Electro-mechanical (dys-)function in long QT syndrome type 1

Ziupa, David; Menza, Marius; Koppermann, Susanne; Moss, Robin; Beck, Julia; Franke, Gerlind; Feliz, Stefanie Perez; Brunner, Michael; Mayer, S.; Bugger, Heiko; Koren, Gideon; Zehender, Manfred; Jung, Bernd; Seemann, Gunnar; Foell, Daniela; Bode, Christoph; Odening, Katja E.

doi:10.1016/j.ijcard.2018.07.050

Cited by 6 publications

(11 citation statements)

References 34 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%

“…The reason for this was that genetic manipulation has for a long time nearly exclusively been feasible in mice and not in other larger mammals such as rabbits. Transgenic models based on mutations in human potassium channel genes or knock-out/knock-in models of mouse potassium channel genes could only partially mimic the characteristics of human patients with impaired repolarization reserve [reviewed in detail in (Nerbonne et al, 2001); (Lang et al, 2016); (Ziupa et al, 2019)], while genetically modified mouse models with mutations in the sodium channel gene (SCN5A; LQT3) more closely mimic the human long QT disease phenotype with AP duration (APD) and QT prolongation as well as spontaneous life-threatening ventricular arrhythmia (Nuyens et al, 2001;Fabritz et al, 2003), since SCN5A drives the majority of depolarizing Na + currents in both human and murine cardiomyocytes (Derangeon et al, 2012).…”

Section: Genetically Modified Mouse Models With Reduced Repolarizatiomentioning

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: Genetically Modified Mouse Models With Reduced Repolarizatiomentioning

confidence: 99%

Transgenic Rabbit Models in Proarrhythmia Research

et al. 2020

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“…These studies demonstrated a regionally heterogeneously reduced diastolic function and prolonged contraction duration, leading to an increased mechanical dispersion in transgenic LQT2 rabbits (Odening et al, 2013) (Table 1). In addition, a spatial correlation between the extent of electrical dysfunction (prolongation of action potential duration) and impaired diastolic function (Odening et al, 2013;Ziupa et al, 2019), and a correlation between the extent of mechanical dysfunction/heterogeneity and arrhythmic risk was revealed (Lang et al, 2016). Moreover, studies in LQT2 rabbits could demonstrate sex differences and sex hormone effects not only on electrical function but also on mechanical function with longer contraction duration in female and estradiol-treated animals.…”

Section: Transgenic Lqts Rabbits Provide Insights Into Electro-mechanical Dysfunction In Lqtsmentioning

confidence: 98%

Transgenic rabbit models for cardiac disease research

Hornyik

Rieder

Castiglione

et al. 2021

British J Pharmacology

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To study the pathophysiology of human cardiac diseases and to develop novel treatment strategies, complex interactions of cardiac cells on cellular, tissue and on level of the whole heart need to be considered. As in vitro cell-based models do not depict the complexity of the human heart, animal models are used to obtain insights that can be translated to human diseases. Mice are the most commonly used animals in cardiac research. However, differences in electrophysiological and mechanical cardiac function and a different composition of electrical and contractile proteins limit the transferability of the knowledge gained. Moreover, the small heart size and fast heart rate are major disadvantages. In contrast to rodents, electrophysiological, mechanical and structural cardiac characteristics of rabbits resemble the human heart more closely, making them particularly suitable as an animal model for cardiac disease research. In this review, various methodological approaches for the generation of transgenic rabbits for cardiac disease research, such as pronuclear microinjection, the sleeping beauty transposon system and novel genome-editing methods (ZFN and CRISPR/Cas9)will be discussed. In the second section, we will introduce the different currently available transgenic rabbit models for monogenic cardiac diseases (such as long QT syndrome, short-QT syndrome and hypertrophic cardiomyopathy) in detail, especially in regard to their utility to increase the understanding of pathophysiological disease mechanisms and novel treatment options.

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“…However very few studies exist on this electro-mechanical correlation. Zuya and colleagues performed magnetic resonance imaging (MRI) on rabbit models of LQTS 1 and noticed that an increased QTc interval was associated with increased systolic contraction and decreased diastolic relaxation [27]. In the accompanying editorial, Haugaa and Stokke lamented the lack of focus on electro-mechanics in electrophysiology [28].…”

Section: Long Qt Syndrome (Lqts)mentioning

confidence: 99%