph C.

PY - 2013/9/10

Y1 - 2013/9/10

N2 - BACKGROUND - Drug-induced arrhythmia is one of the most common causes of drug development failure and withdrawal from market. This study tested whether human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) combined with a low-impedance microelectrode array (MEA) system could improve on industry-standard preclinical cardiotoxicity screening methods, identify the effects of well-characterized drugs, and elucidate underlying risk factors for drug-induced arrhythmia. hiPSC-CMs may be advantageous over immortalized cell lines because they possess similar functional characteristics as primary human cardiomyocytes and can be generated in unlimited quantities. METHODS AND RESULTS - Pharmacological responses of beating embryoid bodies exposed to a comprehensive panel of drugs at 65 to 95 days postinduction were determined. Responses of hiPSC-CMs to drugs were qualitatively and quantitatively consistent with the reported drug effects in literature. Torsadogenic hERG blockers, such as sotalol and quinidine, produced statistically and physiologically significant effects, consistent with patch-clamp studies, on human embryonic stem cell-derived cardiomyocytes hESC-CMs. False-negative and false-positive hERG blockers were identified accurately. Consistent with published studies using animal models, early afterdepolarizations and ectopic beats were observed in 33% and 40% of embryoid bodies treated with sotalol and quinidine, respectively, compared with negligible early afterdepolarizations and ectopic beats in untreated controls. CONCLUSIONS - We found that drug-induced arrhythmias can be recapitulated in hiPSC-CMs and documented with low impedance MEA. Our data indicate that the MEA/hiPSC-CM assay is a sensitive, robust, and efficient platform for testing drug effectiveness and for arrhythmia screening. This system may hold great potential for reducing drug development costs and may provide significant advantages over current industry standard assays that use immortalized cell lines or animal models.

AB - BACKGROUND - Drug-induced arrhythmia is one of the most common causes of drug development failure and withdrawal from market. This study tested whether human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) combined with a low-impedance microelectrode array (MEA) system could improve on industry-standard preclinical cardiotoxicity screening methods, identify the effects of well-characterized drugs, and elucidate underlying risk factors for drug-induced arrhythmia. hiPSC-CMs may be advantageous over immortalized cell lines because they possess similar functional characteristics as primary human cardiomyocytes and can be generated in unlimited quantities. METHODS AND RESULTS - Pharmacological responses of beating embryoid bodies exposed to a comprehensive panel of drugs at 65 to 95 days postinduction were determined. Responses of hiPSC-CMs to drugs were qualitatively and quantitatively consistent with the reported drug effects in literature. Torsadogenic hERG blockers, such as sotalol and quinidine, produced statistically and physiologically significant effects, consistent with patch-clamp studies, on human embryonic stem cell-derived cardiomyocytes hESC-CMs. False-negative and false-positive hERG blockers were identified accurately. Consistent with published studies using animal models, early afterdepolarizations and ectopic beats were observed in 33% and 40% of embryoid bodies treated with sotalol and quinidine, respectively, compared with negligible early afterdepolarizations and ectopic beats in untreated controls. CONCLUSIONS - We found that drug-induced arrhythmias can be recapitulated in hiPSC-CMs and documented with low impedance MEA. Our data indicate that the MEA/hiPSC-CM assay is a sensitive, robust, and efficient platform for testing drug effectiveness and for arrhythmia screening. This system may hold great potential for reducing drug development costs and may provide significant advantages over current industry standard assays that use immortalized cell lines or animal models.

KW - Arrhythmias cardiac

KW - Genomics

KW - Myocytes cardiac

KW - Pharmacogenetics

KW - Pharmacology

KW - Stem cells

UR - http://www.scopus.com/inward/record.url?scp=84883791986&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84883791986&partnerID=8YFLogxK

U2 - 10.1161/CIRCULATIONAHA.112.000570

DO - 10.1161/CIRCULATIONAHA.112.000570

M3 - Article

VL - 128

JO - Circulation

JF - Circulation

SN - 0009-7322

IS - SUPPL.1

ER -