Arrhythmogenic right ventricular cardiomyopathy in Boxer dogs: A retrospective study of survival.

A. Caro-Vadillo DVM, PhD1, L. García-Guasch DVM, PhD2, E. Carretón DVM3, J.A. Montoya- Alonso DVM, PhD3, J. Manubens DVM2

1Medicina y Cirugía Animal. Faculty of Veterinary Medicine. University Complutense of Madrid. Madrid, Spain.

2Hospital Veterinari Molins. Barcelona, Spain.

3Internal Medicine, Faculty of Veterinary Medicine. University of Las Palmas de Gran Canaria. Las Palmas de Gran Canaria, Spain

There was a significant association ARVC in Boxer dogs is a familial disease between median survival time (MST) and apparently inherited as an autosomal VT (P< 0.001); between survival and the dominant trait. It is an adult-onset number of VPCs in Holter monitoring myocardial disease. Affected dogs can (P=0.01); between survival and Holter class have many different presentations ranging (P=0.03); between survival and presence or from being totally asymptomatic to sudden absence of syncopal episodes (P=0.012) cardiac death. The aim of the present study and, finally, there was a significant was to retrospectively evaluate survival in a association between survival and age at population of 62 Boxer dogs with initiation of treatment (P<0.001). Figure 1 & arrhythmogenic right ventricular 2 There were no differences with regards to cardiomyopathy (ARVC), without left survival, among the three treatment options ventricular systolic failure, based on the used, with a MST of 365 days for sotalol following factors: age of diagnosis, treatment, a MST of 365 days for mexiletine presence of syncopal episodes, Holter plus atenolol treatment and a MST of 547 arrhythmia classification and administered for procainamide treatment. The probability treatment. of death within a year (odds ratio), of dogs with VT class II is 20 times greater (95% According to this study, the best prognosis CI= 4-99.5; P<0.001) than in the group of is for the younger Boxer without . dogs with VT class I. The probability of There were no differences in survival times death within a year, of dogs with VPCs in relation to the different treatment options class B is 5.43 times greater (95% CI= used. 1.79-16.46; P=0.004) than in the group of dogs with VPCs class A. The probability of The diagnosis inclusion criteria included death within a year, of dogs with syncope is presence of more than 1000 ventricular 4.875 times greater (95% CI= 1.48-15.99; premature complexes (VPCs) in 24 hrs P=0.013) than in dogs without syncope. Holter recording and normal left ventricular The hazard ratio, for the complete duration chamber on echocardiographic of the study, calculated by Cox proportional examination. Some dogs also presented hazard multivariable analysis, for VT was syncope or exercise intolerance and/or 4.8 (95% CI= 2.63-8.99; P<0.001). The VPCs with increased complexity (couplets, hazard ratio, for one year, calculated by triplets) and/or (VT). Cox proportional hazard multivariable The Kaplan-Meier method and plot time to analysis, for VT was 6.05 (95% CI= 2.92- event curves were used to estimate survival 12.51; P<0.001). There were no other function. Survival time differences were variables (VPC, presence/absence of assessed by log Rank test. The crosstabs, syncope, Holter class) statistically Fisher’s exact test and odds ratio were significant for this Cox proportional used to estimate risk of death within a year. stepwise method. A Cox regression multivariable analysis (stepwise method for variable selection) The fact that Boxers with ARVC and was done. A P value <0.05 was considered syncope live less time, has been proved in significant. The statistical analyses were the present study; the probability of death performed using a commercially available within a year is 4.875 times greater for dogs software program: SPSS version 19.0. with syncope. In this report, it has been found that VT means a high risk of death within one year. It is probable that VT degenerate into VF leading to sudden death Ventricular Cardiomyopathy Causing Sudden in the dogs used in this study. Even though Cardiac Death in Boxer Dogs. A New Animal Model of Human Disease. Circulation 109, 1180- this disease seems to be progressive in 11. nature in this report a better survival in younger dogs is found. One reason besides • BASSO C., CORRADO D., MARCUS F.I., NAVA lack of evidences of inflammatory response A. & THIENE G. (2009) Arrhythmogenic right ventricular cardiomyopathy. The Lancet 373, could be that early treatment (drug and 1289–1300. restriction of vigorous exercise) was able to slow down the progression of the disease. • BAUMWART R.D.,MEURS K.M., ATKINS C.E., The presence of frequent VT episodes was BONAGURA J.D., DeFRANCESCO T.C., KEEN B.W., KOPLITZ S., LUIS FUENTES V., MILLER associated negatively with survival in this M.W., RAUSCH W. &SPIER A.W. (2005) study, unlike the findings reported in other Clinical, echocardiographic and studies. On the other hand, this was a electrocardiographic abnormalities in Boxers with retrospective cohort study with a fixed cardiomyopathy and left ventricular systolic dysfunction: 48 cases (1985-2003). J Am Vet sample size and was susceptible to bias. Med Assoc 226, 538-541. Because of the retrospective nature we cannot establish a progression from • BONAGURA J.D., LUIS FUENTES V. (2000) arrhythmia to other forms of left ventricular Echocardiography. In: Ettinger S.J., Feldman E.C. (eds) Textbook of veterinary internal dysfunction. As regards treatment, this medicine 5th. Philadelphia: WB Saunders:834- study only considered the effect of the 873. different protocols on survival time. It did • BOON J.A. (2011) Veterinary Echocardiography not consider other clinical factors (e.g., th frequency of syncope) that could improve 2 edition. Wiley-Blackwell, Iowa USA. the overall condition of the animal prior to • CUNNINGHAM S.M., RUSH J.E., FREEMAN death. L.M., BROWN D.J. & SMITH C.E. (2008) Echocardiographic ratio indices in overtly healthy This study shows a MST significantly longer Boxer dogs screened for heart disease. J Vet Intern Med 22, 924-930. in young Boxers with ARVC, in dogs without syncopal episodes, and in the VT class I group. As regards therapeutic • EICHELBERG H. &SEINE R. (1996) Life options there were no statistically significant expectancy and cause of death in dogs. The situation in mixed breeds and various dogs differences in MST between the three breeds. Berl Munch Tierarztl Wochenschr 109, groups. As far as the probability of death 292-303. within the first year after diagnosis is concerned, this risk is doubled for cohort of dogs with syncope and VPCs more than • FRIEDMAN P.L., MONTGOMERY S. & MATAS N. (2010) Sotalol and a Broken Heart. Journal of 10.000 per day and 6 times more for dogs Cardiovascular Electrophysiology 21, 207-210. with VT episodes over 200 per day. The results of • GELZER A.R.M., KRAUS M.S., RISHNIW M., the present study could be useful as HEMSLEY S.A. & MOïSE N.S. (2010) Combination therapy with mexiletine and sotalol prognosis guide for general suppresses inherited ventricular arrhythmias in veterinarians. German shepherd dogs better than mexiletine or sotalol monotherapy: A randomized cross-over References study. Journal of Veterinary Cardiology 12, 93- 106. • AVRAMIDES D., PROTONOTARIOS N., ASIMAKI A. & MATSAKAS E. (2011) • HARIU C.D. & CARPENTER D. (2010) Arrhythmogenic Right Ventricular Arrhythmogenic right ventricular cardiomyopathy Cardiomyopathy/Dysplasia. Hellenic J Cardiology in Boxers. Compendium: continuing Education for 52, 452-461. Veterinarians pp: E2-E7.

