Gap junctions and 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 It was first described as a right ventricular disease (arrhythmogenic right ventricular cardiomyopathy or ARVC), but is now recognized to include biventricular and left dominant forms which may be misdiagnosed as dilated cardiomyopathy or myocarditis. Arrhythmias occur early in the natural history of arrhythmogenic cardiomyopathy, often preceding structural remodeling of the myocardium.1, 2 This so-called “concealed phase” of the disease is unique among the primary myocardial disorders. In hypertrophic cardiomyopathy, for example, arrhythmic risk is related to the underlying substrate of myocyte disarray, hypertrophy, fibrosis and small-vessel disease. And in dilated cardiomyopathy, arrhythmias generally arise in the context of significant ventricular dilatation and contractile dysfunction accompanied by changes in the expression, activity and spatial distribution of ion channel proteins and currents. In contrast, there is something fundamentally arrhythmogenic about arrhythmogenic cardiomyopathy particularly in its early stage in which frequent arrhythmias arise in otherwise apparently normal hearts. In this sense, arrhythmogenic cardiomyopathy is more reminiscent of the ion channelopathies than other forms of non-ischemic cardiomyopathy. Arrhythmogenic cardiomyopathy has been linked to mutations in genes encoding desmosomal proteins (PKP2, DSG2, DSC2, DSP and JUP).1, 2 Desmosomes are cell-cell adhesion organelles. They are particularly abundant in heart and skin, tissues that normally experience mechanical stress. Not surprisingly therefore, clinical phenotypes in patients with desmosomal mutations take the form of myocardial and cutaneous diseases. In fact, patients with arrhythmogenic cardiomyopathy often exhibit disease flares in response to stress or exercise, emphasizing the importance of biomechanical determinants of disease. However, the relationship between changes in biomechanical properties of the myocardium produced by desmosomal mutations and heart rhythm abnormalities in arrhythmogenic cardiomyopathy is poorly characterized. Advances in understanding this relationship could reveal important basic mechanisms of arrhythmogenesis.