ARVC in Boxers: Case Studies
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Vet Times The website for the veterinary profession https://www.vettimes.co.uk ARVC in boxers: case studies Author : Ruth Willis Categories : Companion animal, Vets Date : December 8, 2014 Arrhythmogenic right ventricular cardiomyopathy (ARVC) is also known as boxer cardiomyopathy. ARVC has been documented in humans, but, in the veterinary context, this condition mainly affects boxers and is more common in middle aged and older dogs. This condition is characterised by ventricular dysrhythmias that have the potential to cause syncope and, in some cases, also systolic dysfunction resulting in congestive heart failure. Although some individuals seem to tolerate this disease, sadly it is also associated with sudden death and is of understandable concern to owners and breeders. Pathology The disease is characterised by fibrofatty infiltration of the right ventricular myocardium and progressing from epicardium to endocardium. The changes generally start around the triangle of dysplasia of the right ventricle and then may spread to involve the interventricular septum, atrial myocardium and sometimes also the left ventricle. The fibrofatty infiltration results in a loss of mechanical and electrical coupling between cells and this is likely to form the substrate for dysrhythmias as the myocytes are no longer an electrical syncytium. At a cellular level, the fibrofatty infiltration may also result in impaired cell-to- cell adhesion, myocyte detachment, cell death and decreased resilience to mechanical stress and pressure. Clinical presentation In the 1990s, three forms of boxer cardiomyopathy were described (Harpster, 1991): • type one – ventricular tachydysrhythmias without clinical signs; • type two – ventricular tachydysrhythmias with clinical signs; or 1 / 12 • type three – ventricular tachydysrhythmias and systolic failure. The type one dogs may have a dysrhythmia detected as an incidental finding, but have no referable clinical signs. Type two dogs will have a history of referable clinical signs such as syncope, but, as the dysrhythmia may be intermittent, may have no dysrhythmia detected during routine examination. The type three dogs may present with signs consistent with congestive heart failure such as dyspnoea, coughing, weight loss, lethargy, exercise intolerance and syncope. Sadly, sudden death may be the first indicator of disease in all three types of this disease. Diagnosis While histopathology is the gold standard for diagnosing ARVC, cardiac tissue is rarely available antemortem in dogs. Therefore, tests used to make a diagnosis in boxers include: • echocardiography; • ambulatory ECG or Holter recording; and • troponin assays. Echocardiography may demonstrate systolic dysfunction in type three disease; however, many cases with type one and two disease have normal systolic function. As the dysrhythmias associated with this condition may be intermittent, ambulatory electrocardiograms (ECGs) are useful in detecting the number of ectopic ventricular beats during a 24-hour period. Ambulatory ECGs are small (approximately 150g) monitors, known as Holter monitors, which are worn on the dog’s dorsal midline between the shoulders. The monitor is attached using three adhesive electrodes and held in place during the recording within a pocket in a snug vest worn for 24 hours (Figure 1). Up to 50 single ventricular premature beats (VPCs) during a 24-hour period would generally be considered to be an acceptable limit, although some studies have suggested this is slightly higher in boxers, with up to 100 single VPCs being considered acceptable (Stern et al, 2010). Boxers with ARVC will have frequent and/or complex ventricular ectopy seen during a 24-hour recording. Complex ectopy is any ventricular ectopy with two or more consecutive ventricular beats and includes couplets, triplets, salvos and also paroxysmal or sustained ventricular tachycardia. As both cardiac and systemic disease can result in increased frequency of ventricular ectopy, other causes need to be excluded and tests to consider include haematology, serum biochemistry and abdominal ultrasound. 