Understanding Mitral Valve Disease
Professor Brendan M Corcoran MVB, DipPharm, PhD, MRCVS
Chair of Veterinary Cardiopulmonary Medicine
University of Edinburgh
Introduction:

Professor Brendan Corcoran has presented a report on the results of their
research project into MVD.

Members will be interested to note the extensive research being conducted on the
heart valve, both here and abroad, and that this research is being co-ordinated
and shared.

Lesley Jupp
CKCS Club Chairman

Understanding Mitral Valve Disease

Acquired mitral valve disease is the single most common heart disease of the dog
and is a major cause of illness and early death in many dogs. It is also a
disease that causes significant levels of distress to owners, in addition to the
financial burden of caring for their beloved pet.

The disease is known by several names including, chronic mitral valve disease,
degenerative mitral valve disease, mitral valve endocardiosis and myxomatous
mitral valve disease (MMVD). The latter term is the preferred scientific name as
it best describes what happens to diseased valves.

MMVD is so common that all dogs will have evidence of the disease if they live
long enough, but for many of these dogs their quality of life will not be
affected. This close association with age is interesting in that it may reflect
changes that normally would be expected to occur with age. What is most striking
about MMVD is that it occurs much earlier in life in certain breeds of dogs, and
it is in some of those breeds that it is most devastating. While all dogs,
including cross-breeds, may have evidence of the disease, it is the small
pedigree breeds and the cavalier King Charles spaniel in particular (CKCS) that
are most adversely affected. In some small breed dogs where the valve pathology
can be extensive resulting in a very loud murmur, there often are no adverse
consequences and these dogs can live into old age unaffected. An important
question in veterinary cardiology is why different breeds of dogs with the same
severity of valve pathology can have completely different disease progression
and outcome? Furthermore, adverse outcome (heart failure and death) is not just
restricted to pedigree breeds, but can occur with equal devastation in mixed
breed dogs. Lastly, there is a lot of interest in dog MMVD and its similarities
to an equivalent disease in humans, and the possibilities of better
understanding of the disease in both species by comparing the similarities and
contrasting the differences.

Since MMVD is clearly recognised to be a problem in the CKCS, clubs in the UK
and North America, and the Kennel Club of England and the American Kennel Club
have actively supported research at the University of Edinburgh Veterinary
School over recent years in an attempt to better understand the disease and
hopefully identify the cause, improve treatments and even identify a cure. It is
worth noting that by supporting MMVD research the CKCS breed societies benefit
not only the CKCS breed but all dogs, both pedigree and mixed, and indirectly
are helping our understanding of the same disease in humans. The veterinary
community know a lot about MMVD, how it presents and progresses, how to diagnose
the disease and have developed better treatments in the last few years. What is
less clearly understood is what damage occurs in the leaflet at the microscopic
and sub-microscopic (molecular level). Edinburgh vet school has been very active
the last 10 years in trying to elucidate the pathological mechanisms that set
the disease in motion, and other researchers worldwide are now also putting
effort into MMVD research. This is all good news because while medical research
is a slow process the more centres that are involved the quicker that process
becomes and the sooner are significant discoveries made.

At Edinburgh we have been researching a variety of features of MMVD. The mitral
valve separates the two chambers on the left side of the heart and when open
allows blood from the left atrium to enter the left ventricle, and when closed
allows the left ventricle to push blood out into the circulation. If the valve
becomes damaged, as occurs with MMVD, a proportion of the blood that should pass
around the body goes in the wrong direction back into the left atrium (referred
to as regurgitation) (Figure 1). This regurgitation generates the heart murmur
typical of MMVD and is the first abnormality noted by the veterinary surgeon. As
a mechanical device the mitral valve is a very important structure and when
viewed it has the appearance of a leather-like flap working by a simple hinge
mechanism. In fact, it is a much more complex structure than it appears. The
valve itself consists of four distinct layers, but also has important anchoring
points to the space between the two chambers and to the heart muscle (papillary
muscles). Combined together, all these elements are referred to as the mitral
valve complex. The layers include two outer cell layers (endothelium)
sandwiching a layer of dense fibrous tissue (fibrosa) and a layer of loose
connective tissue (spongiosa) (Figure 2). The valve contains a lot of collagen
and a lesser quantity of elastin, but together these proteins allow the valve to
flex and bend and also allow it to cope with the large pressures placed on in it
by the heart contracting. This layered arrangement is crucial to its proper
mechanical function and any damage to the valve can affect function or
precipitate changes that in time would irreparably damage the valve (typically
what occurs with MMVD).

From our work at Edinburgh we have shown that damage to the lining cell layer of
the valve occurs with MMVD and we suspect this is an important trigger event
that contributes to the start of valve change (Figure 3). This damage is likely
to be due to repeated trauma to the valve edges, and it is at the edge of the
leaflets that the most dramatic changes indeed occur. In association with the
damage to the endothelium, cells deep in the valve change their type and
function and begin to migrate towards the valve surface (Figure 4). Some of
these cells (valvular interstitial cells or VICs) develop close contacts with
the endothelial cells, some squeeze between the gaps caused by the damage, some
show evidence of apoptosis (the phenomenon of programmed cell death where cells
automatically self-destruct), and others even incorporate themselves into the
endothelium itself. We know that damage occurs to the endothelium in normal
valves and suspect that this becomes too extensive in the diseased valve for it
to cope. The valve attempts to repair the damage, but in the process and over
time is overwhelmed by the continual trauma to the valve edge. The VICs in their
attempt to heal the damage may actually be contributing to the damage that
occurs deeper in the valve.

