Case Report Rapport de cas Arrhythmogenic right ventricular cardiomyopathy in a weimaraner Bryan D. Eason, Stacey B. Leach, Keiichi Kuroki Abstract — Arrhythmogenic right ventricular cardiomyopathy (ARVC) was diagnosed postmortem in a weimaraner dog. Syncope, ventricular arrhythmias, and sudden death in this patient combined with the histopathological fatty tissue infiltration affecting the right ventricular myocardium are consistent with previous reports of ARVC in non-boxer dogs. Arrhythmogenic right ventricular cardiomyopathy has not been previously reported in weimaraners. Résumé — Cardiomyopathie ventriculaire droite arythmogène chez un Weimaraner. Une cardiomyopathie ventriculaire droite arythmogène (CVDA) a été diagnostiquée post-mortem chez un chien Weimaraner. Une syncope, des arythmies ventriculaires et une mort soudaine chez ce patient, combinées à une infiltration histopathologique par du tissu adipeux affectant le myocarde droit, correspondent à des rapports antérieurs de CVDA chez des chiens autres que des Boxers. La cardiomyopathie ventriculaire droite arythmogène n’a pas été signalée antérieurement chez des Weimaraners. (Traduit par Isabelle Vallières)
Can Vet J 2015;56:1035–1039
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Case description
40.7 kg, 4-year-old, neutered male weimaraner dog was referred to the cardiology service at the University of Missouri Veterinary Medical Teaching Hospital for evaluation of syncope. The first syncopal episode was noted approximately 2 mo before referral and a second episode occurred 2 d before presentation. The dog was otherwise healthy. Physical examination revealed an intermittent arrhythmia characterized by frequent premature heart beats and pulse deficits, but was otherwise unremarkable. A standard 6-lead electrocardiogram (ECG) was performed that showed frequent ventricular premature complexes (VPCs) with a right bundle branch block morphology occurring as isolated complexes, couplets, triplets, and periods of ventricular bigeminy and trigeminy (repetitive sequence of 2 sinus complexes followed by 1 VPC). A transthoracic 2-dimensional and Doppler echocardiographic study revealed mild mitral regurgitation, normal chamber dimensions, and normal systolic function. A complete blood (cell) count (CBC) and serum biochemistry panel performed immediately prior to referral were unremarkable. Cardiac tro-
Department of Veterinary Medicine and Surgery (Eason, Leach) and the Veterinary Medical Diagnostic Laboratory (Kuroki), College of Veterinary Medicine, University of Missouri, Columbia, Missouri 65211, USA. Address all correspondence to Dr. Bryan D. Eason; e-mail: [email protected] Dr. Eason’s current address is Purdue University Veterinary Teaching Hospital, West Lafayette, Indiana 47906, USA. Use of this article is limited to a single copy for personal study. Anyone interested in obtaining reprints should contact the CVMA office ([email protected]) for additional copies or permission to use this material elsewhere. CVJ / VOL 56 / OCTOBER 2015
ponin I (cTnI) concentration was analyzed using a point-of-care analyzer (VetScan i-STAT; Abaxis, Union City, California, USA) on referral presentation and was increased at 3.85 ng/mL (normal canine reference range , 0.05 ng/mL, lower limit of detection 0.02 ng/mL). Thoracic and abdominal radiographs and abdominal ultrasound were unremarkable. Dirofilaria immitis antigen and antibodies to Borrelia burgdorferi, Anaplasma phagocytophilum, and Ehrichia canis were negative by serologic testing (SNAP 4Dx; IDEXX Laboratories, Westbrook, Maine, USA). Serum was also submitted to the Texas Veterinary Medical Diagnostic Laboratory (TVMDL) for Trypanosoma cruzi immunofluorescent antibody (IFA) testing and revealed a titer of 1:20, considered seronegative according to TVMDL protocol (1). Prophylactic antibiotic therapy with clindamycin (Watson Pharma Private, Salcette, Goa, India), 14.7 mg/kg body weight (BW), PO, q12h and doxycycline (Teva Pharmaceuticals, Sellersville, Pennsylvania, USA), 9.8 mg/kg BW, PO, q12h, was initiated to treat presumptive protozoal (i.e., Toxoplasma gondii, Neospora caninum) and bacterial (i.e., Borrelia burgdoferi, Rickettsia rickettsia, Erlichia canis, Bartonella spp.) causes of myocarditis, respectively. A 24-hour ambulatory ECG revealed multiform ventricular ectopy with periods of ventricular tachycardia and 32 881 ventricular ectopic events (total beats were 180 880). Approximately 89% of the ventricular ectopic complexes were left bundle branch block morphology and 11% were right bundle branch block morphology with varying coupling intervals. There were periods of ventricular tachycardia composed solely of left bundle branch block and of solely right bundle branch block morphology, and instances in which the morphology changed abruptly from one to the other (Figure 1). Oral antiarrhythmic therapy with sotalol (Qualitest Pharmaceuticals, Huntsville, Alabama, USA), 0.98 mg/kg BW, PO, q12h for 3 d, then 1.96 mg/kg BW, PO, q12h for 3 d was instituted followed by mexiletine (Teva 1035
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Figure 1. Holter monitor recording showing ventricular ectopy. The narrow arrows indicate a couplet of ventricular premature complexes with a left bundle branch block morphology. The rhythm then changes to a sustained monomorphic ventricular tachycardia with a right bundle branch block morphology (thick arrow).
