title: A novel transgenic rabbit model with reduced repolarization reserve: long QT syndrome caused by a dominant-negative mutation of the KCNE1 gene.
abstract: 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.
  
  
  
  We have developed a model for the long QT syndrome type-5 in rabbits (LQT5 ) with cardiac-specific overexpression of a mutant (G52R) KCNE1 β-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.
  
  
  
  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 .
  
  
  
  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.
authors.affiliation: Rabbit Genome and Biomodel Group, NARIC - Agricultural Biotechnology Institute, Gödöllő, Hungary.
authors.forename: Péter
authors.initials: P
authors.lastname: Major
authors.affiliation: Department of Pharmacology & Pharmacotherapy, University of Szeged, Szeged, Hungary.
authors.forename: István
authors.initials: I
authors.lastname: Baczkó
authors.affiliation: Rabbit Genome and Biomodel Group, NARIC - Agricultural Biotechnology Institute, Gödöllő, Hungary.
authors.forename: László
authors.initials: L
authors.lastname: Hiripi
authors.affiliation: Department of Cardiology and Angiology I, Heart Center University of Freiburg, Freiburg, Germany.
authors.forename: Katja E
authors.initials: KE
authors.lastname: Odening
authors.affiliation: Department of Pharmacology & Pharmacotherapy, University of Szeged, Szeged, Hungary.
authors.forename: Viktor
authors.initials: V
authors.lastname: Juhász
authors.affiliation: Department of Pharmacology & Pharmacotherapy, University of Szeged, Szeged, Hungary.
authors.forename: Zsófia
authors.initials: Z
authors.lastname: Kohajda
authors.affiliation: Department of Pharmacology & Pharmacotherapy, University of Szeged, Szeged, Hungary.
authors.forename: András
authors.initials: A
authors.lastname: Horváth
authors.affiliation: Department of Biology, University of Szeged, Szeged, Hungary.
authors.forename: György
authors.initials: G
authors.lastname: Seprényi
authors.affiliation: Department of Pharmacology & Pharmacotherapy, University of Szeged, Szeged, Hungary.
authors.forename: Mária
authors.initials: M
authors.lastname: Kovács
authors.affiliation: Department of Pharmacology & Pharmacotherapy, University of Szeged, Szeged, Hungary.
authors.forename: László
authors.initials: L
authors.lastname: Virág
authors.affiliation: Department of Pharmacology & Pharmacotherapy, University of Szeged, Szeged, Hungary.|MTA-SZTE Research Group of Cardiovascular Pharmacology, Hungarian Academy of Sciences, Szeged, Hungary.
authors.forename: Norbert
authors.initials: N
authors.lastname: Jost
authors.affiliation: Department of Pharmacology & Pharmacotherapy, University of Szeged, Szeged, Hungary.
authors.forename: János
authors.initials: J
authors.lastname: Prorok
authors.affiliation: Department of Pharmacology & Pharmacotherapy, University of Szeged, Szeged, Hungary.
authors.forename: Balázs
authors.initials: B
authors.lastname: Ördög
authors.affiliation: Department of Pathogenetics, National Institute of Oncology, Budapest, Hungary.
authors.forename: Zoltán
authors.initials: Z
authors.lastname: Doleschall
authors.affiliation: Department of Medicine, Montreal Heart Institute, Université de Montréal, Canada.|Department of Pharmacology and Therapeutics, McGill University, Montréal, Canada.|Institute of Pharmacology, West German Heart and Vascular Center, Faculty of Medicine, University Duisburg-Essen, Essen, Germany.
authors.forename: Stanley
authors.initials: S
authors.lastname: Nattel
authors.affiliation: Department of Pharmacology & Pharmacotherapy, University of Szeged, Szeged, Hungary.|MTA-SZTE Research Group of Cardiovascular Pharmacology, Hungarian Academy of Sciences, Szeged, Hungary.
authors.forename: András
authors.initials: A
authors.lastname: Varró
authors.affiliation: Rabbit Genome and Biomodel Group, NARIC - Agricultural Biotechnology Institute, Gödöllő, Hungary.
authors.forename: Zsuzsanna
authors.initials: Z
authors.lastname: Bősze
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D004195:Disease Models, Animal; D005260:Female; D005799:Genes, Dominant; D006801:Humans; D008133:Long QT Syndrome / Q000235:genetics*; D008297:Male; D009154:Mutation; D024642:Potassium Channels, Voltage-Gated / Q000235:genetics*; D011817:Rabbits; D060888:Real-Time Polymerase Chain Reaction
chemical_list: C489622:KCNE1 protein, human; D024642:Potassium Channels, Voltage-Gated