title: Screening drug-induced arrhythmia [corrected] 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.
  
  
  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.
authors.affiliation: Department of Medicine, Division of Cardiology, Stanford University School of Medicine, Stanford, CA (E.G.N., P.L., F.L., V.S.-F., T.G., A.S., P.W.B., A.S.L., H.W., S.M.W., J.C.W.); Institute for Stem Cell Biology and Regenerative Medicine, Stanford, CA (E.G.N., P.L., F.L., V.S.-F., T.G., A.S., P.W.B., A.S.L., H.W., S.M.W.); Stanford Cardiovascular Institute, Stanford, CA (E.G.N., P.L., F.L., V.S.-F., C.S., T.G., P.W.B., B.P., A.S.L., H.W., R.E.B., S.M.W., R.C.R., J.C.W.); Department of Radiology, Stanford, CA (E.G.N., P.L., F.L., V.S.-F., T.G., P.W.B., A.S.L., H.W., J.C.W.); School of Mechanical Engineering, Stanford, CA (C.S.); Department of Cardiothoracic Surgery, Stanford, CA (B.P., R.E.B., R.C.R.); Department of Pharmacology, University of California, Davis, CA (D.M.B.).
authors.forename: Enrique G
authors.initials: EG
authors.lastname: Navarrete
authors.forename: Ping
authors.initials: P
authors.lastname: Liang
authors.forename: Feng
authors.initials: F
authors.lastname: Lan
authors.forename: Verónica
authors.initials: V
authors.lastname: Sanchez-Freire
authors.forename: Chelsey
authors.initials: C
authors.lastname: Simmons
authors.forename: Tingyu
authors.initials: T
authors.lastname: Gong
authors.forename: Arun
authors.initials: A
authors.lastname: Sharma
authors.forename: Paul W
authors.initials: PW
authors.lastname: Burridge
authors.forename: Bhagat
authors.initials: B
authors.lastname: Patlolla
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Lee
authors.forename: Haodi
authors.initials: H
authors.lastname: Wu
authors.forename: Ramin E
authors.initials: RE
authors.lastname: Beygui
authors.forename: Sean M
authors.initials: SM
authors.lastname: Wu
authors.forename: Robert C
authors.initials: RC
authors.lastname: Robbins
authors.forename: Donald M
authors.initials: DM
authors.lastname: Bers
authors.forename: Joseph C
authors.initials: JC
authors.lastname: Wu
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000293:Adolescent; D001145:Arrhythmias, Cardiac / Q000139:chemically induced* / Q000473:pathology / Q000503:physiopathology; D002317:Cardiovascular Agents / Q000009:adverse effects*; D002478:Cells, Cultured; D004353:Drug Evaluation, Preclinical / Q000379:methods; D017097:Electric Impedance; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000187:drug effects* / Q000502:physiology; D008297:Male; D008839:Microelectrodes; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000502:physiology; D046888:Tissue Array Analysis / Q000379:methods*
chemical_list: D002317:Cardiovascular Agents
keywords: arrhythmias, cardiac; genomics; myocytes, cardiac; pharmacogenetics; pharmacology; stem cells
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