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The abstract of Kate Meurs’ paper which was peer  reviewed and published in The Journal of Veterinary Internal Medicine in May  2010, in layman’s terms.

Or you can see this presentation and have your Dobermann tested if you follow this link:  http://www.vetmed.wsu.edu/pets/videos/Doberman/index.aspx

Dilated cardiomyopathy (DCM) is a familial disease in  the Doberman pinscher that often causes sudden death or heart failure. We have  previously shown Doberman pinscher DCM to be inherited as an autosomal dominant  trait. In humans, several causative genes for familial dilated cardiomyopathy  have been identified including cystoskeletal, sarcomeric and mitochondrial  genes. We and others have excluded many of these genes as candidates for DCM in  this breed. We hypothesized that a genome-wide SNP genotyping array might  identify a genetic alteration associated with familial DOBE DCM. 
          
     DNA samples from adult Dobermans with  DCM (LVDD > 4.8 cm and Fractional shortening < 20%) and apparently  unaffected Dobermans over 10 years of age were evaluated with a genome-wide SNP  genotyping array.  We identified an area of statistical significance on  canine chromosome 14. Through additional evaluation we identified a deletion  mutation in a gene that encodes for a mitochondrial protein that contributes to  cardiac regulation of glucose metabolism. The deletion strongly correlated to  the development of this disease in this breed (p = <0.0001). It should be  remembered that in human beings there are more than 20 different genetic  mutations in different genes that cause this disease. It is unlikely that this  is the only cause of DCM in this
breed.

               In human beings, genetic dilated  cardiomyopathy is a disease of variable penetrance. This means that not all  people with the mutation will develop the disease, or to the same disease  severity. In other words, not everyone with a genetic mutation will have the  disease penetrate it to the same extent. It is very likely the same in the  dog-- not every dog with the mutation will show the disease. Finally, since  there is likely to be a high prevalence of this mutation in the Doberman and  the penetrance is variable, we
do not recommend removing all dogs with the  disease.

At this time, these are our recommendations:

            Dilated Cardiomyopathy Mutation (DCM) is a form of heart  disease in the Doberman Pinscher dog. It is inherited and our laboratory has  identified a mutation responsible for the gene in some Doberman Pinschers.  However, it should be noted that in human beings with the same disease, there  are many different genetic mutations which can cause this disease. We do not  yet know if this is the only mutation in the Doberman Pinscher or if there will  be many different mutations. Please keep in mind that we are continually  learning about this disease and recommendations will be altered as we obtain  more information. 

Currently our interpretation of the test is:

Negative results: 

The absence of the mutation in this dog, DOES NOT mean that it will never develop the disease. It means that it does not have the  only known mutation that can cause the disease in the dog at this time.


Positive Results:

Dogs that are positive for the test will not necessarily  develop significant heart disease and die from the disease. Some dogs will  develop a very mild form of the disease and will live quite comfortably, some  may need treatment.  Importantly, breeding decisions should be made  carefully. At this time we do not yet know what percentage of Doberman  Pinschers will be positive for the mutation. However, removal of a significant  number of dogs from the breeding population could be very bad for the Doberman 
Pinscher breed. Remember that dogs that carry this mutation also carry other  important good genes that we do not want to lose from the breed.

Positive Heterozygous (1 copy of the mutated gene and  1 copy of a normal gene)

Dogs that are positive heterozygous should
be carefully  evaluated for signs of disease (Holter monitor and an
echocardiogram). If  abnormalities are detected, possible treatment options
should be discussed with  your veterinarian. Adult dogs that do not show signs
of disease and that have  other positive attributes could be bred to mutation
negative dogs. Puppies may  be screened for the mutation and over a few
generations, mutation negative  puppies may be selected to replace the mutation
positive parent and gradually  decrease the number of mutation positive dogs in
the population.

Positive Homozygous (2 copies of the mutated gene)

We recommend not breeding the homozygous dogs. Dogs that  are homozygous for the mutation appear to have more significant disease and  will certainly pass on the mutation.
              I hope that helps- I will keep you updated as to the  date of the webinar so you may distribute that.
Thank you for your interest! 

All the best
Kate Meurs

This article is published with the kind permission of Dr.
Joanna Dukes-McEwan           and first appeared in the Spring/Summer 2002
edition of Lifeline


Dilated
Cardiomyopathy           (DCM) in Dobermanns



Dr.
Joanna Dukes-McEwan           BVMS, MVM, PhD, DVC, MRCVS
          RCVS
recognised Specialist in Veterinary Cardiology


Cardiology Service,
          Liverpool
University



What is
DCM?


