It is 35 years since the first description of arrhythmogenic right ventricular cardiomyopathy (ARVC) and more than 20 years since the first reports establishing desmosomal gene mutations as a major cause of the disease. Early advances in the understanding of the clinical, pathological and genetic architecture of ARVC resulted in consensus diagnostic criteria, which proved to be sensitive but not entirely specific for the disease. In more recent years, clinical and genetic data from families and the recognition of a much broader spectrum of structural disorders affecting both ventricles and associated with a propensity to ventricular arrhythmia have raised many questions about pathogenesis, disease terminology and clinical management. In this paper, we present the conclusions of an expert round table that aimed to summarise the current state of the art in arrhythmogenic cardiomyopathies and to define future research priorities.

BackgroundArrhythmogenic right ventricular dysplasia/cardiomyopathy is characterized by ventricular arrhythmias and sudden cardiac death. Once the diagnosis is established, risk stratification to determine whether implantable cardioverter‐defibrillator (ICD) placement is warranted is critical.Methods and ResultsThe cohort included 312 patients (163 men, age at presentation 33.6±13.9 years) with definite arrhythmogenic right ventricular dysplasia/cardiomyopathy who received an ICD. Over 8.8±7.33 years, 186 participants (60%) had appropriate ICD therapy and 58 (19%) had an intervention for ventricular fibrillation/flutter. Ventricular tachycardia at presentation (hazard ratio [HR]: 1.86; 95% confidence interval [CI], 1.38–2.49; P<0.001), inducibility on electrophysiology study (HR: 3.14; 95% CI, 1.95–5.05; P<0.001), male sex (HR: 1.62; 95% CI, 1.20–2.19; P=0.001), inverted T waves in ≥3 precordial leads (HR: 1.66; 95% CI, 1.09–2.52; P=0.018), and premature ventricular contraction count ≥1000/24 hours (HR: 2.30; 95% CI, 1.32–4.00; P=0.003) were predictors of any appropriate ICD therapy. Inducibility at electrophysiology study (HR: 2.28; 95% CI, 1.10–4.70; P=0.025) remained as the only predictor after multivariable analysis. The predictors for ventricular fibrillation/flutter were premature ventricular contraction ≥1000/24 hours (HR: 4.39; 95% CI, 1.32–14.61; P=0.016), syncope (HR: 1.85; 95% CI, 1.10–3.11; P=0.021), aged ≤30 years at presentation (HR: 1.76; 95% CI, 1.04–3.00; P<0.036), and male sex (HR: 1.73; 95% CI, 1.01–2.97; P=0.046). Younger age at presentation (HR: 3.14; 95% CI, 1.32–7.48; P=0.010) and high premature ventricular contraction burden (HR: 4.43; 95% CI, 1.35–14.57; P<0.014) remained as independent predictors of ventricular fibrillation/flutter. Complications occurred in 66 participants (21%), and 64 (21%) had inappropriate ICD interventions. Overall mortality was low at 2%, and 4% underwent heart transplantation.ConclusionThese findings represent an important step in identifying predictors of ICD therapy for potentially fatal ventricular fibrillation/flutter and should be considered when developing a risk stratification model for arrhythmogenic right ventricular dysplasia/cardiomyopathy.

Background Analysis of myocardium has revealed mechanistic insights into arrhythmogenic cardiomyopathy but cardiac samples are difficult to obtain from probands and especially from family members. To identify a potential surrogate tissue, we characterized buccal mucosa cells. Methods and Results Buccal cells from patients, mutation carriers and controls were immunostained and analyzed in a blinded fashion. In additional studies, buccal cells were grown in vitro and incubated with SB216763. Immunoreactive signals for the desmosomal protein plakoglobin and the major cardiac gap junction protein Cx43 were markedly diminished in buccal mucosa cells from arrhythmogenic cardiomyopathy patients with known desmosomal mutations when compared with controls. Plakoglobin and Cx43 signals were also reduced in most family members who carried disease alleles but showed no evidence of heart disease. Signal for the desmosomal protein plakophilin-1 was reduced in buccal mucosa cells in patients with PKP2 mutations but not in those with mutations in other desmosomal genes. Signal for the desmosomal protein desmoplakin was reduced in buccal mucosa cells from patients with mutations in DSP, DSG2 or DSC2 but not in PKP2 or JUP. Abnormal protein distributions were reversed in cultured cells incubated with SB216763, a small molecule that rescues the disease phenotype in cardiac myocytes. Conclusions Buccal mucosa cells from arrhythmogenic cardiomyopathy patients exhibit changes in the distribution of cell junction proteins similar to those seen in the heart. These cells may prove useful in future studies of disease mechanisms and drug screens for effective therapies in arrhythmogenic cardiomyopathy.

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While the algorithm differentiates arrhythmic risk well overall, it did not distinguish ventricular fibrillation/flutter risks of patients with Class I and IIa implantable cardioverter-defibrillator indications. Limited differentiation was seen for primary prevention cases. As these are vital uncertainties in clinical decision-making, refinements to the algorithm are suggested prior to implementation.

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