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Pathogenic variants in the filamin C (FLNC) gene are associated with inherited cardiomyopathies including dilated cardiomyopathy with an arrhythmogenic phenotype. We evaluated FLNC variants in arrhythmogenic cardiomyopathy (ACM) and investigated the disease mechanism at a molecular level.

AIMS: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a genetically determined heart muscle disorder associated with an increased risk of life-threatening arrhythmias in some patients. Risk stratification remains challenging. Therefore, we sought a non-invasive, easily applicable risk score to predict sustained ventricular arrhythmias in these patients. METHODS: Cohort of Patients who fulfilled the 2010 ARVC task force criteria were consecutively recruited. Detailed clinical data were collected at baseline and during follow up. The clinical endpoint was a composite of recurrent sustained ventricular arrhythmias and hospitalization due to ventricular arrhythmias. Multivariable logistic regression was used to develop models to predict the arrhythmic risk. A cohort including patients from other registries in UK, Canada and Switzerland was used as a validation population. RESULTS: One hundred and thirty-five patients were included of whom 35 patients (31.9%) reached the endpoint. A model consisting of filtered QRS duration on signal-averaged ECG, non-sustained VT (NSVT) on 24 h-ECG, and absence of negative T waves in lead aVR on 12‑lead surface ECG was able to predict arrhythmic events with a sensitivity of 81.8%, specificity of 84.0% and a negative predictive value of 95.5% at the first presentation of the disease. This risk score was validated in international ARVC registry patients. CONCLUSION: A risk score consisting of a filtered QRS duration ≥117 ms, presence of NSVT on 24 h-ECG and absence of negative T waves in lead aVR was able to predict arrhythmic events at first presentation of the disease.

JACC

The 1996 American Heart Association consensus panel recommendations stated that pre-participation cardiovascular screening for young competitive athletes is justifiable and compelling on ethical, legal, and medical grounds. The present article represents the consensus statement of the Study Group on Sports Cardiology of the Working Group on Cardiac Rehabilitation and Exercise Physiology and the Working Group on Myocardial and Pericardial diseases of the European Society of Cardiology, which comprises cardiovascular specialists and other physicians from different European countries with extensive clinical experience with young competitive athletes, as well as with pathological substrates of sudden death. The document takes note of the 25-year Italian experience on systematic pre-participation screening of competitive athletes and focuses on relevant issues, mostly regarding the relative risk, causes, and prevalence of sudden death in athletes; the efficacy, feasibility, and cost-effectiveness of population-based pre-participation cardiovascular screening; the key role of 12-lead ECG for identification of cardiovascular diseases such as cardiomyopathies and channelopathies at risk of sudden death during sports; and the potential of preventing fatal events. The main purpose of the consensus document is to reinforce the principle of the need for pre-participation medical clearance of all young athletes involved in organized sports programmes, on the basis of (i) the proven efficacy of systematic screening by 12-lead ECG (in addition to history and physical examination) to identify hypertrophic cardiomyopathy-the leading cause of sports-related sudden death-and to prevent athletic field fatalities; (ii) the potential screening ability in detecting other lethal cardiovascular diseases presenting with ECG abnormalities. The consensus document recommends the implementation of a common European screening protocol essentially based on 12-lead ECG.

OBJECTIVES We tested the hypothesis that defective interactions between adhesion junctions and the cytoskeleton caused by the plakoglobin mutation in Naxos disease lead to remodeling of gap junctions and altered expression of the major gap junction protein, connexin43. BACKGROUND Naxos disease, a recessive form of arrhythmogenic right ventricular cardiomyopathy, is associated with a high incidence of arrhythmias and sudden cardiac death. Naxos disease is caused by a mutation in plakoglobin, a protein that links cell-cell adhesion molecules to the cytoskeleton. METHODS Myocardial expression of connexin43 and other intercellular junction proteins was characterized in 4 patients with Naxos disease. Immunohistochemistry was performed in all 4 patients, and immunoblotting and electron microscopy were performed in 1 patient who died in childhood before overt arrhythmogenic right ventricular cardiomyopathy had developed. RESULTS Connexin43 expression at intercellular junctions was reduced significantly in both right and left ventricles in all patients with Naxos disease. Electron microscopy revealed smaller and fewer gap junctions interconnecting ventricular myocytes. Mutant plakoglobin was expressed but failed to localize normally at intercellular junctions. Localization of N-cadherin, alpha- and beta-catenins, plakophilin-2, desmoplakin-1, and desmocollin-2 at intercalated disks appeared normal. CONCLUSIONS Remodeling of gap junctions occurs early in Naxos disease, presumably because of abnormal linkage between mechanical junctions and the cytoskeleton. Gap junction remodeling may produce a coupling defect which, combined with the subsequent development of pathologic changes in myocardium, could contribute to a highly arrhythmogenic substrate and enhance the risk of sudden death in Naxos disease. (C) 2004 Elsevier Inc. All rights reserved.

Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is a heart muscle disease characterized by peculiar right ventricular involvement and electrical instability that precipitates ventricular arrhythmias and sudden death. The purpose of the present consensus report of the Study Group of the European Society of Cardiology and the Scientific Council on Cardiomyopathies of the World Heart Federation is to review the considerable progress in our understanding of the etiopathogenesis, morbid anatomy, and clinical presentation of ARVD/C since its first description in 1977. This article will focus on the important but still unanswered issues, mostly regarding risk stratification, clinical outcome, and management of affected patients. Because ARVD/C is relatively uncommon and any one center may have experience with only a few patients, an international registry is being established to accumulate information and enhance the numbers of patients that can be analyzed to answer the pending questions. The registry also will facilitate pathologic, molecular, and genetics research on the etiology and pathogenesis of the disease. Furthermore, availability of an international database will enhance awareness of this largely unrecognized condition among the medical community. Physicians are encouraged to enroll patients in the International Registry of ARVD/C.

Background Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an autosomal dominant heart muscle disorder that causes arrhythmia, heart failure, and sudden death. Previously we mapped the genetic locus for the triad of autosomal recessive ARVC, palmoplantar keratoderma, and woolly hair (Naxos disease) to chromosome 17q21, in which the gene for plakoglobin is encoded, This protein is a key component of desmosomes and adherens junctions, and is important for the tight adhesion of many cell types, including those in the heart and skin. Methods We studied 19 individuals with Naxos disease, as well as unaffected family members and unrelated individuals from the neighbouring Greek islands of Naxos and Miles. Gene sequence was determined by reverse transcriptase PCR from RNA isolated from the skin of an affected individual and mutations in other cases were confirmed by restriction-enzyme analysis. Findings A homozygous 2 base pair deletion in the plakoglobin gene was identified only in the 19 affected individuals. This deletion caused a frameshift and premature termination of the protein, which was shown by western blot analysis. 29 clinically unaffected family members were heterozygous for the mutation; 20 unrelated individuals from Naxos and 43 autosomal dominant ARVC probands were homozygous for the normal allele. Interpretation The finding of a deletion in plakoglobin in ARVC suggests that the proteins involved in, cell-cell adhesion play an important part in maintaining myocyte integrity, acid when junctions are disrupted, cell death, and fibrofatty replacement occur. Therefore, the discovery of a mutation in a protein with functions in maintaining cell junction integrity has important implications for other dominant forms of ARVC, related cardiomyopathies, and other cutaneous diseases.