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Compendium December 2010 (Vol 32, No 12)

Arrhythmogenic Right Ventricular Cardiomyopathy in Boxers [CE]

by Crystal D. Hariu, DVM, Dewey H. Carpenter, Jr., DVM, DACVIM , (Cardiology)

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    Abstract

    Arrhythmogenic right ventricular cardiomyopathy, formerly termed boxer cardiomyopathy, is a familial primary myocardial disease that is prevalent in boxers. Unique histopathologic changes in the myocardium lead to conduction abnormalities that typically manifest as ventricular tachyarrhythmias with left bundle branch block morphology. Affected dogs can be asymptomatic or may have syncope and/or exercise intolerance. Diagnosis can be difficult, and indications for antiarrhythmic therapy are not always clear. A small number of dogs present with systolic dysfunction and/or congestive heart failure. Screening in asymptomatic breeding dogs was difficult until the recent development of genetic testing.

    Harpster1 was the first to describe a primary myocardial disease in the boxer breed. It is considered a degenerative myocardial disease that is characterized by fatty or fibrofatty infiltration of the right, and sometimes left, ventricle.1–3 Formerly termed boxer cardiomyopathy, the disease is now referred to as arrhythmogenic right ventricular cardiomyopathy (ARVC) due to similarities between the disease in boxers and ARVC in humans, including presentation, genetic etiology, and histopathology.3,4 Hallmarks of the disease include ventricular arrhythmias, syncope, and sudden death.1,2

    ARVC in boxers is a familial disease inherited as an autosomal dominant trait.4 Variable penetrance is considered probable based on the variability in clinical presentation. Genetic mutations of the cardiac ryanodine receptor (RyR2) and their effect on the associated stabilizing protein calstabin-2 (FKBP12.6) have been demonstrated in some humans with ARVC.5 Dysfunction of these proteins leads to disruption of calcium homeostasis, which is critical to normal cardiac contractility and rhythm. Veterinary studies have shown that boxers with ARVC have decreased RyR2 protein expression6 and a calstabin deficiency in the left ventricle7 compared with controls. Additionally, mutations of the genes encoding the desmosomal proteins plakophilin-2,8 plakoglobin,9 desmoplakin,10 desmoglein-2,11 and desmocollin12 have been demonstrated in some humans with ARVC. Meurs et al13 did not identify any mutations in these desmosomal genes in ARVC-affected boxers.

    Clinical Presentation

    ARVC in boxers is typically a disease of adult onset, but the clinical presentation is variable.1,2 Harpster1 originally described three forms: asymptomatic dogs with occasional ventricular premature complexes (VPCs); dogs with episodes of syncope, weakness, or exercise intolerance associated with ventricular tachyarrhythmias; and dogs with tachyarrhythmias, usually ventricular, and some degree of myocardial dysfunction or congestive heart failure (CHF). Additionally, some dogs die suddenly, even with no previous clinical signs.

    Diagnosis

    Until recently, there was no genetic test to aid in diagnosis. Family history and multiple diagnostic tests are routinely used to aid in diagnosis (BOX 1). In addition to the cardiac-specific diagnostic tests listed in this article, general blood work should be performed to rule out any underlying metabolic cause of arrhythmia (e.g., anemia, hypokalemia, acidosis, hypoxia).14 Abdominal imaging should also be considered in appropriate cases because abdominal masses (especially splenic) can cause ventricular arrhythmias.15

    Physical Examination

    Many boxers with ARVC have no abnormalities on physical examination, but a tachyarrhythmia may be auscultated,16 characterized by extrasystolic beats and pulse deficits.17 A systolic murmur or gallop sound may be auscultated at the left apex in dogs with the myocardial dysfunction form of ARVC.1,2,18 Left basilar systolic murmurs are common in boxers; these are thought to be physiologic or due to aortic stenosis19,20 and should not be associated with ARVC.

    Thoracic Radiography

    Thoracic radiography findings are typically normal unless systolic dysfunction or CHF is present.1,2,20 The most common findings in one study of boxers with the myocardial dysfunction form of ARVC were generalized cardiomegaly, left atrial enlargement, pulmonary edema, and pleural effusion.18

    Electrocardiography

    ARVC is a disease characterized by ventricular arrhythmias1,2; therefore, electrocardiography (ECG) is critical to diagnosis. The most common ventricular arrhythmia in boxers originates in the right ventricle and manifests as VPCs with left bundle branch block morphology, primarily positive deflections of the QRS complexes in leads II, III, and aVF (FIGURE 1).21 VPC complexity varies: VPCs may be seen as single complexes, couplets, or runs of ventricular tachycardia. Supraventricular tachyarrhythmias, such as atrial fibrillation, have also been noted in boxers with the myocardial dysfunction form of ARVC.2,18

