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A novel transgenic rabbit model with reduced repolarization reserve: long QT syndrome caused by a dominant‐negative mutation of the KCNE1 gene
Author(s) -
Major Péter,
Baczkó István,
Hiripi László,
Odening Katja E.,
Juhász Viktor,
Kohajda Zsófia,
Horváth András,
Seprényi György,
Kovács Mária,
Virág László,
Jost Norbert,
Prorok János,
Ördög Balázs,
Doleschall Zoltán,
Nattel Stanley,
Varró András,
Bősze Zsuzsanna
Publication year - 2016
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.13500
Subject(s) - herg , dofetilide , qt interval , repolarization , cardiology , long qt syndrome , medicine , short qt syndrome , ventricular action potential , sudden cardiac death , proarrhythmia , potassium channel , pharmacology , electrophysiology
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. Experimental Approach 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 (I Ks ). ECG parameters, including short‐term variability of the QT interval (STV QT ), a biomarker for proarrhythmic risk, and arrhythmia development were recorded. In vivo , arrhythmia susceptibility was evaluated by i.v. administration of the I Kr blocker dofetilide. K + currents were measured with the patch‐clamp technique. Key Results Patch‐clamp studies in ventricular myocytes isolated from LQT5 rabbits revealed accelerated I Ks and I Kr deactivation kinetics. At baseline, LQT5 animals exhibited slightly but significantly prolonged heart‐rate corrected QT index (QTi) and increased STV QT . Dofetilide provoked Torsade‐de‐Pointes arrhythmia in a greater proportion of LQT5 rabbits, paralleled by a further increase in STV QT . 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.