Case 3 -

Arrhythmogenic Right Ventricular Dysplasia with Predominant Left Ventricular Involvement Allen P. Burke Armed Forces Institute of Pathology Washington, DC

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Clinical History A 35-year old man with a history of palpitations collapsed while playing basketball. There was no documented history of syncope, and the patient had had no prior cardiac evaluation. There was no family history of sudden death. At autopsy, the heart was 300 grams. There was mildly increased epicardial fat. The foramen ovale was closed. The left ventricular chamber dimensions were normal: the left ventricular cavity diameter was 32 mm, the left ventricular free wall was 11 mm thick, the ventricular septum 10 mm thick. There was mild dilatation of right atrium and right ventricle, and the right ventricle was 4 mm thick, without gross scars or abnormal fat infiltrates. The valves and endocardium were grossly unremarkable. There was circumferential scarring in left ventricle, subepicardial in the free wall, and in the right ventricular aspect of ventricular septum. A histologic section is provided of the lateral wall of the left ventricle. Case 3 - Figure 1 - The left ventricle stained with Masson trichrome demonstrates subepicardial scarring and fat. Case 3 - Figure 2 - A higher magnification of the subepicardial scar of the left ventricle. Case 3 - Figure 3 - Vacuolated myocytes within fibrosis, typical of ARVD. Case 3 - Figure 4 - There was a microscopic area of fibrofatty change in the right ventricle. Note the normal right ventricular fat (arrowheads) with "marbling" present in virtually all human right ventricles within a wide variation. The arrows show an abnormal patch of fat. Case 3 - Figure 5 - A higher magnification demonstrates the fibrofatty focus. For some reason, most scars in the right ventricle elicit a more prominent fatty response, as compared to scars in the left (compare to figure 2), possibly because of the normal fat in the right ventricle. Diagnosis Arrhythmogenic right ventricular dysplasia, with predominant left ventricular involvement (so-called arrhythmogenic left ventricular dysplasia). Comment Arrhythmogenic right ventricular dysplasia (cardiomyopathy) is an uncommon etiology of sudden cardiac death, comprising less than 5% of sudden cardiac deaths in young men and women (aged younger than 40 years) in the United States. Because arrhythmias are triggered by exercise, the proportion of sudden exertional deaths that is due to ARVD is greater. Although there are reports of the disease in infants, documented examples of the typical form of ARVD that result in sudden death occur from ages 8-45. ARVD may occur in families, but the majority of cases are sporadic. Although in some familial cases, the disease has been linked to specific chromosomal loci, the genetic basis for ARVD is currently unknown. The pathologic features of ARVD are somewhat heterogeneous, which has led to a degree of confusion and debate regarding diagnosis. Initial descriptions of the disease focused on two features that are variably present: aneurysmal thinning of the right ventricle, and marked fat accumulation in the right ventricle. These two features happen to be those that are most readily imaged. However, it must be appreciated that there is a wide variation in the degree of fat infiltration in the right ventricle, especially in the anterior wall. Even massive fat deposits with the walls of the right and left ventricle, and within the epicardium, is likely a metabolic condition completely unrelated to ARVD. Whether massive fat deposits in the heart are particularly arrhythmogenic and represent a likely cause of unexpected death remains unclear. The second feature of ARVD that was initially emphasized, aneurysmal thinning of the wall, is unfortunately present in only a minority of patients with ARVD who die suddenly and are initially diagnosed at autopsy. What, then are the diagnostic features of ARVD that allow for a reliable autopsy diagnosis? Experience with a large number of cases of ARVD that have led to sudden cardiac death demonstrates that the characteristic histologic finding is the presence of biventricular subepicardial scars, which result in a fatty metaplasia. The degree of fat is variable, and ranges from a striking accumulation in areas where fat is not physiologically present (for example, the right ventricular outflow, the right ventricular posterior wall), to no gross fat at all. The distribution of the fibrofatty