Pronounced Effects of HERG-Blockers E-4031 and Erythromycin on APD, Spatial APD Dispersion and Triangulation in Transgenic Long-QT Type 1 Rabbits

Ziupa, David; Beck, Julia; Franke, Gerlind; Feliz, Stefanie Perez; Hartmann, Maximilian; Koren, Gideon; Zehender, Manfred; Bode, Christoph; Brunner, Michael; Odening, Katja E.

doi:10.1371/journal.pone.0107210

Cited by 16 publications

(9 citation statements)

References 35 publications

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“…When the repolarization reserve of LQT1 rabbits were further challenged by continuous tachypacing or AVablation to induce cardiac tachymyopathy (Lau et al, 2015), or complete AV-block (Kim et al, 2015), respectively, however, significant APD dispersion and discordant alternans developed and VT/VF was easily inducible and even occurred spontaneously (Lau et al, 2015). The model also demonstrated the development of pseudo-AV blocks and drug-induced TdP upon I Kr -blockade by dofetilide and E4031 (Odening et al, 2010;Ziupa et al, 2014;Major et al, 2016;Ziupa et al, 2019) ( Figure 6B).…”

Section: Investigation Of In Vivo Susceptibility To Arrhythmia Of Tramentioning

confidence: 97%

“…LQT1 and LQT5 models; on the other hand, were especially sensitive to I Kr blockade (dofetilide, E4031, and erythromycin), as demonstrated in vivo by a pronounced increase in QTc, STV QT , and T peak-end and ex vivo by a prolongation of APD and (in LQT1) APD dispersion (Odening et al, 2010;Ziupa et al, 2014;Major et al, 2016).…”

Section: Investigation Of Drug-induced Changes In Proarrhythmia Markementioning

confidence: 99%

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Transgenic Rabbit Models in Proarrhythmia Research

et al. 2020

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Drug-induced proarrhythmia constitutes a potentially lethal side effect of various drugs. Most often, this proarrhythmia is mechanistically linked to the drug's potential to interact with repolarizing cardiac ion channels causing a prolongation of the QT interval in the ECG. Despite sophisticated screening approaches during drug development, reliable prediction of proarrhythmia remains very challenging. Although drug-induced long-QT-related proarrhythmia is often favored by conditions or diseases that impair the individual's repolarization reserve, most cellular, tissue, and whole animal model systems used for drug safety screening are based on normal, healthy models. In recent years, several transgenic rabbit models for different types of long QT syndromes (LQTS) with differences in the extent of impairment in repolarization reserve have been generated. These might be useful for screening/prediction of a drug's potential for long-QT-related proarrhythmia, particularly as different repolarizing cardiac ion channels are impaired in the different models. In this review, we summarize the electrophysiological characteristics of the available transgenic LQTS rabbit models, and the pharmacological proof-of-principle studies that have been performed with these models-highlighting the advantages and disadvantages of LQTS models for proarrhythmia research. In the end, we give an outlook on potential future directions and novel models.

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Section: Investigation Of In Vivo Susceptibility To Arrhythmia Of Tramentioning

confidence: 97%

Section: Investigation Of Drug-induced Changes In Proarrhythmia Markementioning

confidence: 99%

Transgenic Rabbit Models in Proarrhythmia Research

et al. 2020

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“…In addition, the LQT2 rabbits show a high incidence of sudden death, attributed to increased dispersion of repolarization and polymorphic ventricular tachycardia. 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%

Potassium currents in the heart: functional roles in repolarization, arrhythmia and therapeutics