Pharmaceuticals), 6.25 mg/kg BW, PO, q8h. The T. cruzi IFA test was repeated after 3 wk and remained negative at 1:20. A repeat 24-hour ambulatory ECG performed 2 mo after initiation of antiarrhythmic therapy showed marked improvement in both the frequency and complexity of the arrhythmia as there was a 96% reduction in the frequency of ventricular ectopy and a 99% reduction of ventricular tachycardic episodes compared with the baseline ambulatory ECG. Repeat cTnI concentration at that time was normal at 0.02 ng/mL. Despite a marked decrease in the frequency and complexity of ventricular ectopy and strict exercise restriction by the owners, sudden death occurred approximately 3 mo after initial evaluation. The heart was collected by the referring veterinarian and submitted for postmortem examination. Multiple formalinfixed myocardial specimens and the remaining fresh heart were submitted to the University of Missouri Veterinary Medical Diagnostic Laboratory. On gross examination of the tissue, no apparent hemorrhagic or necrotic changes were noted. Externally, the right ventricle was paler than the left. On cut sections, the right ventricular wall had a pale, greasy appearance that was multifocal and transmural in distribution. The remainder of the gross examination and the heart dimensions were unremarkable. Sections of the interventricular septum and the right ventricular and left ventricular free wall at the level of the papillary muscles were prepared for histopathologic examination. The right ventricular myocardium had multifocal, transmural, and coalescing fatty tissue infiltration covering approximately 60% of the tissue. The most severe lesions were located near the epicardium (Figure 2A). Similarly, approximately 30% of the interventricular septum and approximately 10% of the left ventricle were replaced by fatty infiltrates (Figure 2B). The surviving myocytes in each section appeared atrophied and occasionally exhibited vacuolar degeneration. There was minimal interstitial 1036
fibrosis with no inflammatory cells or infectious agents noted. The myocardial fatty infiltration and replacement of the myocardium, most severe in the right ventricular free wall, and lack of inflammatory cells or infectious agents was most consistent with a diagnosis of arrhythmogenic right ventricular cardiomyopathy (ARVC).
Discussion Syncope, defined as sudden but transient loss of consciousness and postural tone, can be divided into broad categories of cardiac and non-cardiac causes with the most commonly reported cause of syncope being cardiac arrhythmias (2). Physical examination of the dog in the present report was highly suggestive of a cardiac cause of syncope based on the presence of an arrhythmia on auscultation; however, a diagnosis of ARVC as the etiology of heart disease in this patient was only made on postmortem histopathologic examination. Arrhythmogenic right ventricular cardiomyopathy is a myocardial disease that is characterized clinically by syncope, ventricular arrhythmias of left bundle branch block morphology, and sudden death with no premonitory clinical signs. Arrhythmogenic right ventricular cardiomyopathy has been described in humans, cats, and dogs (3–5). The most common breed of dog affected is the boxer and a familial pattern of autosomal dominance has been established (6). Recently, a causative mutation in the gene encoding striatin has been identified in a population of boxers, although other genetic mutations are also suspected (7). Isolated cases of ARVC without an obvious familial pattern have been reported in other breeds (8–13). Arrhythmogenic right ventricular cardiomyopathy has not been previously reported in weimaraner dogs. Ante-mortem diagnosis of ARVC presents a unique clinical challenge as sudden death can be the first clinical sign. In humans, standardized criteria have been proposed for the CVJ / VOL 56 / OCTOBER 2015
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200 mm
Figure 2. Photomicrograph of histopathology of the right (A) and left (B) ventricular free wall. Note that the right ventricular myocardium is severely infiltrated and replaced by fatty tissue. The most severely affected zone was the epicardium indicated by the black arrows; however, the fatty infiltration was multifocally and transmurally distributed (A). In the left ventricle (B), cardiomyocytes are multifocally and occasionally separated and replaced by fatty tissue and sparse connective tissue. Note the predominant pattern of infiltration in both A and B is fatty tissue without inflammation. Masson’s trichrome stain. A and B are the same magnification. Bar = 200 mm. 279 3 105 mm (72 3 72 DPI).
