2016
DOI: 10.1111/bph.13500
|View full text |Cite
|
Sign up to set email alerts
|

A novel transgenic rabbit model with reduced repolarization reserve: long QT syndrome caused by a dominant‐negative mutation of the KCNE1 gene

Abstract: *These two authors contributed equally to this work. †These two senior authors contributed equally to this work. BACKGROUND AND PURPOSEThe reliable assessment of proarrhythmic risk of compounds under development remains an elusive goal. Current safety guidelines focus on the effects of blocking the KCNH2/HERG ion channel-in tissues and animals with intact repolarization. Novel models with better predictive value are needed that more closely reflect the conditions in patients with cardiac remodelling and reduce… Show more

Help me understand this report

Search citation statements

Order By: Relevance

Paper Sections

Select...
1
1
1
1

Citation Types

3
50
0

Year Published

2016
2016
2023
2023

Publication Types

Select...
4
3
1

Relationship

1
7

Authors

Journals

citations
Cited by 40 publications
(53 citation statements)
references
References 65 publications
3
50
0
Order By: Relevance
“…As shown in Figures and , the QT interval of the acute AVB rabbit at pre‐drug control was around 300 ms during ventricular pacing at 60 beats min −1 , which was longer than action potential duration (APD) of the isolated papillary muscle from rabbits that was electrically driven at 1 Hz (APD 90 = 150 ms; Nakaya et al , ). Also, the QT interval of the acute AVB rabbit was longer than that of normal rabbits (139–192 ms), those receiving α 1 ‐adrenoceptor agonist (131–163 ms), transgenic LQT1 rabbits (241 ms), LQT2 rabbits (264 ms) or LQT5 rabbits (140 ms) during sinus rhythm (200–250 beats min −1 ) without AVB (Carlsson et al , ; Lu et al , ; Brunner et al , ; Hagiwara et al , ; Major et al , ). The sensitivity of the heart to QT‐interval prolonging drugs is modified by the contribution of I Ks in the repolarization phase (Jost et al , ; So et al , ), whereas the density of I Ks in the isolated ventricular myocytes from rabbits is lower than those from other species like guinea pigs (Lu et al , ).…”
Section: Discussionmentioning
confidence: 99%
See 1 more Smart Citation
“…As shown in Figures and , the QT interval of the acute AVB rabbit at pre‐drug control was around 300 ms during ventricular pacing at 60 beats min −1 , which was longer than action potential duration (APD) of the isolated papillary muscle from rabbits that was electrically driven at 1 Hz (APD 90 = 150 ms; Nakaya et al , ). Also, the QT interval of the acute AVB rabbit was longer than that of normal rabbits (139–192 ms), those receiving α 1 ‐adrenoceptor agonist (131–163 ms), transgenic LQT1 rabbits (241 ms), LQT2 rabbits (264 ms) or LQT5 rabbits (140 ms) during sinus rhythm (200–250 beats min −1 ) without AVB (Carlsson et al , ; Lu et al , ; Brunner et al , ; Hagiwara et al , ; Major et al , ). The sensitivity of the heart to QT‐interval prolonging drugs is modified by the contribution of I Ks in the repolarization phase (Jost et al , ; So et al , ), whereas the density of I Ks in the isolated ventricular myocytes from rabbits is lower than those from other species like guinea pigs (Lu et al , ).…”
Section: Discussionmentioning
confidence: 99%
“…to increase intracellular Ca 2+ concentration, leading to increased triggered activity and increased susceptibility to ventricular arrhythmias (Carlsson et al , ; Carlsson, ). Recently, other rabbit proarrhythmia models have been developed using genetic or pharmacological methods to suppress the slow component of the delayed rectifier K + currents (I Ks ), leading to reduction of the repolarization reserve, due to the redundant nature of myocardial repolarization capacity (Roden, ; Husti et al , ; Major et al , ). In the normal rabbit heart, whose sinoatrial rate is usually 200–300 beats min −1 in vivo , contribution of the I Ks to the ventricular repolarization may be higher than that in human, because the slow deactivation kinetics of I Ks allows it to accumulate at higher frequencies (Stengl et al , ).…”
Section: Introductionmentioning
confidence: 99%
“…More recently, a novel transgenic rabbit LQT5 model, produced by cardiac specific expression of a KCNE1 mutant that functions as a dominant negative, was described with markedly altered repolarization reserve attributed to changes in both I Ks and I Kr (Major et al . ).…”
Section: Experimental Models In the Study Of Cardiac K+ Channel Functionmentioning
confidence: 99%
“…These transgenic rabbit models have enabled further studies focused on detailing arrhythmia mechanisms, as well as efforts to explore the effects of drugs and hormones on conduction, dispersion and arrhythmia susceptibility (Ziv et al 2009;Odening et al 2010Odening et al , 2012Odening et al , 2013Ziupa et al 2014;Kim et al 2015). More recently, a novel transgenic rabbit LQT5 model, produced by cardiac specific expression of a KCNE1 mutant that functions as a dominant negative, was described with markedly altered repolarization reserve attributed to changes in both I Ks and I Kr (Major et al 2016).…”
Section: Large Animal Models Of Congenital and Acquired Cardiac Arrhymentioning
confidence: 99%
“…The KCNE1 coding region of the transgene was amplified and analysed by automated sequencing. The MYH7-G52R-KCNE1-bGHpolyA insert was isolated and used to microinject rabbit embryos [62]. Out of 497 injected embryos, 466 were transferred into 21 pseudo pregnant recipients through laparoscopy.…”
Section: Creation Of Lqt5-tg Rabbitsmentioning
confidence: 99%