Chiamvimonvat

Chen‐Izu

Clancy

et al. 2017

The Journal of Physiology

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This is the second of the two White Papers from the fourth UC Davis Cardiovascular Symposium Systems Approach to Understanding Cardiac Excitation-Contraction Coupling and Arrhythmias (3-4 March 2016), a biennial event that brings together leading experts in different fields of cardiovascular research. The theme of the 2016 symposium was 'K channels and regulation', and the objectives of the conference were severalfold: (1) to identify current knowledge gaps; (2) to understand what may go wrong in the diseased heart and why; (3) to identify possible novel therapeutic targets; and (4) to further the development of systems biology approaches to decipher the molecular mechanisms and treatment of cardiac arrhythmias. The sessions of the Symposium focusing on the functional roles of the cardiac K channel in health and disease, as well as K channels as therapeutic targets, were contributed by Ye Chen-Izu, Gideon Koren, James Weiss, David Paterson, David Christini, Dobromir Dobrev, Jordi Heijman, Thomas O'Hara, Crystal Ripplinger, Zhilin Qu, Jamie Vandenberg, Colleen Clancy, Isabelle Deschenes, Leighton Izu, Tamas Banyasz, Andras Varro, Heike Wulff, Eleonora Grandi, Michael Sanguinetti, Donald Bers, Jeanne Nerbonne and Nipavan Chiamvimonvat as speakers and panel discussants. This article summarizes state-of-the-art knowledge and controversies on the functional roles of cardiac K channels in normal and diseased heart. We endeavour to integrate current knowledge at multiple scales, from the single cell to the whole organ levels, and from both experimental and computational studies.

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“…S3). Moreover, compared to controls, 1b-R25W significantly enhanced two important metrics of cellular proarrhyhmia: AP triangulation and AP variability (Altomare et al, 2015; Gallacher et al, 2007; Hondeghem et al, 2001; Jacobson et al, 2011; Ziupa et al, 2014). AP triangulation was assessed using the ratio of Phase 2 (APD 40 -APD 30 ) divided by Phase 3 (APD 80 -APD 70 ).…”

Section: Resultsmentioning

confidence: 90%

Dominant negative consequences of a hERG 1b-specific mutation associated with intrauterine fetal death

Jones

Liu

Dombrowski

et al. 2016

Progress in Biophysics and Molecular Biology

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The human ether-a-go-go related gene (hERG) encodes two subunits, hERG 1a and hERG 1b, that combine in vivo to conduct the rapid delayed rectifier potassium current (IKr). Reduced IKr slows cardiac action potential (AP) repolarization and is an underlying cause of cardiac arrhythmias associated with long QT syndrome (LQTS). Although the physiological importance of hERG 1b has been elucidated, the effects of hERG 1b disease mutations on cardiac IKr and AP behavior have not been described. To explore the disease mechanism of a 1b-specific mutation associated with a case of intrauterine fetal death, we examined the effects of the 1b-R25W mutation on total protein, trafficking and membrane current levels in HEK293 cells at physiological temperatures. By all measures the 1b-R25W mutation conferred diminished expression, and exerted a temperature-sensitive, dominant-negative effect over the WT hERG 1a protein with which it was co-expressed. Membrane currents were reduced by 60% with no apparent effect on voltage dependence or deactivation. The dominant-negative effects of R25W were demonstrated in iPSC-CMs, where 1b-R25W transfection diminished native IKr compared to controls. R25W also slowed AP repolarization, and increased AP triangulation and variability in iPSC-CMs, reflecting cellular manifestations of pro-arrhythmia. These data demonstrate that R25W is a dominant-negative mutation with significant pathophysiological consequences, and provide the first direct link between hERG 1b mutation and cardiomyocyte dysfunction.

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Pronounced Effects of HERG-Blockers E-4031 and Erythromycin on APD, Spatial APD Dispersion and Triangulation in Transgenic Long-QT Type 1 Rabbits

Cited by 16 publications

References 35 publications

Transgenic Rabbit Models in Proarrhythmia Research

Transgenic Rabbit Models in Proarrhythmia Research

Potassium currents in the heart: functional roles in repolarization, arrhythmia and therapeutics

Dominant negative consequences of a hERG 1b-specific mutation associated with intrauterine fetal death

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