Dilated Cardiomyopathy in Leonbergers 

Link to French research project:
http://www.eiwc.org/pdf/health/Rech_DCM-chien-US_mars08%20_2_.pdf

In the summer of 2004, the Leonberger Club of Great Britain invited Dr Joanna Dukes-McEwan to present a seminar on Dilated Cardiomyopathy for the benefit of club members. The event was generously hosted at the Guide Dogs for the Blind centre. The following is a summary of the discussion, drawn from a video recording done at the time. It has since been revised by Dr. Dukes-McEwan to bring it up to date.

Dr. Joanna Dukes-McEwan
BVMS, MVM, PhD, DVC, Dip. ECVIM-CA (Cardiology), MRCVS,
RCVS and European Recognised Specialist in Veterinary Cardiology.

 This was the second time Dr Dukes-McEwan has made a presentation to the LCGB, the previous having been sometime in 1996.  

Her work in DCM research was originally supported by the Kennel Club (1996-1999), with an initial focus on echocardiogram diagnosis. It then developed into looking at familial relations in the Newfoundland, as there were a number of cases then apparent to trace genealogies through. The British Heart Foundation also gave huge support, with three years funding (1999 – 2002), with a genome wide search for a marker linked to Newfie DCM. Unfortunately, the marker has not yet been discovered. Further funding from the Kennel Club and a researcher called Anje Wiersma  (2004-5) looked at some candidate genes for Newfie DCM, but again, the gene or a marker has proved elusive! 

The initial work started at the University of Edinburgh, but it has moved now to the University of Liverpool (since 2004).  

DCM in Leonbergers: 
The Leo Watch health survey (USA), dated 2002 showed 3% heart disease across all US Leonbergers. That survey showed DCM as the most common heart related cause of death in leos. There is also some incidence of congenital heart disease as well, but nowhere near as common as DCM. Dilated Cardiomyopathy is acquired during the lifetime of the dog and so often shows in older dogs. Overall, heart failure showed up as the cause of death in 9% of the respondants in this 2002 survey. A further 8% showed as suffering from so-called ‘sudden death’ with uncertain cause, and she suspects that a proportion of these may also be due to DCM.

What is DCM:
The disease is characterised by dilation and impaired contraction of the left or in some cases both ventricles. The heart is grossly enlarged, rounded and loses its form and firmness. It is a progressive condition. The condition affects hearts at a cellular level, causing individual muscle fibres to separate and take on a lax and ‘wavy’ appearance, with greatly increased fluid levels within them. In some breeds, such as Boxers and Dobermans, the cellular changes differ, in that they show a great deal of fibrous or fatty materials within the individual muscle cells. These fatty deposits actually begin to replace muscle tissues, separating the individual fibres, reducing their ability to function and often leading to sudden death. She does not know if this form is present in leos, but suggests that it should be looked for in post mortem examinations on those leos who suffer these unexplained, so-called ‘sudden deaths’. 

Diagnosis:
In Humans, DCM can be caused by a number of known factors. These include:

 Coronary artery disease- if the vessels of the heart begin to ‘fur up’ with fatty deposits it can cause changes in the heart tissues themselves, causing them to become flabby and weak. This is probably the most common cause in humans. 

Following some flu-like illnesses the heart muscles can be seen to change in ways similar to DCM. It is thought that this is either because of viral damage to the heart cells themselves, or through auto-immune response targeting viral affected cells. In either case, the cells are damaged, leading to expansion and impaired function. 

Alcohol consumption can also cause dilation of the heart through depression of heart muscle function. 

However, recent evidence (since 1992), indicates that in as many as 30% of human sufferers, DCM can be a genetic disease, with clear familial inheritance. In humans, there are thought to be at multiple possible modes of inheritance; Autosomal Dominant, x-linked, and Mitochondrial and Autosomal recessive. Most cases are autosomal dominant.

Dr. Dukes-McEwan then reviewed the specific efforts being undertaken to locate the mode of inheritance in humans, specifically which genes were being investigated, such as those that control the structural formation of each heart muscle cell. She then ran through an explanation of cellular anatomy.  