Dilated
cardiomyopathy (DCM) is a disease affecting the heart muscle (the myocardium)   
            which results in pump failure. Each individual heart
muscle cell is unable to                 contract normally, which means that the
heart chambers become progressively                 more dilated. Pressures
build up within the heart chambers, which means that                 blood dams
back in the circulation, both from the lungs and (in later stages)              
   from the body. The onset of symptoms associated with this circulation failure 
                is called congestive heart failure.


The
blood damming back in the lungs             results in some fluid comes out of
the circulation and fills the normally air-filled             spaces (the
alveoli) which interferes with the breathing and gas-exchange in             the
lungs. This results in symptoms such as breathlessness and coughing. When       
      this is very severe, the dog may show great respiratory distress
(dyspnoea).             Blood damming back in the veins of the body can result
in problems with liver             function, and fluid also builds up in the
belly, causing a pot-bellied appearance             (ascites).


The
pump failure means that the heart             is unable to pump enough blood
flow via the arteries to all the organs of the             body. Lack of blood
flow to the muscles results in muscle wasting and poor exercise            
capacity and weakness. Lack of blood flow to the skin and extremities means     
        that the dog may feel cold, even on a warm day (best detected from ears,
feet             etc), and the gums may be very pale. Lack of blood flow to the
brain means the             dog will feel depressed or faint. Lack of blood flow
to the kidneys means that             toxins are not excreted from the body
normally.


In some
cases, the diseased heart             muscle cells and the increased pressure
within these cells results in abnormal             heart rhythms, such as atrial
fibrillation, ventricular premature complexes             (VPCs) and ventricular
tachycardia. A run of fast ventricular tachycardia can             result in
lack of forward blood flow and the dog may collapse, usually on exertion        
     or excitement. If the normal rhythm is not restored, this can result in the 
            death of the dog. These abnormal rhythms need an electrocardiogram
(ECG) to             diagnose them (Figure 1).





Figure 1.
              A three lead recording
(simultaneously recorded) from a dog showing frequent               VPCs. These
are best seen in the middle trace (called lead II). There are four              
normal complexes at the end of this trace. Although occasional normal complexes 
              canFigure 1.
              A three lead recording
(simultaneously recorded) from a dog showing frequent               VPCs. These
are best seen in the middle trace (called lead II). There are four              
normal complexes at the end of this trace. Although occasional normal complexes 
              can be seen prior to this, most complexes are large, wide and
bizzare, the VPCs
.


Who is affected             by
DCM?


DCM affects humans and various
dog breeds and even the Syrian hamster! In humans,               it is the
leading reason for a heart transplant. Dog breeds affected by DCM              
include the large and giant breeds, boxers, spaniels (cockers and springers),   
            Dobermanns and Weimaraners. It rarely affects cross bred dogs. Within
these               breeds, the disease is prevalent in certain family lines and
therefore the disease               has long suspected to have a genetic basis.

              In what way are Dobermanns affected by DCM?
             
DCM is a very common cause of death in Dobermanns. It has been estimated both   
            in the USA and the UK and Europe that it may be the cause of death in
over 25%               of Dobermanns. Dobermanns are believed by veterinary
cardiologists and veterinary               surgeons familiar with treating
Dobermanns to have a more severe and more rapidly               progressive form
of DCM than other breeds. After showing symptoms, the average              
survival time is only 6 weeks. However, with more modern treatments and better  
             monitoring techniques available now, and with earlier detection of
disease,               before onset of the life-threatening symptoms, some
Dobermanns may live much               longer with a reasonable quality of life.


In the form of DCM seen in Dobermanns, abnormal heart rhythms are common. Many Dobermanns show occasional or frequent ventricular premature complexes (VPCs) or runs of ventricular tachycardia. As well as possibly causing the dog to faint (syncope), they can result in sudden cardiac death. These abnormal rhythms can occur at any stage during the progression of the disease. They precede the heart chamber dilatation in Dobermanns. They are the usual reason for sudden death of Dobermanns. Sudden death may occur without any previous warning. Some dogs have not previously fainted, and they appear very healthy to both the owner and to the veterinary surgeon at the most recent examination.


How
does DCM develop?