diagnosis of ARVC and include a combination of structural, electrocardiographic, arrhythmic, histopathologic, and familial features (14). These guidelines have since been modified given the emergence of advanced diagnostic imaging modalities such as cardiac magnetic resonance imaging (cMRI) and identification of causative genetic mutations (15). In humans, cMRI has become increasingly utilized for non-invasively evaluating the function and structure of the right ventricle. It has become the gold standard for ante-mortem diagnosis of ARVC, with major criteria consisting of wall motion abnormalities and aneurysmal dilation of the right ventricle (15). Other less specific findings include intramyocardial fat deposits seen as an intense signal compared with surrounding more normal myocardium and abnormal late gadolinium enhancement suggestive of intramyocardial fibrosis (16,17). In veterinary studies, cMRI was able to detect fatty infiltrative changes in explanted hearts (18), while another study failed to show fatty infiltration but did reveal right ventricular dysfunction (19). This discrepancy may be due to the difference in ages of dogs in each study, suggesting that cMRI evidence of fatty infiltration may become more apparent with chronicity. Although cMRI is becoming increasingly available in veterinary medicine, it requires general anesthesia and may be cost-prohibitive. A presumptive diagnosis can be made based on history/clinical signs, familial history, ECG abnormalities (ventricular ectopy with a left bundle branch block morphology), and the absence of significant structural abnormalities on echocardiogram to explain abnormal ECG findings (20). Echocardiographic changes may be present in both humans and dogs in more severe cases, but specificity and sensitivity are not high. In humans, right ventricular enlargement or dilation and hypokinetic regions may be associated with ARVC (16). In a recent study, there was a positive association between the development of DCM and a homozygous striatin mutation in boxer dogs (21). Echocardiographically evident right ventricular CVJ / VOL 56 / OCTOBER 2015
aneurysm has been reported in a case of segmental ARVC in a non-boxer dog (9). Syncope is one of the most commonly reported clinical signs associated with ARVC in boxers and may be the presenting complaint in up to 68% of cases (22). A 24-hour ambulatory ECG is often utilized to support an ante-mortem diagnosis as dogs may have normal ECGs in the hospital. Normal dogs have a very low incidence of ventricular ectopy. A study of healthy adult dogs showed a median of 2 VPCs in 24 h when boxers were excluded from the population (23). Boxers seem to have a greater tendency toward ventricular ectopy with 75% of healthy adult boxers reportedly having , 75 VPCs in a 24-hour period (20), though this population may include dogs with ARVC not manifesting clinical signs. Recommended guidelines for interpretation of 24-hour ambulatory ECG recordings in boxers suggest that . 100 VPCs is suspicious for ARVC and treatment is generally recommended if . 1000 VPCs are recorded over a 24-hour period (20). Whether or not these guidelines can be extrapolated to other breeds has not been established and warrants further investigation. The decision to use antiarrhythmic therapy in this case was made in light of the dog’s clinical signs and documentation of frequent sustained ventricular tachycardia. Multi-drug anti-arrhythmic therapy was used in this case; however, monotherapy was considered. When combination therapy is used, anti-arrhythmic drugs are often added in a staggered protocol as was done in this case to evaluate for potential adverse effects. Efficacy of anti-arrhythmic therapy is optimally evaluated with a repeated 24-hour ambulatory ECG. This can present additional cost to owners if multiple changes to medications are required. Because the underlying mechanism of the ventricular arrhythmias in the present case could not be determined based on ante-mortem diagnostic tests performed, combination therapy was elected in the hope of greater 1037
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a rrhythmia suppression. Mexilitine is a class Ib anti-arrhythmic drug, inhibiting fast sodium channels, whereas sotalol is a class III antiarrhythmic with non-selective beta blocking properties. Sotalol monotherapy and combination therapy with atenolol-mexiletine have both been shown to be effective at reducing the frequency and severity of ventricular ectopy in boxer dogs with ARVC (24). Combination sotalol-mexilitine has also been shown to be more effective than sotalol monotherapy in reducing the frequency of VPCs in boxer dogs with ARVC (25). However, in German shepherd dogs with inherited ventricular arrhythmias, sotalol monotherapy was found to be proarrhythmic, likely by worsening early afterdepolarization induced triggered activity, while mexilitine-sotalol combination was superior to mexilitine monotherapy in reducing the frequency of VPCs (26). The decision to use multi-drug anti arrhythmic therapy in this case was based on clinical judgment and the owner’s financial concerns regarding cost of repeated ambulatory ECG for monitoring response to therapy. The mechanism of the ventricular arrhythmias characteristic of ARVC is thought to be fatty or fibrofatty replacement of the normal myocardium generating macro-reentrant electrical circuits, though associated myocarditis may also play a role (4,16). Myocyte degeneration, atrophy, and replacement of myocardium by fatty or fibrofatty tissue can be associated with other diseases such as dilated cardiomyopathy in dogs (27). In ARVC, however, these histologic changes are most prominent in the right ventricle as seen in this case. These findings are similar to the changes noted in humans affected by this disease (18,28). The disease predominates in the right ventricle but is also seen in the left ventricle in both humans and dogs (18,28). Because of the distribution, ventricular tachycardia tends to be monomorphic. In patients with multifocal areas of disease involving the interventricular septum and parts of the left ventricle, the arrhythmias may have multiple arrhythmogenic foci (4). The presence of myocarditis has also been postulated as a potential cause or contributory factor of arrhythmogenesis with multifocal lymphocytic infiltrates and myocyte death being present in all boxer dogs that died suddenly in one study (18). Histopathologic lesions suggesting myocarditis appear to be more commonly associated with the fibrofatty form of myocyte replacement in both boxers and other breeds with ARVC, though the exact role of myocarditis in the progression of this disease remains unclear (8,27). Thinning and aneurysmal dilation of the right ventricular free wall are more commonly seen with the fibrofatty form of ARVC in both humans and boxer dogs (18). The dog in this report had predominantly fatty replacement of cardiomyocytes, without evidence of myocarditis or right ventricular thinning or aneurysmal dilations. Whether the fatty and fibrofatty forms of ARVC represent different stages of the same disease process remains unknown. Additionally, some of the reported cases of ARVC in both human and veterinary literature may actually be cases of Uhl’s anomaly, in which there is partial or complete loss of the myocardium in the right ventricular free wall, with only the epicardial and endocardial layers remaining. It has been previously thought that Uhl’s anomaly was a more severe form of ARVC, as both may be mediated by unregulated apoptosis, though a more recent study suggests they may be distinct entities (29). 1038
