Arrhythmogenic Cardiomyopathy

Abstract

Arrhythmogenic cardiomyopathy is the most arrhythmogenic form of human heart disease and a major cause of sudden death in the young.1,2 Originally described as a right ventricular disease (arrhythmogenic right ventricular cardiomyopathy),3 it is now recognized to include a spectrum of biventricular and left-dominant forms that may be misdiagnosed as dilated cardiomyopathy or myocarditis.4–7 Arrhythmias occur early in the natural history of arrhythmogenic cardiomyopathy, often preceding structural remodeling of the myocardium.1,8 Thus, in its early manifestations, arrhythmogenic cardiomyopathy is more reminiscent of the ion channelopathies than other forms of nonischemic cardiomyopathy. Arrhythmogenic cardiomyopathy has been linked to mutations in genes encoding desmosomal proteins ( PKP2, DSG2, DSC2, DSP , and JUP ).9,10 Desmosomes, cell-cell adhesion organelles, are especially abundant in heart and skin, tissues that normally experience mechanical stress.11 Therefore, it is not surprising that clinical phenotypes in patients with desmosomal mutations take the form of myocardial and cutaneous diseases. Indeed, patients with arrhythmogenic cardiomyopathy are particularly prone to disease exacerbations in response to strenuous exercise, emphasizing the importance of biomechanical determinants of disease. However, compared with other familial cardiomyopathies and ion channelopathies associated with sudden death, arrhythmogenic cardiomyopathy has low penetrance and unusually variable disease expression, even within members of the same family who carry the same disease-associated mutation.8–10 This indicates the presence of powerful genetic and/or epigenetic modifiers that interact with environmental factors such as exercise to determine the risk of sudden death or other adverse events. It also helps explain why diagnosis and risk stratification can be so challenging. In 1994, an International Task Force proposed criteria for the diagnosis of arrhythmogenic cardiomyopathy.12 In practice, these criteria were found to be highly specific but not very sensitive, especially in detecting …