It is clear from research carried out over a number of years,
particularly in                 the USA and Canada, but also by the
cardiologists in Edinburgh, that once the                 Dobermann shows any
symptoms of heart failure, that is the tip of the iceberg.                 For a
number of years before this, the dog does show abnormalities during detailed    
             cardiological investigations. Until the disease is far advanced, it
is not usually                 possible to pick it up by clinical examination or
by auscultation (examination                 with a stethoscope). Veterinary
Cardiologists including Dr. Mike O'Grady from                 Guelph, Canada and
Dr. Clay Calvert from Texas have shown that the initial abnormality             
    are increased numbers of ventricular premature complexes (VPCs) on a special 
                24 hour ECG recording of the heart rhythm, often called a Holter
recording.                 The dog wears the recording system on a harness, with
stick-on electrodes on                 the chest wall, so he is able to carry
out his normal daily activities. Unfortunately,                 a standard ECG
(a recording taken of a couple of minutes) is not sensitive enough.             
    Within about one year, the start of heart chamber dilatation and pump failure
                 can be detected with an echocardiogram. An echocardiogram is a
special ultrasound                 examination of the heart, where the chambers
can be viewed, measured and blood                 flow recorded as it moves
through the heart (Doppler) (Figure 2). As there is                 now a huge
amount of work published in veterinary journals about these very                
early stages of DCM, with reference measurements from normal Dobermanns and     
            measurements which can be regarded as abnormal, it is possible for
veterinary                 cardiologists to examine a Dobermann and to give the
owner an answer as to whether                 the dog is normal, or may have the
early stages of DCM (called occult DCM) or                 has DCM with symptoms
of heart failure. Once the early echo abnormalities are                
detected, they progress over 2 - 6 years to eventually result in signs of heart 
                failure. Sudden death may occur at any point over this course,
and the goal                 of cardiologists is to recognise those Dobermanns
at risk of sudden death to                 start treatment to try and prevent
it. The progression tends to occur faster                 in dogs who are young
(e.g. 2 years) at initial abnormality, and is slower in                 dogs not
showing abnormalities on echo or Holter monitor until they are 5 years          
       or older. Some very elderly Dobermanns may die of other causes even with
occult                 DCM (e.g. gastric dilatation/volvulus or bloat, cancer
etc.). The progression                 into congestive heart failure is faster
in dogs than bitches, and males may                 be at increased risk of
sudden death as well.









Figure
2.
            On the left is a 2D echo image showing the heart in a
Dobermann with DCM. The             left atrium (LA) collects blood from the
lungs. Pressures are very high, so             the septum bulges into the right
atrium (RA). The left ventricle is dilated,             thin-walled and
rounded.


On the
right is             an M-mode scan from the same Dobermann. The septum (IVS)
between right and left             ventricles and the LV wall can be measured,
as well as the LV chamber. The walls             are moving very little, since
contractility is very low. One of the measurements             of contractility
is the fractional shortening. Here it is 5%, normally it is             over
25%.







How can I tell if my Dobermann will get
DCM?


DCM typically
affects dogs in middle to older age. As a puppy or a young dog,                
there are no abnormalities detected before the disease develops, and currently, 
                we have no diagnostic test to identify dogs at risk. It is
recommended that                 dogs are screened for the presence of DCM or
the early abnormalities which precede                 the development of DCM
every year, particularly if they have a close family                 relative
with a history of DCM (e.g. sibling, sire, dam). As the screening tests         
        are specialised, they should be carried out by a veterinary cardiologist.
These                 tests include:


· Detailed clinical
examination
            Occasionally, abnormalities will be detected in the
early stages, such as a             weak pulse, an irregular heart rhythm or a
heart murmur.

            · ECG
            A normal ECG is carried
out to identify any abnormal complexes or evidence that             the heart
chambers are enlarged. See Figure 1.

            · Holter monitor
   
         This is the 24 hour ECG recording so that the number of VPCs over 24
hours can             be counted. The result is compared with normal numbers for
Dobermanns in different             age groups.

            ·
Echocardiogram/Doppler examination
            The most sensitive method of
detecting heart chamber enlargement or pump failure             is by the
ultrasound examination called an echo. See Figure 2. The dog lies             on
an ultrasound table, and the transducer is positioned through a hole in the     
        table to contact the lower chest wall. It is better if the dog is fully
conscious,             not sedated for the examination, and most Dobermanns
tolerate the procedure             well, some even falling asleep. Detailed
measurements are taken, and compared             to normal values from
Dobermanns of different weights.