The increased cTnI concentrations at initial evaluation supported the presence of myocarditis clinically, which led to tests for infectious diseases. Potential infectious causes of myocarditis in dogs include Rickettsial disease, Lyme disease, leptospirosis, toxoplasmosis, Chagas’ disease, and bartonellosis and may potentially increase serum concentration of cardiac troponins (30). Histopathology combined with clinical abnormalities may be beneficial in diagnosing the causative agent of myocarditis, but myocardial biopsy is rarely performed in veterinary medicine as an ante-mortem diagnostic test. Characteristic histopathologic findings associated with Chagas’ cardiomyopathy in humans include myocardial fibrosis resulting from multiple mechanisms including myocarditis and persistence of parasites within cardiac tissue (31). Dogs experimentally infected with T. cruzi similarly showed varying degrees of myocardial fibrosis on histopathology (32). In one study of naturally occurring T. cruzi infections in dogs, histopathologic evidence of myocarditis was noted in almost 98% of cases (1). Cardiac toxins and envenomation may also be considered as potential causes of myocarditis and elevation of cTnI when clinical history indicates possible exposure (30,33). In the present case, no history of exposure to toxins was noted by the owners and no microorganisms, inflammatory changes, evidence of toxin exposure such as necrosis, or ischemic damage was noted on histopathologic examination and only minimal fibrosis was present, making infectious and inflammatory diseases or toxins unlikely. The initial increase in cTnI concentrations may have been secondary to ischemia from the frequent tachyarrhythmia or due to the fatty replacement and atrophy of cardiac myocytes seen histologically (34,35). It has been previously shown that boxers with ARVC have significantly greater serum cTnI concentrations compared with both control boxers and non-boxer dogs, and that there was a significant correlation between serum cTnI concentrations and both frequency and complexity of ventricular ectopy (35). This report presents the diagnosis of ARVC in a breed in which it has not been previously reported. Unfortunately, sudden death remains a common clinical outcome of this disease despite successful response to anti-arrhythmic therapy. A definitive diagnosis was made postmortem based on the combination of clinical signs, extensive diagnostic testing and imaging, and histopathologic findings of fatty myocardial replacement without myocarditis. Arrhyhmogenic right ventricular cardiomyopathy should be considered as a differential diagnosis for syncope and ventricular ectopy in non-boxer dogs without echocardiographic evidence of structural heart disease. CVJ
References 1. Kjos SA, Snowden KF, Craig TM, Lewis B, Ronald N, Olson JK. Distribution and characterization of canine Chagas disease in Texas. Vet Parasitol 2008;152:249–256. 2. Kraus MS, Calvert CA. Syncope. In: Bonagura JD, Twedt DC, eds. Kirk’s Current Veterinary Therapy. 14th ed. Philadelphia, Pennsylvania: Elsevier Saunders, 2009:709–712. 3. Fox PR, Maron BJ, Basso C, Lui SK, Thiene G. Spontaneously occurring arrhythmogenic right ventricular cardiomyopathy in the domestic cat: A new animal model similar to the human disease. Circulation 2000;102:1863–1870. 4. Gemayel C, Pelliccia A, Thompson PD. Arrhythmogenic right ventricular cardiomyopathy. J Am Coll Cardiol 2001;38:1773–1781.
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21. Meurs KM, Stern JA, Sisson DD, et al. Association of dilated cardiomyopathy with the striatin mutation genotype in boxer dogs. J Vet Intern Med 2013;6:1437–1440. 22. Caro-Vadillo A, Garcia-Guasch L, Carreton E, Montoya-Alonso JA, Manubens J. Arrhythmogenic right ventricular cardiomyopathy in boxer dogs: A retrospective study of survival. Vet Rec 2013;172:268–273. 23. Meurs KM, Spier AW, Hamlin RL, Wright NA. Use of ambulatory electrocardiography for detection of ventricular premature complexes in healthy dogs. J Am Vet Med Assoc 2001;218:1291–1292. 24. Meurs KM, Spier AW, Wright NA, et al. Comparison of the effects of four antiarrhythmic treatments for familiar ventricular arrhythmias in Boxers. J Am Vet Med Assoc 2002;221:522–527. 25. Prosek R, Estrada A, Adin D. Comparison of sotalol and mexiletine versus stand alone sotalol in treatment of boxer dogs with ventricular arrhythmias (Abstr.). Proc ACVIM Forum, Louisville, Kentucky, May 31 to June 3, 2006;24:777. 26. Gelzer A, Kraus MS, Rishniw M, Hemsley SA, Moise NS. Combination therapy with mexiletine and sotalol suppresses inherited ventricular arrhythmias in German shepherd dogs better than mexiletine or sotalol monotherapy: A randomized cross-over study. J Vet Cardiol 2010;12:93–106. 27. Tidholm A, Jonsson L. Histologic characterization of canine dilated cardiomyopathy. Vet Pathol 2005;42:1–8. 28. Corrado D, Basso C, Thiene G, et al. Spectrum of clinicopathologic manifestations of arrhythmogenic right ventricular cardiomyopathy/ dysplasia: A multicenter study. J Am Coll Cardiol 1997;30:1512–20. 29. Pamuru PR, Dokuparthi MV, Remersu S, Calambur N, Nallari P. Comparison of Uhl’s anomaly right ventricular outflow tract ventricular tachycardia (RVOT VT) & arrhythmogenic right ventricular dysplasia/ cardiomyopathy (ARVD/C) with an insight into genetics of ARVD/C. Indian J Med Res 2010;131:35–45. 30. Schober KE. Myocarditis. In: Bonagura JD, Twedt DC, eds. Kirk’s Current Veterinary Therapy. 14th ed. Philadelphia, Pennsylvania: Elsevier Saunders, 2009:804–808. 31. Nunes MC, Dones W, Morillo CA, Encina JJ, Ribeiro AL. Chagas disease: An overview of clinical and epidemiological aspects. J Am Coll Cardiol 2013;62:767–776. 32. Caldas IS, da Matta Guedes PM, dos Santos FM, et al. Myocardial scars correlate with electrocardiographic changes in chronic Trypanosoma cruzi infection for dogs treated with benznidazole. Trop Med Int Health 2013;18:75–84. 33. Langhorn R, Persson F, Ablad B, et al. Myocardial injury in dogs with snake envenomation and its relation to systemic inflammation. J Vet Emerg Crit Care (San Antonio) 2014;24:174–181. 34. de Gennaro L, Brunetti ND, Cuculo A, et al. Increased troponin levels in nonischemic cardiac conditions and noncardiac diseases. J Interv Cardiol 2008;21:129–139. 35. 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;68:524–528.