In dogs, DCM has only really been recognised within the veterinary literature since the 1970s. Since most breeds are relatively recently evolved, (within the last 200 years), and since knowledge of pedigrees is now quite extensive, breed predisposition and familial predisposition within breeds for DCM are well recognised. Whereas it is thought that cases of ‘non-genetic’ DCM in humans are very rare, (e.g. caused by excess alcohol, viral agent, etc.), these are presumed to be virtually non-existent in dogs. In other words, DCM in dogs is always assumed to have a genetic element. 

Investigation into the genetic basis of DCM in dogs did not start until the mid 1990s. It was prompted by reports of familial DCM in humans. Until that time, DCM in humans was considered to be a ‘sporadic’ disease, with numerous causes.

In Human cases, DCM is most commonly thought to be autosomal dominantly transmitted.

Autosomal dominant:
An affected parent will have at least one affected grand parent, and will produce offspring where an average of 50% are affected. There are no skipped generations and males and females are affected equally. If the gene is present, the condition will also ultimately manifest, unless there is a prior cause of death. However, non-affected offspring are clear of the condition and will not be carriers of the affected gene. For our purposes, this means that if these individuals can be identified, they will be safe to breed from, as there is no transmission of the faulty gene.

Autosomal recessive:
If the condition proves to be autosomal recessive, then an individual will need two copies of the affected gene, one from each parent, to succumb to the condition. However, if they have one healthy and one faulty gene, they may live their entire lives free of the affects of the disease, but will carry a faulty copy of the gene, which can be passed on to the next generation. Two such silent carriers will produce a litter where on average 25% will be affected, 50% will be carriers, and the remainder 25% will be completely clear. Also, this condition can appear to skip a generation.  

X-linked:
Essentially, this condition produces female carriers with affected sons. Since males have only one x-chromosome, if their one copy is affected, the condition will manifest. Females carry two x-chromosomes, so if they have one healthy and one faulty, the healthy one will override and produce a normal life. If, on the other hand, she is unfortunate enough to inherit a faulty x chromosome from both parents, then she too will be affected. This mode of inheritance can also appear to skip a generation.

There is also the more obscure mitochondrial mode of inheritance, which is carried through the female line, but can affect males as well as females. This involves the portion of the cell concerned with energy production.

In dog studies with Irish wolfhounds, Dobermans, Boxers and Newfoundlands, evidence so far indicates an autosomal dominant mode of inheritance. Males tend to become affected at an earlier age, which can give a false impression that there is an x-link, but she is fairly confident that this is ultimately based on incomplete evidence and that autosomal dominant is the likely mode. In Dobermans, there has been a suggestion of both a dominant and recessive mode of inheritance however. In Portuguese Waterdogs there is a juvenile form of Cardiomyopathy which can cause death in puppies of 8 weeks old. They have found that in this case it is a recessive condition, liked through pedigree analysis to one founder dog in the United States. There has been a suggestion in Great Danes that there might be an x-linked inheritance, but she thinks this is likely just a reflection of the pattern of males becoming affected on average at an earlier age than females. She sees equal numbers of male and female Great Danes affected in the UK. 

She then showed us a more complex genetic analysis of 4 generations in a Newfoundland family with some incidence of DCM, which she talked through in detail. Many dogs showed cardiac abnormalities and some were diagnosed positive with DCM. This sort of overview of entire family trees and health screening of entire litters is an invaluable aspect of the ongoing research into this condition and an essential part of building up a full understanding of its patterns of inheritance.  

DCM In Leonbergers:
In her experience, she feels that males and females are equally likely to be affected by DCM. 

Sudden unexplained deaths in leos also appears to be uncomfortably common, especially in young males it seems.  

Confirmed cases of DCM do seem to be able to demonstrate a relation to other known cases, which underlines the likely genetic basis of the condition, but clearly more details needed to build up a complete pattern for analysis.  

