Medizinische Kleintierklinik
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Dilated cardiomyopathy (DCM) in Doberman Pinschers – genetic, diagnostic, and therapeutic studies

Gerhard Wess1, Peter Holler1, Pascale Smets1, Karin Weber1, Tosso Leeb2, Ingo Schimke3

1Clinic of Small Animal Medicine, Centre for Clinical Veterinary Medicine, Faculty of Veterinary Medicine, LMU, Munich
2
Institute of Genetics, Vetsuisse Faculty, University of Bern
3
Institute of Laboratory Medicine, Clinical Chemistry and Pathobiochemistry, Charité, Universitiy Medicine, Berlin

Background

Cardiomyopathy is one of the most common cardiac diseases in dogs and humans. Doberman Pinschers are one of the most commonly affected breeds, and DCM in this breed is an inherited, slowly progressive disease. Ventricular premature contractions (VPCs) are a common finding in the occult phase of the disease, and about 30% of affected dogs die suddenly.

Cardiomyopathy in Doberman Pinschers can serve as as a model for human cardiomyopathy and is for many years one of the major research topics of the cardiology section of the LMU University’s Clinic of Small Animal Medicine. Beside the evaluation of new diagnostic tests to establish early diagnosis, one aim was to unravel the genetic defect of this disease within the EU-sponsored LUPA-program. New and so far unknown genetic defects might be of importance also for human medicine.

Research highlights

Prevalence of dilated cardiomyopathy in Doberman Pinschers in various age groups
The prevalence of cardiomyopathy in Doberman Pinschers was unknown until the publication of this study. Breeding associations had denied the existance or clinical importance of this disease in Germany. This study, however, showed a high prevalence (58.8%) of cardiomyopathy in Doberman Pinschers in Europe, comparable to that reported in the United States and Canada. The disease is equally distributed in male and female dogs, but there appears to be different disease manifestations between sexes. Female dogs have significantly more often VPCs detected as the only abnormality, whereas male dogs show echocardiographic changes earlier than do female dogs. Screening for occult cardiomyopathy should be started in Dobermans at two years of age and include Holter monitoring and echocardiography. The screening should be repeated on a yearly basis.

Evaluation of N-terminal pro-B-type natriuretic peptide as a diagnostic marker of various stages of cardiomyopathy in Doberman Pinschers
N-terminal pro-B-type natriuretic peptide (NT-proBNP) is a new biomarker in dogs. The aim of this study was to evaluate, if NT-proBNP could be used as additional diagnostic test besides the gold-standard echocardiography and 24-hour-ECG. The study included 328 Doberman Pinschers in various stages of the disease. A special feature was the inclusion of a group called „last normal“, which consisted of dogs that were considered normal during initial examination but developed DCM within 1.5 years after this assessment. Plasma concentrations of NT-proBNP were increased in dogs with DCM and in apparently healthy dogs that developed DCM within 1.5 years after samples were obtained, compared to concentrations in control dogs. This study showed, that NT-proBNP is a clinically useful additional test for the detection of early DCM in Doberman Pinschers.

A locus on chromosome 5 is associated with dilated cardiomyopathy in Doberman Pinschers
Currently, many human DCM cases exist in which no causative mutation can be identified. DCM also occurs with high prevalence in several large dog breeds. In the Doberman Pinscher, a specific DCM form characterized by arrhythmias and/or echocardiographic changes has been intensively studied by veterinary cardiologists. We performed a genome-wide association study in Doberman Pinschers. Using 71 cases and 70 controls collected in Germany we identified a genome-wide significant association to DCM on chromosome 5. We validated the association in an independent cohort collected in the United Kingdom. There is no known DCM candidate gene under the association signal. Therefore, DCM in Doberman Pinschers offers the chance of identifying a novel DCM gene that might also be relevant for human health.

Future perspectives

Currently we evaluate several new diagnostic tools and methods that might enable earlier diagnosis of the disease, such as miRNA as a new biomarker. The genetic study is continuing with the aim to provide a working genetic test, and also to potentially evaluate this genetic test in humans with DCM. Additionally, several randomized therapeutic studies are ongoing to evaluate the best antiarrhythmic strategy to prevent sudden death, as well as other drugs to delay progression of the disease. In a new study collaboration with the Charite we are evaluating Aptamers against auto-antibodies, which we have been able to detect recently in Dobermans with DCM.

Selected references

  • Wess G, Schulze A, Butz V, Simak J, Killich M, Keller LJ, Maeurer J, Hartmann K: Prevalence of dilated cardiomyopathy in Doberman Pinschers in various age groups. J Vet Intern Med 2010; 24:533-538
  • Wess G, Butz V, Mahling M, Hartmann K: Evaluation of N-terminal pro-B-type natriuretic peptide as a diagnostic marker of various stages of cardiomyopathy in Doberman Pinschers. Am J Vet Res 2011;72:642-649
  • Mausberg TB, Wess G, Simak J, Keller L, Drogemuller M, Drogemuller C, Webster MT, Stephenson H, Dukes-McEwan J, Leeb T: A locus on chromosome 5 is associated with dilated cardiomyopathy in Doberman Pinschers. PLoS One 2011;6:e20042

Funding

  • LUPA-Program - a European initiative taking advantage of the canine genome architecture for unravelling complex disorders in both human and dogs
  • Böhringer Ingelheim – funding of several drug studies
  • Charité Research grant – Aptamere study

External collaborations

Tosso Leeb, Institut für Genetik, Vetsuisse-Fakultät, Universität Bern
Ingolf Schimke, Medizinische Chemie und Pathobiochemie Medizinische Chemie und Pathobiochemie, Charité, Universitätsmedizin, Berlin