Boxer cardiomyopathy (ARVC): update on the current genetic situation
Paul Wotton, Jo Dukes-McEwan, Hannah Copeland & Bruce Cattanach
Paul Wotton BVSc, PhD, DVC, MRCVS; University of Glasgow; p.wotton@vet.gla.ac.uk
Acknowledgement: Dr. Kate Meurs kindly provided slides used in her presentation at the 2009
ACVIM Forum; a paper based on this work has been submitted for publication.
Cardiomyopathy in boxers
The first published description of ‘boxer cardiomyopathy’ (BCM) was in 1983 (Harpster1), and
there have since been several clinical descriptions of this disease, mainly from the USA 2-5. Three
clinical categories of disease are classically described:
1) ‘Concealed’ (occult or pre-clinical) disease: no signs, but arrhythmias present;
2) ‘Overt’ disease: episodic syncope (usually with exertion or excitement) with arrhythmias.
Various arrhythmias are seen, but VPCs with a left bundle-branch block (LBBB) pattern
(implying right ventricular origin6) are common;
3) ‘Myocardial dysfunction’ stage: congestive heart failure, esp. involving the left ventricle,
resembling ‘classical’ dilated cardiomyopathy (DCM).
It is not known whether these 3 phases represent a continuum of the same disease, different
variants of the same disease or different diseases altogether, but progression from 1) to 2) and
sometimes 2) to 3) is seen.
Whereas in ‘classical’ DCM* histological changes in the myocardium are often mild or non-specific,
out of proportion to the functional disturbances seen, the pathological and histological findings in
BCM are striking, and involve7:
 Right ventricular (RV) enlargement or aneurisms;
 Early focal, later widespread, severe RV myocyte atrophy with replacement by fatty and fibrofatty tissue, especially in the cranio-lateral and infundibular RV;
 Focal fibro-fatty lesions are also present in both atria and the left ventricle;
 Evidence of myocarditis may be seen especially in dogs that die suddenly, with patchy lysis,
necrosis, haemorrhage and a mononuclear response.
(*DCM is probably not a single disease, but rather it probably represents a common phenotypic
end-point for several pathological or genetic processes. Attenuated wavy fibres are seen
histologically in a proportion of cases.)
Boxer cardiomyopathy is often referred to as arrhythmogenic right ventricular cardiomyopathy,
ARVC, because of its resemblance to this condition in humans. This is also characterised by
fibro-fatty replacement of the RV myocardium. It is familial, inherited as an autosomal dominant
trait and a number of mutations have been identified, e.g. in the ryanodine receptor 2 and
desmoplakin genes.
Human ARVC results in ventricular tachyarrhythmias (with a LBBB
morphology) and/or sudden unexpected death especially during exercise in young adults.
Cardiomyopathies, including HCM & ARVC, are the most common causes of sudden death in young
adults, especially athletes, when trauma and suicide are excluded. In some cases, however, CHF
comes first8-9.
The search for a genetic marker in dogs
Much research effort, primarily by Meurs and associates, has been put into trying to identify a
mutation or genetic abnormality linked to BCM, targeting especially the genes implicated in
humans. Meurs & others10 looked at RV, IVS & LV myocardium from normal dogs and ARVC
boxers and found that cardiac ryanodine receptor (RyR2) protein & RNA expression (implicated in
ARVC2 in people) were lowest in the RV of normal dogs and were reduced in all chambers in
ARVC dogs. This might explain the apparently increased susceptibility of the RV to an abnormality
that affects the whole heart. However subsequent work failed to identify any genetic linkage with
the RyR2 gene in cases of ARVC, and this may be a secondary rather than a primary abnormality.
Another research group11 has used immunofluorescence to look at the molecular composition of
the intercalated disc structure in boxers with ARVC, as molecular remodeling of intercalated disc
has been noted in human patients. Compared with control dogs, there was loss of staining for
connexin43 at the intercalated discs. However gene sequencing failed to find mutations for
desmoplakin, plakoglobin, connexin43, or plakophilin 2. Again, it is possible that these molecular
changes might be secondary rather than primary.
This group has also demonstrated
ultrastructural changes in the desmosomes and gap junctions of affected dogs 12.
Oyama and others13 have looked at the expression of the gene for calstabin2 (FKBP12.6), a
regulatory molecule for RyR2 that stabilises its closed state in diastole, preventing calcium
‘leakage’. Diastolic leakage of calcium could trigger arrhythmias and reduces the efficiency of
calcium cycling. They found that calstabin2 mRNA expression is significantly down-regulated in
myocardium from ARVC boxers compared with healthy controls and dobermanns with DCM.