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5. Meurs KM, Stern JA, Reina-Doreste Y, Spier AW, Koplitz SL, Baumwart RD. Natural history of arrhythmogenic right ventricular cardiomyopathy in the boxer dog: A prospective study. J Vet Intern Med 2014;28:1214–1220. 6. Meurs KM, Spier AW, Miller MW, Lehmkuhl LB, Towbin JA. Familial ventricular arrhythmias in boxers. J Vet Intern Med 1999;13:437–439. 7. Meurs KM, Mauceli E, Lahmers S, Acland GM, White SN, LindbladToh K. Genome-wide association identifies a deletion in the 39 untranslated region of striatin in a canine model of arrhythmogenic right ventricular cardiomyopathy. Hum Genet 2010;128:315–324. 8. Nakao S, Hirakawa A, Yamamoto S, Kobayashi M, Machida N. Pathologic features of arrhythmogenic right ventricular cardiomyopathy in middle-aged dogs. J Vet Med Sci 2011;73:1031–1036. 9. Santilli RA, Bontempi LV, Perego M, Fornai L, Basso C. Outflow tract segmental arrhythmogenic right ventricular cardiomyopathy in an English Bulldog. J Vet Cardiol 2009;11:47–51. 10. Bright JM, McEntee M. Isolated right ventricular cardiomyopathy in a dog. J Am Vet Med Assoc 1995;207:64–66. 11. Mohr AJ, Kirberger RM. Arrhythmogenic right ventricular cardiomyopathy in a dog. J S Afr Vet Assoc 2000;71:125–130. 12. Simpson KW, Bonagura JD, Eaton KA. Right ventricular cardiomyopathy in a dog. J Vet Intern Med 1994;8:306–309. 13. Fernandez del Palacio MJ, Bernal LJ, Bayon A, Bernabe A, Montes de Oca R, Seva J. Arrhythmogenic right ventricular dysplasia/ cardiomyopathy in a Siberian husky. J Small Anim Pract 2001;42: 137–142. 14. McKenna WJ, Thiene G, Nava A, et al. Diagnosis of arrhythmogenic right ventricular dysplasia/cardiomyopathy. Task Force of the Working Group Myocardial and Pericardial Disease of the European Society of Cardiology and of the Scientific Council on Cardiomyopathies of the International Society and Federation of Cardiology. Br Heart J 1994;71:215–218. 15. Marcus FI, McKenna WJ, Sherrill D, et al. Diagnosis of arrhythmogenic right ventricular cardiomyopathy/dysplasia: Proposed modification of the task force criteria. Circulation 2010;121:1533–1541. 16. Frances RJ. Arrhythmogenic right ventricular dysplasia/cardiomyopathy. A review and update. Int J Cardiol 2006;110:279–287. 17. Liu T, Pursnani A, Sharma UC, et al. Effect of the 2010 task force criteria on reclassification of cardiovascular magnetic resonance criteria for arrhythmogenic right ventricular cardiomyopathy. J Cardiovasc Magn Reson 2014;16:47. 18. Basso C, Fox PR, Meurs KM, et al. Arrthymogenic right ventricular cardiomyopathy causing sudden cardiac death in boxer dogs: A new animal model of human disease. Circulation 2004;09:1180–1185. 19. Baumwart RD, Meurs KM, Raman SV. Magnetic resonance imaging of right ventricular morphology and function in boxer dogs with arrhythmogenic right ventricular cardiomyopathy. J Vet Intern Med 2009; 13:271–274. 20. Meurs KM. Boxer dog cardiomyopathy: An update. Vet Clin Small Anim 2004;34:1235–1244.