VICs are the cells that produce the collagen and elastin and the cement that
holds it all together, glycosaminoglycans. Together all these constituents are
known as the valve matrix. In the healthy valve, the VICs sit quietly in a
collagen rich environment and it is thought they produce more matrix as needed
and constantly remodel the matrix, but apart from that remain reasonably
quiescent (Figure 5). When the valve is injured, the VICs become more active and
start to migrate towards the site of damage (see above), but by being activated
they probably cause damage to the matrix and fail in their main task of
maintaining matrix integrity. In time the normally tight collagen bundles start
to break apart and any new collagen formed is either of an abnormal type or
fails to organise (Figure 6). The valve now begins to loose its mechanical
strength, becomes distorted and starts to leak. Once this degenerative process
begins it appears to be unstoppable and the valve continues to change over time.
This whole process may take several years which would fit in with how the
disease is seen in affected dogs.

So the process of maintaining the integrity and structure of the valve is
ongoing and is believed to be part of a process of normal life-long remodelling.
In young dogs and during maturity into early adulthood this process is
maintained and successful, but as on entering middle age the reparative
processes appear to fail or possibly become overwhelmed. The production of
collagen, elastin and the other important matrix proteins is very complex and
not completely understood. It also depends on close interaction and inter-play
between a wide range of different proteins and all this is controlled by
cellular activity. It is the balanced interaction between all these elements
that is crucial for maintaining a healthy valve. Work at Edinburgh has shown
that this balanced interaction is not maintained and thereby contributes to
disease development. For example, production of collagen alone is not
sufficient, but it has to be organised into fibrils and bundles and has to
develop maturity. Using nuclear facilities in Darnesbury in the UK, Grenoble,
France and Trieste, Italy, we have shown that there is a failure of collagen
organisation in MMVD such that the collagen is not of the right type, fails to
bind tightly to form strong bundles, and is aligned in the wrong direction. All
this contributes to the mechanical failure of the valve, which in itself leaves
the valve prone to further damage (perpetuating the problem) and results in
valve leaking (Figure 7.).

To complicate the problem further, using a technique called Proteomics, we have
identified the loss of crucial proteins in diseases valves, some of which are
important in matrix production and organisation and others that are necessary
for normal VIC function. Together, all these findings suggest MMVD is a
dyscollagenesis problem that is abnormality of collagen production rather than a
loss of collagen.

From all the work carried out at Edinburgh we have a much clearer picture of
what is happening in the valves of dogs with MMVD, but there are still many
unanswered questions with this disease. The issue of why certain breeds are more
rapidly and more severely affected by MMVD is being addressed through the
European LUPA project which is attempting to identify genes that may be involved
in the disease. Complimentary to that work, in Edinburgh we are using similar
techniques to look at the inheritance of the disease in CKCS and possible gene
involvement. Other groups in the USA are looking at the type of tissue and
cellular changes we have been concentrating on in recent years, and all told a
large amount of high quality scientific research is being brought to bear on the
problem of MMVD in the dog. From our own work in Edinburgh, a favoured
hypothesis at present is that the normal damage that occurs to the valve during
its constant use eventually overwhelms the systems in place for self-repair.
This raises the possibility that what we are seeing is a normal aging process,
but what is of major concern is why this process should be accelerated in some
dogs and not other. There is much more work that needs to be done.


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Figure 1.
A colour Doppler echocardiographic image of blood regurgitating back through the
mitral valve of a dog with MMVD. The regurgitation is show by the large patch of
blue colour with the rainbow coloured core. This generates the murmur typical of
MMVD.





Figure 2.
Normal (upper) and abnormal (lower) dog mitral valves. Note how the valve
consists of layers, but in particular how the leaflet becomes markedly thickened
toward the free edge (right side of pictures).






Figure 3.
High powered electron microscopy image of a disease leaflet showing damage to
the endothelial lining. The lower part of the images shows where the cells have
been removed exposing the underlying valve tissue.





Figure 4.
A high powered electron microscopy image of the damaged valve showing a valvular
interstitial cell (ic) migrating from the extracellular matrix (ecm) and pushing
between two endothelial cells (e). The interstitial cell is very unhealthy and
is in the process of dying.





Figure 5.
High powered electron microscopy image of the normal appearance of the centre of
the dog mitral valve. In the centre is a valvular interstitial cell and
surrounding it are packed bundles of well organised collagen.





Figure 6.
An electon microscopy image showing poorly organised and thread-like collagen in
an affected dog mitral valve.





Figure 7.
A nuclear diffraction image, showing loss of organised collagen close to the
valve edge (blue), contrasting with relatively normal collagen away from the
valve edge (green/orange/red).





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© Prof Corcoran & The CKCS Club