In the most promising development to date, Meurs and others 14 have now identified (the following
is quoted directly from the research abstract) ‘a 7 base pair deletion within a non-coding
conserved element in a regulatory region of a calcium modulating gene (striatin) [was identified]
and observed to be highly associated with the disease status (p<0.0001). The deletion was not
observed in unaffected Boxer dogs or in any of 31 dogs from other breeds tested. Affected dogs
were either homozygous or heterozygous for the deletion. Homozygous dogs (N=15) had a
statistically greater number of VPC/24 hours than heterozygous (mean of 7860 and 2845,
respectively) (p<0.05). We conclude that this 7 base pair deletion is associated with the
development of Boxer ARVC and that dogs that are homozygous for the mutation appear to have
a more severe degree of arrhythmias.’
The identification of this striatin gene mutation has resulted in widespread screening for this
mutation in affected and apparently normal boxers. Unfortunately striatin genotype does not
appear to correlate with phenotype in UK dogs, and similar findings have been made in other
countries, including the USA. Thus it appears that the striatin gene mutation may merely enhance
of modify expression of an ARVC gene, and further searches for a primary causative mutation are
under discussion.
Diagnosis of BCM
As discussed by Meurs4, the diagnosis of BCM may be challenging, and may often be a diagnosis
of exclusion. Changes in the criteria for diagnosis of ARVC in humans have recently been made
due to a number of factors, including increasing recognition of the familial nature of the disease
and early left ventricular involvement on some cases15. Holter ECG recordings are often regarded
as a gold standard for clinical diagnosis, but considerable variability in arrhythmia frequencies has
been found16. Serum levels of cardiac troponin I (cTnI) appeared to be a better marker for BCM
than plasma BNP concentrations in work performed by Meurs’ group 17, 18. The potential value of
cTnI as a screening test for boxer cardiomyopathy in the UK, especially in trying to pick out the
best dogs to target for closer examination (e.g. a Holter ECG), is currently being assessed, but
has been frustrated by lack of follow-up/definitive diagnoses. Magnetic resonance imaging has
been found to be useful in humans with ARVC 19, especially for early detection of RV fatty
infiltrates, but this has not so far been found to be useful in boxer dogs 20.
References
1) Harpster, N. (1983). Boxer cardiomyopathy. In: Kirk R, editor. Current Veterinary Therapy
VIII. Philadelphia, WB Saunders. 329-337
2) Wotton, P.R. (1999). Dilated cardiomyopathy (DCM) in closely related boxer dogs and its
possibly resemblance to arrhythmogenic right ventricular cardiomyopathy (ARVC) in humans.
Proceedings of the 17th Annual Veterinary Medical Forum, ACVIM, Chicago. p88-89
3) Meurs, K.M. et al. (1999). Familial ventricular arrhythmias in boxers. J Vet Intern Med 14,
437-439
4) Meurs, K.M. (2004). Boxer dog cardiomyopathy: an update. Vet Clin N Am Small Anim Pract
34, 1235-1244
5) Baumwart, R.D. et al. (2005). Clinical, echocardiographic and electrocardiographic
abnormalities in boxers with cardiomyopathy and left ventricular systolic dysfunction: 48 cases
(1985-2003). J Am Vet Med Assoc 226, 538-541
6) Kraus, M.S. et al. (2002). Morphology of ventricular arrhythmias in the Boxer as measured by
12-lead electrocardiography with pace-mapping comparison. J Vet Intern Med 16, 153-8
7) Basso, C. et al. (2004). Arrhythmogenic right ventricular cardiomyopathy causing sudden
cardiac death in boxer dogs. A new animal model of human disease. Circulation 109, 11801185
8) Calabrese, F. et al. (2006). Arrhythmogenic right ventricular cardiomyopathy/dysplasia: is
there a role for viruses? Cardiovascular Pathology 15, 11-17
9) Corrado, D. et al. (2009). Arrhythmogenic right ventricular cardiomyopathy: an update. Heart
95, 766-773
10) Meurs, K.M. et al. (2006). Differential expression of the cardiac ryanodine receptor in normal
and arrhythmogenic right ventricular cardiomyopathy canine hearts. Human Genetics 120,
111-118
11) Oxford, E.M. et al. (2007). Molecular composition of the intercalated disc in a spontaneous
canine animal model of arrhythmogenic right ventricular dysplasia/cardiomyopathy. Heart
Rhythm 4, 1196-1205
12) Oxford, E.M. et al. (2009). Phenotypic differences in the ultrastructure of cardiomyocytes from
boxer dogs afflicted with arrhythmogenic right ventricular cardiomyopathy (ARVC).
