Pathology and pathogenesis of arrhythmogenic right ventricular cardiomyopathy

Arrhythmogenic right ventricular cardiomyopathy is a primary heart muscle disease characterized by progressive myocardial atrophy of the right ventricle, with transmural fatty or fibrofatty replacement, either segmental or diffuse, accounting for electrical instability at risk of life-threatening ventricular arrhythmias. It was recently included among cardiomyopathies in the revised WHO classification. The disease was found to be a major cause of sudden death in the young and in athletes of the Veneto Region, Italy. A familial occurrence with autosomic dominant inheritance was then discovered with a prevalence estimated to be 6/10,000 inhabitants and 5 loci have been identified by linkage analysis so far, 2 mapping to chromosome 14 and to chromosome 1, 2 and 3 one each. A recessive form associated with palmoplantar keratosis has also been reported, mapping to chromosome 17. Nonetheless, the specific gene defects as well as the defective coded proteins have not yet been identified. At gross examination, the right side of the heart appears yellowish or whitish as to suggest a fatty or fibrofatty infiltration of the underlying myocardium; the myocardial loss frequently accounts for a parchment like, translucent look of the right ventricular free wall. Aneurysms of the right ventricular free wall, whether single or multiple, were reported in about 50% of cases in a recent pathologic investigation, and are considered a pathognomonic feature of arrhythmogenic right ventricular cardiomyopathy; they are typically located in the inferior, diaphragmatic wall, underneath the posterior leaflet of the tricuspid valve, as well as in the infundibulum and at the apex. Right ventricular enlargement, whether mild, moderate or severe, is a constant feature. Involvement of the left ventricle has been reported in almost 50% of cases. At histology, the pathologic process generally starts from the subepicardium and extends to the endocardium in a wave-front phenomenon. The residual, spared myocytes are located within the subendocardial trabeculae and few myocardial fascicles are scattered throughout the fibrofatty tissue. All stages of myocardial injury and repair are recognizable: acute cell death with sarcolysis and inflammatory infiltrates; subacute damage with "active fibrosis", including dying myocytes, lymphocytes and macrophages, or otherwise adipocytes replacing vanished myocytes; and, eventually, chronic stage with fibrous tissue and adipocytes surrounding residual surviving myocytes. Both the etiology and pathogenesis of arrhythmogenic right ventricular cardiomyopathy are still unknown. In particular, the mechanisms leading to progressive loss of myocardium and fibrofatty replacement are speculative. According to the frequent finding of inflammatory infiltrates at histology, an inflammatory theory has been advanced and infective, toxic or immune mechanisms have been investigated. Recently, apoptosis has been documented both in autoptic and bioptic material, suggesting that recurrent bouts of apoptosis may account for progressive atrophy of the myocardium which is then replaced by fibrofatty tissue. Apoptosis may be triggered by T-lymphocytes.