• AZAOUAGH A., CHURZIDSE S., KONORZA T. & • HARPSTER, N. (1983) Boxer cardiomyopathy. In: ERBEL R. (2011) Arrhythmogenic right Current Veterinary Therapy VIII. Ed Kirk R. WB ventricular cardiomyopathy/dysplasia: a review Saunders. pp 329-337. and update. Clin Res Cardiol 100,383–394. • HARPSTER, N. (1991) Boxer cardiomyopathy: A • BARNETT L., MARTIN M. W. S. , TODD J. , review of the long-term benefits of antiarrhythmic SMITH S. & COBB M. (2011)A retrospective therapy. Vet Clin N Am Small Anim Pract 21, 989- study of 153 cases of undiagnosed collapse, 1004. syncope or exercise intolerance: the outcomes. Journal of Small Animal Practice52, 26–31. • KRAUS M.S., MOÏSE N.S., RISHNIW M., KYKES N. & ERB H.N. (2002) Morphology of ventricular • BASSO C., FOX P.R., MEURS K.M., TOWBIN arrhythmias in the Boxer as measured by 12- J.A., SPIER A.W., CALABRESE F., MARON B.J. lead with pace-mapping & THIENE G. (2004)Arrhythmogenic Right comparison. J Vet Intern Med 16, 153-158. Implantable Cardioverter Defibrillator in a Boxer • MARCUS G.M., GLIDDEN D.V., PLONSKY B., Dog to Control Clinical Signs of Arrhythmogenic ZAREBA W., SMITH L.M., CANNOM D.S., Right Ventricular Cardiomyopathy. J Vet Intern ESTES M., MARCUS F. & SCHEINMAN M.M. Med 20, 1232–1237. (2009) Efficaccy of antiarrhythmic drugs in arrhythmogenic right ventricular cardiomyopathy: • PALERMO V., STAFFORD JOHNSON M.J., a report from the North American ARVC registry. SALA E., BRAMBILLA P.G. & MARTIN M.W.S. J Am Coll Cardiol 54, 609-615. (2011) Cardiomyopathy in Boxer dogs: A retrospective study of the clinical presentation, • MARKEL D.T., GOLD L.S., ALLEN J., diagnostic findings and survival. Journal of FAHRENBRUCH C.E., REA T.D. EISENBERG Veterinary Cardiology 13, 45-55. M.S. & KUDENCHUK P.J. (2010) Procainamide and survival in out-of- • PINAMONTI B., DRAGOS A.M., PYXARAS S.A., hospital . Academic emergency MERLO M., PIVETTA A., BARBATI G., DI medicine 17, 617-623. LENARDA A., MORGERA T., MESTRONI L. & SINAGRA G. (2011) Prognostic predictors in • MEURS, K.M. SPIER A.W., MILLER M.W., arrhythmogenic right ventricular cardiomyopathy: LEHMKUHL L. & TOWBIN J.A. (1999) Familial results from a 10-year registry. European Heart ventricular arrhythmias in boxers. J Vet Intern Journal 32, 1105-1113. Med 14, 437-439. • PROSEK R., ESTRADA A. & ADIN D. (2006) • MEURS, K.M., SPIER A.W., WRIGHT N.A., Comparison of sotalol and mexiletine versus ATKINS C.E., DeFRANCESCO T.C., GORDON stand alone sotalol in treatment of Boxer dogs S.G., HAMLIN R.L., KEENE B.W., MILLER M.W. with ventricular arrhythmias. Proceedings of the & MOÏSE N.S. (2002) Comparison of the effects ACVIM Forum. Louisville USA, May 31-June 3 of four antiarrhythmic treatments for familial 2006. pp 748. ventricular arrhythmias in Boxers. J Am Vet Med Assoc 221, 522-527. • SMITH C.E., FREEMAN L.M., RUSH J.E., CUNNINGHAM S.M. & BIOURGE V. (2007) • MEURS, K.M. (2004) Boxer dog cardiomyopathy: Omega-3 Fatty Acids in Boxer Dogs with an update. Vet Clin N Am Small Anim Pract 34, Arrhythmogenic Right Ventricular 1235-1244. Cardiomyopathy. J Vet Intern Med 21, 265–273.

