PortalPublikationenA novel transgenic rabbit model with reduced repolarization ...

A novel transgenic rabbit model with reduced repolarization reserve

Standard

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

in: BRIT J PHARMACOL, Jahrgang 173, Nr. 12, 06.2016, S. 2046-61.

Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung

Harvard

Major, P, Baczkó, I, Hiripi, L, Odening, KE, Juhász, V, Kohajda, Z, Horváth, A, Seprényi, G, Kovács, M, Virág, L, Jost, N, Prorok, J, Ördög, B, Doleschall, Z, Nattel, S, Varró, A & Bősze, Z 2016, 'A novel transgenic rabbit model with reduced repolarization reserve: long QT syndrome caused by a dominant-negative mutation of the KCNE1 gene', BRIT J PHARMACOL, Jg. 173, Nr. 12, S. 2046-61. https://doi.org/10.1111/bph.13500

APA

Major, P., Baczkó, I., Hiripi, L., Odening, K. E., Juhász, V., Kohajda, Z., Horváth, A., Seprényi, G., Kovács, M., Virág, L., Jost, N., Prorok, J., Ördög, B., Doleschall, Z., Nattel, S., Varró, A., & Bősze, Z. (2016). A novel transgenic rabbit model with reduced repolarization reserve: long QT syndrome caused by a dominant-negative mutation of the KCNE1 gene. BRIT J PHARMACOL, 173(12), 2046-61. https://doi.org/10.1111/bph.13500

Vancouver

Major P, Baczkó I, Hiripi L, Odening KE, Juhász V, Kohajda Z et al. A novel transgenic rabbit model with reduced repolarization reserve: long QT syndrome caused by a dominant-negative mutation of the KCNE1 gene. BRIT J PHARMACOL. 2016 Jun;173(12):2046-61. https://doi.org/10.1111/bph.13500

Bibtex

@article{388622559e2b426ea87b0ff14f2f058f,
title = "A novel transgenic rabbit model with reduced repolarization reserve: long QT syndrome caused by a dominant-negative mutation of the KCNE1 gene",
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.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 (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.KEY RESULTS: 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.",
keywords = "Animals, Animals, Genetically Modified, Disease Models, Animal, Female, Genes, Dominant, Humans, Long QT Syndrome, Male, Mutation, Potassium Channels, Voltage-Gated, Rabbits, Real-Time Polymerase Chain Reaction, Journal Article, Research Support, Non-U.S. Gov't",
author = "P{\'e}ter Major and Istv{\'a}n Baczk{\'o} and L{\'a}szl{\'o} Hiripi and Odening, {Katja E} and Viktor Juh{\'a}sz and Zs{\'o}fia Kohajda and Andr{\'a}s Horv{\'a}th and Gy{\"o}rgy Sepr{\'e}nyi and M{\'a}ria Kov{\'a}cs and L{\'a}szl{\'o} Vir{\'a}g and Norbert Jost and J{\'a}nos Prorok and Bal{\'a}zs {\"O}rd{\"o}g and Zolt{\'a}n Doleschall and Stanley Nattel and Andr{\'a}s Varr{\'o} and Zsuzsanna B{\H o}sze",
note = "{\textcopyright} 2016 The British Pharmacological Society.",
year = "2016",
month = jun,
doi = "10.1111/bph.13500",
language = "English",
volume = "173",
pages = "2046--61",
journal = "BRIT J PHARMACOL",
issn = "0007-1188",
publisher = "Wiley-Blackwell",
number = "12",

}

RIS

TY - JOUR

T1 - A novel transgenic rabbit model with reduced repolarization reserve

T2 - long QT syndrome caused by a dominant-negative mutation of the KCNE1 gene

AU - Major, Péter

AU - Baczkó, István

AU - Hiripi, László

AU - Odening, Katja E

AU - Juhász, Viktor

AU - Kohajda, Zsófia

AU - Horváth, András

AU - Seprényi, György

AU - Kovács, Mária

AU - Virág, László

AU - Jost, Norbert

AU - Prorok, János

AU - Ördög, Balázs

AU - Doleschall, Zoltán

AU - Nattel, Stanley

AU - Varró, András

AU - Bősze, Zsuzsanna

N1 - © 2016 The British Pharmacological Society.

PY - 2016/6

Y1 - 2016/6

N2 - 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 (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.KEY RESULTS: 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.

AB - 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 (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.KEY RESULTS: 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.

KW - Animals

KW - Animals, Genetically Modified

KW - Disease Models, Animal

KW - Female

KW - Genes, Dominant

KW - Humans

KW - Long QT Syndrome

KW - Male

KW - Mutation

KW - Potassium Channels, Voltage-Gated

KW - Rabbits

KW - Real-Time Polymerase Chain Reaction

KW - Journal Article

KW - Research Support, Non-U.S. Gov't

U2 - 10.1111/bph.13500

DO - 10.1111/bph.13500

M3 - SCORING: Journal article

C2 - 27076034

VL - 173

SP - 2046

EP - 2061

JO - BRIT J PHARMACOL

JF - BRIT J PHARMACOL

SN - 0007-1188

IS - 12

ER -