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Updated: Jun 28, 2025
Ambulatory ECG Recording in Mice
Published on: May 27, 2010
An inherited life-threatening arrhythmia model established by screening randomly mutagenized mice
Yuta Okabe1, Nobuyuki Murakoshi1, Nagomi Kurebayashi2
1Department of Cardiology, Faculty of Medicine, University of Tsukuba, Tsukuba 305-8575, Japan.
Abstract:
Inherited arrhythmia syndromes (IASs) can cause life-threatening arrhythmias and are responsible for a significant proportion of sudden cardiac deaths (SCDs). Despite progress in the development of devices to prevent SCDs, the precise molecular mechanisms that induce detrimental arrhythmias remain to be fully investigated, and more effective therapies are desirable. In the present study, we screened a large-scale randomly mutagenized mouse library by electrocardiography to establish a disease model of IASs and consequently found one pedigree that exhibited spontaneous ventricular arrhythmias (VAs) followed by SCD within 1 y after birth. Genetic analysis successfully revealed a missense mutation (p.I4093V) of the ryanodine receptor 2 gene to be a cause of the arrhythmia. We found an age-related increase in arrhythmia frequency accompanied by cardiomegaly and decreased ventricular contractility in the Ryr2I4093V/+ mice. Ca2+ signaling analysis and a ryanodine binding assay indicated that the mutant ryanodine receptor 2 had a gain-of-function phenotype and enhanced Ca2+ sensitivity. Using this model, we detected the significant suppression of VA following flecainide or dantrolene treatment. Collectively, we established an inherited life-threatening arrhythmia mouse model from an electrocardiogram-based screen of randomly mutagenized mice. The present IAS model may prove feasible for use in investigating the mechanisms of SCD and assessing therapies.
Insights
Researchers developed a novel inherited arrhythmia syndrome mouse model to study life-threatening arrhythmias and sudden cardiac death. This model aids in investigating disease mechanisms and testing new therapies like flecainide and dantrolene.
Area of Science:
- Cardiovascular Genetics
- Molecular Cardiology
- Sudden Cardiac Death Research
Background:
- Inherited arrhythmia syndromes (IASs) are a significant cause of sudden cardiac death (SCD).
- Current understanding of IAS molecular mechanisms and effective therapies remains incomplete.
- Novel disease models are crucial for advancing IAS research.
Purpose of the Study:
- To establish a novel mouse model for inherited life-threatening arrhythmia syndromes.
- To investigate the molecular basis and progression of arrhythmias in the developed model.
- To evaluate potential therapeutic interventions for these conditions.
Main Methods:
- Large-scale electrocardiography screening of a randomly mutagenized mouse library.
- Genetic analysis to identify causative mutations, specifically in the ryanodine receptor 2 (Ryr2) gene.
- Phenotypic characterization of mutant mice, including arrhythmia assessment, cardiac function, and Ca2+ signaling analysis.
Main Results:
- A novel mouse model (Ryr2I4093V/+) exhibiting spontaneous ventricular arrhythmias and SCD was identified.
- The mutation (p.I4093V) in Ryr2 resulted in a gain-of-function phenotype with enhanced Ca2+ sensitivity.
- Age-dependent increases in arrhythmia frequency, cardiomegaly, and reduced ventricular contractility were observed.
- Flecainide and dantrolene treatments significantly suppressed ventricular arrhythmias in the model.
Conclusions:
- An effective inherited arrhythmia syndrome mouse model was successfully generated using electrocardiogram-based screening.
- This Ryr2I4093V/+ mouse model provides a valuable platform for studying SCD mechanisms.
- The model facilitates the assessment of novel therapeutic strategies for inherited arrhythmias.
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