process is not uniform, and often results in a random, or spotty areas of fat within the ventricles. The question of biventricularity brings up the possibility that ARVD is, in a sense, a misnomer, and that the right ventricular component of the disease was the tip of the iceberg highlighted by initial clinical and pathologic reports. It is been increasingly shown that the left ventricle is frequently, in fact typically, involved in ARVD. Furthermore, because fat normally occurs in the right ventricle, and the gross features of right ventricular involvement of ARVD may be subtle at best, the gross diagnosis at autopsy is often more readily made by looking at the left, and not the right ventricle. There are few, if any entities other than ARVD which result in circumferential, subepicardial left ventricular scars that, on histologic evaluation, show fat as well. The cause of ARVD is unknown, and there is no inherent property of the disease that should restrict it to the right ventricle. Therefore, it is inevitable that hearts with typical gross and histologic findings restricted to the left ventricle, that are seen in the usual biventricular form of the ARVD, will occur. Indeed, examples of ARVD localized to the left ventricle have been reported in the forensic literature, and have been termed left ventricular dysplasia. If ARVD is a form of idiopathic scarring, it should follow that it really is a form of cardiomyopathy. It should be kept in mind that fibrosis of any etiology, including ischemia, may result in fatty metaplasia; indeed, in some infarcts, large areas of fat may occur. The etiology of the scarring in ARVD is unknown, but there is evidence that it may be the sequela of an inflammatory process (myocarditis). In many cases of ARVD, there is a patchy lymphocytic infiltrate, but overt myocarditis with necrosis is unusual. The separation of ARVD into the “fatty” and “fibrofatty” variants is essentially one of degree: both types have some degree of fibrosis (the sine qua non of ARVD), but have a prominent fatty metaplasia in the “fatty” type, with a relatively mild degree of fat in the “fibrofatty” type. Simple increased fat within the right ventricle, in which there is a “marbled”, uniform pattern of fat within the wall, is a normal finding, and if accentuated, represents a morphologic variant unrelated to ARVD. The diagnosis of ARVD rests, therefore, on the presence of scarring in a typical distribution (subepicardial in both ventricles) in the absence of clear etiology, with variable amounts of fat. Of diagnostic help to forensic pathologists is the frequent finding of degenerating myocytes within the scars, with a typical bubbly cytoplasm. Although characteristic of ARVD, such myocytes may be present in other types of cardiomyopathy, but in the context of subepicardial scarring, they are essentially diagnostic. This particular case for review demonstrated predominantly subepicardial scars in the left ventricle, with fatty metaplasia and characteristic degenerating myocytes. The initial right ventricular sections submitted for histologic evaluation were normal. An additional section from the posterior wall demonstrated a single microscopic focus of degenerating myocytes with fibrosis and fat that was clearly not part of the normal, regular fat present in all right ventricular walls. References Burke AP, Robinson S, Radentz S, Smialek J, Virmani R. Sudden death in right ventricular dysplasia with minimal gross abnormalities. J Forensic Sci. 1999;44:438-43. Fontaine G, Fontaliran F, Zenati O, Guzman CE, Rigoulet J, Berthier JL, Frank R. Fat in the heart. A feature unique to the human species? Observational reflections on an unsolved problem. Acta Cardiol. 1999;54:189-94. Lobo FV, Silver MD, Butany J, Heggtveit HA. Left ventricular involvement in right ventricular dysplasia/cardiomyopathy. Can J Cardiol. 1999;15:1239-47. Shrapnel M, Gilbert JD, Byard RW. “Arrhythmogenic left ventricular dysplasia” and sudden death. Med Sci Law. 2001;41:159-62. Thiene G, Basso C, Calabrese F, Angelini A, Valente M. Pathology and pathogenesis of arrhythmogenic right ventricular cardiomyopathy. Herz. 2000;25:210-5. Burke AP, Farb A, Tashko G, Virmani R. Arrhythmogenic right ventricular cardiomyopathy and fatty replacement of the right ventricular myocardium: are they different diseases? Circulation. 1998;97:1571-80. Lobo FV, Heggtveit HA, Butany J, Silver MD, Edwards JE. Right ventricular dysplasia: morphological findings in 13 cases. Can J Cardiol. 1992;8:261-8.