Arrhythmogenic Right Ventricular Cardiomyopathy Causing Sudden Cardiac Death in Boxer Dogs

Abstract

Background-Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a primary familial heart muscle disease associated with substantial cardiovascular morbidity and risk of sudden death. Efforts to discern relevant pathophysiological mechanisms have been impaired by lack of a suitable animal model. Methods and Results-ARVC was diagnosed in 23 boxer dogs (12 male; 9.1Ϯ2.3 years old). Clinical events alone or in combination included sudden death (nϭ9; 39%), ventricular arrhythmias of suspected right ventricular (RV) origin (nϭ19; 83%), syncope (nϭ12, 52%), and heart failure (nϭ3; 13%). Right ventricular enlargement or aneurysms occurred in 10 (43%). Striking histopathological abnormalities were present in each boxer dog but not in controls, including severe RV myocyte loss with replacement by fatty (nϭ15, 65%) or fibrofatty (nϭ8, 35%) tissue. Focal fibrofatty lesions were also present in both atria (nϭ8) and the left ventricle (LV) (nϭ11). Fatty replacement occupied substantially greater RV wall area in ARVC dogs than controls (40.4Ϯ18.8% versus 13.8Ϯ3.4%, respectively) (PϽ0.001); residual myocardium was correspondingly reduced (56.6Ϯ19.2% versus 84.8Ϯ3.8% in controls) (PϽ0.001). MRI demonstrated bright anterolateral and/or infundibular RV myocardial signals, confirmed as fat by histopathology. Myocarditis appeared in the RV (nϭ14, 61%) and LV (nϭ16, 70%) and in each dog with sudden death, but not in controls. Familial transmission was evident in 10 of the 23. Key Words: models, animal Ⅲ cardiomyopathy Ⅲ pathology Ⅲ death, sudden A rrhythmogenic right ventricular cardiomyopathy (ARVC) is a primary familial cardiomyopathy associated with substantial cardiovascular morbidity and sudden death in the young. 1-3 ARVC is transmitted as an autosomal dominant trait, and 2 mutations have been identified at the cardiac ryanodine receptor 2 gene (ARVD2) and the desmoplakin gene (ARVD8). 4,5 It has been noted for many years that the boxer canine breed is predisposed to ventricular arrhythmias and sudden death, 6,7 but the underlying disease responsible for these clinical features has been incompletely defined. In light of advances in genomic mapping of the domestic dog, 8 a spontaneous canine model of ARVC and sudden death would provide a unique opportunity to study this disease genome and contribute valuable insights into its pathogenesis. Therefore, the purpose of the present study was to define the clinical and pathological features of a naturally occurring myocardial disease in boxer dogs and assess its suitability as an animal model of ARVC. Conclusions-We Methods Selection of Animal SubjectsAs part of an ongoing study to evaluate the heritability of ventricular arrhythmias in boxer dogs, 239 such animals, including 6 large families, were prospectively recruited for Holter ECG between 1997 and 1999 at the Ohio State University College of Veterinary Medicine. Of those with substantial ectopy or syncope that died or were euthanized, 23 boxer dogs (12 male, 11 female) had autopsy examination and constitute the study group....

Abnormal atrial activation is common in patients with arrhythmogenic right ventricular cardiomyopathy

“…Atrial involvement in the ARVC disease process has been neglected until recently, when several animal models of the disease reported the loss of atrial myocardium and bilateral focal fibro-fatty atrial lesions in up to one third of affected boxer dogs 7 and cats. 8 Even higher number of affected animals were present with atrial enlargement due to the dilatation of the right ventricle and tricuspid regurgitation.…”

“…5 Despite the desmosomal proteins that are commonly involved in the pathogenesis of the disease 6 are present both in ventricles and atria, there has not been any study that systematically evaluates possible signs of atrial involvement in ARVC. Studies in animal models of the disease consistently report the presence of fibro-fatty replacements in atrial myocardium in affected animals, 7,8 while human data on this topic are limited to a handful of case reports. [9][10][11] The aim of the present study was to assess the presence of atrial abnormalities using signalaveraged P-wave (PSA-ECG) analysis of P-wave duration and morphology in patients with ARVC.…”

Arrhythmogenic right ventricular cardiomyopathy/dysplasia: a not so rare “disease of the desmosome” with multiple clinical presentations

“…The histological analysis of the right ventricle showing massive fibrofatty replacement of the myocardium remains a hallmark of ARVC/D. Several animal models exist, including dogs, cats, minks, and mice 21 , 22 , 23 to study this rare disease entity.…”

Bilateral ventricular myocardial dysplasia in a Shar-Pei dog

“…Dysplasia of the myocardium, also known as arrhythmogenic right ventricular dysplasia (ARVD), arrhythmogenic right ventricular cardiomyopathy (ARVC) or arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) (Basso et al, 2004;Harvey et al, 2005;Noszczyk-Nowak and Nowak, 2009) is a myocardial disease and an important cause of sudden death in humans, but has rarely been described in animals (Harvey et al, 2005).…”

“…The replacement extends from the epicardial surface towards the endocardium (Basso et al, 2004). The clinical signs of ARVD may include ventricular arrhythmias, syncope, heart failure or sudden death, or the animal can be asymptomatic (Hyun and Filippich, 2006).…”