    Brief, in-house ECG is a useful, convenient way to assess heart rhythm, but it is insensitive to intermittent ventricular arrhythmias.22 Although the frequency of VPCs varies little throughout the day in boxers with ARVC,23 it can change by as much as 80% from day to day.24 If VPCs are present on brief ECG, further evaluation is strongly indicated; however, normal in-house ECG findings do not rule out ARVC.22

    A 24-hour ambulatory ECG (Holter monitor) provides a more complete picture of the patient’s VPC frequency and complexity (FIGURE 2). Healthy, mature dogs typically have infrequent VPCs in a 24-hour period.25 The presence of numerous VPCs (i.e., >100) or complex VPCs (e.g., couplets, triplets, bigeminy, runs of ventricular tachycardia) on a Holter monitor should be considered abnormal and strongly suggestive of ARVC.26

    Echocardiography

    Although ARVC is best characterized by ventricular arrhythmias, it is a primary myocardial disease.1 However, the myocardial changes are most notable at the microscopic level, and most boxers with ARVC have normal echocardiographic findings.2 Only boxers with the myocardial dysfunction form of ARVC typically have echocardiographic abnormalities, which are seen as left ventricular dilation and systolic dysfunction.2,18 Although technically difficult, careful examination of the right ventricle in these cases may identify enlargement.16 In one study, echocardiographic assessment of right ventricular structure and function did not provide prognostic information.27

    Magnetic Resonance Imaging

    Although magnetic resonance imaging (MRI) is becoming a more common diagnostic tool in veterinary medicine, motion artifacts have hindered its routine use for cardiac imaging.28 Basso et al3 used MRI postmortem to document fatty replacement within the right ventricle of ARVC-affected boxers. A recent study using MRI antemortem did not find such morphologic changes, although there was abnormal right ventricular function in boxers with ARVC compared with controls.29 Further studies of antemortem imaging may help define how MRI could be used as a noninvasive diagnostic tool.

    Histopathology

    ARVC is a primary myocardial disease characterized histologically by fatty or fibrofatty replacement of cardiac myocytes in the right, and sometimes left, ventricle1–3 ( FIGURE 3 and FIGURE 4 ). In human medicine, evidence of fibrofatty replacement on endomyocardial biopsy is considered a major diagnostic criterion.30 Endomyocardial biopsies are not routinely performed in veterinary medicine, but histopathology can be useful at necropsy for postmortem diagnosis in cases of sudden death of a previously healthy boxer.

    Genetic Testing

    Meurs et al31 recently identified an eight–base pair deletion within the striatin gene that was highly associated with disease status in ARVC-affected boxers and was not identified in unaffected boxers or other breeds of dogs tested. Affected boxers were either homozygous or heterozygous for the mutation, and homozygous dogs had a higher number of VPCs per 24 hours than heterozygous dogs.31 Testing for this genetic mutation is commercially available, and information can be found through the Washington State University Web site (www.vetmed.wsu.edu/deptSVCGL/Boxer/test.aspx).

    Screening in Asymptomatic Breeding Dogs

    With evidence of the familial nature of ARVC,4 there is a strong interest in screening boxers that are to be used in breeding programs. Before the development of the readily available genetic test, annual Holter monitoring was the only test that could be recommended for screening these dogs.26 Although not based on long-term studies, a screening system was proposed by Meurs26 based on the prevalence of arrhythmias in the asymptomatic population (TABLE 1).

    Before a genetic test was available, studies tried to develop other screening methods to identify the presence or severity of ARVC in boxers. Although QT dispersion may be an indicator of a re-entrant mechanism for arrhythmia, values did not correlate with disease severity in boxers with ARVC.32 Unlike humans with ARVC,33 plasma brain natriuretic peptide concentrations were not increased in boxers with ARVC.34 Signal-averaged ECG, used to detect abnormal conduction, has shown some usefulness in identifying ARVC-affected boxers that are more likely to die from cardiac-related causes.35 However, further study is needed to determine its clinical utility. A recent study has shown that the serum concentration of cardiac troponin I is higher in ARVC-affected boxers and that there is a positive correlation with the number of VPCs.36 Although this shows promise for a new diagnostic test, it should be noted that overlap existed between values for healthy and affected boxers. Further study is needed to clarify the clinical utility of this test in individual patients.

    The identification of a genetic mutation associated with affected boxers and the commercial availability of a genetic test offers a new method of screening in asymptomatic breeding dogs. However, Holter monitoring still has a place in initial screening and annual monitoring of affected boxers due to incomplete genetic penetrance of the mutation (not all dogs positive for the mutation are clinically affected) and in determining whether therapy should be instituted.

