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Building up a knowledge base

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01 September 2010, at 12:00am

Veterinary Practice talks to Adrian Boswood at the Royal Veterinary College about his work on mitral valve disease and other heart problems.

Listening to the dog’s chest, the whistling murmur of early mitral valve disease is clearly apparent. But lots of small dogs have audible murmurs with no clinical relevance. So will this one go on to develop severe disease – or will it expire as a result of other causes, long before its valve function degenerates enough to become life-threatening? 

For general practitioners, the absence of any reliable prognostic indicators is probably the most frustrating aspect of dealing with many common heart conditions, according to veterinary cardiologist Adrian Boswood. 

So the goal of his research at the Royal Veterinary College is to build up a knowledge base which will allow colleagues to identify and focus their attention on those patients that will benefit most from careful monitoring and appropriate treatment.  

Professor Boswood works at the Queen Mother Hospital for Animals, home to the largest assembly of talent in the field of veterinary cardiology in the country. In addition to Adrian himself, there are three other holders of the European diploma in that particular discipline: David Connolly, Virginia Luis Fuentes and Simon Dennis. 

So there will always be a diplomate on duty at the hospital to oversee the work of the clinical students and the two cardiology residents in the department.  

Those clinicians have access to all the latest technologies – echocardiography, fluoroscopy, CT and MRI – when dealing with the difficult cases which present at the hospital as secondary or tertiary referrals. The same hospital runs an out-of-hours’ emergency service for about 20 local practices and a first opinion practice at the Beaumont hospital in Camden Town. 

Routine cases 

This creates the steady stream of routine cases needed to ensure that students are properly prepared for the sort of caseload that they will face on graduation. But it also provides the clinical material needed for Adrian’s clinical research projects. 

A 1989 graduate of the Cambridge school, Adrian spent a year in mixed practice before being accepted on the RVC’s intern programme and has remained there ever since. During that time he has developed a theory about
clinical research in which he believes studies can be broadly classified into two categories: “top up” and “top down” research. 

The former includes research into advanced imaging methods such as the promising new technique of 3D echocardiography or novel MRI-guided interventional procedures. Such methods are developed by those at the top of the pyramid of expertise in any particular discipline and will mainly be used by their peers. 

The techniques will make those people who are already expert in their discipline even better but they are unlikely to be of immediate benefit to less experienced clinicians working to develop their skills in general practice, he points out. 

“Top down research would include the studies that will create the evidence to show which therapy is best, and at what particular stage in the development of the disease it should be given. It also includes the studies which will produce reliable diagnostic and prognostic tests that can be used in general practice, which is something that we don’t always have at the moment, even for some of the commonest conditions that we see.”

Developing techniques 

Both these types of research are important. “It is important,” he says, “to develop techniques like 3D echocardiography. Unlike CT, for example, this method can be performed in a fully conscious animal, which is important when you are looking at the effects of a disease which would be altered if you have to use general anaesthesia or even sedation.  

“But even if it turns out to be the best thing since sliced bread in cardiac disease diagnosis, it won’t do much to raise the overall standard of veterinary care in this country if there are only 10 people who have access to the equipment and know how to use it.” 

So the efforts of Adrian and his research team have focused on developing the sort of tests that can easily be adapted for use in a typical practice laboratory. They have been looking at the value of biochemical markers, such as natriuretic peptides including N-terminal pro-BNP, which have already been shown to have potential in monitoring human cardiac patients. 

“What we want is a test, or more likely a sequence of tests, which will help us to stratify our patients into different risk groups and to treat them accordingly.”

Better understanding needed 

But to underpin this work, there is a need for a better understanding of the natural history of the disease. Adrian points out that most studies on conditions like mitral valve disease are conducted retrospectively or as crosssectional studies, in which researchers will usually see the animal only once. Neither gives an opportunity to observe how the disease progresses in that particular individual animal. 