More details are needed, and for this one must start with confirmed diagnosis, which means that if a dog is suspected of having a heart condition, a qualified veterinary cardiologist should be sought to get positive confirmation of the condition. This, along with the affected dog’s pedigree, then becomes a valuable piece of evidence in trying to decipher the mode of inheritance of this illness. Only then can efforts move on to trying to positively identify the gene or genes responsible, their mode of inheritance, and from there a method of screening that might eventually lead to the elimination of this devastating condition.

At present, because it is an acquired condition, (one which only emerges over time), screening must be ongoing to be of any value. In other words, screening a 2-year-old dog will only show if the condition is apparent at that age, not whether it will emerge in years to come.  

Dr Dukes-McEwan mentioned the recent establishment of the UK Companion Animal DNA Archive, which could help in this and other areas of research by building up a genetic history of the breeds for current and future researchers to tap into in their efforts to find a genetic marker for these conditions. What is essential for this to be most effective is to get a confirmed diagnosis of the condition and then submit a DNA sample, which is verifiably from the known affected individual. ‘The pedigree goes with the DNA from the confirmed case’.   If the blood sample and DNA is taken from a young dog, it is very helpful for owners to update the archive with any illnesses their pet is diagnosed with over time. The DNA archive is keen to collect samples from both healthy and diseased dogs of a wide range of breeds, and for a wider variety of conditions. More information is available on the web-site:

http://pcwww.liv.ac.uk/DNA_Archive_for_Companion_Animals/

Abnormal Heart Rhythms are common in DCM and can be a helpful first-step diagnostic tool. Dukes-McEwan went on to give a complex explanation of ECG traces and what to look out for, especially in the giant breeds such as leos that are vulnerable to DCM. Atrial Fibrillation in particular is commonly seen in DCM case. It is characterised by a very fast (200-220 beats per minute), irregular heart rate.  

In some cases, notably Irish Wolfhounds, some rather more slow Atrial Fibrillation (so-called “Lone”), may be seen in otherwise asymptomatic individuals years before they then go on to develop full-blown cases of cardio myopathy. Their heart rates will be irregular when examined via ECG, but they otherwise appear in everyway to be normal healthy dogs, and hear rates may be only 90 – 120 beats per minute, so normal. This allows a fairly good tool for pre-diagnosis of this condition.

 Ventricular Premature Complexes or VPCs are caused by the build-up of scar tissues within the cells as the condition progresses. These cause abnormal electrical firing disrupting the normal heart rhythm. If they take over the heart rhythm, it can lead to ventricular tachycardia, a very rapid inefficient heart rhythm, which does not allow for the effective pumping of blood throughout the body. This can cause collapse or even sudden death. Abnormal ventricular rhythms are most common in cardiomyopathy in Dobermanns and boxers, but are seen in other giant breeds such as great Danes. Again, the ECG trace (or a 24 hour ECG trace called a Holter monitor) can help make this diagnosis. The abnormal rhythms can occur before the heart chambers are dilated.   

What are they symptoms of DCM?
There may be none at all. Many affected dogs show no clinical signs in the early phases of the disease and will appear in everyway to be fit healthy individuals. Once they are into actual stages of acute heart failure, one or all of the following signs may be apparent:

• Weight loss and muscle wasting,
• Exercise intolerance,
• Collapsing,
• Coughing and breathlessness, due to fluid within the lungs (pulmonary oedema), or in the space surrounding the lungs (pleural fluid).
• Fluid retention in the belly (Ascites):  this is one of the clearest signs of final stages of the condition. If the right ventricle is more affected, the dog’s abdomen will expand as excess fluids build up, showing clear signs of a distended stomach.

She then gave a quick overview of the two main functions of the heart and how right side activity has a greater affect on draining blood and excess fluids from the body, whereas left side function is more closely associated with the lungs, so failure here results in fluid build-up within the lungs themselves, hence the coughing.

 Listening for heart murmurs (auscultation) is not necessarily the best way to diagnose early onset DCM, as affected dogs usually do not manifest a murmur until well on into the condition. So, even a fully affected dog may only present with a very slight murmur, and such slight murmurs could be caused by a wide range of other things. Early cases of DCM are unlikely to be picked up through basic stethoscope examination.