    Treatment and Prognosis

    Treatment for boxers with ARVC generally consists of only antiarrhythmic agents, unless there is evidence of systolic dysfunction and/or CHF (BOX 2). Although antiarrhythmic treatment has been shown to decrease VPC frequency and complexity, as well as the number of syncopal episodes,37 there is no evidence that treatment affects long-term survival or risk of sudden death.2,37,38 Additionally, treatment is not benign; antiarrhythmic agents may have a proarrhythmic effect.39

    Asymptomatic Dogs

    Without evidence that treatment affects survival or the risk of sudden death, the benefit of treating asymptomatic dogs is uncertain. A firm relationship between the number of VPCs and the onset of clinical signs has not been established. Meurs et al40 found that dogs with syncope had more VPCs per 24 hours and more complex arrhythmias than control dogs, suggesting a causative relationship. However, significant variability existed, with some asymptomatic boxers having highly complex arrhythmias and thousands of VPCs per 24 hours.40 Therefore, it has been suggested that it may be reasonable to begin treatment in asymptomatic boxers that have ≥1000 VPCs over 24 hours, runs of ventricular tachycardia, or evidence of the R-on-T phenomenon.26 Ultimately, the decision to treat an asymptomatic dog should be approached on a case-by-case basis with the risks of treatment in mind, taking into account all diagnostic information and the family history (if known).

    Syncope/Exercise Intolerance

    Treatment is typically initiated for boxers with clinical signs of syncope or exercise intolerance due to ventricular arrhythmias. Two protocols have been shown to be well tolerated and to decrease VPC frequency and complexity: (1) sotalol, 1.5 to 3.5 mg/kg PO q12h, and (2) the combination of mexiletine, 5 to 8 mg/kg PO q8h, and atenolol, 0.3 to 0.6 mg/kg PO q12h.37 Pretreatment Holter monitoring should be conducted, unless delaying initial treatment for 24 hours would not be in the best interest of the patient. Holter monitoring should also be conducted 2 to 4 weeks after treatment to assess response. Because there is great daily variability in VPC frequency among ARVC-affected boxers,24 a decrease in VPC frequency >80% should be achieved for therapy to be considered successful.

    A recent study compared the standard sotalol dosage (1.5 to 3.5 mg/kg PO q12h) with therapy combining sotalol (1.5 to 3.5 mg/kg PO q12h) and mexiletine (5 to 7.5 mg/kg PO q8h).38 Although the combination therapy significantly decreased VPC number and arrhythmia complexity in more dogs, it showed no advantage over sotalol alone in decreasing episodes of syncope.38

    Myocardial Dysfunction and Congestive Heart Failure

    Boxers with the myocardial dysfunction form of ARVC may benefit from the treatment protocol for dilated cardiomyopathy in addition to antiarrhythmic therapy. A family of boxers that was found to have a deficiency in myocardial l-carnitine demonstrated improved systolic function after supplementation.41 Although this deficiency is not thought to be the underlying cause of ARVC in most boxers, supplementation with l-carnitine (50 mg/kg PO q8–12h) can be considered. Boxers that initially present with CHF should be stabilized and then evaluated for evidence of ARVC. The presence of ventricular arrhythmias would indicate the need for antiarrhythmic therapy in addition to CHF treatment.

    Recent Therapeutic Advancements

    Although the optimal dose and duration of treatment still remain to be elucidated, a recent study has shown that supplementation with omega-3 fatty acids resulted in a decreased VPC frequency in asymptomatic boxers with >95 VPCs per 24 hours.42 The dogs in this study received 780 mg of eicosapentaenoic acid and 497 mg of docosahexaenoic acid per day for 6 weeks. The effect on mortality was not evaluated.

    The first treatment of a boxer with ARVC using an implantable cardioverter–defibrillator was reported in 2006.43 While this is not currently a routine therapeutic option for veterinary patients, it may become more available with further device advancement and study.

    Prognosis

    Many boxers can be managed using antiarrhythmic agents without recurrence of clinical signs for months to years.2,26 However, all dogs with ARVC are at risk for sudden death, with or without treatment. If the disease presents as or progresses to CHF, the prognosis becomes much more guarded.

    Conclusion

    Although treatment of symptomatic boxers with ARVC has not been shown to affect survival, it can decrease clinical signs and improve quality of life. In addition, it is hoped that increasing awareness of ARVC, its genetic origin, and the availability of genetic testing will bring more breeders to exert active control over its propagation.