• MEURS, K.M. (2005) Right ventricular arrhythmic • SMITH W. (2011) Guidelines for the Diagnosis cardiomyopathy: an update on Boxer and Management of Arrhythmogenic Right cardiomyopathy. Proceedings of The North Ventricular Cardiomyopathy. Heart, Lung and American Veterinary Conference. Orlando Circulation 20,757–760. January 8-12 2005. Pp 122-123.

• MEURS K.M., LAHMERS S. & KEENE B.W. • THOMASON J.D., KRAUS M.S., SURDYK K.K., (2011) Characteristics of ARVC Boxer with FALLAW T. & C.A. CALVERT (2008) sudden death. Proceedings of the ACVIM Forum. Bradycardia-Associated Syncope in 7 Boxers with Denver, USA. June 15-18 2011, p 649. Ventricular Tachycardia (2002 –2005). J Vet Intern Med 22,931–936. • NAKAO S., HIRAKAWA A., YAMAMOTO S., KOBAYASHI M. & MACHIDA N. (2011)Pathological Features of arrhythmogenic Right Ventricular Cardiomyopathy in Middle-Aged Dogs. J. Vet. Med. Sci. 73, 1031–1036.

• NELSON O.L., LAHMERS S., SCHNEIDER T. & THOMPSON P. (2006) The Use of an

Figure 1: Kaplan-Meier survival curves in the Boxer dogs with ARVC according to: (A) VT classification a. Kaplan-Meier survival curve in ARVC dogs, VT class I b. Kaplan-Meier survival curve in ARVC dogs, VT class II (B) VPC classification c. Kaplan-Meier survival curve in ARVC dogs, VPC class A d. Kaplan-Meier survival curve in ARVC dogs, VPC class B (C) Holter classification e. Kaplan-Meier survival curve in ARVC dogs, Holter class 2 f. Kaplan-Meier survival curve in ARVC dogs, Holter class 4 (D) Presence or absence of syncope g. Kaplan-Meier survival curve in ARVC dogs without syncope h. Kaplan-Meier survival curve in ARVC dogs with syncopal episodes

Figure 2: Kaplan-Meier survival curves in the different groups of Boxer with ARVC according to age of initial diagnosis. a. Kaplan-Meier survival curve in ARVC dogs younger than 4 years old b. Kaplan-Meier survival curve in ARVC dogs between 4 and 8 years old c. Kaplan-Meier survival curve in ARVC dogs older than 8 years