Sudden unexplained death in the young: epidemiology, aetiology and value of the clinically guided genetic screening.

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.

Arrhythmic risk assessment in genotyped families with arrhythmogenic right ventricular cardiomyopathy.

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.

Clinical Significance of Epsilon Waves in Arrhythmogenic Cardiomyopathy.

INTRODUCTION: Epsilon waves are hallmark features of arrhythmogenic cardiomyopathy (ACM) but information about their clinical significance is variable. We evaluated epsilon wave prevalence, characteristics, and their clinical significance in an ACM population. METHODS AND RESULTS: Eighty-six unselected patients fulfilling the 2010 Task Force criteria were enrolled. Seventy-six of them were carriers of desmosomal mutations. All subjects were serially evaluated with standard 12-lead ECG and 2-dimensional echocardiography. Epsilon waves were evaluated in all precordial and inferior leads. Novel parameters assessed included their duration and precordial/inferior lead extension. Twenty-five subjects (29%) had epsilon waves that were present in lead V3 and beyond in 9, and in the inferior leads in 7. Epsilon waves were associated with right ventricular outflow tract (RVOT) (P = 0.001) but not RV posterior wall (P = 0.21), RV apex (P = 0.30), or left ventricular (P = 0.94) wall motion abnormalities. Patients with epsilon waves had increased RVOT diameter (P < 0.0001). Extension of epsilon waves in lead V3 and beyond was associated with increased epsilon wave duration (P = 0.002) and RVOT diameter (P = 0.04). The duration of epsilon waves was positively correlated with RVOT diameter (r = 0.70, P = 0.0001). Epsilon waves were also associated with episodes of sustained ventricular tachycardia (P = 0.004) but not with heart failure (P = 0.41) or sudden cardiac death (P = 0.31). CONCLUSION: Detection of epsilon waves on 12-lead ECG reflects significant RVOT involvement, which was associated with episodes of sustained ventricular tachycardia but not sudden cardiac death.

Endocardial late potentials during sinus rhythm define the re-entry circuit of ventricular tachycardia in arrhythmogenic right ventricular cardiomyopathy.

Arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) is an inherited cardiomyopathy characterized by progressive fibro-fatty replacement of the right ventricular myocardium. We report a case where mapping of endocardial potentials during sinus rhythm identified the re-entry circuit of a recurrent ventricular tachycardia in a patient with ARVC. The tachycardia was subsequently ablated successfully.

Arrhythmogenic right ventricular cardiomyopathy: the challenge of genetic interpretation in clinically suspected cases.

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.

Arrhythmogenic right ventricular cardiomyopathy/dysplasia.

We describe the case of a 51-year-old woman with a 10-year history of dyspnoea and fatigue on slight effort, presyncopal episodes, and ventricular extrasystolic arrhythmia. Tests were negative for coronary artery disease, valvular disease, or left ventricular dysfunction. The patient fulfilled the clinical criteria for arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) and the diagnosis was confirmed histologically with an endomyocardial biopsy. During 5-year follow up she also exhibited significant structural progression to the left ventricle. This is a rare case of ARVC/D manifested in middle age, with a negative family history, negative test for desmosome mutations, and negative myocardial immunohistochemical analysis, evidence that tends to suggest an acquired form of the disease. We also present a brief review of the clinical, electrocardiographic, structural, pathological/anatomical and genetic characteristics of the disease, the diagnostic criteria, prognosis, management, and sudden death prevention, as well as the way we have managed our patient until the present day.

Altered desmosomal proteins in granulomatous myocarditis and potential pathogenic links to arrhythmogenic right ventricular cardiomyopathy.

