Transgenic rabbit models to investigate the cardiac ion channel disease long QT syndrome

Lang, Corinna N.; Koren, Gideon; Odening, Katja E.

doi:10.1016/j.pbiomolbio.2016.05.004

Cited by 23 publications

(15 citation statements)

References 130 publications

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“…Both drug-induced and genetically modified animal models with impaired repolarization reserve have been generated in various species (such as dogs, mice, and rabbits) and utilized to investigate drug-induced proarrhythmia and its underlying mechanisms [reviewed in (Salama and London, 2007;Lang et al, 2016)]. In addition, animal models with cardiac diseases -e.g.…”

Section: In Vivo Proarrhythmia Models With Reduced Repolarization Resmentioning

confidence: 99%

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: In Vivo Proarrhythmia Models With Reduced Repolarization Resmentioning

confidence: 99%

Transgenic Rabbit Models in Proarrhythmia Research

et al. 2020

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“…82 The greater similarity between rabbits and humans in this respect is one major reason that the rabbit has become an important model for understanding the mechanisms and clinical manifestations of both drug-induced and congenital LQT syndrome. 89–92 Although a full treatment of clinical and preclinical implications of different LQT models is beyond the scope of this review, we direct the reader to other excellent recent reviews. 78,91 …”

Section: Species Differences In Cardiomyocyte Electrophysiologymentioning

confidence: 99%

“…89–92 Although a full treatment of clinical and preclinical implications of different LQT models is beyond the scope of this review, we direct the reader to other excellent recent reviews. 78,91 …”

Section: Species Differences In Cardiomyocyte Electrophysiologymentioning

confidence: 99%

Species-Dependent Mechanisms of Cardiac Arrhythmia: A Cellular Focus

Edwards

Louch

2017

Clin Med Insights Cardiol

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Although ventricular arrhythmia remains a leading cause of morbidity and mortality, available antiarrhythmic drugs have limited efficacy. Disappointing progress in the development of novel, clinically relevant antiarrhythmic agents may partly be attributed to discrepancies between humans and animal models used in preclinical testing. However, such differences are at present difficult to predict, requiring improved understanding of arrhythmia mechanisms across species. To this end, we presently review interspecies similarities and differences in fundamental cardiomyocyte electrophysiology and current understanding of the mechanisms underlying the generation of afterdepolarizations and reentry. We specifically highlight patent shortcomings in small rodents to reproduce cellular and tissue-level arrhythmia substrate believed to be critical in human ventricle. Despite greater ease of translation from larger animal models, discrepancies remain and interpretation can be complicated by incomplete knowledge of human ventricular physiology due to low availability of explanted tissue. We therefore point to the benefits of mathematical modeling as a translational bridge to understanding and treating human arrhythmia.

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“…Ageing increased QT intervals and susceptibility to E‐4031 or terfenadine‐induced QT prolongation in conscious female guinea pigs, though not to cisapride‐induced QT prolongation in isolated guinea pig hearts . Transgenic LQT2 and LQT3 rabbit models have helped clarify roles of spatial and temporal dispersions of repolarisation as arrhythmogenic substrates and the effects of potential anti‐arrhythmic agents, such as free polyunsaturated fatty acids, in preventing TdP …”

Section: Experimental Studies Of Arrhythmic Phenotypesmentioning

confidence: 99%

Ion channels, long QT syndrome and arrhythmogenesis in ageing

Jeevaratnam

Chadda

Salvage

et al. 2017

Clin Exp Pharma Physio

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SummaryAgeing is associated with increased prevalences of both atrial and ventricular arrhythmias, reflecting disruption of the normal sequence of ion channel activation and inactivation generating the propagated cardiac action potential. Experimental models with specific ion channel genetic modifications have helped clarify the interacting functional roles of ion channels and how their dysregulation contributes to arrhythmogenic processes at the cellular and systems level. They have also investigated interactions between these ion channel abnormalities and age‐related processes in producing arrhythmic tendency. Previous reviews have explored the relationships between age and loss‐of‐function Nav1.5 mutations in producing arrhythmogenicity. The present review now explores complementary relationships arising from gain‐of‐function Nav1.5 mutations associated with long QT3 (LQTS3). LQTS3 patients show increased risks of life‐threatening ventricular arrhythmias, particularly after 40 years of age, consistent with such interactions between the ion channel abnormailities and ageing. In turn clinical evidence suggests that ageing is accompanied by structural, particularly fibrotic, as well as electrophysiological change. These abnormalities may result from biochemical changes producing low‐grade inflammation resulting from increased production of reactive oxygen species and superoxide. Experimental studies offer further insights into the underlying mechanisms underlying these phenotypes. Thus, studies in genetically modified murine models for LQTS implicated action potential recovery processes in arrhythmogenesis resulting from functional ion channel abnormalities. In addition, ageing wild type (WT) murine models demonstrated both ion channel alterations and fibrotic changes with ageing. Murine models then suggested evidence for interactions between ageing and ion channel mutations and provided insights into potential arrhythmic mechanisms inviting future exploration.

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Transgenic rabbit models to investigate the cardiac ion channel disease long QT syndrome

Cited by 23 publications

References 130 publications

Transgenic Rabbit Models in Proarrhythmia Research

Transgenic Rabbit Models in Proarrhythmia Research

Species-Dependent Mechanisms of Cardiac Arrhythmia: A Cellular Focus

Ion channels, long QT syndrome and arrhythmogenesis in ageing

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