2 / 12 Figure 2 shows an extract from a Holter monitor readout from a boxer with ARVC. Three leads are recorded simultaneously and, reading from left to right, there are five sinus beats followed by a short paroxysm of rapid monomorphic ventricular tachycardia, then resumption of sinus rhythm for two beats followed by a couplet of ventricular beats and then a sinus beat. Troponin Troponin is a protein that is integral to myocyte contraction. When there is myocyte damage, serum troponin concentrations tend to increase, but the sensitivity of the test for detecting ARVC may be suboptimal with overlap seen in the serum troponin concentrations of unaffected and affected dogs (Baumwart et al, 2007). Diagnostic tests under investigation Myocardial biopsies are done relatively frequently in human patients and, in future, this technique may become more widely accepted and practised in dogs. MRI is widely used in human patients as it can detect right ventricular enlargement, fatty infiltration, fibrosis and wall motion abnormalities, and studies are under way in dogs (Baumwart et al, 2009). Prevalence and the role of genetic testing The propensity for boxers to develop heart disease is well recognised – in addition to ARVC this breed is also predisposed to aortic valve stenosis and neurocardiogenic (or vasovagal) syncope. The prevalence of ARVC in the UK population of boxers is not known, but the impression of cardiologists is it seems to be increasing. A study from the US performed Holter recordings on 301 clinically normal boxers and found 23 per cent had an increase in the number of ectopic ventricular beats over a 24-hour period (Stern, 2010); however, this study may have underestimated the true prevalence as clinically affected dogs were excluded. As ARVC is known to be a familial disease inherited in an autosomal dominant pattern, genetic testing may yield further information. There is much debate about the genetic mutation(s) responsible for the ARVC phenotype and a single genetic test that detects all cases has not yet been established. Striatin is a desmosomal protein involved in linking myocytes and striatin deletion has also been implicated in the development of ARVC in human patients. A study (Meurs et al, 2013) suggested deletion of the striatin gene may be involved in the genesis 3 / 12 of some cases of ARVC. In this study of 33 dogs with type three disease, 30 were positive for a striatin mutation. However, five dogs in the control group (which contained 16 dogs) were also positive heterozygous, but did not demonstrate the ARVC phenotype. These findings demonstrate three dogs with the disease did not have the striatin mutation, and five dogs without disease did have the mutation; therefore, some caution is required when discussing results of this test with owners and breeders. The early results of genetic testing a large number of individuals (more than 1,600 dogs) for the striatin mutation gave a potentially higher prevalence, with 41 per cent of dogs tested being heterozygous and six per cent positive homozygous. However, ARVC is thought to have variable penetrance and the phenotype of all of these dogs is yet to be established. For more information visit www.ncstatevets.org/genetics Another study (Meurs et al, 2013) suggested penetrance of the striatin mutation may be 82 per cent in positive heterozygous and 100 per cent in positive homozygous dogs. Given this variable penetrance in dogs carrying a potentially affected gene, it seems plausible environmental factors and modifying genes may also be involved in the development of this condition. Another protein under investigation regarding its role in ARVC in both humans and boxers is beta catenin (Oxford et al, 2014). This protein appears to be involved in remodelling the adult heart and could help to explain the changes seen in cell structure and also adipocyte proliferation seen in the ARVC phenotype. Case study one A 12-year-old, neutered male boxer (Figure 3) was presented for treatment of haematuria. A dysrhythmia was detected as an incidental finding. The haematuria was associated with a urinary tract infection and was treated accordingly, but the dysrhythmia persisted. On examination, the dog was found to be subdued, was reported to have osteoarthritis, but had reasonable exercise tolerance. There was no reported syncope or signs suggestive of congestive heart failure. Clinical examination revealed a heart rate of 140bpm with occasional single premature beats associated with a pulse deficit. Otherwise, cardiac output signs were normal at rest and no abnormalities detected. On auscultation there was a soft grade 1-2/6 systolic murmur audible at the left cranial heart base. 4 / 12 Haematology and serum biochemistry were unremarkable. Echocardiography showed normal cardiac chamber dimensions and good systolic function. Although the left ventricular outflow tract and aortic valve appeared grossly normal, the velocity of blood flow in the aorta was 2.2m/s from a subcostal view suggesting mild aortic stenosis could account for the systolic murmur. The ECG during the echocardiogram showed single ventricular premature beats, therefore a 24-hour Holter monitor recording was performed and the ventricular beat summary table is shown in Figure 4. Figure 4 shows the frequency and complexity of ventricular ectopy during the 24-hour recording and the total aberrant beat count exceeds the acceptable limit of 50 single VPCs/24hr,