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Background Pathogenicity of truncating or splice site mutations in arrhythmogenic right ventricular cardiomyopathy (ARVC) patients has been widely accepted. However, pathogenicity of missense variants remains controversial. We assessed pathogenicity of ARVC-related missense variants and associated phenotype. Methods Pathogenic mutations were found in 571 patients (239 families, age 43 ± 18 years) from US/Dutch ARVC cohorts by screening of desmosomal (PKP2, DSC2, DSG2, DSP, JUP) and/or nondesmosomal (PLN, TMEM43) genes. Patients with >1 mutation or variant were excluded. Missense variants were considered pathogenic when (1) algorithms SIFT and PolyPhen-2 predicted pathogenicity (SIFT: tolerance index score ≤0.05, PolyPhen-2: pathogenicity score >0.90) and (2) minor allele frequency in 1000 genomes was Results A pathogenic missense mutation was found in 86/571 patients (15%). Frequently occurring mutation was PKP2 c.2386T>C (p.Cys796Arg; 34/86). Survival curves (P = .065) and, more importantly, sustained arrhythmia (ventricular tachycardia/fibrillation or appropriate ICD therapy) free survival curves (P = .810) of patients with a missense mutation were similar to those with pathogenic non-missense (330/571 truncating, 129/571 splice site) mutations (Figure). Conclusions ARVC-related missense mutations have a similar pathogenic character as non-missense mutations regarding survival and substantial arrhythmic burden. Pathogenicity of missense mutations can be correctly predicted by combined criteria from SIFT, PolyPhen-2, and 1000 genomes. Download : Download high-res image (120KB) Download : Download full-size image

Kayser et al 1 reported the usefulness of magnetic resonance imaging (MRI) in diagnosis of arrhythmogenic right ventricular dysplasia (ARVD) in patients presenting with left bundle branch block-ventricular tachycardia. The article makes an original and potentially useful diagnostic observation, that patients with ARVD have diastolic dysfunction that can be detected by MRI. A similar observation has been reported with 2-dimensional echocardiography. 2 The diagnosis of ARVD is made in the presence of major and minor criteria proposed by the ARVD Task Force in 1994. 3 Of the 25 patients with left bundle branch block-ventricular tachycardia in the study, 14 were diagnosed with ARVD, not based on Task Force criteria, but solely based on the presence or absence of MRI abnormalities compatible with ARVD described by Midiri et al. 4 The diagnosis of ARVD by MRI has not been compared with other imaging techniques like angiography or 2-dimensional echocardiography. First

Objectives The aim of this study was to identify the incremental value and optimal role of cardiac magnetic resonance (CMR) imaging in arrhythmic risk stratification of arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C)–associated desmosomal mutation carriers without histories of sustained ventricular arrhythmia. Background Risk stratification of ARVD/C mutation carriers is challenging. Methods Sixty-nine patients (mean age 27.0 ± 15.3 years, 42% men) harboring ARVD/C-associated pathogenic mutations (83% plakophilin 2) without prior sustained ventricular arrhythmias were included. Electrocardiographic and 24-h Holter monitoring findings closest to presentation were analyzed for electrical abnormalities per revised task force criteria. CMR studies were done to identify abnormal cardiac structure and function according to the revised task force criteria. Results Overall, 42 patients (61%) presented with electrical abnormalities on the basis of electrocardiography and Holter monitoring, of whom 20 (48%) had abnormal results on CMR. Only 1 of 27 patients (4%) without electrical abnormalities at initial evaluation had abnormal CMR results. Over a mean follow-up period of 5.8 ± 4.4 years, 11 patients (16%) experienced sustained ventricular arrhythmias, exclusively in patients with both electrical abnormalities (electrocardiography and/or Holter monitoring) and abnormal CMR results. Conclusions These results suggest that electrical abnormalities on electrocardiography and Holter monitoring precede detectable structural abnormalities in ARVD/C mutation carriers. Therefore, evaluation of cardiac structure and function using CMR is probably not necessary in the absence of baseline electrical abnormalities. Among ARVD/C mutation carriers, the presence of both electrical and CMR abnormalities identifies patients at high risk for events and thus patients who might benefit from prophylactic implantable cardioverter-defibrillator placement.

Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is a rare cardiomyopathy characterized by myocardial fibro-fatty replacement predominantly affecting the RV. However, several studies have demonstrated a high incidence of biventricular or even isolated left ventricular (LV)

Arrhythmogenic right ventricular dysplasia (ARVD) is a genetic cardiomyopathy characterized clinically by ventricular arrhythmias and progressive right ventricular (RV) dysfunction. The histopathologic hallmark is fibro-fatty replacement of RV myocardium. It is inherited in an autosomal pattern with variable penetrance. ARVD is unique in that it most commonly presents in young, otherwise healthy and highly athletic individuals. The cause of ARVD is not well-known but recent evidence suggests strongly that it is a disease of desmosomal dysfunction. The disease involvement is not limited only to the RV as left ventricle (LV) has also been reportedly affected. Diagnosis of ARVD is challenging and is currently based upon a multi-disciplinary work-up of the patient as defined by the Task Force. Currently, implanted cardioverter defibrillators (ICD) are routinely used to prevent sudden death in patients with ARVD. Cardiovascular MR is an important non-invasive diagnostic modality that allows both qualitative and quantitative evaluation of RV. This article reviews the genetics of ARVD, current status and role of CMR in the diagnosis of ARVD and LV involvement in ARVD.