Desmosome-Dyad Crosstalk

Abstract

A rrhythmogenic cardiomyopathy is an inheritable disease characterized by a fibrofatty infiltration of the heart muscle, often (although not always) of right ventricular predominance, arrhythmias, and sudden death in the young. 1 Because of the predominant right ventricular phenotype, the disease has been referred to as arrhythmogenic right ventricular dysplasia or arrhythmogenic right ventricular cardiomyopathy (ARVC). 1 Mutations in genes coding for desmo-somal proteins (Figure A) are the most common cause of gene-positive familial cases. 1 Among desmosomal genes, PKP2, coding for the protein PKP2 (Plakophilin-2), is the most commonly affected, in particular, in the adult population. 1 The high propensity to arrhythmias in ARVC has been identified since the early description of the disease. Life-threatening ventricular arrhythmias occur mostly in the early (concealed) stage of the disease, often before the overt structural phenotype. 2 As shown by the analysis of 1001 cases related to ARVC, syncope or sudden cardiac arrest was the first disease manifestation in 11% of the probands. 2 Understanding the arrhythmia mechanisms in the early stage of the disease is therefore paramount to lessen the risk, and potentially prevent lethal arrhythmias in the affected population. Ventricular arrhythmias in ARVC have a strong catecholaminergic component: they are highly inducible by isoproterenol, are most likely to appear during exercise or heightened sympathetic input, and respond well to sympathectomy. 3,4 Adrener-gic stimulation increases cardiac performance in great part by increasing Ca 2+ entry and Ca 2+ i transient amplitude, but these effects also increase arrhythmia vulnerability attributable to higher propensity for spontaneous Ca 2+ release (SCR) and triggered activity. 5 Given that most cases of gene-positive familial ARVC associate with desmosomal genes, the existence of a desmosome-Ca 2+ i (or desmosome-dy-ad) axis as an arrhythmia mechanism is a tantalizing possibility that, if established, may uncover new targets for therapy. Cerrone et al 6 and Kim et al 7 examined the cardiac endophenotype of PKP2 in adult murine hearts and showed that cardio-myocyte-specific knockout of PKP2 predisposes the heart to triggered activity and ventricular arrhythmias, and causes aberrant SCR from RyR2 (ryanodine receptor 2) channels eager to release Ca 2+ from the junctional sarcoplasmic reticulum. These and other results indicate a relation between desmosomal integrity and the control of Ca 2+ i homeostasis in cardiac myocytes. The data also point to RyR2 channels as key substrates for arrhythmias in ARVC. The concept of a desmosome-dyad axis and hyperactive RyR2 channels has now been expanded by the elegant study of Wang et al 8 published in this issue of Circulation. These authors analyzed by mass spectrometry 4 explanted failing hearts with a diagnosis of ARVC (3 of them with a missense mutation in a desmosomal