    Downloadable PDF

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    2. Harpster NK. Boxer cardiomyopathy: a review of the long-term benefits of antiarrhythmic therapy. Vet Clin North Am Small Anim Pract 1991;21(5):989-1004.

    3. Basso C, Fox PR, Meurs KM, et al. Arrhythmogenic right ventricular cardiomyopathy causing sudden death in boxer dogs: a new animal model of human disease. Circulation 2004;109:1180-1185.

    4. Meurs KM, Spier AW, Miller MW, et al. Familial ventricular arrhythmias in boxers. J Vet Intern Med 1999;13:437-439.

    5. Tiso N, Stephan DA, Nava A, et al. Identification of mutations in the cardiac ryanodine receptor gene in families affected with arrhythmogenic right ventricular cardiomyopathy type 2 (ARVD2). Hum Mol Genet 2001;10(3):189-194.

    6. Meurs K, Lacombe VA, Dryburgh K, et al. Differential expression of the cardiac ryanodine protein in normal dogs and arrhythmogenic right ventricular cardiomyopathy hearts. Hum Genet 2006;120:111-118.

    7. Oyama MA, Reiken S, Lehnart SE, et al. Arrhythmogenic right ventricular cardiomyopathy in boxer dogs is associated with calstabin-2 deficiency. J Vet Cardiol 2008;10:1-10.

    8. Gerull B, Heuser A, Wichter T, et al. Mutations in the desmosomal protein plakophilin-2 are common in arrhythmogenic right ventricular cardiomyopathy. Nat Genet 2004;36:1162-1164.

    9. McKoy G, Protonotarios N, Crosby A, et al. Identification of a deletion in plakoglobin in arrhythmogenic right ventricular cardiomyopathy with palmoplantar keratoderma and woolly hair (Naxos disease). Lancet 2000;355:2119-2124.

    10. Rampazzo A, Nava A, Malacrida S, et al. Mutation in human desmoplakin domain binding to plakoglobin causes a dominant form of arrhythmogenic right ventricular cardiomyopathy. Am J Hum Genet 2002;71:1200-1206.

    11. Pilichou K, Nava A, Basso C, et al. Mutations in desmoglein-2 gene are associated with arrhythmogenic right ventricular cardiomyopathy. Circulation 2006;113(9):1171-1179.

    12. Heuser A, Plovie ER, Ellinor PT, et al. Mutant desmocollin-2 causes arrhythmogenic right ventricular cardiomyopathy. Am J Hum Genet 2006;79(6):1081-1088.

    13. Meurs KM, Ederer M, Stern J. Evaluation of five desmosomal genes in boxer arrhythmogenic right ventricular cardiomyopathy. AJVR 2007;68:1338-1341.

    14. Côté E, Ettinger SJ. Electrocardiography and cardiac arrhythmias. In: Ettinger SJ, Feldman EC, eds. Textbook of Veterinary Internal Medicine: Diseases of the Dog and Cat. St. Louis: Elsevier Saunders; 2005:1040-1076.

    15. Knapp DW, Aronsohn MG, Harpster NK. Cardiac arrhythmias associated with mass lesions of the canine spleen. JAAHA 1993;29:122-128.

    16. Meurs KM. Primary myocardial disease in the dog. In: Ettinger SJ, Feldman EC, eds. Textbook of Veterinary Internal Medicine: Diseases of the Dog and Cat. St. Louis: Elsevier Saunders; 2005:1077-1082.

    17. Kienle R. Pulse alterations. In: Ettinger SJ, Feldman EC, eds. Textbook of Veterinary Internal Medicine: Diseases of the Dog and Cat. St. Louis: Elsevier Saunders; 2005:200-204.

    18. Baumwart RD, Meurs KM, Atkins CE, et al. Clinical, echocardiographic, and electrocardiographic abnormalities in boxers with cardiomyopathy and left ventricular systolic dysfunction: 48 cases (1985-2003). JAVMA 2005;226(7):1102-1104.

    19. Koplitz SL, Meurs KM, Spier AW, et al. Aortic ejection velocity in healthy boxers with soft cardiac murmurs and boxers without cardiac murmurs: 201 cases (1997-2001). JAVMA 2003;222(6):770-774.

    20. Kvat C, French AT, Luis Fuentes V, et al. Analysis of murmur intensity, duration and frequency components in dogs with aortic stenosis. J Small Anim Pract 1998;39:318-324.

    21. Kraus MS, Moïse NS, Rishniw M, et al. Morphology of ventricular arrhythmias in the boxer as measured by 12-lead electrocardiography with pace-mapping comparison. J Vet Intern Med 2002;16:153-158.

