Desmosome Mutations in Arrhythmogenic Right Ventricular Cardiomyopathy

Abstract

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is not a common disease, but it is a deadly one. A detailed understanding of its pathogenesis could provide insights into fundamental mechanisms pertinent to much more common cardiac conditions associated with sudden death. There are several reasons why this might be so. First, ARVC is the most arrhythmogenic form of heart disease in humans. The rate of appropriate shocks in patients with ARVC and implantable defibrillators far exceeds that rate in patients with other highly arrhythmogenic diseases such as long-QT syndrome or hypertrophic cardiomyopathy (data from the North American ARVC registry). Second, arrhythmias are a cardinal feature of ARVC and typically appear early in the disease before significant structural remodeling of the myocardium and contractile dysfunction develop.1 In this sense, ARVC may be as much akin to the ion channelopathies (arrhythmias in a structurally normal heart) as to other types of cardiomyopathies associated with sudden death, such as idiopathic dilated cardiomyopathy or hypertrophic cardiomyopathy in which arrhythmias typically develop in hearts with considerable structural and functional derangements. This does not mean that fibrofatty replacement of the right ventricle plays no role in sudden death. Tissue remodeling in ARVC undoubtedly contributes to arrhythmia substrates, but there is also something about the “unaffected” myocardium that seems to make this such an arrhythmogenic disease. Third, ARVC is a familial disease, usually inherited in an autosomal dominant pattern.2 However, genetic penetrance and disease expression are highly variable. It is not unusual for individuals who carry the same disease-causing mutation to have markedly different clinical manifestations. Even within families, a proband may die suddenly at a young age, whereas first-degree relatives with the same mutation can have a far more benign course.1,2 Knowing the monogenic causes certainly focuses attention on specific genes and provides an entry …