Can Vet J 2015;56:1035–1039
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Case description
40.7 kg, 4-year-old, neutered male weimaraner dog was referred to the cardiology service at the University of Missouri Veterinary Medical Teaching Hospital for evaluation of syncope. The first syncopal episode was noted approximately 2 mo before referral and a second episode occurred 2 d before presentation. The dog was otherwise healthy. Physical examination revealed an intermittent arrhythmia characterized by frequent premature heart beats and pulse deficits, but was otherwise unremarkable. A standard 6-lead electrocardiogram (ECG) was performed that showed frequent ventricular premature complexes (VPCs) with a right bundle branch block morphology occurring as isolated complexes, couplets, triplets, and periods of ventricular bigeminy and trigeminy (repetitive sequence of 2 sinus complexes followed by 1 VPC). A transthoracic 2-dimensional and Doppler echocardiographic study revealed mild mitral regurgitation, normal chamber dimensions, and normal systolic function. A complete blood (cell) count (CBC) and serum biochemistry panel performed immediately prior to referral were unremarkable. Cardiac tro-
Department of Veterinary Medicine and Surgery (Eason, Leach) and the Veterinary Medical Diagnostic Laboratory (Kuroki), College of Veterinary Medicine, University of Missouri, Columbia, Missouri 65211, USA. Address all correspondence to Dr. Bryan D. Eason; e-mail: [email protected] Dr. Eason’s current address is Purdue University Veterinary Teaching Hospital, West Lafayette, Indiana 47906, USA. Use of this article is limited to a single copy for personal study. Anyone interested in obtaining reprints should contact the CVMA office ([email protected]) for additional copies or permission to use this material elsewhere. CVJ / VOL 56 / OCTOBER 2015
ponin I (cTnI) concentration was analyzed using a point-of-care analyzer (VetScan i-STAT; Abaxis, Union City, California, USA) on referral presentation and was increased at 3.85 ng/mL (normal canine reference range , 0.05 ng/mL, lower limit of detection 0.02 ng/mL). Thoracic and abdominal radiographs and abdominal ultrasound were unremarkable. Dirofilaria immitis antigen and antibodies to Borrelia burgdorferi, Anaplasma phagocytophilum, and Ehrichia canis were negative by serologic testing (SNAP 4Dx; IDEXX Laboratories, Westbrook, Maine, USA). Serum was also submitted to the Texas Veterinary Medical Diagnostic Laboratory (TVMDL) for Trypanosoma cruzi immunofluorescent antibody (IFA) testing and revealed a titer of 1:20, considered seronegative according to TVMDL protocol (1). Prophylactic antibiotic therapy with clindamycin (Watson Pharma Private, Salcette, Goa, India), 14.7 mg/kg body weight (BW), PO, q12h and doxycycline (Teva Pharmaceuticals, Sellersville, Pennsylvania, USA), 9.8 mg/kg BW, PO, q12h, was initiated to treat presumptive protozoal (i.e., Toxoplasma gondii, Neospora caninum) and bacterial (i.e., Borrelia burgdoferi, Rickettsia rickettsia, Erlichia canis, Bartonella spp.) causes of myocarditis, respectively. A 24-hour ambulatory ECG revealed multiform ventricular ectopy with periods of ventricular tachycardia and 32 881 ventricular ectopic events (total beats were 180 880). Approximately 89% of the ventricular ectopic complexes were left bundle branch block morphology and 11% were right bundle branch block morphology with varying coupling intervals. There were periods of ventricular tachycardia composed solely of left bundle branch block and of solely right bundle branch block morphology, and instances in which the morphology changed abruptly from one to the other (Figure 1). Oral antiarrhythmic therapy with sotalol (Qualitest Pharmaceuticals, Huntsville, Alabama, USA), 0.98 mg/kg BW, PO, q12h for 3 d, then 1.96 mg/kg BW, PO, q12h for 3 d was instituted followed by mexiletine (Teva 1035
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Figure 1. Holter monitor recording showing ventricular ectopy. The narrow arrows indicate a couplet of ventricular premature complexes with a left bundle branch block morphology. The rhythm then changes to a sustained monomorphic ventricular tachycardia with a right bundle branch block morphology (thick arrow).
Pharmaceuticals), 6.25 mg/kg BW, PO, q8h. The T. cruzi IFA test was repeated after 3 wk and remained negative at 1:20. A repeat 24-hour ambulatory ECG performed 2 mo after initiation of antiarrhythmic therapy showed marked improvement in both the frequency and complexity of the arrhythmia as there was a 96% reduction in the frequency of ventricular ectopy and a 99% reduction of ventricular tachycardic episodes compared with the baseline ambulatory ECG. Repeat cTnI concentration at that time was normal at 0.02 ng/mL. Despite a marked decrease in the frequency and complexity of ventricular ectopy and strict exercise restriction by the owners, sudden death occurred approximately 3 mo after initial evaluation. The heart was collected by the referring veterinarian and submitted for postmortem examination. Multiple formalinfixed myocardial specimens and the remaining fresh heart were submitted to the University of Missouri Veterinary Medical Diagnostic Laboratory. On gross examination of the tissue, no apparent hemorrhagic or necrotic changes were noted. Externally, the right ventricle was paler than the left. On cut sections, the right ventricular wall had a pale, greasy appearance that was multifocal and transmural in distribution. The remainder of the gross examination and the heart dimensions were unremarkable. Sections of the interventricular septum and the right ventricular and left ventricular free wall at the level of the papillary muscles were prepared for histopathologic examination. The right ventricular myocardium had multifocal, transmural, and coalescing fatty tissue infiltration covering approximately 60% of the tissue. The most severe lesions were located near the epicardium (Figure 2A). Similarly, approximately 30% of the interventricular septum and approximately 10% of the left ventricle were replaced by fatty infiltrates (Figure 2B). The surviving myocytes in each section appeared atrophied and occasionally exhibited vacuolar degeneration. There was minimal interstitial 1036
fibrosis with no inflammatory cells or infectious agents noted. The myocardial fatty infiltration and replacement of the myocardium, most severe in the right ventricular free wall, and lack of inflammatory cells or infectious agents was most consistent with a diagnosis of arrhythmogenic right ventricular cardiomyopathy (ARVC).
