PMID- 23702537
OWN - NLM
STAT- MEDLINE
DCOM- 20140210
LR  - 20220310
IS  - 1873-488X (Electronic)
IS  - 1056-8719 (Linking)
VI  - 68
IP  - 1
DP  - 2013 Jul-Aug
TI  - Drug-induced functional cardiotoxicity screening in stem cell-derived human and 
      mouse cardiomyocytes: effects of reference compounds.
PG  - 97-111
LID - S1056-8719(13)00255-4 [pii]
LID - 10.1016/j.vascn.2013.05.005 [doi]
AB  - INTRODUCTION: Early prediction of drug-induced functional cardiotoxicity requires 
      robust in-vitro systems suitable for medium/high throughput and easily accessible 
      cardiomyocytes with defined reproducible properties. The xCELLigence Cardio 
      system uses 96-well plates with interdigitated electrodes that detect the 
      impedance changes of rhythmic contractions of stem cell-derived cardiomyocyte 
      (SC-CM) layers. Here, we report on our initial screening experience in comparison 
      to established (multi)cellular and in-vivo models. METHODS: Impedance signals 
      from human iPSC-CM (iCells) and mouse eSC-CM (Cor.At) were analyzed for 
      contraction amplitude (CA) and duration, rise/fall time, beating rate (BR) and 
      irregularity. RESULTS: Following solution exchange, impedance signals 
      re-approximated steady-state conditions after about 2 (Cor.At) and 3h (iCells); 
      these time points were used to analyze drug effects. The solvent DMSO (</=1%) 
      hardly influenced contraction parameters in Cor.At, whereas in iCells DMSO 
      (>0.1%) reduced CA and enhanced BR. The selective hERG K(+) channel blockers E-4031 
      and dofetilide reduced CA and accelerated BR (>/=30 nM) according to the analysis 
      software. The latter, however, was due to burst-like contractions (300 nM) that 
      could be detected only by visual inspection of recordings, and were more 
      pronounced in Cor.At as in iCells. In cardiac myocytes and tissue preparations, 
      however, E4031 and dofetilide have been reported to increase cell shortening and 
      contractile force and to reduce BR. Compounds (pentamidine, HMR1556, ATX2, TTX, 
      and verapamil) with other mechanisms of action were also investigated; their 
      effects differed partially between cell lines (e.g. TTX) and compared to 
      established (multi)cellular models (e.g. HMR1556, ouabain). CONCLUSION: Mouse and 
      human stem cell-derived cardiomyocytes respond differently to drugs and these 
      responses occasionally also differ from those originating from established 
      in-vitro and in-vivo models. Hence, drug-induced cardiotoxic effects may be 
      detected with this system, however, the predictive or even translational value of 
      results is considered limited and not yet firmly established.
CI  - Copyright (c) 2013 Elsevier Inc. All rights reserved.
FAU - Himmel, Herbert M
AU  - Himmel HM
AD  - Safety Pharmacology, Bayer Pharma AG, Wuppertal, Germany. 
      herbert.himmel@bayer.com
LA  - eng
PT  - Comparative Study
PT  - Journal Article
DEP - 20130520
PL  - United States
TA  - J Pharmacol Toxicol Methods
JT  - Journal of pharmacological and toxicological methods
JID - 9206091
RN  - 0 (Solvents)
RN  - YOW8V9698H (Dimethyl Sulfoxide)
SB  - IM
MH  - Animals
MH  - Dimethyl Sulfoxide/chemistry
MH  - Electric Impedance
MH  - High-Throughput Screening Assays/methods
MH  - Humans
MH  - Induced Pluripotent Stem Cells/*cytology
MH  - Mice
MH  - Myocardial Contraction/*drug effects
MH  - Myocytes, Cardiac/*drug effects/metabolism
MH  - Reproducibility of Results
MH  - Solvents/chemistry
MH  - Species Specificity
MH  - Time Factors
MH  - Toxicity Tests/*methods
OTO - NOTNLM
OT  - AP
OT  - AP duration
OT  - APD
OT  - ATX-II
OT  - Beating rate
OT  - Contraction
OT  - DMSO
OT  - ECG
OT  - FP
OT  - FP duration
OT  - FPD
OT  - HEK
OT  - I(Ca.L)
OT  - I(Na)
OT  - Impedance method
OT  - In-vitro
OT  - Ion channel modulators
OT  - L-type Ca(2+) current
OT  - Na(+) current
OT  - PF
OT  - PM
OT  - Purkinje fiber
OT  - RTCA
OT  - SC-CM
OT  - Stem cell-derived cardiomyocytes
OT  - action potential
OT  - anemonia sulcata toxin 2
OT  - dimethylsulfoxide
OT  - eSC
OT  - electrocardiogram
OT  - embryonic stem cell
OT  - field potential
OT  - hERG
OT  - human embryonic kidney
OT  - human ether-a-go-go-related gene
OT  - iPSC
OT  - induced pluripotent stem cell
OT  - papillary muscle
OT  - real-time cellular analyzer
OT  - stem cell-derived cardiomyocytes
EDAT- 2013/05/25 06:00
MHDA- 2014/02/11 06:00
CRDT- 2013/05/25 06:00
PHST- 2013/02/07 00:00 [received]
PHST- 2013/05/10 00:00 [revised]
PHST- 2013/05/10 00:00 [accepted]
PHST- 2013/05/25 06:00 [entrez]
PHST- 2013/05/25 06:00 [pubmed]
PHST- 2014/02/11 06:00 [medline]
AID - S1056-8719(13)00255-4 [pii]
AID - 10.1016/j.vascn.2013.05.005 [doi]
PST - ppublish
SO  - J Pharmacol Toxicol Methods. 2013 Jul-Aug;68(1):97-111. doi: 
      10.1016/j.vascn.2013.05.005. Epub 2013 May 20.