Introduction

Arrhythmogenic right ventricular cardiomyopathy (ARVC/D) is a paradigm shifting disorder that primarily affects the right ventricular (RV) myocardium early in the course of disease with later-onset left ventricular (LV) disease [1]. Clinically, the disease is classically characterized by ventricular arrhythmias of RV origin, as noted by ventricular tachycardia (VT) with a left bundle branch block (LBBB) morphology, commonly associated with syncope or sudden cardiac death (SCD) [2]. In addition, affected individuals may develop right heart failure and ultimately biven-tricular failure. In most cases, age of onset occurs in the teenage years or beyond, more often in males than females [3]. In the Veneto region of Italy, the disorder has been described as the most common cause of SCD in young, healthy, and athletic individuals, in contradistinction to that title given to hypertrophic cardiomyopathy (HCM) in the United States (US) [2, 4, 5]. In the US, ARVC/D is believed to be responsible for approximately 5% of unexplained cases of SCD in young athletic individuals while this number rises to 25%-30% in Italy [5].

The pathology of ARVC/D is also a classical feature of this disease that sets it apart from other heart muscle disorders. It is characterized by fi-brofatty infiltration of the myocardium, primarily the RV myocardium, resulting in a thin-walled, dilated, and dysfunctional RV [1,2,6]. The LV may also become affected, leading to LV dilation and dysfunction as well [4]. In a subset of cases, the LV appears to be the predominant site of involvement [7]. In a relatively high percentage of affected individuals, inflammatory infiltrates within the RV and/or LV is also seen, suggesting myocarditis [8,9].

Until recently, the underlying basis of ARVC/D was completely unknown. Over the past 5 years, however, significant progress has been made in understanding the underlying causes of this cardiomyopathy. The new information, which has come from the translational medicine bedside-to-bench-to-bedside approach in which clinical diagnosis and therapy was linked to molecular-based scientific investigation, has defined a series of disease-causing genes and nongenetic causes of ARVC/D. As we previously suggested, this disease is caused by disruption of a "final common pathway" via genetic mutation in a series of genes encoding proteins of similar function or those interacting with such protein, or via "cascade pathways" (in other words, pathways that interact with the "final common pathway" and secondarily disrupt its function) which cause a "domino-effect" that disrupts the function of the primary pathway [10-13]. In the case of ARVC/D, an autosomal dominant disease with variable penetrance, the genes that have been identified include desmoplakin (chromosome 6p24) [14], plakophilin-2 (chromosome 12p11) [15,16], desmoglein-2 (chromosome 18q12) [17], and desmocollin in which heterozygous mutations result in the clinical disease. In addition, junctional plakoglobin (chromosome 17q21 ) [18] has been associated with the autosomal recessive Naxos disease [19], a skin-heart disorder caused by homozygous mutations in this gene which results in ARVC/D associated with nonepidermolytic palmo-plantar keratoderma and woolly hair. A similar autosomal recessive cardiocutaneous disease, Carvajal syndrome [20], which is characterized by similar skin and hair abnormalities as Naxos syndrome but usually has a predominant LV cardiomyopathy, results from homozygous mutations in desmoplakin [21]. All of the genes outlined above encode proteins of the desmosome, an important part of the cell-cell contact machinery [22, 23]. Another gene associated with ARVC/D, transforming growth factor^3

(TGFp3) [24], is thought to interact with the desmo-somes to cause its response. The other gene reported to cause ARVC/D, the ryanodine receptor (RyR2) [25], has more recently been shown to cause cate-cholaminergic polymorphic ventricular tachycardia (CPVT) [26, 27] and is now believed to cause only CPVT and not any form of ARVC/D. Hence, the genetic basis and "final common pathway" of ARVC/D is disruption of the desmosome.

Based on this knowledge, the next question becomes the following: what is the pathologic mechanism responsible for the characteristic features and clinical findings seen in ARVC/D? Unfortunately, studying human subjects with ARVC/D to determine these answers is not practical. Therefore, development of animal models to define these mechanisms becomes necessary.

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