INITIAL REPORT; January 2007.

RESEARCH PROJECT ON CANINE MITRAL VALVE DISEASE
EDINBURGH UNIVERSITY

Sponsored by The Cavalier King Charles Spaniel Club and the Kennel Club Charitable Trust.

Introduction:

Brendan Corcoran has presented an initial report on the results of their three-year project. This report follows.

Dr Corcoran said that their research has clarified a whole range of changes that occur in diseased valves and they now know a lot more about what is going on in the mitral valve than previously. But they still do not know why the disease occurs.

He and his colleagues will spend the next few months analysing the data collected and then decide the best way forward. He considers that the major conundrum that still exists is why the CKCS is more prone to the disease at an earlier stage in life than other breeds. He mentions that nearly all the geriatric dogs from which the valve samples were collected, showed evidence of the disease. They had only limited success in obtaining heart valves from Cavaliers. The majority supplied came from cross breeds and some pedigree dogs including Beagles which are also prone to MVD.

When the data has been thoroughly considered, Dr Corcoran has promised to provide a more detailed overview of the research in a form that has less specific scientific jargon.

Lesley Jupp
CKCS Club Chairman

Canine Mitral Disease Project Report

Introduction

This study is financed by the Cavalier King Charles Spaniel Club and the Kennel Club Charitable Trust. The main use of funds is in the support of a PhD student Richard Han. Mr Han is due to finish his course of study end of January 2007, and expects to submit his thesis in Autumn 2007.

The study's broad aims are to better understand the pathological changes that occur in the mitral valves of dogs with myxomatous degeneration (endocadiosis). The project has utilised a variety of techniques to try and elucidate the changes that occur in diseased valves, and some of the results to date have been presented at scientific meetings. Additionally, complimentary studies have been organised involving other students and staff at the R(D)SVS and utilising the resources that have become available from the main study.

Project work

The work to date can be divided into the following categories. For some of these studies we have recruited other students and staff members as the project has evolved, and Richard Hans role has been to coordinate tissue sourcing and provide technical support and guidance.
  1. Immunohistochemical localisation and identification of cell types in affected valves.
    • Immunophenotyping of the valve stromal cells using antibodies against vimentin, desmin, smooth muscle actin, smooth muscle myosin; work completed reported at ECVIM congress, Amsterdam 2006 and to be shortly submitted for publication.
    • Identification of role of macrophages and mast cells in disease pathology; initial work completed and reported at the ECVIM congress, Amsterdam 2006 and prepared for publication.
    • Identification of the expression of CD34 in valve cells; work shortly to be completed.
    • Identification of stem cells/mast cells in valve leaflets using CD117; laboratory work in progress and shortly to be completed.
    • Immunohistochernical localisation of neural elements in valves; work close to completion and will be submitted for publication early 2007.
  2. Quantification of cellular changes in diseased valves.
    • Use of image analysis techniques to map cellular density and distribution in disease valves; work completed and presented at the IA.MC congress, Liverpool 2006, shortly to be prepared for publication.
  3. Identification of alteration in connective tissue elements and the factors that control these elements.
    • Histological staining for the expression of connective tissue structures in diseased valves; work completed and shortly to be partly submitted for publication. More detailed publication in the next 6 months.
    • Immunohistochemical localisation of metalloproteinases in affected valves; work completed and will be prepared for publication in the next 6 months.
    • Immunohistochemical localisation of fibrillin; data to be analysed and prepared for publication in the next 6 months.
    • Mapping of connective tissue using X-ray and Nuclear Diffraction techniques; a complimentary project with data reported at the Biophysical Society Congress, Salt Lake City 2006, and submitted for publication.
    • Electron microscopic evaluation of the connective tissue derangement in affected valves; work in progress and likely to be completed in the next 6 months with submission for publication shortly afterwards.
  4. Evaluation of alteration in endothelial cell morphology and function.
    • Light and Electron microscopic description of changes in the endothelial and immediate sub-endothelial zone: work partially complete but requires inclusion of further cases, likely to be completed in next 9 months.
    • Immunohistochemical localisation of Von Willebrand's Factor, a marker for endothelial cells in disease valves; work to start in the January 2007 with completion expected by March, data to be reported in conjunction with microscopic data.
  5. Differential protein and gene expression in diseased valves.
    • Analysis of protein expression using 2-D gel electrophoresis and mass spectrometry; work close to completion and due to be reported at BSAVA Congress, Birmingham 2007. Publication will depend on how much data can be extracted from this study, but is likely to require significant funding in the future to be completed satisfactorily. In the meantime the study provides useful pilot data.
    • Differential expression of genes of interest (partially based on the immunohistochemica data) using PCR; work about to start and data available early in 2007. We have explored the option of using subtractive hybridization to identify differential gene expression but decided this would require an additional project.
Conclusion

This project has tackled a variety of questions relevant to canine mitral valve disease in an attempt to gives us a better overview of what is happening in diseased valves. We have identified fundamental changes in the valve that were not previously known and we have also identified the nature of change that occurs with disease progression. We have begun to look at the more fundamental changes that occur at the gene expression level and the consequence of changes in gene expression, namely what protein are expressed or absent.

Like all research, this project has answered some questions, but has also raised new questions that will need investigation. Historically, we have known very little about the mitral valve disease in either dogs or humans and by its very nature this type of research slowly fills in the gaps in our knowledge hopefully eventually leading to the answer to the question of why does mitral valve disease occur.

 Dr Brendan Corcoran
Principal Investigator
January 2007


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