An effective diagnostic tool for left-sided heart failure is a simple chest x-ray, which will show the outline and size of the dog’s heart as well as any excess fluid build-up within the lungs.  A chest X-ray will not be abnormal in very early cases, and so this is not a screening tool in asymptomatic dogs.

 The most sensitive way of positively diagnosing DCM is however through the use of Cardiac Ultrasound (Doppler Echocardiography). This is a completely safe and non-invasive technology - essentially the same as is used for checking pregnancies. Dogs normally need not even be sedated for this examination, but are simply positioned lying on their sides quietly. She reports that many find the whole experience so relaxing that they may fall asleep during the procedure. A small amount of the coat will need to be clipped from the chest overlying the heart, behind the elbow and forearm.

 This form of examination allows for a live real-time moving image of the heart. The walls can be seen, and how well and how synchronously they are moving, and the blood filled chamber can be measured. Each heart valve is visualised. With colour flow Doppler, the pattern and speed of blood moving through the heart can be assessed, and whether flow is normal or turbulent (such as a leaky valve, resulting in a heart murmur). All of this information can be recorded and retained for comparison with future examinations.

 Dr. Dukes-McEwan showed a number of visual examples from the Doppler echocardiograph, both healthy and ill, to illustrate the technique and its value as a diagnostic tool. One of the things that she pointed to as being needed by the research community is echocardiography data from healthy examples of the vulnerable breeds gathered over the course of their lifetimes, or so-called serial scans. These would provide a valuable model of the lifespan of a normal heart, against which to compare future data from affected individuals.

 Although echocardiography can be the best tool for early diagnosis of the condition, it must be kept in mind that this condition evolves slowly over a long time with only very gradual changes building up. Therefore, for this device to be used for an effective early diagnostic tool, one must compare results over time and look for gradual changes. In other words, serial testing is necessary for early detection to even be possible. Also, it must be kept in mind that a dog that scans as being clear at one stage in its life, may still go on in later years to develop the condition, so it is not a method that can certify a dog as being clear for life, only clear at the time of the scan. In this way, it is not a “one-off” screening test. The older a dog is that scans clear, the more likely you are to have a dog that is free of the condition, but it is still not guaranteed.

 There is no cure for DCM. As the condition progresses the rate of degeneration in the heart accelerates and things worsen rapidly. The main emphasis of the treatment available is aimed specifically at slowing this rate of degeneration and hopefully prolonging the dog’s life.

 Treatment options include: 

• Drugs to counteract the fluid retention in lungs and abdomen. These are the diuretics, such as Frusemide.  Spironolactone is also sometimes proscribed in addition as it has been shown to counteract some of the scarring of the heart muscle, which are caused by the disease.
   
• ACE inhibitors are used to counteract the body’s hormones which are elevated in response to the cardiomyopathy and heart failure, which are known to accelerate and exacerbate the deterioration of the disease. For example, these hormones can constrict blood vessels against which the already weakened heart has to work against, so it has to work even harder against that resistance. There are a number of these ACE Inhibitors available to us in the UK and although not cheap, they are proven to significantly extend survival times and quality of life in DCM. They have also been shown to slow the progression of DCM even in its earliest stages
  .
• Atrial fibrillation is one of the main dangers of this condition in giant breeds and to help control these hazardous heart rates, vets will prescribe Digoxin, possibly with other drugs working together, which helps to slow, steady and regulate heartbeat, so that each beat is more efficient in transporting blood around the body.
   
• Finally, a relatively new drug called Vetmedin, (Pimobendan), is now available which has been shown to improve the heart’s ability to pump efficiently, and also dilated blood vessels, reducing the work-load of the failing heart. It is proving to be a very effective drug for this condition and has been shown to slow the rate of progression of the disease.

In conclusion, Dr. Dukes-McEwen reiterated that if there is a concern about DCM within the Leonberger community, then screening is advised, particularly of all living relatives and descendants of known affected animals, so that results can be added to pedigrees and used to analyse possible patterns of inheritance. Remember that they do need to be serial exams, not one-offs. The clear advantage of early diagnosis is to be able to start treatment that will provide your dog with the best quality of life as the condition progresses, and of course to help make decisions about possible breeding. If, as is currently believed, DCM is an autosomal dominant condition, then up to 50% of the progeny of an affected dog can also be affected, and will suffer the devastating consequences. The other 50% however will be completely free and therefore could be perfectly safe to breed from. What we ultimately need of course is a genetic screening test, but sadly, this is still some time off, although it is possible that such a test for one breed may apply to leos as well, but this is by no means certain.

