Systematic monitoring and pathologic investigation of sudden death in young people and athletes of the Veneto Region of Italy showed that ARVC/D is the most common pathologic substrate accounting for nearly one fourth of fatal events on the athletic field [6,12]. The incidence of sudden death from ARVC/D in athletes is estimated to be 0.5 per 100,000 persons per year (Fig. 22.1). Sudden death victims with ARVC/D were all males with a mean age of 22.6±4 years .
The hallmark lesion of the disease is the extensive replacement of the RV myocardium by fibrofatty tissue (Fig. 22.2). The autopsied hearts demonstrate massive regional or diffuse fibrofatty infiltration, parchment-like and translucence of the RV free wall, and mild to moderate RV dilatation, together with aneurysmal dilatations of postero-basal, apical, and outflow tract regions. These RV pathologic features allow differential diagnosis with training-induced RV adaptation ("athlete's heart"), usually consisting c.6
Fig. 22.1 • Incidence and relative risk (RR) of sudden death from major cardiovascular causes among young athletes and nonathletes. ARVC/D, arrhythmogenic right ventricular cardiomyopathy/dysplasia; CAD, coronary artery disease; CCA, congenital coronary artery anomalies. Modified from 
of global RV enlargement without regional dilatation/dysfunction. Histologically, fibro-fatty infiltration is usually associated with focal myocardial necrosis and patchy inflammatory infiltrates. It is noteworthy that fibrofatty scar and aneurysms are potential sources of life-threatening ventricular arrhythmias. The histopathologic arrangement of the surviving myocardium embedded in the replacing fi-brofatty tissue may lead to non-homogeneous intra-ventricular conduction predisposing to re-entrant mechanisms.
The advent of molecular genetic era has provided new insights in understanding the pathogenesis of ARVC/D, showing that it is a desmosomal disease resulting from defective cell adhesion proteins such as plakoglobin, desmoplakin, plakophilin-2, desmo-glein-2, and desmocollin-2 . It has been hypothesized that the lack of the protein, or the incorporation of mutant protein into cardiac desmosomes, may provoke detachment of myocytes at the intercalated discs, particularly under the condition of mechanical stress during training and competitive sports activity [27, 28]. As a consequence, there is progressive myocyte death with subsequent repair by fibrofatty replacement. Life-threatening ventricular arrhythmias may occur either during the "hot phase" of myocyte death as abrupt ventricular fibrillation or later in the form of scar-related macro-re-entrant ventricular tachycardia .
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