Discussion Syncope, defined as sudden but transient loss of consciousness and postural tone, can be divided into broad categories of cardiac and non-cardiac causes with the most commonly reported cause of syncope being cardiac arrhythmias (2). Physical examination of the dog in the present report was highly suggestive of a cardiac cause of syncope based on the presence of an arrhythmia on auscultation; however, a diagnosis of ARVC as the etiology of heart disease in this patient was only made on postmortem histopathologic examination. Arrhythmogenic right ventricular cardiomyopathy is a myocardial disease that is characterized clinically by syncope, ventricular arrhythmias of left bundle branch block morphology, and sudden death with no premonitory clinical signs. Arrhythmogenic right ventricular cardiomyopathy has been described in humans, cats, and dogs (3–5). The most common breed of dog affected is the boxer and a familial pattern of autosomal dominance has been established (6). Recently, a causative mutation in the gene encoding striatin has been identified in a population of boxers, although other genetic mutations are also suspected (7). Isolated cases of ARVC without an obvious familial pattern have been reported in other breeds (8–13). Arrhythmogenic right ventricular cardiomyopathy has not been previously reported in weimaraner dogs. Ante-mortem diagnosis of ARVC presents a unique clinical challenge as sudden death can be the first clinical sign. In humans, standardized criteria have been proposed for the CVJ / VOL 56 / OCTOBER 2015
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200 mm
Figure 2. Photomicrograph of histopathology of the right (A) and left (B) ventricular free wall. Note that the right ventricular myocardium is severely infiltrated and replaced by fatty tissue. The most severely affected zone was the epicardium indicated by the black arrows; however, the fatty infiltration was multifocally and transmurally distributed (A). In the left ventricle (B), cardiomyocytes are multifocally and occasionally separated and replaced by fatty tissue and sparse connective tissue. Note the predominant pattern of infiltration in both A and B is fatty tissue without inflammation. Masson’s trichrome stain. A and B are the same magnification. Bar = 200 mm. 279 3 105 mm (72 3 72 DPI).
diagnosis of ARVC and include a combination of structural, electrocardiographic, arrhythmic, histopathologic, and familial features (14). These guidelines have since been modified given the emergence of advanced diagnostic imaging modalities such as cardiac magnetic resonance imaging (cMRI) and identification of causative genetic mutations (15). In humans, cMRI has become increasingly utilized for non-invasively evaluating the function and structure of the right ventricle. It has become the gold standard for ante-mortem diagnosis of ARVC, with major criteria consisting of wall motion abnormalities and aneurysmal dilation of the right ventricle (15). Other less specific findings include intramyocardial fat deposits seen as an intense signal compared with surrounding more normal myocardium and abnormal late gadolinium enhancement suggestive of intramyocardial fibrosis (16,17). In veterinary studies, cMRI was able to detect fatty infiltrative changes in explanted hearts (18), while another study failed to show fatty infiltration but did reveal right ventricular dysfunction (19). This discrepancy may be due to the difference in ages of dogs in each study, suggesting that cMRI evidence of fatty infiltration may become more apparent with chronicity. Although cMRI is becoming increasingly available in veterinary medicine, it requires general anesthesia and may be cost-prohibitive. A presumptive diagnosis can be made based on history/clinical signs, familial history, ECG abnormalities (ventricular ectopy with a left bundle branch block morphology), and the absence of significant structural abnormalities on echocardiogram to explain abnormal ECG findings (20). Echocardiographic changes may be present in both humans and dogs in more severe cases, but specificity and sensitivity are not high. In humans, right ventricular enlargement or dilation and hypokinetic regions may be associated with ARVC (16). In a recent study, there was a positive association between the development of DCM and a homozygous striatin mutation in boxer dogs (21). Echocardiographically evident right ventricular CVJ / VOL 56 / OCTOBER 2015
aneurysm has been reported in a case of segmental ARVC in a non-boxer dog (9). Syncope is one of the most commonly reported clinical signs associated with ARVC in boxers and may be the presenting complaint in up to 68% of cases (22). A 24-hour ambulatory ECG is often utilized to support an ante-mortem diagnosis as dogs may have normal ECGs in the hospital. Normal dogs have a very low incidence of ventricular ectopy. A study of healthy adult dogs showed a median of 2 VPCs in 24 h when boxers were excluded from the population (23). Boxers seem to have a greater tendency toward ventricular ectopy with 75% of healthy adult boxers reportedly having , 75 VPCs in a 24-hour period (20), though this population may include dogs with ARVC not manifesting clinical signs. Recommended guidelines for interpretation of 24-hour ambulatory ECG recordings in boxers suggest that . 100 VPCs is suspicious for ARVC and treatment is generally recommended if . 1000 VPCs are recorded over a 24-hour period (20). Whether or not these guidelines can be extrapolated to other breeds has not been established and warrants further investigation. The decision to use antiarrhythmic therapy in this case was made in light of the dog’s clinical signs and documentation of frequent sustained ventricular tachycardia. Multi-drug anti-arrhythmic therapy was used in this case; however, monotherapy was considered. When combination therapy is used, anti-arrhythmic drugs are often added in a staggered protocol as was done in this case to evaluate for potential adverse effects. Efficacy of anti-arrhythmic therapy is optimally evaluated with a repeated 24-hour ambulatory ECG. This can present additional cost to owners if multiple changes to medications are required. Because the underlying mechanism of the ventricular arrhythmias in the present case could not be determined based on ante-mortem diagnostic tests performed, combination therapy was elected in the hope of greater 1037
