A novel transgenic rabbit model with reduced repolarization reserve: long QT syndrome caused by a dominant-negative mutation of the KCNE1 gene.
Br J Pharmacol
; 173(12): 2046-61, 2016 06.
Article
em En
| MEDLINE
| ID: mdl-27076034
ABSTRACT
BACKGROUND AND PURPOSE:
The 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 reduced repolarization reserve. EXPERIMENTALAPPROACH:
We have developed a model for the long QT syndrome type-5 in rabbits (LQT5 ) with cardiac-specific overexpression of a mutant (G52R) KCNE1 ß-subunit of the channel that carries the slow delayed-rectifier K(+) -current (IKs ). ECG parameters, including short-term variability of the QT interval (STVQT ), a biomarker for proarrhythmic risk, and arrhythmia development were recorded. In vivo, arrhythmia susceptibility was evaluated by i.v. administration of the IKr blocker dofetilide. K(+) currents were measured with the patch-clamp technique. KEYRESULTS:
Patch-clamp studies in ventricular myocytes isolated from LQT5 rabbits revealed accelerated IKs and IKr deactivation kinetics. At baseline, LQT5 animals exhibited slightly but significantly prolonged heart-rate corrected QT index (QTi) and increased STVQT . Dofetilide provoked Torsade-de-Pointes arrhythmia in a greater proportion of LQT5 rabbits, paralleled by a further increase in STVQT . CONCLUSION AND IMPLICATIONS We have created a novel transgenic LQT5 rabbit model with increased susceptibility to drug-induced arrhythmias that may represent a useful model for testing proarrhythmic potential and for investigations of the mechanisms underlying arrhythmias and sudden cardiac death due to repolarization disturbances.
Texto completo:
1
Coleções:
01-internacional
Contexto em Saúde:
6_ODS3_enfermedades_notrasmisibles
Base de dados:
MEDLINE
Assunto principal:
Síndrome do QT Longo
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Canais de Potássio de Abertura Dependente da Tensão da Membrana
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Genes Dominantes
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Mutação
Tipo de estudo:
Prognostic_studies
Limite:
Animals
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Female
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Humans
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Male
Idioma:
En
Revista:
Br J Pharmacol
Ano de publicação:
2016
Tipo de documento:
Article