Canine myxomatous mitral valve disease (MMVD)

14 January 2025

Professor Melanie Hezzell of the University of Bristol received BSAVA PetSavers funding and that of the Veterinary Cardiovascular Society to undertake a longitudinal study of canine myxomatous mitral valve disease entitled Do measurements of circulating fibrosis markers change with disease progression in canine myxomatous mitral valve disease?

Myxomatous mitral valve disease (MMVD) is the most common heart disease of dogs. It primarily affects smaller breeds, especially the Cavalier King Charles Spaniel (CKCS), in which it is almost ubiquitous. Nevertheless, the phenotype varies widely; some dogs develop MMVD at a young age, experience rapidly progressive disease and die from congestive heart failure, while other dogs develop the disease at a much older age and experience very slow progression. Less than half of dogs diagnosed with MMVD will die as a direct result of their disease; however, the reasons for this wide variation in phenotype remain poorly understood.

Using a longitudinal study of MMVD to provide new insights into the disease

With support from the Bristol Veterinary School research nurse Jade Ward, and my postgraduate research students (Marco Mazzarella, Chia-Hsuan Chang, Metaxia Tsakiroglou, Wasutorn Yangwanitset and Brooke Bennett), I have established a longitudinal study of canine MMVD, in which enrolled dogs undergo cardiac evaluation every 6 months. To facilitate collaborative research, the study design is very similar to Professor Boswood’s Mitral Valve Clinic at the Royal Veterinary College. Recruitment commenced in September 2019 and, to date, 140 dogs of a variety of breeds have been enrolled. This longitudinal study provides a supply of data and surplus clinical samples (those remaining once diagnostic testing is complete) that can be used for a wide array of projects that support undergraduate and postgraduate student research. An example of such a study is described below.

How do changes in the myocardial extracellular matrix contribute to cardiac remodelling?

The mitral valve regurgitation that occurs in MMVD may trigger the development of compensatory left atrial and left ventricular dilation (eccentric hypertrophy). This results in mitral valve annular dilation, exacerbating regurgitation and thereby setting up a vicious cycle of ongoing remodelling. In human patients, differences in the left ventricular response to mitral regurgitation influence disease progression, and left ventricular function can deteriorate even when mitral regurgitation is mild, i.e. progression is not solely determined by the severity of valvular pathology. In canine MMVD, we know that the development of cardiomegaly predicts the onset of congestive heart failure and reduced survival, but eccentric hypertrophy is not an inevitable consequence of mitral regurgitation. The remodelling response is, in fact, variable, with breed-specific differences, particularly in CKCS. It is possible, therefore, that these differences in the remodelling response play a part in determining the disease phenotype.

Changes to the components of the myocardial extracellular matrix are important in the development of eccentric hypertrophy. The extracellular matrix contains a metabolically active collagen matrix that responds dynamically to changes in cardiac load via increases in the rate of turnover of collagen fibrils. The balance of collagen fibril synthesis and breakdown is important in determining overall myocardial structure and function.

In an experimental canine model of acute mitral regurgitation, eccentric hypertrophy is associated with reduced left ventricular collagen content; the resultant decline in extracellular matrix tensile strength allows the heart to dilate. However, cardiac interstitial and perivascular fibrosis are common features of advanced MMVD in dogs; as fibrosis develops, collagen fibre synthesis predominates over collagen fibre breakdown. Both collagen breakdown and fibrosis are therefore important pathophysiological mechanisms in the remodelling seen in canine MMVD.

Although myocardial fibrosis is known to be present in the latter stages of MMVD, its study in earlier disease stages has proved challenging, due to a lack of suitable, non-invasive methods for its assessment. Our current knowledge therefore relies on post-mortem studies, which also do not allow changes in myocardial collagen content over time to be assessed.

How can we use circulating biomarkers of collagen turnover to help us better understand myocardial remodelling?

Type I and III collagen fibres predominate in the myocardial extracellular matrix, with approximately 75–80% type I and 15–20% type III. The amino-terminal peptide of procollagen type III (PIIINP) is a marker of collagen type III turnover, rather than of synthesis alone. Although the majority of PIIINP is released during collagen synthesis, it is incompletely cleaved from the procollagen precursor of type III collagen and the remaining PIIINP is released during degradation of the mature collagen fibril. In human patients, serum PIIINP is used as a biomarker of myocardial fibrosis, as it is positively correlated with myocardial collagen content. During my PhD, we found that PIIINP is also positively associated with fibrosis in dogs with MMVD. However, in the same studies, PIINP was also negatively associated with left ventricular dimensions in this disease, which might reflect a decrease in collagen turnover associated with the development of ventricular dilation, as shown in the experiment model described above. The apparently complex relationship between the development of fibrosis and collagen breakdown associated with the development of eccentric hypertrophy complicates the interpretation of serum PIIINP measurements in canine MMVD.

However, the assessment of type I collagen metabolism might be more straightforward, as separate markers of type I collagen synthesis (amino-terminal pro-peptide of collagen type I [PINP] and carboxy-terminal pro-peptide of collagen type I [PICP]) and degradation (carboxy-terminal telopeptide of collagen type I [ICTP] and hydroxyproline) can be measured. The ratio of PICP to ICTP is used to reflect the balance between collagen type I synthesis and breakdown. Measurements of PINP, PICP, ICP and hydroxyproline have not previously been reported in canine MMVD. However, as type I collagen predominates in the myocardium and distinct biomarkers are available for the assessment of type I collagen synthesis and degradation, it is reasonable to assume that measurement of these markers will allow more nuanced interpretation of the balance of collagen synthesis and degradation in MMVD, compared with measurement of serum PIIINP. This is important as it appears that fibrosis (i.e., increased synthesis) and dilation (i.e., increased degradation) develop simultaneously in MMVD.

What progress have we made so far?

In the present study, Metaxia Tsakiroglou will measure PINP, PICP, ICP, PIIINP and hydroxyproline in 40 dogs with MMVD at three timepoints: baseline, 12 months and 24 months. Sample collection is complete, with surplus serum being stored at -80°C for batched analysis in the coming months. In the future we hope that information gained from this project will enable us to both more fully evaluate existing therapies (e.g. those that are hypothesized to reduce fibrosis) and to identify new therapeutic targets for MMVD.

About the author

Melanie Hezzell graduated from the University of Cambridge in 1997. She worked in mixed and small animal practices in the UK, Australia and New Zealand for 10 years, during which time she gained the RCVS Certificates in Veterinary Diagnostic Imaging and Veterinary Cardiology and developed a keen interest in the management of heart disease in primary-care practice. She then undertook a rotating small animal internship at the Royal Veterinary College, followed by a PhD on the epidemiology of mitral valve disease at the same institution. Following a residency in veterinary cardiology at the University of Pennsylvania, she joined the University of Bristol where she is currently an Associate Professor in Veterinary Cardiology. She is a previous member of both the BSAVA Metropolitan and South-West Regional committees and is a current member of the BSAVA Scientific Committee. She was interviewed in the Meet the Researcher series in the June 2020 issue of BSAVA Companion.

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