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a rrhythmia suppression. Mexilitine is a class Ib anti-arrhythmic drug, inhibiting fast sodium channels, whereas sotalol is a class III antiarrhythmic with non-selective beta blocking properties. Sotalol monotherapy and combination therapy with atenolol-mexiletine have both been shown to be effective at reducing the frequency and severity of ventricular ectopy in boxer dogs with ARVC (24). Combination sotalol-mexilitine has also been shown to be more effective than sotalol monotherapy in reducing the frequency of VPCs in boxer dogs with ARVC (25). However, in German shepherd dogs with inherited ventricular arrhythmias, sotalol monotherapy was found to be proarrhythmic, likely by worsening early afterdepolarization induced triggered activity, while mexilitine-sotalol combination was superior to mexilitine monotherapy in reducing the frequency of VPCs (26). The decision to use multi-drug anti arrhythmic therapy in this case was based on clinical judgment and the owner’s financial concerns regarding cost of repeated ambulatory ECG for monitoring response to therapy. The mechanism of the ventricular arrhythmias characteristic of ARVC is thought to be fatty or fibrofatty replacement of the normal myocardium generating macro-reentrant electrical circuits, though associated myocarditis may also play a role (4,16). Myocyte degeneration, atrophy, and replacement of myocardium by fatty or fibrofatty tissue can be associated with other diseases such as dilated cardiomyopathy in dogs (27). In ARVC, however, these histologic changes are most prominent in the right ventricle as seen in this case. These findings are similar to the changes noted in humans affected by this disease (18,28). The disease predominates in the right ventricle but is also seen in the left ventricle in both humans and dogs (18,28). Because of the distribution, ventricular tachycardia tends to be monomorphic. In patients with multifocal areas of disease involving the interventricular septum and parts of the left ventricle, the arrhythmias may have multiple arrhythmogenic foci (4). The presence of myocarditis has also been postulated as a potential cause or contributory factor of arrhythmogenesis with multifocal lymphocytic infiltrates and myocyte death being present in all boxer dogs that died suddenly in one study (18). Histopathologic lesions suggesting myocarditis appear to be more commonly associated with the fibrofatty form of myocyte replacement in both boxers and other breeds with ARVC, though the exact role of myocarditis in the progression of this disease remains unclear (8,27). Thinning and aneurysmal dilation of the right ventricular free wall are more commonly seen with the fibrofatty form of ARVC in both humans and boxer dogs (18). The dog in this report had predominantly fatty replacement of cardiomyocytes, without evidence of myocarditis or right ventricular thinning or aneurysmal dilations. Whether the fatty and fibrofatty forms of ARVC represent different stages of the same disease process remains unknown. Additionally, some of the reported cases of ARVC in both human and veterinary literature may actually be cases of Uhl’s anomaly, in which there is partial or complete loss of the myocardium in the right ventricular free wall, with only the epicardial and endocardial layers remaining. It has been previously thought that Uhl’s anomaly was a more severe form of ARVC, as both may be mediated by unregulated apoptosis, though a more recent study suggests they may be distinct entities (29). 1038
The increased cTnI concentrations at initial evaluation supported the presence of myocarditis clinically, which led to tests for infectious diseases. Potential infectious causes of myocarditis in dogs include Rickettsial disease, Lyme disease, leptospirosis, toxoplasmosis, Chagas’ disease, and bartonellosis and may potentially increase serum concentration of cardiac troponins (30). Histopathology combined with clinical abnormalities may be beneficial in diagnosing the causative agent of myocarditis, but myocardial biopsy is rarely performed in veterinary medicine as an ante-mortem diagnostic test. Characteristic histopathologic findings associated with Chagas’ cardiomyopathy in humans include myocardial fibrosis resulting from multiple mechanisms including myocarditis and persistence of parasites within cardiac tissue (31). Dogs experimentally infected with T. cruzi similarly showed varying degrees of myocardial fibrosis on histopathology (32). In one study of naturally occurring T. cruzi infections in dogs, histopathologic evidence of myocarditis was noted in almost 98% of cases (1). Cardiac toxins and envenomation may also be considered as potential causes of myocarditis and elevation of cTnI when clinical history indicates possible exposure (30,33). In the present case, no history of exposure to toxins was noted by the owners and no microorganisms, inflammatory changes, evidence of toxin exposure such as necrosis, or ischemic damage was noted on histopathologic examination and only minimal fibrosis was present, making infectious and inflammatory diseases or toxins unlikely. The initial increase in cTnI concentrations may have been secondary to ischemia from the frequent tachyarrhythmia or due to the fatty replacement and atrophy of cardiac myocytes seen histologically (34,35). It has been previously shown that boxers with ARVC have significantly greater serum cTnI concentrations compared with both control boxers and non-boxer dogs, and that there was a significant correlation between serum cTnI concentrations and both frequency and complexity of ventricular ectopy (35). This report presents the diagnosis of ARVC in a breed in which it has not been previously reported. Unfortunately, sudden death remains a common clinical outcome of this disease despite successful response to anti-arrhythmic therapy. A definitive diagnosis was made postmortem based on the combination of clinical signs, extensive diagnostic testing and imaging, and histopathologic findings of fatty myocardial replacement without myocarditis. Arrhyhmogenic right ventricular cardiomyopathy should be considered as a differential diagnosis for syncope and ventricular ectopy in non-boxer dogs without echocardiographic evidence of structural heart disease. CVJ
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