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Aims: Arrhythmogenic right-ventricular cardiomyopathy (ARVC) is a genetically determined disorder, mostly caused by mutations in genes encoding desmosomal proteins. We evaluated phenotype/genotype characteristics to predict the risk for the first major arrhythmic event in desmosomal-mutation-associated ARVC families.Methods and Results: A cohort of 105 desmosomal-mutation carriers belonging to 39 consecutive ARVC families was evaluated. Serial clinical work-up consisting of history, physical examination, 12-lead/signal-averaged/24 h ambulatory ECG, and two-dimensional echocardiography was performed every 6-12 months. The predictive value of gender and genotype for the first major arrhythmic event was investigated within the cohort using time-to-event analysis. ECG/echocardiographic features were evaluated at the time of event and associated with the outcome using an age-matched nested case-control study within the cohort. Forty-three (41%) participants experienced the primary arrhythmic outcome at median age of 29 (21-46) years. The first event was sustained ventricular tachycardia in 31 and sudden cardiac death in 12. Definite diagnosis according to the 2010 Task Force criteria, showed 57% positive and 100% negative predictive value for the occurrence of arrhythmic outcome. Male gender (hazard ratio = 3.26, 95%CI, 1.63-6.51), predicted the first major arrhythmic event, independently of genotype, on multivariable analysis. Repolarization abnormalities and left-ventricular dysfunction independently associated with clinical disease profile at the time of event.Conclusion: Male gender, independently of genotype is an arrhythmic risk predictor in ARVC-associated desmosomal-mutation carriers. Repolarization abnormalities and left-ventricular dysfunction are important components of the first event-associated clinical disease profile. [ABSTRACT FROM AUTHOR]

Aims: To determine the incidence and the causes of sudden death (SD) in persons aged 1-35 years old and the diagnostic yield of clinically guided genetic screening in the sudden arrhythmic death syndrome (SADS) victims' families., Methods and Results: Incidence and causes of SD in the Attica region of Greece in 2002-10 were determined using death certificates and autopsy reports. We evaluated clinically consecutive families of SADS victims and if a clinical diagnosis was established, we proceeded to targeted genetic analysis. Out of 6030 deaths, 56% were due to traumatic or violent causes, 40.5% were natural deaths, and 3.3% were of undetermined cause. There were 349 SD cases. Cardiovascular causes accounted for 65%, non-cardiovascular causes for 17%, and SADS for 18%. Clinical evaluation identified an inherited heart disease in 5/20 SADS families (25%). Targeted genetic analysis identified a causative mutation in all of the five screened families and reconfirmed the diagnosis in three of five proband victims. Clinical and genetic evaluation of 28 family members identified eight affected carriers and eight non-affected carriers. Molecular autopsy failed to identify any of these families., Conclusion: Sudden death in the young is of cardiovascular origin in the majority of cases. A considerable rate of SD cases remains of unknown cause on post-mortem. Apart from channelopathies, subclinical forms of inherited structural heart diseases would appear to be implicated in SADS. Clinically guided genetic screening has a significant diagnostic yield and identifies affected families that would have been missed by the current suggested molecular autopsy panel., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2017. For Permissions, please email: journals.permissions@oup.com.)

Aims: To evaluate clinical disease expression, non-invasive diagnosis, and prognosis in families with dominant vs. recessive arrhythmogenic right ventricular cardiomyopathy (ARVC) due to mutations in related desmosomal proteins plakophilin-2 (PKP2) and plakoglobin (JUP), respectively., Methods and Results: One hundred and eighty-seven individuals belonging to ARVC families, four with dominant PKP2 mutations and 12 with recessive JUP mutation underwent serial non-invasive cardiac assessment. Survival and arrhythmic events were evaluated prospectively up to 21 years (median 8.5 years). Sixteen of 22 PKP2 carriers and all 26 homozygous JUP carriers fulfilled the diagnostic criteria for ARVC, the youngest by the age of 13 years. Clinical disease expression did not differ significantly between PKP2 and JUP carriers. T-wave inversion in leads V1-V3, right ventricular wall motion abnormalities, and frequent ventricular extrasystoles were the most sensitive/specific markers for identification of mutation carriers. QRS dispersion > or =40 ms was an independent predictor of syncope but not of sudden death., Conclusion: Mutations in PKP2 and JUP express similar cardiac phenotype. Non-invasive family screening may largely be based on T-wave inversion, right ventricular wall motion abnormalities, and frequent ventricular extrasystoles to identify mutation carriers.