BACKGROUND: Immunoreactive signal for the desmosomal protein plakoglobin (γ-catenin) is reduced at cardiac intercalated disks in patients with arrhythmogenic right ventricular cardiomyopathy (ARVC), a highly arrhythmogenic condition caused by mutations in genes encoding desmosomal proteins. Previously, we observed a false-positive case in which plakoglobin signal was reduced in a patient initially believed to have ARVC but who actually had cardiac sarcoidosis. Sarcoidosis can masquerade clinically as ARVC but has not been previously associated with altered desmosomal proteins. METHODS AND RESULTS: We observed marked reduction in immunoreactive signal for plakoglobin at cardiac myocyte junctions in patients with sarcoidosis and giant cell myocarditis, both highly arrhythmogenic forms of myocarditis associated with granulomatous inflammation. In contrast, plakoglobin signal was not depressed in lymphocytic (nongranulomatous) myocarditis. To determine whether cytokines might promote dislocation of plakoglobin from desmosomes, we incubated cultures of neonatal rat ventricular myocytes with selected inflammatory mediators. Brief exposure to low concentrations of interleukin (IL)-17, tumor necrosis factor-α (TNF-α), and IL-6 (cytokines implicated in granulomatous myocarditis) caused translocation of plakoglobin from cell-cell junctions to intracellular sites, whereas other potent cytokines implicated in nongranulomatous myocarditis had no effect, even at much higher concentrations. We also observed myocardial expression of IL-17 and TNF-α and elevated levels of serum inflammatory mediators, including IL-6R, IL-8, monocyte chemoattractant protein 1, and macrophage inflammatory protein 1ß, in patients with ARVC (all P<0.0001 compared with controls). CONCLUSIONS: The results suggest novel disease mechanisms involving desmosomal proteins in granulomatous myocarditis and implicate cytokines, perhaps derived in part from the myocardium, in disruption of desmosomal proteins and arrhythmogenesis in ARVC.

Epsilon-like waves and ventricular conduction abnormalities in subjects with type 1 ECG pattern of Brugada syndrome.

BACKGROUND: Previous studies have demonstrated an overlap between the arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) and Brugada syndrome (BS). Conduction delay in the right ventricle has been demonstrated in both entities. OBJECTIVE: This study investigated specific ARVC/D electrocardiographic (ECG) markers in subjects with spontaneous or drug-induced type 1 ECG pattern of BS. METHODS: The study population consisted of 47 apparently healthy individuals (38 men, mean age 44.1 ± 13.3 years) with spontaneous (n = 17) or drug-induced (n = 30) type 1 ECG phenotype of BS. The clinical records of these individuals were retrospectively analyzed. RESULTS: Fifteen subjects (31.9%) were symptomatic, with a history of syncope. A family history of BS or sudden cardiac death was reported in 10 (21.3%) and 8 (17.0%) cases, respectively. Epsilon-like waves in leads V1-V3 were observed in 6 subjects (12.7%). Epsilon-like waves were seen in spontaneous type 1 ECGs in 2 cases and after sodium channel blocking test in 4 cases. In baseline ECGs, localized prolongation (>110 ms) of the QRS complex in leads V1-V3, QRS duration ratio in (V1+V2+V3)/(V4+V5+V6) ≥ 1.2, and prolonged S wave upstroke (>55 ms) in leads V1-V3 were seen in 48.8%, 29.8%, and 40.4% of subjects, respectively. Epsilon-like waves and delayed S wave upstroke were more commonly observed in subjects with family history of BS (P = .014 and P = .038, respectively). CONCLUSION: Specific ECG markers that reflect ventricular conduction delay in ARVC/D are commonly observed in subjects with spontaneous or drug-induced type 1 ECG pattern of BS as well. These depolarization abnormalities may be related to subtle underlying structural abnormalities.

Arrhythmogenic right ventricular cardiomyopathy/dysplasia on the basis of the revised diagnostic criteria in affected families with desmosomal mutations.

AIMS: To evaluate arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) in affected families with desmosome mutations on the basis of the recently revised Task Force Criteria (TFC). METHODS AND RESULTS: One hundred and three consecutive carriers of pathogenic desmosome mutations and 102 mutation-negative relatives belonging to 22 families with dominant and 14 families with recessive ARVC/D were evaluated according to the original and revised TFC. Serial cardiac assessment with 12-lead, signal-averaged, and 24 h ambulatory ECG and two-dimensional echocardiography was performed. Clinical events and outcome were prospectively analysed up to 24 years (median 4 years). With the revised criteria, 16 carriers were newly diagnosed on the basis of ECG abnormalities in 100%, ventricular arrhythmias in 79%, and functional/structural alterations in 31%, increasing diagnostic sensitivity from 57 to 71% (P = 0.001). Task Force Criteria specificity improved from 92 to 99% (P = 0.016). In dominant mutation carriers, penetrance changed significantly (61 vs. 42%, P = 0.001); no changes were observed in recessive homozygous carriers (97 vs. 97%, P = 1.00). Affected carriers according to the revised TFC (n = 73) had 12-lead ECG abnormalities in 96%, ventricular arrhythmias in 91%, and functional/structural alterations fulfilling echocardiographic criteria in 76%. Cumulative and event-free survival did not differ significantly between dominant and recessive affected carriers, being at 78.6 vs. 76 and 51.7 vs. 55.4%, respectively, by the age of 40 years. CONCLUSION: Revised TFC increased diagnostic sensitivity particularly in dominant ARVC/D. Serial family evaluation may rely on electrocardiography which seems to have the best diagnostic utility particularly in early disease that is not detectable by two-dimensional echocardiography.

