Dilated Cardiomyopathy DCM updates as of February 2011 Taken from the health report Rebecca Barber The page consists of three parts - Screening Programme Announcement Dilated Cardiomyopathy (DCM) in Dobermanns (Joanna Dukes-McEwan) About the DCM Screening Programme DOBERMANN BREED COUNCIL HEALTH REPORT DBC Health co-ordinator DBC Health Co-ordinator Rebecca Barber email Rebecca 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.   How can Dobermann owners or breeders help advance the work to elucidate the genetic cause of Dobermann DCM? 1. I am collating pedigrees of Dobermanns confirmed to have DCM to help the pedigree analysis. Of course, clinical information about the individual dog and its pedigree is treated in utmost confidence. Pedigrees of Dobermanns who have been confirmed as normal (e.g. had a normal echo at an advanced age, and died of non-cardiac disease) are equally useful. 2. If your Dobermann needs to have a blood sample taken, because (s)he has DCM, and your vet is willing to take a little extra, please contact me so I can give the vet details of the samples required so that we are able to extract and store DCM. DNA is useful from Dobermanns who have DCM or who are confirmed as normal - this means that the results of an echo examination need to be available. 3. Keep family records if DCM is identified, so that inheritance patterns can be worked out in different families. Ideally, as many siblings as possible in a litter and as many relatives in the parent's generation need to be screened by echo or Holter to ensure this information is as robust as possible. 4. Screen Dobermanns at risk of developing DCM with echo and possibly Holter monitor on a regular basis (e.g. annually). I am not able to offer a free screening service of Dobermanns currently (which I did between 1996 and 1999). However, I am willing to collate data, and funding may become available in the future to carry out this screening. Most cardiologists in the UK will screen Dobermanns for DCM for a reasonable fee. 5. Please note that a DNA sample is still useful from a rescue Dobermann, where you have not got the pedigree information, as long as the dog's status is known (confirmed normal or DCM). 6. Please feel free to contact me if you wish to discuss any of this in more detail. Dobermanns have a terrible disease, and the more that is known, the more chance we have of finding a cure or a marker enabling breeders to select dogs not at risk of developing this disease. My contact details are at the top of this article. I hope to be able to devote more time to Dobermanns in the future.   DCM updates as of February 2011 Taken from the health report Rebecca Barber As many of you will now be aware Dr Kate Meurs, the cardiologist in the USA has reported that she has found the gene for Dobermann DCM and they are running a DNA test. I have had correspondence from both Jo Dukes-McEwan and Kate Meurs about this and it appears that although she has found a gene there may be many other genes still to identify. It is likely that the researchers working on the LUPA study are looking at a different gene to the gene that Kate Meurs has identified. This basically means that it is extremely likely that there is more than one gene that causes DCM in the breed. The best way to know this for sure is to collate all of the data of Dobermanns tested in this country to see if it matches with the disease. I think that as long as we can get permission off all owners that have had their dogs tested in the UK then this is our next mission. Below is the abstract from Kate Meurs’ recent paper which she has altered to layman’s terms so that it is more easily understandable. I hope that this, along with my brief report above will help all Dobermann owners and breeders understand what is going on a little bit more. We have written to KC/BVA about the possibility of setting up a heart scheme for DCM in Dobermanns. After very recent correspondence with Jo Dukes McEwan we are now looking at a more cost effective blood test called the Troponin I test. This is a simple blood test done by any vet in the country and should only cost around £30. This test will detect if your dog is showing signs of a heart defect. If the results come back with a higher level of Troponin than normal then the next step would be to get Echo and Holter so that the screening is more focused. More information on this test and the DBC’s involvement with this will follow shortly.   DBC Health Co-ordinator Rebecca Barber email Rebecca 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. 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   Menu