PMID- 26117837
OWN - NLM
STAT- MEDLINE
DCOM- 20160523
LR  - 20220408
IS  - 1096-0929 (Electronic)
IS  - 1096-0929 (Linking)
VI  - 147
IP  - 1
DP  - 2015 Sep
TI  - Proarrhythmia Risk Assessment in Human Induced Pluripotent Stem Cell-Derived 
      Cardiomyocytes Using the Maestro MEA Platform.
PG  - 286-95
LID - 10.1093/toxsci/kfv128 [doi]
AB  - Evaluation of stem cell-derived cardiomyocytes (SC-CM) using multi-electrode 
      array (MEA) has attracted attention as a novel model to detect drug-induced 
      arrhythmia. An experiment was conducted to determine if MEA recording from human 
      induced pluripotent SC-CM (hiPSC-CM) could assess proarrhythmic risk. Ten hERG 
      blockers, 4 Na(+) blockers, and 1 IKs blocker were evaluated blindly. Eight drugs 
      are associated with Torsades de Pointes (TdP) and 4 are not. Multiple parameters, 
      including field potential duration (FPD), Na(+) slope, Na(+) amplitude, beat rate 
      (BR), and early after-depolarization (EAD) were recorded. Minimum effective 
      concentrations (MEC) that elicited a significant change were calculated. Our 
      results determined that FPD and EAD were unable to distinguish torsadogenic from 
      benign compounds, Na(+) slope and amplitude could not differentiate Na(+) channel 
      blockade from hERG blockade, BR had an inconsistent response to pharmacological 
      treatment, and that hiPSC-CM were, in general, insensitive to IKs inhibition. A 
      ratio was calculated that relates MEC for evoking FPD prolongation, or triggering 
      EAD, to the human therapeutic unbound Cmax (MEC/Cmax). The key finding was that 
      the ratio was sensitive, but specificity was low. Consistently, the ratio had 
      high positive predictive value and low negative predictive value. In conclusion, 
      MEA recordings of hiPSC-CM were sensitive for FPD and EAD detection, but unable 
      to distinguish agents with low- and high-risk for TdPs. Although some published 
      reports suggested great potential for MEA recordings in hSC-CM to assess 
      preclinical cardiac toxicity, the current evaluation implies that this model 
      would have a high false-positive rate in regard to proarrhythmic risk.
CI  - (c) The Author 2015. Published by Oxford University Press on behalf of the Society 
      of Toxicology.All rights reserved. For Permissions, please e-mail: 
      journals.permissions@oup.com.
FAU - Qu, Yusheng
AU  - Qu Y
AD  - Integrated Discovery and Safety Pharmacology, Amgen Inc., Thousand Oaks, 
      California 91320 yqu@amgen.com.
FAU - Vargas, Hugo M
AU  - Vargas HM
AD  - Integrated Discovery and Safety Pharmacology, Amgen Inc., Thousand Oaks, 
      California 91320.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20150627
PL  - United States
TA  - Toxicol Sci
JT  - Toxicological sciences : an official journal of the Society of Toxicology
JID - 9805461
RN  - 0 (Intermediate-Conductance Calcium-Activated Potassium Channels)
RN  - 0 (Potassium Channel Blockers)
RN  - 0 (Sodium Channel Blockers)
SB  - IM
MH  - Arrhythmias, Cardiac/*chemically induced/pathology
MH  - Dose-Response Relationship, Drug
MH  - Heart Rate/drug effects
MH  - Humans
MH  - Induced Pluripotent Stem Cells/*drug effects
MH  - Intermediate-Conductance Calcium-Activated Potassium Channels/drug effects
MH  - Membrane Potentials/drug effects
MH  - Microelectrodes
MH  - Myocytes, Cardiac/*drug effects
MH  - Potassium Channel Blockers/toxicity
MH  - Predictive Value of Tests
MH  - Reproducibility of Results
MH  - Risk Assessment
MH  - Sodium Channel Blockers/toxicity
MH  - Torsades de Pointes/chemically induced/physiopathology
OTO - NOTNLM
OT  - Torsades de Pointes
OT  - cardiac myocytes
OT  - early after-depolarization
OT  - field potential
OT  - human induced pluripotent stem cells
OT  - minimal effective concentrations
OT  - multi-electrode array
OT  - proarrhythmia
EDAT- 2015/06/29 06:00
MHDA- 2016/05/24 06:00
CRDT- 2015/06/29 06:00
PHST- 2015/06/29 06:00 [entrez]
PHST- 2015/06/29 06:00 [pubmed]
PHST- 2016/05/24 06:00 [medline]
AID - kfv128 [pii]
AID - 10.1093/toxsci/kfv128 [doi]
PST - ppublish
SO  - Toxicol Sci. 2015 Sep;147(1):286-95. doi: 10.1093/toxsci/kfv128. Epub 2015 Jun 
      27.