During my PhD studies,
which were             funded by The Kennel Club Charitable Trust, I identified
a number of echo abnormalities             which proved to precede the
development of DCM.


How
is DCM treated?


Unfortunately,
there is no cure for DCM. The treatments available are directed              
against the congestive heart failure signs, or the abnormal rhythms. There is   
            nothing which can reverse the actual disease process. However, with
modern treatment               and advances in new drugs, many Dobermanns can
have a good quality of life for               some time. Some of the drugs which
may be prescribed by a veterinary cardiologist               or veterinary
surgeon include:


Frusemide
         
   This is a diuretic drug. Excessive fluid which is retained in the circulation,
             lungs and belly is eliminated in the urine by this group of drugs.
It is life-saving             in Dobermanns with a severe cough and respiratory
distress due to the heart             enlargement or fluid in the lungs.



ACE inhibitors
    
        The ACE inhibitors are one of the most important drugs. They counteract
the             adverse effects of some of the hormones which are increased in
heart failure.             They are the one group of drugs which significantly
improve quality of life             and survival time in dogs and humans with
congestive heart failure. Some of             the ACE inhibitors licensed for
use in dogs in the UK include: Enalapril (EnacardR,             previously
called CardiovetR), ramipril (VasotopR) and Benazepril (FortekorR).


Digoxin
           
Digoxin is an old drug which has two major effects. It slows down the heart     
        rate in excessively fast rates (due to atrial fibrillation or sinus
tachycardia)             and it may increase heart contractility. More recently,
it has been shown to             counteract some of the adverse hormonal effects
of heart failure, even at low             doses (by blocking some of the effects
of the sympathetic nervous system). Although             very effective and
useful, digoxin can easily be over-dosed to result in toxic             levels.
In part, this may be due to compromised kidney function as a result            
of the heart failure. Dobermanns are particularly susceptible to digoxin
toxicity,             so veterinary cardiologists usually advise that this breed
are given a much             lower dose than other breeds, and that blood levels
are checked after 5-7 days             of starting the drug and periodically
thereafter, particularly in the dog shows             any signs which may
reflect toxicity. These include depression, inappetance,             excessive
borborygmi ("rumbling tummy") but digoxin toxicity may also             result
in worsening heart rhythm.

            Pimobendan
           
Pimobendan (VetmedinR) is a drug which has recently been made available to treat
             DCM. It has two major effects (i) it improves the contractility and
therefore             improves pump function and (ii) it reduces the work load
of the heart. In studies             carried out by one of my former colleagues
in Edinburgh, Dr. Virginia Luis Fuentes,             pimobendan, given in
addition to frusemide, an ACEI inhibitor and digoxin to             Dobermanns
with heart failure due to DCM, was shown to significantly improve            
their quality of life and survival, compared with Dobermanns on the same
standard             therapy but with placebo (sugar-pills) instead of
pimobendan. Pimobendan appears             to make dogs feel better and eat
better.


Antiarrhythmic
drugs
If
a Dobermann has been shown to have a severe ventricular arrhythmia, which       
        is judged to be life-threatening, drugs to counteract these abnormal
ventricular               rhythms are indicated. Drugs such as mexilitine or
sotalol are often used. A               group of drugs called the beta-blockers
may also be considered (see below).


Beta-blockers



            The
beta-blockers are drugs which block the beta receptors on the heart. These      
       are the receptors which are affected by adrenaline and noradrenaline, the
hormones             of the sympathetic nervous system. Levels of these hormones
are very high in             heart failure and correlate with the risk of death.
Beta-blockers are also very             effective at controlling the
life-threatening ventricular arrhythmias. Counteracting             these
hormones would therefore appear to be a good thing. However, these drugs        
     actually tend to depress contractility and most Dobermanns with heart
failure             actually become worse on beta-blockers. However, because
beta-blockers have             been shown to be very beneficial in human
patients with DCM, although it may             take 3 - 6 months to show an
improvement, it is probable that in Dobermanns             who are able to
tolerate the drugs, they should be beneficial. The dose of the             drug
has to be started very, very low, and gradually increased while carefully       
      monitoring the dog. Beta blockers are best tried in the Dobermanns with
early             or occult disease, since once congestive heart failure has
developed, most dogs             fail to tolerate these drugs at all. Certainly,
as a cardiologist treating Dobermanns             with heart disease, my
priority is to maintain the dog's quality of life, and             I would not
use the beta-blockers if the dog appeared to feel unwell on them.


