Project Report; 27th February 2006.

Mitral Valve Endocardiosis Project Report.

Investigators; Dr Brendan Corcoran & Mr Richard Han
Hospital for Small Animals
Easter Bush Veterinary Centre
University of Edinburgh
EH25 9RG

1. Introduction:

This project is a co-funded PhD studentship supported by the Cavalier King Charles Spaniel Club and the Kennel Club Charitable Trust. The project is investigating the ultrastructural and morphological changes in the mitral valve of dogs with myxomatous degeneration (endocardiosis). This disease is the single most common cardiac disease of the dog and is a particular problem in the CKCS breed. The studentship has been running since February 2004 and is due to be completed in January 2007. Mr Richard Han, a graduate of the University of Capetown, is the PhD student and the project is a collaborative venture with the Department of Anatomy, University College Galway

2. Progress to date:

The project is following several strands of investigation of this disease using a variety of techniques. In tandem with the work of the PhD student, additional avenues of research are being explored and developed. To date, the project has also involved three veterinary undergraduate students, an additional PhD student and a clinical lecturer.

Materials: The availability of valve material for this project is dependent on clients willing to donate tissue from their pets, and can be unpredictable. However, the project has been very successful in obtaining material from clients of the Hospital for Small Animals at the University of Edinburgh and from colleagues in practice. Continued collection of material will be necessary to achieve sufficient sample numbers in order to complete the different projects. The collection of age-matched normal control samples is a particular problem of this study, but the project is on target to obtain enough normal valve material to allow meaningful conclusions to be made.

Pathology: overall assessment of the structural changes in the valves are being carried out using standard pathological techniques. This enables evaluation of the localisation of lesions along the length of the valve, the types of changes that occur at different sites, and the degree of cellularity and change in the structural matrix at these different sites. This work will greatly improve our understanding of the changes that occur in the valve and we believe will clarify contentious issues regarding what actually happens to the valve during disease.

Immunohistocytochemistry: staining of cells using this technique allows changes in cell type to be identified. Coupled with standard staining techniques, the profile of the cellularity of the valve can be mapped. This tells us what cells are present and how their function might be altered.

Electron Microscopy: The structural changes in the valve are being identified using this powerful imaging technique. This includes identification of changes in cell type and the valve matrix and is complimentary to the other techniques being used. The technique is particularly sensitive in identifying changes affecting the surface of the valve.

Proteomics: the techniques summarised above are all evaluating the structure of the valve. To date, the study has identified distinct changes in the cell profile of the valves, but the next stage will be to try identifying what are the consequences of these changes. Proteomics is the science of identifying the proteins present in (or absent from) a tissue and these proteins are a function of what genes are being expressed. Gene expression is related to the cell types present in the tissue. This work is being conducted using facilities at the Moredun Research Institute. To date we have run 22 high quality gels. The differences between normal and affected dogs have been analysed and approximately 12 differences in protein expression have been selected for further analysis. This will involve identification of these proteins by comparing to published data bases. From this we hope to identify potential genes of interest that might be linked to the disease and would then proceed to start analysing the expression of' these genes. This work will only be partly undertaken in the present study, because of constraints of time and funding, but would provide important information for applications for further grant funding.

3. Conclusion:

The project is running well with a variety of areas of investigation and with development of' ideas for other areas of study. Overall the project is providing us with valuable information as to what is actually happening in the valves of affected dogs. More work needs to be done to complete the various strands of investigation, but so far we can be confident that there are recognisable changes in the cell types that are crucial for maintaining healthy valves, and preliminary data suggests this is resulting in altered protein expression by the valve cells. The next stage will to be to try and work out exactly what these changes are and how they could explain the pathological changes with this disease.

4. Related projects:

Two projects have developed for the original work and Richard Han is providing assistance to both these projects.

The structural change in the valve is poorly understood, particularly the spatial arrangement of the matrix, which gives the valves their structural rigidity and which is disorganised in disease. We are using a powerful x-ray technique to investigate this problem, using the Syncotron facility at the Centre for the Central laboratories of the Research Councils (CCLRC, Daresbury, Liverpool), and similar facilities at Trieste in Italy and Grenoble in France (EU supported).

Innervation (nerve supply) of the mitral valve is poorly understood, and in fact most clinical cardiologists would be unaware that the mitral valve has a nerve supply. We know that a derangement of nerve supply has an adverse effect on valve function and we suspect on valve cells. This study is using immunohistochemistry to map the innervation of the valve in normal and diseased dogs and is supported by funds from the University of Edinburgh Veterinary School.

Dr Brendan Corcoran (Project Organiser)   27th February 2006

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