    22. Meurs KM, Spiers AW, Wright NA, Hamlin RL. Comparison of in-hospital versus 24-hour ambulatory electrocardiography for detection of ventricular premature complexes in mature boxers. JAVMA 2001;218(2):222-224.

    23. Scansen BA, Meurs KM, Spier AW, et al. Temporal variability of ventricular arrhythmias in boxer dogs with arrhythmogenic right ventricular cardiomyopathy. J Vet Intern Med 2009;23:1020-1024.

    24. Spier AW, Meurs KM. Evaluation of spontaneous variability in the frequency of ventricular arrhythmias in boxers with arrhythmogenic right ventricular cardiomyopathy. JAVMA 2004;224(4):538-541.

    25. Meurs KM, Spier AW, Wright NA, Hamlin RL. Use of ambulatory electrocardiography for detection of ventricular premature complexes in healthy dogs. JAVMA 2001;218(8):1291-1292.

    26. Meurs KM. Boxer dog cardiomyopathy: an update. Vet Clin North Am Small Anim Pract 2004;34:1235-1244.

    27. Carpenter DH, Tobias AH. Can echocardiography predict survival in boxers with ventricular ectopy [abstract]. J Vet Intern Med 2004;18(3):453.

    28. Gavin PR. Cardiac MRI. Proc ACVIM Forum 2005;23:108.

    29. Baumwart RD, Meurs KM, Raman SV. Magnetic resonance imaging in right ventricular morphology and function in boxer dogs with arrhythmogenic right ventricular cardiomyopathy. J Vet Intern Med 2009;23:271-274.

    30. Corrado D, Basso C, Nava A, Thiene G. Arrhythmogenic right ventricular cardiomyopathy: current diagnostic and management strategies. Cardiology in Review 2001;9(5):259-265.

    31. Meurs KM, Mauceli E, Lahmers S, et al. Genome-wide association identifies a mutation in the 3’ untranslated region of striatin in a canine model of arrhythmogenic right ventricular cardiomyopathy. Hum Genet 2010;128:315-324.

    32. Spier AW, Meurs KM, Muir WW, et al. Correlation of QT dispersion with indices used to evaluate the severity of familial ventricular arrhythmias in boxers. Am J Vet Res 2001;62(9):1481-1485.

    33. Matuso K, Nishikimi T, Yutani C, et al. Diagnostic value of plasma levels of brain natriuretic peptide in arrhythmogenic right ventricular dysplasia. Circulation 1998;98:2433-2440.

    34. Baumwart RD, Meurs KM. Assessment of plasma brain natriuretic peptide concentration in boxers with arrhythmogenic right ventricular cardiomyopathy. Am J Vet Res 2005;66(12):2086-2089.

    35. Spier AW, Meurs KM. Use of signal-averaged electrocardiography in the evaluation of arrhythmogenic right ventricular cardiomyopathy in boxers. JAVMA 2004;225(7):1050-1055.

    36. Baumwart RD, Orvalho J, Meurs KM. Evaluation of serum cardiac troponin I concentration in boxers with arrhythmogenic right ventricular cardiomyopathy. Am J Vet Res 2007;68(5):524-528.

    37. Meurs KM, Spier AW, Wright NA, et al. Comparison of the effects of four antiarrhythmic treatments for familial ventricular arrhythmias in boxers. JAVMA 2002;221(4):522-527.

    38. Prošek R, Estrada A, Adin D. Comparison of sotalol and mexiletine versus standalone sotalol in treatment of boxer dogs with ventricular arrhythmias [abstract]. Proc ACVIM Forum 2006;24:777.

    39. Buss J, Lasserre JJ, Heene DL. The cardiac arrhythmia suppression trial. N Engl J Med 1992;327(25):1818.

    40. Meurs KM, Spier AW, Wright NA. Evaluation of the ambulatory electrocardiogram of boxer dogs with ventricular tachyarrhythmias and syncope [abstract]. J Vet Intern Med 2002;16:338.

    41. Keene B, Panciera DP, Atkins CE, et al. Myocardial L-carnitine deficiency in a family of dogs with dilated cardiomyopathy JAVMA 1991;198:647.

    42. Smith CE, Freeman LM, Rush JE, et al. Omega-3 fatty acids in boxer dogs with arrhythmogenic right ventricular cardiomyopathy. J Vet Intern Med 2007;21:265-273.

    43. Nelson OL, Lahmers S, Schneider T, Thompson P. The use of an implantable cardioverter defibrillator in a boxer dog to control clinical signs or arrhythmogenic right ventricular cardiomyopathy. J Vet Intern Med 2006;20:1232-1237.

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