AimsRecent immunohistochemical studies observed the loss of plakoglobin (PG) from the intercalated disc (ID) as a hallmark of arrhythmogenic right ventricular cardiomyopathy (ARVC), suggesting a final common pathway for this disease. However, the underlying molecular processes are poorly understood.Methods and resultsWe have identified novel mutations in the desmosomal cadherin desmocollin 2 (DSC2 R203C, L229X, T275M, and G371fsX378). The two missense mutations (DSC2 R203C and T275M) have been functionally characterized, together with a previously reported frameshift variant (DSC2 A897fsX900), to examine their pathogenic potential towards PG's functions at the ID. The three mutant proteins were transiently expressed in various cellular systems and assayed for expression, processing, localization, and binding to other desmosomal components in comparison to wild-type DSC2a protein. The two missense mutations showed defects in proteolytic cleavage, a process which is required for the functional activation of mature cadherins. In both cases, this is thought to cause a reduction of functional DSC2 at the desmosomes in cardiac cells. In contrast, the frameshift variant was incorporated into cardiac desmosomes; however, it showed reduced binding to PG.ConclusionDespite different modes of action, for all three variants, the reduced ability to provide a ligand for PG at the desmosomes was observed. This is in agreement with the reduced intensity of PG at these structures observed in ARVC patients.

Inducibility of ventricular tachycardia/ventricular fibrillation was associated with an increased likelihood of subsequent ICD activation and sudden cardiac death surrogate.

Prolonged QTcd in association with ECG evidence of LVH appears to be the specific feature of CD. This may be relevant in the choice of medical therapy for CD and for consideration of treatment of the comorbidities that are associated with hypercortisolaemia.

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We report the case of a Brugada syndrome patient with a history of syncopal and presyncopal episodes and evidence of sinus node and atrioventricular (AV) conduction abnormalities. The patient developed sinus bradycardia, sinoatrial conduction abnormalities, prolonged HV interval, early appearance of AV block, AV nodal reentrant tachycardia and polymorphic ventricular tachycardia in the electrophysiological study. He was treated with a dual-chamber pacemaker defibrillator. At the 9-year follow-up, the patient remained asymptomatic with several episodes of 1:1 AV-relationship tachycardia, interrupted with antitachycardia pacing, while the predominant pacing states of the device were AP-VS and AS-VP for most of the time.

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This is the case of a 43-year-old Caucasian man with frequent episodes of paroxysmal atrial fibrillation (AF) and normal resting electrocardiogram (ECG), who fulfilled two minor diagnostic criteria for arrhythmogenic right ventricular cardiomyopathy (ARVC): late potentials by signal-averaged ECG and regional right ventricular outflow tract (RVOT) dyskinesia with mildly dilated RVOT end-diastolic diameter. Genetic test results revealed a disease-associated missense mutation in DSC2 (p.E102K), adding a major diagnostic criterion according to recently published modified Task Force Criteria. However, 2 years after successful ablative therapy for AF, the patient remains completely asymptomatic, without any clinical signs of ARVC. Both ventricular and supraventricular arrhythmias had vanished after AF ablation. Our patient mainly suffered AF without significant ventricular arrhythmias, a very uncommon clinical presentation of ARVC.

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