First 10 Month Report; 15th November 2004.

Mitral Valve Disease Project

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

1. Introduction
The aim of this study is to characterise the cellular changes that occur in the mitral valve of dogs with myxomatous degeneration. The hypothesis is that altered cell function changes the way in which the structural components of the valve (mainly collagen) are produced, broken down in the valve, are organised and metabolised, and so affect the structural integrity of the valve resulting in a murmur.

2. Work-to-date
The initial period of any PhD research involves the PhD student identifying what information is already available in the published literature (both human and veterinary) and identifying potential research of promise. The student should also consolidate any work in hand or close to completion and explore possible novel avenues for future research.

2.1. Tissue Collection
So far the project has developed a system for tissue collection and has obtained promise of assistance from the main Cardiology Referral practices in the UK, has developed potential collaborative links with researchers in Scandinavia and the USA and has identified a potentially valuable sources of valve material from colleagues in Sweden. Valve material has been collected from 20 affected dogs and has been processed for a variety of purpose.

2.2. Cell Characterisation Studies
Affected valves have been assessed for the presence of a variety of markers that allow us to identify cell types. These markers included vimentin, desmin, smooth muscle actin and myosin. Additionally, work has begun in determining if there is increased cell enzymatic activity (which could result in valve destruction) and data is now available for the expression of an enzyme known as MMP-2.

2.3. Ultrastructural Morphology
We are also interested in reviewing the pathology of mitral valve disease and have been evaluating the structural changes to the valve using routine and special stains for light microscopy. This allows us to describe in greater detail than previous what changes are occurring in the valve. In association with this work we are investigating changes in cell numbers in disease valve areas, and had a vacation scholarship student (funded by the Veterinary School) for 8 weeks in the summer to assist with this part of the project.

2.4. Protein Expression
Some preliminary work has been carried out looking at the expression of immunoglobulins in affected dogs and has provided interesting, although puzzling initial findings. This work is using a technique known as Western Blotting and further work will be carried out in due course.

3. Further Developments
In order to explore new avenue of research and formulate new ideas as to what way be happening in disease valves, we have been in discussion with molecular geneticists on applying some new techniques. To that end we are actively seeking additional financial support to cover the consumable costs of such work.

We have recently appointed an additional self-funding PhD study to supplement the current work, and now have collaborative involvement with a colleague biochemist, which has given us access to state-of-the art tissue imaging facilities in Darnesbury (near Warrington) and Trieste in Northern Italy. These techniques will allow us to look more closely at structural elements (collagen and elastin) in the valves and determine the nature of the structural alteration that is present in diseased animals. This is a totally novel use of this technique in Valve research either in human and animals.

4. Communications and Publications
We have presented work to date at a prestigious international conference on mitral valve disease in Paris (29th - 31st October 2004). We have submitted an abstract for presentation at the British Small Animal Veterinary Association meeting in April 2005. And details of the work will also be presented at the Veterinary Cardiovascular Society Winter meeting in Longhborough.

A second paper describing the changes in cell type seen with mitral valve disease has just been accepted for publication in the American Journal of Veterinary Research (the most widely read veterinary research journal in the world).

All these presentations and published articles have fully acknowledged the contribution of the CKCS Club and the Kennel Club and serve to heighten awareness of this disease and the effects that are being made to find out the cause of mitral valve disease.

5. Future Plans
The future plan is to consolidate the work done so far. This mainly involves completion of work using as many tissue samples as possible. In tandem with this will be the exploration of new avenue of research so we can get as complete a picture as possible of what is happening in diseased valves.

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