PMID- 20303332
OWN - NLM
STAT- MEDLINE
DCOM- 20100818
LR  - 20231213
IS  - 1876-7753 (Electronic)
IS  - 1873-5061 (Linking)
VI  - 4
IP  - 3
DP  - 2010 May
TI  - Quantified proarrhythmic potential of selected human embryonic stem cell-derived 
      cardiomyocytes.
PG  - 189-200
LID - 10.1016/j.scr.2010.02.001 [doi]
AB  - To improve proarrhythmic predictability of preclinical models, we assessed 
      whether human ventricular-like embryonic stem cell-derived cardiomyocytes 
      (hESC-CMs) can be selected following a standardized protocol. Also, we quantified 
      their arrhythmogenic response and compared this to a contemporary used rabbit 
      Purkinje fiber (PF) model. Multiple transmembrane action potentials (AP) were 
      recorded from 164 hESC-CM clusters (9 different batches), and 12 isolated PFs 
      from New Zealand White rabbits. AP duration (APD), early afterdepolarizations 
      (EADs), triangulation (T), and short-term variability of repolarization (STV) 
      were determined on application of the I(Kr) blocker E-4031 (0.03/0.1/0.3/1 muM). 
      Isoproterenol (0.1 muM) was used to assess adrenergic response. To validate the 
      phenotype, RNA isolated from atrial- and ventricular-like clusters (n=8) was 
      analyzed using low-density Taqman arrays. Based on initial experiments, slow 
      beating rate (<50 bpm) and long APD (>200 ms) were used to select 31 
      ventricular-like clusters. E-4031 (1 muM) prolonged APD (31/31) and induced EADs 
      only in clusters with APD90>300 ms (11/16). EADs were associated with increased T 
      (1.6+/-0.2 vs 2.0+/-0.3) and STV (2.7+/-1.5 vs 6.9+/-1.9). Rabbit PF reacted in a 
      similar way with regards to EADs (5/12), increased T (1.3+/-0.1 vs 1.9+/-0.4), 
      and STV (1.2+/-0.9 vs 7.1+/-5.6). According to ROC values, hESC-CMs (STV 0.91) 
      could predict EADs at least equivalent to PF (STV 0.69). Isoproterenol shortened 
      APD and completely suppressed EADs. Gene expression analysis revealed that 
      HCN1/2, KCNA5, and GJA5 were higher in atrial/nodal-like cells, whereas KCNJ2 and 
      SCN1B were higher in ventricular-like cells (P<0.05). Selection of hESC-CM 
      clusters with a ventricular-like phenotype can be standardized. The proarrhythmic 
      results are qualitatively and quantitatively comparable between hESC-CMs and 
      rabbit PF. Our results indicate that additional validation of this new safety 
      pharmacology model is warranted.
CI  - Copyright 2010 Elsevier B.V. All rights reserved.
FAU - Jonsson, Malin K B
AU  - Jonsson MK
AD  - Department of Medical Physiology, Division Heart & Lungs, University Medical 
      Center Utrecht, Utrecht, The Netherlands. m.k.b.jonsson@umcutrecht.nl
FAU - Duker, Goran
AU  - Duker G
FAU - Tropp, Charlotte
AU  - Tropp C
FAU - Andersson, Birgit
AU  - Andersson B
FAU - Sartipy, Peter
AU  - Sartipy P
FAU - Vos, Marc A
AU  - Vos MA
FAU - van Veen, Toon A B
AU  - van Veen TA
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20100217
PL  - England
TA  - Stem Cell Res
JT  - Stem cell research
JID - 101316957
RN  - 0 (Connexins)
RN  - 0 (Cyclic Nucleotide-Gated Cation Channels)
RN  - 0 (HCN1 protein, human)
RN  - 0 (Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels)
RN  - 0 (Ion Channels)
RN  - 0 (Kir2.1 channel)
RN  - 0 (Kv1.5 Potassium Channel)
RN  - 0 (Potassium Channels)
RN  - 0 (Potassium Channels, Inwardly Rectifying)
RN  - 0 (RNA, Messenger)
RN  - 0 (Sodium Channels)
RN  - L628TT009W (Isoproterenol)
SB  - IM
CIN - Stem Cell Res. 2010 May;4(3):155-6. PMID: 20493455
MH  - Action Potentials/physiology
MH  - Animals
MH  - Cell Line
MH  - Connexins/metabolism
MH  - Cyclic Nucleotide-Gated Cation Channels/metabolism
MH  - Electrocardiography
MH  - Embryonic Stem Cells/*cytology
MH  - Humans
MH  - Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels
MH  - Ion Channels/metabolism
MH  - Isoproterenol/pharmacology
MH  - Kv1.5 Potassium Channel/metabolism
MH  - Models, Biological
MH  - Myocytes, Cardiac/cytology/metabolism/*physiology
MH  - Phenotype
MH  - Potassium Channels/metabolism
MH  - Potassium Channels, Inwardly Rectifying/metabolism
MH  - Purkinje Fibers/cytology/physiology
MH  - RNA, Messenger/metabolism
MH  - Rabbits
MH  - Sodium Channels/metabolism
MH  - Gap Junction alpha-5 Protein
EDAT- 2010/03/23 06:00
MHDA- 2010/08/19 06:00
CRDT- 2010/03/23 06:00
PHST- 2009/12/30 00:00 [received]
PHST- 2010/02/10 00:00 [revised]
PHST- 2010/02/10 00:00 [accepted]
PHST- 2010/03/23 06:00 [entrez]
PHST- 2010/03/23 06:00 [pubmed]
PHST- 2010/08/19 06:00 [medline]
AID - S1873-5061(10)00014-0 [pii]
AID - 10.1016/j.scr.2010.02.001 [doi]
PST - ppublish
SO  - Stem Cell Res. 2010 May;4(3):189-200. doi: 10.1016/j.scr.2010.02.001. Epub 2010 
      Feb 17.