So for the past five years, with the help of two PhD students, he has been following a cohort of dogs at the Beaumont Animals’ Hospital and the Blue Cross in Victoria. These dogs undergo a full examination every six months. To date, around 200 dogs have been recruited, some have since died as a result of their cardiac disease or unrelated conditions but there are many that remain from the original sample. 

These dogs are from a wide range of breeds but around a third are Cavalier King Charles spaniels, in which there is evidence for an earlier onset and more rapid progression than in other breeds. 

The team has recently published the first of what they hope will be many scientific papers generated by this project. “The longer that you study a disease, the more accurate will be the picture that you build up of how it behaves. The study is currently supported by the Pet Plan Charitable Trust and the grant has another 12 months to run. When that finishes we will be very keen to secure further funding to continue this work.”

Lead investigator 

As well as providing practitioners with a better understanding of how the disease may progress in different patient groups, Adrian’s research interests focus increasingly on treatments for this very common condition. 

Although many different medical therapies have been tested in canine mitral valve disease prior to the onset of heart failure, there is no unequivocal evidence that any one of them improves outcomes for patients. 

So Adrian has been appointed as the lead investigator for a major study being supported by a multi-national animal health company. The study is a good example of the increasingly global nature of veterinary research and it is hoped that it will involve about 36 researchers on four continents. 

When it is completed the study may help to provide unequivocal evidence of the benefits of treatment, something that is still relatively uncommon in any branch of medicine. 

Veterinary scientists around the world are also looking into the genetic factors that determine the progression of a disease in which very few other predisposing factors have been identified to date. 

Jens Häggström, a Swedish veterinarian from the University of Uppsala and someone with whom Adrian regularly collaborates, is leading an investigation to try and identify specific genes which may underlie the rapid disease progression seen in CKC spaniels. 

With the completion of a first draft of the canine genome, many veterinary teams are looking to define the genetic basis of a huge range of diseases, with a view to developing gene tests. Is it possible that this approach will work in mitral valve disease? Adrian cautions that it seems unlikely that there will be simple answers to preventing this particular condition. 

The disease is probably multifactorial with many different genes interacting with environmental and other factors. Moreover, there is strong evidence to suggest that valvular degeneration is a normal consequence of ageing in a large percentage of the canine population and so it may be tricky to define exactly when this becomes abnormal.   

But he is not without hope that genetic tests will have some impact on the overall prevalence of cardiac disease. Single gene defects have been shown to have a role in an increasing number of veterinary conditions such as dilated cardiomyopathy in some dobermanns and hypertrophic cardiomyopathy in Maine coon cats.

Cats different from dogs 

The latter is one of the few cardiac conditions in feline patients to be reasonably well characterised. The clinical picture for heart disease in feline patients is very different from that of dogs, with conditions affecting the cardiac muscle being much more common than valvular disease. 

Cat owners are unlikely to notice any significant changes in their pet’s ability to exercise and as heart murmurs are a  less consistent manifestation of heart disease in this species, their attending vets may not detect anything sinister during a routine examination. For these and other reasons, most cardiac disease is apparently silent in cats until it reaches a fairly advanced stage. 

So Adrian’s colleague, Virginia Luis Fuentes, is trying to assemble the same type of basic data on disease progression in cats that they have been gathering in dogs. She is examining cats in rehoming centres for evidence of cardiac disease with routine echocardiography and other screening tests and hopes to follow a cohort of cats to monitor disease progression. 

With such a growing emphasis on comparative data, is there anything that veterinary science can offer to aid understanding of cardiac disease in humans, conditions that in the long run are likely to prove fatal for up to a third of the readers of this publication? 

Adrian notes that obstructive coronary vascular disease, the most common cause of heart failure in human patients, is extremely rare in companion animals. But the differences between man and beast in the clinical picture of heart disease have started to blur. 

“As we have got better at dealing with some heart diseases in the human population, people are living longer and they are starting to develop other forms of cardiac disease which were less obvious before. Certainly, degenerative valve disease is becoming much more common in human patients and so there will probably be growing interest in the comparative aspects of this sort of condition.