Echocardiographic analysis of a murine model with a mutation in the Nav1.5 channel gene Scn5a

Andaleeb, Sosan (2021). Echocardiographic analysis of a murine model with a mutation in the Nav1.5 channel gene Scn5a. University of Birmingham. M.Sc.

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Abstract

Cardiomyopathy is defined as a disorder of heart muscle in terms of structure, function or both. It can be defined as dilated, hypertrophic, arrhythmogenic, restrictive or infiltrative all of which contribute significantly to cardiovascular disease burden. The difference in their presentation, prognosis and treatment is dictated by their underlying pathophysiology and changes on a cellular level which manifests itself on cardiovascular imaging using various modalities. Echocardiography is a very useful and convenient tool for heart imaging. Linking cellular changes to phenotype in real time, echocardiographic imaging is a great clinical need which can potentially unlock the understanding and treatment of complex disease processes. Mutations in the cardiac sodium channel Nav1.5 can lead to long QT syndrome, familial AF, Brugada syndrome or cardiomyopathy. In our experiments, a new murine knock-in model M1875T+/- SCN5A was investigated. This causes a gain of function defect in the Nav1.5 channel leading to altered ion transport across the myocyte membrane. This work is primarily based on the echocardiographic assessment of gross cardiac structure and function of this model. This work also describes methods of histological analysis to be applied in mutant (M1875T+/-) mice. The Visualsonics Vevo 2100 echo system was used to perform echocardiography in 79 mice from both the SV129 and FVB genetic strain background variants. TThe gross differences in wall thickness and chamber dimensions were analysed for the complete cohort. This did not show any difference between young adults of the two groups. However, mature mice (≥25 up to 40 weeks) with the mutation showed significantly larger LV dimensions and volumes during systole and diatole when compared to the wild-type (M1875T+/+) littermates. Analysis of the left atrium and right ventricle revealed no significant differences between the two groups. Some phenotypic changes of the heart are known to manifest with time and therefore the M1875T+/- gene mutation may be associated with the development of cardiomyopathy in older mice. This makes a strong case to further study the effect of this gene mutation in a larger and older sample population.

Type of Work:

Thesis (Masters by Research > M.Sc.)

Award Type:

Masters by Research > M.Sc.

Supervisor(s):