Arrhythmogenic Cardiomyopathy

Abstract

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.