Proceedings ACVIM Forum 2009, p685
13) Oyama, M.A. et al. (2008). Arrhythmogenic right ventricular cardiomyopathy in Boxer dogs is
associated with calstabin2 deficiency. J Vet Cardiol 10, 1-10
14) Meurs, K.M. et al. (2009). Genome-wide association identifies a mutation for arrhythmogenic
right ventricular cardiomyopathy in the Boxer. Proceedings ACVIM Forum 2009, p684-685
15) Marcus, F.I. et al. (2010). Diagnosis of arrhythmogenic right ventricular cardiomyopathy/
dysplasia. Proposed modification of the task force criteria. Circulation 121 (ePub. ahead of
publication)
16) Spier, A.W. & Meurs, K.M. (2004). Evaluation of spontaneous variability in the frequency of
ventricular arrhythmias in Boxers with arrhythmogenic right ventricular cardiomyopathy. J Am
Vet Med Assoc 224, 538-541
17) Baumwart, R.D. & Meurs, K.M. (2005). Assessment of plasma brain natriuretic peptide
concentration in Boxers with arrhythmogenic right ventricular cardiomyopathy. Am J Vet Res.
66, 2086-2089
18) Baumwart, R.D., Orvalho, J. & Meurs, K.M. (2007). Evaluation of serum cardiac troponin I
concentration in Boxers with arrhythmogenic right ventricular cardiomyopathy. Am J Vet Res.
68, 524-528
19) Conen, D. et al. (2006). Value of repeated cardiac magnetic resonance imaging in patients
with suspected arrhythmogenic right ventricular cardiomyopathy. Journal of Cardiovascular
Magnetic Resonance 8, 361-366
20) Baumwart, R.D. et al. (2009). Magnetic resonance imaging of right ventricular morphology
and function in boxer dogs with arrhythmogenic right ventricular cardiomyopathy. J Vet Intern
Med. 23, 271-4
APPENDIX: BCM DIAGNOSIS, SAMPLE SUBMISSION & CONSENT FORMS
To submit blood samples to LUPA the UK DNA archive form is available at the following weblink
http://www.liv.ac.uk/dna_archive_for_companion_animals/PDFDocs/More%20canine/New_Boxer
_cardiomyopathy_form__doc.pdf
SAMPLES WITH THIS FORM can be sent directly to:
VETERINARY DNA ARCHIVE
Centre for Integrated Genomic Medical Research
University of Manchester
Stopford Building
Oxford Road
Manchester,
M13 9PT
EDTA blood samples and pedigrees may also be submitted with the form shown below to
Dr. Bruce Cattanach (address on the form), or to Paul Wotton:
Dr. Paul Wotton BVSc, PhD, DVC, MRCVS
Small Animal Hospital
Faculty of Veterinary Medicine
University of Glasgow
Bearsden Road
Glasgow, G61 1QH
Confirmation of diagnosis form: ‘Boxer cardiomyopathy’
(upper section to be completed by owner)
Registered name …………………………………………………… Pet name…………………………………………
Date of birth…………………………… Sex (D/B)…………… Colour…………………………………….................
Sire…………………………………………………………………………………………………………………………….
Dam……………………………………………………………………………………………………………………………
Copy of full pedigree provided – yes/no;
Date (mth/yr) of final diagnosis………………………………..
Attending veterinary surgeon…………………………………………………………………………………..................
Consulting cardiologist…………………………………………………………………………………………………….
Owner consent
I agree that stored blood samples may be used for genetic (DNA) research
I agree that the above information, along with relevant clinical details, may be shared with other
researchers/geneticists for the study of cardiomyopathy in Boxers. I am aware that this information may be
published, but without names of individual dogs or owners. The identities of individual dogs will be known to
geneticists, breeders and cardiologist researchers to facilitate genetic counseling and to limit the impact of this
disease on the breed in the future.
Owner name/address (please print) ………………………………………………………………………….................
…………………………………………………………………………………………………………………………………
Telephone/email ……………………………………………………………………………………………………………
Signature……………………………………………………………………........................ Date………………………
Confirmation of diagnosis (to be completed by cardiologist)
I confirm that I have examined the above-named Boxer and/or examined its records and that the clinical signs
and results of diagnostic tests are consistent with a diagnosis of cardiomyopathy.
Cardiologist name/address (please print)………………………………………… ……………………………………
…………………………………………………………………………………………………………………………...........
Telephone/email ……………………………………………………………………………………………………............
Major sign(s) …………………………………………………………………………………………………………….....
Criteria used for diagnosis (please circle); please add these details if possible/available - further details may be
added overleaf if required:
Echo changes: abnormal RV ……………………….; abnormal LV ………………..……..; FS/EF low …….…%
Arrhythmia: ECG findings ………………………; Holter…………………………………; Post mortem? ………
Troponin: Result:………..ng/ml Laboratory used:………………………… Reference range:……………………
Signature…………………………………………………………….
Date …………………………………………
CertSAC/CertVC/DVC/DipECVIM/other ………………… (please circle)
Please return the completed form to:
Dr BM Cattanach, Downs Edge, Reading Road, Harwell, Oxfordshire OX11 0JJ
Tel/Fax: 01235 835410; email bcattanach@steynmere.freeserve.co.uk