With their propensity to lead to sudden death, cardiac arrhythmias are a major clinical problem. They also represent an
exciting
medical challenge which needs gene-to-bedside studies to unravel the underlying arrhythmogenic mechanisms. In this approach, animal models play a central role. This seminar presents an overview of current animal models of arrhythmias with a focus on genetically-modified mouse models which are promising tools for understanding the pathophysiological sequence of genetically-inherited arrhythmias (channelopathies). Although rare, cardiac channelopathies have broadened our understanding of proarhythmic mechanisms, largely thanks to animal models, as demonstrated with SCN5A-related arrhythmias. Mutations in this gene, which encodes the voltage-gated Na
+ channel
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1.5, underlie cardiac channelopathies such as the type 3 long QT syndrome, cardiac conduction diseases, Brugada syndrome, sick sinus syndrome, atrial standstill
and
numerous overlap syndromes. Although patch-clamp studies in heterologous expression systems have provided key information to understand the genotype-phenotype relationships of these diseases, they could not clarify how mutations can be responsible for such a large spectrum of diseases, for the late age of onset or the progressiveness of some of them
and
for the overlapping syndromes. Mouse models turned out to be powerful tools to elucidate the pathophysiological mechanisms of gene-related arrhythmic diseases
and
offer the opportunity to investigate the cellular consequences of gene mutations such as the remodelling of other gene expression that might participate to the overall phenotype.
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