What can be done if
cardiac screening detects occult DCM               in my
Dobermann?


              The
main aim of screening is to identify dogs with the early stages of DCM,         
      so that they can be closely monitored in the future. Another aim is to try
and               prevent the sudden "crash" into heart failure which so many
Dobermanns               appear to do. The main group of drugs are the ACE
inhibitors. In humans with               asymptomatic DCM and Dobermanns with
Occult DCM (Mike O'Grady's work), treatment               with an ACE inhibitor
delays progression into heart failure and appears to slow               down the
course compared with untreated patients.


In Dobes identified
with significant             ventricular arrhythmias, judged to be at risk of
fainting or sudden death, treatment             with one of the antiarrhythmic
drugs or beta-blockers are indicated. Only drugs             with beta-blocker
effect have been shown to actually reduce the risk of sudden             death.
Whether they are used or not depends on whether an individual Dobermann         
    is able to tolerate them.


What causes             DCM?


Until recently, the cause of
DCM in any species was not known. In dogs, a genetic               cause was
suspected, since it affected specific breeds or lines within breeds.            
   In the last decade, human DCM is now recognised to be a familial disease in   
            a large proportion of patients. However, there are other causes of
cardiomyopathy               in people, including alcoholism (the alcohol
adversely affects the heart muscle)               and coronary artery disease.
These are very rare or non-existent causes in the               dog! In human
families, a number of genetic markers and some actual disease              
genes have been linked to the disease. Since different human families have
different               gene defects, it is apparent there is more than one
"cause" of DCM.               In a single dog breed, which is comparatively
recently evolved, it is likely               that there is a single defect (but
the genetic mutation causing DCM in a Dobe               may not be the same
gene defect causing DCM in an Irish wolfhound). In the last               few
years, the genetic cause of DCM in the Syrian hamster was found to be due       
        to a mutation in the delta-sarcoglycan gene. This gene, and some of the
others               responsible for human DCM (e.g. actin, desmin etc), is one
of a group of genes               encoding proteins forming the "scaffolding" or
cytoskeleton of the               cell. If there is a problem with the
cytoskeleton, the heart muscle cells are               unable to withstand the
"wear and tear" of constantly beating, and               individual cells get
more and more "stretched" and fail to pump normally,               which affects
the entire heart.


 


Research into the genetic basis of          
   canine DCM
        
      Since some "candidate genes" implicated in human DCM could also be         
      responsible for DCM in Dobermanns or other dog breeds, these can be
assessed,               and normal and affected dogs compared. Dr. Kate Meurs
(Ohio State University)               did not find any difference in the cardiac
actin gene in Dobermanns, so it does               not appear to be the cause of
Dobermann DCM.


There have been huge
advances into             the canine genome map, although it is well behind the
human or the mouse genome             maps. These maps include many genes and
genetic markers on the individual chromosomes.             These markers are
very useful, since they are very variable between individuals,             and
so they can be assessed to see if they are linked to the disease causing        
     gene - if linked, it shows the marker is close to the disease gene. Such a
marker             could be used to identify dogs at risk of developing a
disease (e.g. a puppy             could be tested to see if it was at risk of
developing DCM in middle or older             age). More importantly, the region
of the chromosome can be carefully examined             for the actual disease
gene.


My research is with a
very large             extended Newfoundland family (owned by many owners and
breeders throughout the             UK). We are carrying out an entire
canine-genome screen to try and identify             a marker linked to DCM in
Newfs. This is funded by The British Heart Foundation.             Any
significant findings may be useful in other dog breeds including Dobermanns     
        and even humans.


A PhD student, who is
a veterinary             surgeon, called Polona Stabej at the University of
Utrecht, is looking at markers             close to the known DCM causing genes
in Dobermanns who are normal and Dobermanns             with DCM. I am
collaborating with her and her supervisor, Professor Bernard             van
Oost, in this work. These markers can be tested on DNA obtained from European   
          and UK bred Dobermanns.


In Dobermann families
we have studied             to date, and autosomal dominant transmission appears
most likely. This is consistent             with that reported by Kate Meurs in
the USA, and that reported for other dog             breeds, including the
Newfoundlands, and most human families. An autosomal dominant            
transmission means that only one parent needs to be affected, and up to 50%     
        progeny are at risk of developing the disease.

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