PMID- 29456831
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20231103
IS  - 2045-452X (Print)
IS  - 2045-4538 (Electronic)
IS  - 2045-452X (Linking)
VI  - 6
IP  - 6
DP  - 2017 Nov 1
TI  - Early afterdepolarisation tendency as a simulated pro-arrhythmic risk indicator.
PG  - 912-921
LID - 10.1039/c7tx00141j [doi]
AB  - Drug-induced Torsades de Pointes (TdP) arrhythmia is of major interest in 
      predictive toxicology. Drugs which cause TdP block the hERG cardiac potassium 
      channel. However, not all drugs that block hERG cause TdP. As such, further 
      understanding of the mechanistic route to TdP is needed. Early 
      afterdepolarisations (EADs) are a cell-level phenomenon in which the membrane of 
      a cardiac cell depolarises a second time before repolarisation, and EADs are seen 
      in hearts during TdP. Therefore, we propose a method of predicting TdP using 
      induced EADs combined with multiple ion channel block in simulations using 
      biophysically-based mathematical models of human ventricular cell 
      electrophysiology. EADs were induced in cardiac action potential models using 
      interventions based on diseases that are known to cause EADs, including: 
      increasing the conduction of the L-type calcium channel, decreasing the 
      conduction of the hERG channel, and shifting the inactivation curve of the fast 
      sodium channel. The threshold of intervention that was required to cause an EAD 
      was used to classify drugs into clinical risk categories. The metric that used 
      L-type calcium induced EADs was the most accurate of the EAD metrics at 
      classifying drugs into the correct risk categories, and increased in accuracy 
      when combined with action potential duration measurements. The EAD metrics were 
      all more accurate than hERG block alone, but not as predictive as simpler 
      measures such as simulated action potential duration. This may be because 
      different routes to EADs represent risk well for different patient subgroups, 
      something that is difficult to assess at present.
FAU - McMillan, Beth
AU  - McMillan B
AUID- ORCID: 0000-0002-2605-1733
AD  - Computational Biology , Dept. of Computer Science , University of Oxford , Oxford 
      , OX1 3QD , UK . Email: beth.mcmillan@cs.ox.ac.uk ; ; Tel: +44 (0)1865 273838.
FAU - Gavaghan, David J
AU  - Gavaghan DJ
AUID- ORCID: 0000-0001-8311-3200
AD  - Computational Biology , Dept. of Computer Science , University of Oxford , Oxford 
      , OX1 3QD , UK . Email: beth.mcmillan@cs.ox.ac.uk ; ; Tel: +44 (0)1865 273838.
FAU - Mirams, Gary R
AU  - Mirams GR
AUID- ORCID: 0000-0002-4569-4312
AD  - Centre for Mathematical Biology , School of Mathematical Sciences , University of 
      Nottingham , Nottingham , NG7 2RD , UK.
LA  - eng
GR  - Wellcome Trust/United Kingdom
PT  - Journal Article
DEP - 20170914
PL  - England
TA  - Toxicol Res (Camb)
JT  - Toxicology research
JID - 101587950
PMC - PMC5779076
EDAT- 2018/02/20 06:00
MHDA- 2018/02/20 06:01
PMCR- 2018/09/14
CRDT- 2018/02/20 06:00
PHST- 2017/05/18 00:00 [received]
PHST- 2017/09/12 00:00 [accepted]
PHST- 2018/02/20 06:00 [entrez]
PHST- 2018/02/20 06:00 [pubmed]
PHST- 2018/02/20 06:01 [medline]
PHST- 2018/09/14 00:00 [pmc-release]
AID - c7tx00141j [pii]
AID - 10.1039/c7tx00141j [doi]
PST - ppublish
SO  - Toxicol Res (Camb). 2017 Nov 1;6(6):912-921. doi: 10.1039/c7tx00141j. Epub 2017 
      Sep 14.