Introduction

Dilated cardiomyopathy (DCM) is defined as a primary myocardial disease characterized by cardiac enlargement and impaired systolic function in the absence of other cardiac or non-cardiac causes. Dilated cardiomyopathy is prevalent in certain large to giant sized breeds of dogs and the disease contributes to a large proportion of the overall mortality in these breeds in dogs <10 years of age. Population-based European actuarial data showed that out of the 12 breeds with the highest cardiac mortality, 11 were breeds prone to develop DCM (Irish wolfhound, Great Dane, St. Bernard, Newfoundland, Leonberger, Doberman pinscher, Finnish hound, boxer, giant schnauzer, cocker spaniels). The impact of DCM on mortality is striking in affected breeds; the mortality ranged from 3.6% per year at risk (Irish wolfhound). This cause specific mortality can only be matched by MMVD in CKCS (2.5% per year at risk). Dilated cardiomyopathy is most common in large-breed dogs, but not all large breeds are affected. For instance German shepherds and Labrador retrievers had cardiac mortality comparable to the "average breed" in the European actuarial data. Dilated cardiomyopathy is uncommon in small-breed dogs and findings indicative of DCM in such dogs should always be questioned. Because of the high incidence of DCM in affected breeds, there is a growing interest among breeders and pet owners to take actions to reduce the occurrence of DCM. Screening programs have been initiated in some breeds in several countries. These programs aim to identify affected dogs at an early stage and exclude them from breeding. The prognosis after diagnosis of symptomatic DCM is poor and the median survival time ranges between 27 to 140 days, but there are breed differences. For diagnostic, prognostic, therapeutic, and breeding purposes, it is essential to detect the asymptomatic (preclinical) phase of the disease. For the pet owner with a dog with DCM, it is important that the clinician establish an accurate diagnosis to allow adequate therapy to improve the dog’s quality of life and improve survival.

Clinical Presentation and Classification of Disease

The clinical presentation may be subtle and include the gradual development of exercise intolerance and weight loss. However, more commonly, these early indications are overlooked and the diagnosis of DCM is not established until CHF develops and the patient is presented for coughing, dyspnea, tachypnea, wasting, arrhythmia, syncope, and sometimes ascites. Indeed, increasing interest in screening families of dogs where DCM is prevalent has led to an appreciation that there is a very long phase of the disease that is not associated with clinical signs evident to the owner or veterinarian. Indeed, the phase with clinical signs, usually associated with the presence of CHF, is the final stage of several years of insidious progression. For the symptomatic patient, it is important for the clinician to rule out other possible causes for the clinical signs, such as pericardial effusion, pneumonia, neoplastic disease, undiscovered congenital heart disease. For the asymptomatic patient, the challenge lies in differentiating normal variation and other cardiac or non-cardiac pathologies from DCM.

Histopathological characterization of dogs with DCM suggests that there are two phenotypes that presumably precipitate different clinical presentations. Most dogs with DCM present with systolic dysfunction and cardiac dilatation, often accompanied with an arrhythmia, most commonly atrial fibrillation. The histopathological findings commonly found in these dogs include thin myocytes with a wavy appearance that are separated by a clear space, indicating edematous fluid that is generally free from cellular infiltrates. There may also be diffuse infiltration of subendocardial fibrosis. However, a proportion of boxers and Doberman pinschers (not all), present with ventricular tachyarrhythmias, causing fainting and weakness, but cardiac dilatation and systolic dysfunction is not apparent. These Doberman pinschers and boxers presenting with ventricular tachyarrhythmias often have myocardial lesions that include myocytolysis, myofibre degeneration, vacuolization and myocyte atrophy with extensive fibrosis and fatty infiltration.

Although DCM is currently considered to be a genetic disease, diagnosis is currently based on phenotypic characterization. Because of the two histopathological phenotypes, dogs of different breeds are screened differently for preclinical disease. Most breeds are screened using echocardiography, whereas Doberman pinschers and boxers are also screened with 24-hour (Holter) recordings because a single ECG trace only corresponds to a small fraction of the dog's rhythm over a 24-hour period, and identification of intermittent abnormalities may be entirely fortuitous. Evidence of ventricular arrhythmia may precede echocardiographic evidence of DCM in the Doberman pinscher by some months or even years. In Doberman pinschers and boxer dogs, therefore, Holter monitoring is of proven value in the identification of dogs destined to develop DCM and guidelines have been produced for these breeds for acceptable number of ventricular depolarizations over a 24-hour period. The echocardiographic diagnosis of DCM is based on the identification of myocardial (predominantly but not solely) systolic dysfunction with the active exclusion of other acquired or congenital cardiac diseases.

Genetic Aspects of DCM

Dilated cardiomyopathy has been described to be inherited as an autosomal dominant trait in most breeds where it has been studied, the exceptions being Great Danes and Portuguese water dogs (see below). At present date, only two causative mutations have been suggested, one in Dobermann pinschers, mitochondrial enzyme pyruvate dehydrogenase kinase 4 (PDK4), and one in boxer dogs, striatin. The mutation in the PDK4 gene was tested in a cohort of European dogs from Germany and the UK, but the association could not be replicated in this population of dogs. This is suggestive of other causative genes in European dogs and/or geographic stratification of the breed. A genome-wide significant association to DCM was recently found in German Doberman pinschers, classified according to both echocardiographic and 24-hour (Holter) findings on chromosome 5 (p_raw = 3.54 x 10^-8). The association was replicated in an independent cohort collected in the UK. There is no currently known DCM candidate gene under the association signal. For the boxer dogs, an attempt has been made to replicate the association between the striatin mutation and ARVC in UK boxer dogs, but failed to do so. The results showed that the striatin mutation was very common in this population of UK boxers. However, the proportion of dogs in the phenotypically normal and phenotypically affected dogs was not significantly different. Furthermore, in contrast to the boxers from USA, the genotype was not correlated to the number of VPCs recorded over 24 hours in the UK population. However, genome wide association analyses have also been performed in Irish wolfhounds, Newfoundlands and Great Dane dogs, and preliminary results of significant genome wide associations have been presented, but no candidate genes have yet been brought forward in these breeds. In people, mutations in the genes encoding the thick filament components myosin heavy chain and myosin binding protein C together explain 75% of inherited cases of hypertrophic cardiomyopathy (HCM) (which is a rare disease in dogs, but not in cats), which is suggestive of that HCM is a disease of the sarcomere. In contrast, DCM in people appears to be far more genetically heterogeneous, with mutations in genes encoding cytoskeletal, nucleoskeletal, mitochondrial, and calcium-handling proteins. Private mutations account for most DCMs, with few hotspots or recurring mutations. More than 50 single genes are linked to inherited DCM in people, including many genes that also link to HCM. There are still many human DCM forms, where the causative mutation remains unknown.

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