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Abstract
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. LINKED ARTICLES: This article is part of a themed issue on Preclinical Models for Cardiovascular disease research (BJP 75th Anniversary). To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.5/issuetoc.
Highlights
All available transgenic Long QT interval in surface ECG (QT) syndrome (LQTS) rabbit models have been engineered by cardio-selective over-expression of dominant negative mutated human genes encoding for voltage-gated K+ channels alpha subunit to IKs-conducting potassium channel (KCNQ1)/ KvLQT1 (KvLQT1-Y315S, LQT1), KCNH2/HERG (HERG-G628S, long QT type 2 (LQT2)) or beta subunit to IKs-conducting potassium channel (KCNE1)/minK (KCNE1-G52R) driven by beta-myosin heavy chain promoters (Brunner et al, 2008; Major et al, 2016) (Table 1)
In transgenic LQT2 rabbit models, ventricular arrhythmia and sudden cardiac death often occur in stressful situations such as mating or after anaesthesia (Brunner et al, 2008; Odening et al, 2012) and were pronounced in situations of altered sex hormone levels during the postpartum phase and with chronic estradiol treatment (Brunner et al, 2008; Odening et al, 2012), suggesting the existence of similar arrhythmia-triggering mechanisms as in human LQTS patients (Figure 2c)
With further modification and improvement of this technique, the insertion of targeted point mutations will be feasible, allowing the generation of transgenic rabbit models for monogenic cardiac diseases that mimic the human diseases phenotypically and mimic the underlying genetic heterozygote structure
Summary
All available transgenic LQTS rabbit models have been engineered by cardio-selective over-expression of dominant negative mutated human genes encoding for voltage-gated K+ channels KCNQ1/ KvLQT1 (KvLQT1-Y315S, LQT1), KCNH2/HERG (HERG-G628S, LQT2) or KCNE1/minK (KCNE1-G52R) driven by beta-myosin heavy chain promoters (Brunner et al, 2008; Major et al, 2016) (Table 1). In LQT2 rabbit hearts, an increased spatial dispersion of action potential duration was observed (Brunner et al, 2008; Odening et al, 2013), leading to increased VT/VF inducibility and even spontaneous polymorphic VT and sudden cardiac death (Brunner et al, 2008; Odening et al, 2012), representing the first transgenic animal models mimicking the complete electrical phenotype of LQT2 (Table 1).
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