Note: There was a great deal more technical detail presented in this seminar. Anyone interested in the full content should seek a DVD copy of the recording, which should soon be available through the leo club shop.

 Dr. Dukes-McEwen then took some questions- some of which are summarised here: 

“How many leos would need to be scanned to gather a useful amount of information to study this disease in the breed?” 

…..To do a proper linkage analysis, looking at positive diagnosis and pedigrees, one needs to have a fairly thorough set of data from at least three generations of dogs, and as much information as possible about ALL the progeny within those generations. Not simply results from the odd individual…. 

“How can the club organise an annual echo-doppler testing event with a cardiologist that would allow a wide set of dogs to have serial testing?”

….The equipment is expensive and costs are steep, not less than £100, but through approaching a qualified veterinary cardiologist one might be able to reduce the costs from a group of examinations and arrange such a service. It is a time consuming examine, so doing more than 10 in a day would not be likely. This would also be a limiting factor. …. 

“Over how many years would one start to see signs of abnormality (via the echo-cardiogram) in a dog developing this disease until they have full blown DCM?” 

…..A dog might test clear at 4 or five years and then go on to develop this illness and so still end up passing it on to his progeny. Listening for a heart murmur is not an effective screening method. If however, you are doing serial testing you would be likely to see the condition developing over the course of 5 or 6 years before it becomes critical. The gradual changes in the heart would be apparent through such a series of exams, and in Newfoundlands, time periods of between 2 and 6 years can from the earliest abnormality on the scan to heart failure have been recorded.  The younger the dog is at first abnormality on the scan, the more rapid the progression; an older dog often has a slower rate of progression…  

“Is there value in doing echo-Doppler scans on older dogs after their breeding age has passed?” 

…The older a dog is when it is scanned, the more reliable the results in that it is less likely that they will develop the condition the more years pass. If they do eventually show positive, then their progeny can be looked at more closely. Even if they never show signs of the illness, this alone is a valuable piece of data for future analysis ……

“Is it useful to give Taurine and L-carnitine supplements?” 

….Cats can develop DCM if they are deficient of taurine, and they are cured with supplementing the taurine. In some breeds of dog (Newfies included0, they may have low blood taurine levels, and supplementing taurine improves them, but this is not cause and effect, we do not cure them. L-Carnitine is more helpful in boxers, (certain families only however). L-carnitiine is very expensive. Taurine is cheap, Neither supplement will do any harm and may help, no clear evidence as yet in Leos. Too low meat-based protein (20% or less), could contribute to low taurine, chicken better than lamb as a source…. 

“Is there evidence of a cumulative effect of DCM?” 

This is not the way inheritance works. Sometimes offspring are affected before parent, but not always.
No evidence of environment making a difference outside of diet points already mentioned.  

“How far off from DNA test?” 

For other heart diseases, such as hypertrophic cardiomyopathy in Maine coon cats, there is now a genetic test available.  

There are genetic tests for a range of dog diseases, particularly some of the eye diseases.  

It will come in for DCM in dogs…. But more work is needed. Despite spending over three years looking in Newfoundlands, we have not yet found a gene-based test yet. Some degree of luck is needed as well! Also, we need to be aware that finding a gene for DCM in one breed does not mean that this applies to other breeds (and we can presume that Newfie and Leos and St. Bernards may have a similar gene….). 

Let us collect echo data, clinical data and DNA and pedigrees from normal and DCM leonbergers, so we can be ready if a test become available, to see if it applies to Leos as well.  

Contact details. 

If you have any information either on affected Leos, or any relevant echo-doppler results that you would like to submit to Dr. Dukes-McEwan, she can be reached at the newly established Small Animal Teaching Hospital from the 1^st of April 2007. Details here: