| Tackling DCM
Dorothy Foegen was unconcerned when she signed up her 5-year old Doberman Pinscher Trisanna's Corry von Diessen, CD, RN, for the heart clinic being held at the United Doberman Club Nationals last May. After all, "Corry" had undergone annual echocardiogram testing without any problems. When Nancy Morris, D.V.M., DACVIM, a board-certified veterinary cardiologist, told Foegen that the 24-hour Holter monitor test conducted as part of the clinic indicated that Corry had the potentially fatal heart disease dilated cardiomyopathy (DCM), Foegen was floored. "I didn't have a worry at all about Corry," says Foegen of Greenwood Village, Colo. "Because she had tested healthy in previous heart examinations, I just knew she wasn't going to have any cardiac problems." The Holter monitor test showed that Corry experienced ventricular tachycardia, or erratic heartbeats, around 4 a.m. in the hotel with Foegen. "The lines on the graph spiked up and down, up and down," she says. "At least 10 to 15 irregular heartbeats occurred in a row. It really shook me." Doberman Pinschers experience the highest incidence of dilated cardiomyopathy. In fact, DCM and ventricular arrhythmia account for 30 percent of Dobermans dying suddenly due to ventricular arrhythmia.' In Great Danes, DCM is the No. 1 cause of death among male Danes - about 90 percent of affected dogs are males - suggesting a possible X-linked mode of inheritance in the breed. Morris, who practices at Mass. Veterinary Cardiology Services in Pembroke, Mass., explains that DCM develops in two ways. "Younger dogs, 3 to 5 years of age, tend to experience ventricular arrhythmia and sudden death, while dilated cardiomyopathy and eventual congestive heart failure typically affect dogs around 5 to 10 years of age. DCM usually has been present for six to 18 months, and maybe as long as two years before signs appear. It may seem to be a 'sudden' death because without testing, it often goes undiagnosed." Echocardiogram and 24-hour Holter monitor testing are recommended for all Dobermans and Great Danes to help detect DCM. Combining the tests and repeating them on a regular basis is considered the most comprehensive way to identify dogs in the early stages of the disease. The theory is that while one test may produce normal results, the other may pick up an abnormality, or vice versa. Detection of DCM at the earliest possible stage may enable drug therapy to slow the progression of the eventually fatal disease, ease symptoms and improve quality, if not quantity, of life. Other breeds experience DCM as well. Boxers, for example, develop a form of DCM in which the primary defect is in the heart's electrical conduction systern. Scottish Deerhounds, Irish Wolfhounds, Dalmatians, Newfoundlands, Saint Bernards, Portuguese Water Dogs, Afghan Hounds, Old English Sheepdogs, Golden Retrievers and Labrador Retrievers are other DCM-affected breeds. Breeds and individual dogs may vary in age of onset, rate of progression, type of arrhythmia, and frequency of sudden death versus congestive heart failure. Reduced Heart Muscle Function Dilated cardiomyopathy is a disease that also occurs in humans, most commonly in adult men. It is the most common cause of heart failure and is due to an enlarged and weakened heart muscle that no longer pumps adequate oxygen-rich blood to the body. In people, DCM is caused by conditions such as coronary artery disease, viral infections and genetic disposition. Similarly, dogs with DCM experience a gradual reduction in heart muscle function. Over time, the heart dilates to compensate for the weakened heart muscle, which causes it to hold a greater blood volume while the thinned heart walls continue to weaken. Eventually the diseased heart muscle fails to generate enough force to pump the blood, causing a sequence of events to occur. If the heart's right ventricle fails, fluid backs up in the dog's abdomen. If the left ventricle fails, which happens most often, fluid backs up into the lungs. Dogs with fluid in the lungs, known as pulmonary edema, often develop a cough, rapid breathing and lethargy. Ventricular arrhythmia also may occur. By the time these signs are present, the disease may be well-progressed and the prognosis grim. Congestive heart failure occurs when the heart can no longer pump blood out fast enough to meet the needs of body tissues. The good news for breeders and owners of dogs affected by DCM is that researchers are working diligently to better understand the disease. At Imulan BioTherapeutics in Scottsdale, Ariz., researchers are developing a vaccine that holds promise in managing the immune dysregulation that accompanies certain forms of cardiovascular disease, including cardiomyopathy. Meanwhile, collaboration between researchers at the University of Pennsylvania and State University of New York at Albany focuses on identifying the genetic mutation in affected breeds. Therapeutic vaccination for canine genetic diseases, such as DCM and certain types of cancer, represents a new strategy. Efforts to undue a health problem by reversing the disease mechanism involve understanding the disease process. The theory behind Imulan's vaccine relies on correcting an immune system imbalance observed in humans and laboratory animals with DCM and suspected in dogs with DCM. Craig Woods, D.V.M., founder and CEO of Imulan, explains, "Until recently we had limited understanding of the immune system's association with cardiac diseases. Now we know that the immune system plays a substantial role in certain cardiac diseases. The basic principle is that immune cells produce chemical messengers, called cytokines. The cytokines affect a variety of other cells and their gene expression, including cells within the heart. "In certain diseases these cytokines become unbalanced causing a downward spiral. Our approach is to correct this cytokine problem using a vaccine that regulates T helper cells, a group of immune cells that produce a number of cytokines. In rodent studies, the vaccine restores the normal cytokine balance in DCM subjects, an effect that results in tissue remodeling and improvement in cardiac function. These results are fascinating, and we hope the same effect translates to dogs." Woods continues, "DCM is a very complex disease in which numerous pathways become disrupted. Many drugs have typically failed in adequately controlling the disease because they normally are restricted to influencing a single metabolic pathway. Our vaccine differs because it results in a more comprehensive approach to disease management by modulating cytokine-producing immune cells for a multipathway intervention. Think of it like moving treatment from the manager level to the executive level. We are going straight to the CEO." A small pilot study using the vaccine will begin this fall focusing on breeds susceptible to die condition. Researchers plan to examine the effects of the vaccine in diseased patients with a goal of restoring cardiac function similar to what has occurred in mouse models. Woods is optimistic, but guarded, that the research could one day have application in treating dogs and humans diagnosed with dilated cardiomyopathy. "We may find out that the vaccine doesn't work to treat DCM in dogs, but we are compelled to at least explore this revolutionary approach," he says. "Even if the vaccine has marginal effects, this would be a major advance in veterinary medicine by finding a novel, nontraditional approach for treatment." A Search for Candidate Genes The genetic predisposition of Doberman Pinschers, Great Danes and Boxers to developing DCM is obvious to Mark Oyama, D.V.M., DACVIM, associate professor at the University of Pennsylvania, and Sridar Chittur, Ph.D., of the Center for Functional Genomics at the State University of New York at Albany. Using state-of-the-art GeneChip Canine Genome Array technology, they are fastforwarding through thousands of gene simultaneously searching for candidate genes responsible for DCM. "Microarrays, such as the GeneChip technology, are a useful tool that allows us to look at thousands of genes involved in cellular metabolism or cellular physiology at the same time," Chittur explains. "We can look at disease biomarkers or possible targets for intervention." When the GeneChip technology was introduced two years ago, Chittur and Oyama used it to analyze gene activity in Doberman Pinschers with DCM. They found nearly 500 genes that were significantly "turned on" or "turned off' compared to healthy dogs. Of these genes, 173 were upregulated (turned on), with increased gene activity, and 305 were downregulated (turned off), with no gene activity. From this pool, they identified 167 genes that may play a role in the development and progression of DCM. "The significance in identifying on and off genes is that potentially we can use the information to reverse the switch and thereby treat disease," says Chittur. The researchers currently are using the microarray technology to study DCM in Great Danes by comparing it with DCM in Boxers and Dobermans. "By comparing the information across breeds we hope to narrow down the genes involved and identify biomarkers," Chittur says. "If we can come up with a list of five or so genes that are up or down in DCM, we could use this information to make a diagnostic kit that could be used for early detection. Our goal is to find the genetic mutation that causes DCM as well as develop treatment therapies. If we can do what has been done with human cardiovascular disease in dogs, it will be worth it." Until effective therapies and the genetic mutation that causes DCM can be found, breeders and owners of dogs susceptible to the potentially fatal heart condition are advised to test their dogs regularly and to report findings to canine health registries. Morris, the veterinary cardiologist who diagnosed Foegen's Doberman Pischer Corry, tells breeders not to breed dogs diagnosed with dilated cardiomyopathy due to the genetic implications. Unfortunately, because DCM may not appear until a dog is 8 or 9 years old, affected dogs may have already been bred before being diagnosed. "Some people think that if a dog develops dilated cardiomyopathy around the ages of 8 or 9 it is something normal that happens with old age," Morris says. "Cardiomyopathy isn't a condition that normally comes with old age. It is a serious disease." Testing to Detect DCM "In breeds where disease incidence is high, such as Dobermans and Great Danes, echocardiogram and Holter monitor testing are recommended for all dogs to help detect DCM," Morris says. "Dobermans should receive an echocardiogram when they are 1 to 2 years old along with a baseline 24-hour Holter monitor test. Dobermans 4 years old and older being used in breeding programs should receive both tests every six months." An echocardiogram is used to detect heart structure and function abnormalities; however, the testing could occur when the heart appears normal, which is when the disease is in the subclinical or occult phase. Thus, a dog would be considered asymptomatic. In contrast, the Holter monitor provides information about the heart rhythm over a 24-hour period. An abnormal Holter monitor test is useful in predicting Dobermans that might later experience sudden death or develop DCM and congestive heart failure during the symptom-free phase of the disease. Basically a portable electrocardiogram (EKG) recorder, the Holter monitor consists of a recorder with five leads attached to the dog's chest to collect the electrical activity of the heart The dog wears the apparatus in a vest while going about normal activities, other than swimming or bathing, while the owners keep a log of the dog's activities. A scan of the cassette tape is performed and all ventricular premature contractions (VPCs), also known as PVCs, are tabulated by the cardiologist. Health clinics such as the one at the United Doberman Club Nationals often reach people who may not have access to a veterinary cardiologist. Marjorie Brooks, chairwoman of the Doberman Pinscher Club of America (DPCA) Breeder Education Committee, feels strongly that all breeding Dobermans should be tested. Having been involved with Dobermans since 1962, Brooks says, "We used to call it 'sudden death,' but now we recognize it as DCM. "Too many Dobermans die without warning," she says. "An owner may be watching his dog play, and the dog simply drops dead in front of his eyes. What is really frightening is that this is happening to younger dogs. I feel health testing is the only way to begin to put an end to this." Brooks recently helped her local Redwood Empire Doberman Pinscher Club buy a Holter monitor so all Dobermans in the club could be tested for DCM. Her dog, CH Manorie Dobe's Five Star General, CD, RE, CGC, ROM, was diagnosed with occult DCM, meaning he is asymptomatic, following a Holter monitor test. As for Foegen's Doberman Corry, drug therapy has helped treat the disease and the dog appears healthy despite having DCM. "I'm just relieved we caught it early," she says. Brooks shares those sentiments about her dog "General." "It was a relief in knowing that General was diagnosed early enough to receive effective treatment. Since I was able to learn about the condition, I can make sure that he receives proper treatment." ' Calvert CA, Wall M. Results of ambulatory electrocardiography in overtly healthy Doberman Pinschers with equivocal echocardiographic evidence of dilated cardiomyopathy. J Am VetMedAssoc. 2001, Sept. 15; 219(6):782-784. ..... An important step for breeders and owners of dogs diagnosed with dilated cardiomyopathy (DCM) is to report the results from cardiac health testing to canine health registries. The benefits are multifaceted. The Canine Health Information Center (CHIC) program, sponsored by the Orthopedic Foundation for Animals and the AKC Canine Health Foundation, provides a centralized health database on individual dogs. Registering health tests with CHIC helps to advance epidemiological research, breeding knowledge about individual dogs, increased awareness of health issues, and proviedes important tools for researchers. Through the CHIC DNA Repository, samples for genetic research are available for researchers to use with perission from parent clubs. The repository collects and stores canine DNA samples along with information about geneaology, phenotype, and a dog's lifetime health history. For information, visit www.caninehealthinfo.org. The Clinical Animal Registration and Education (CARE) Foundation provides a health registry for naturally occurring diseases, such as DCM. CARE began in 2004 with support from the Great Dane Health Foundation of America with a goal of collecting information about dogs with DCM so researchers could study the genetic mutation. Today, CARE provides comprehensive information about individual dogs entered in the database and assists researchers working on a wide range of health problems by providing clinical information and access to dogs for clinical trials. For information about CARE, visit www.careanimalfoundation.org. ..... "Today's Breeder," Nestle Purina PetCare Company. |
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| An article concerning Dilated Cardiomyopathy courtesy "Today's Breeder," Nestle Purina PetCare Company. |