Mechanistic insights into arrhythmogenic right ventricular cardiomyopathy caused by desmocollin-2 mutations.

AIMS: Recent 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 RESULTS: We 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. CONCLUSION: Despite 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.

Isolated left ventricular apical hypoplasia: a newly recognized unclassified cardiomyopathy.

We describe two relatively asymptomatic cases diagnosed with the newly recognized unclassified cardiomyopathy, isolated left ventricular apical hypoplasia. The disease has been described mainly in cardiac magnetic resonance, whereas this study presents the echocardiographic characteristics of this new cardiomyopathy.

Diagnosis of arrhythmogenic right ventricular cardiomyopathy/dysplasia: proposed modification of the task force criteria.

BACKGROUND: In 1994, an International Task Force proposed criteria for the clinical diagnosis of arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) that facilitated recognition and interpretation of the frequently nonspecific clinical features of ARVC/D. This enabled confirmatory clinical diagnosis in index cases through exclusion of phenocopies and provided a standard on which clinical research and genetic studies could be based. Structural, histological, electrocardiographic, arrhythmic, and familial features of the disease were incorporated into the criteria, subdivided into major and minor categories according to the specificity of their association with ARVC/D. At that time, clinical experience with ARVC/D was dominated by symptomatic index cases and sudden cardiac death victims-the overt or severe end of the disease spectrum. Consequently, the 1994 criteria were highly specific but lacked sensitivity for early and familial disease. METHODS AND RESULTS: Revision of the diagnostic criteria provides guidance on the role of emerging diagnostic modalities and advances in the genetics of ARVC/D. The criteria have been modified to incorporate new knowledge and technology to improve diagnostic sensitivity, but with the important requisite of maintaining diagnostic specificity. The approach of classifying structural, histological, electrocardiographic, arrhythmic, and genetic features of the disease as major and minor criteria has been maintained. In this modification of the Task Force criteria, quantitative criteria are proposed and abnormalities are defined on the basis of comparison with normal subject data. CONCLUSIONS: The present modifications of the Task Force Criteria represent a working framework to improve the diagnosis and management of this condition. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00024505.

Diagnosis of arrhythmogenic right ventricular cardiomyopathy/dysplasia: proposed modification of the Task Force Criteria.

BACKGROUND: In 1994, an International Task Force proposed criteria for the clinical diagnosis of arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) that facilitated recognition and interpretation of the frequently nonspecific clinical features of ARVC/D. This enabled confirmatory clinical diagnosis in index cases through exclusion of phenocopies and provided a standard on which clinical research and genetic studies could be based. Structural, histological, electrocardiographic, arrhythmic, and familial features of the disease were incorporated into the criteria, subdivided into major and minor categories according to the specificity of their association with ARVC/D. At that time, clinical experience with ARVC/D was dominated by symptomatic index cases and sudden cardiac death victims-the overt or severe end of the disease spectrum. Consequently, the 1994 criteria were highly specific but lacked sensitivity for early and familial disease. METHODS AND RESULTS: Revision of the diagnostic criteria provides guidance on the role of emerging diagnostic modalities and advances in the genetics of ARVC/D. The criteria have been modified to incorporate new knowledge and technology to improve diagnostic sensitivity, but with the important requisite of maintaining diagnostic specificity. The approach of classifying structural, histological, electrocardiographic, arrhythmic, and genetic features of the disease as major and minor criteria has been maintained. In this modification of the Task Force criteria, quantitative criteria are proposed and abnormalities are defined on the basis of comparison with normal subject data. CONCLUSIONS: The present modifications of the Task Force Criteria represent a working framework to improve the diagnosis and management of this condition. Clinical Trial Registration clinicaltrials.gov Identifier: NCT00024505.

A new diagnostic test for arrhythmogenic right ventricular cardiomyopathy.

BACKGROUND: The diagnosis of arrhythmogenic right ventricular cardiomyopathy (ARVC) can be challenging because the clinical presentation is highly variable and genetic penetrance is often low. METHODS: To determine whether a change in the distribution of desmosomal proteins can be used as a sensitive and specific diagnostic test for ARVC, we performed immunohistochemical analysis of human myocardial samples. RESULTS: We first tested myocardium from 11 subjects with ARVC; of these samples, 8 had desmosomal gene mutations. We also tested myocardium obtained at autopsy from 10 subjects with no clinical or pathological evidence of heart disease as control samples. All ARVC samples but no control samples showed a marked reduction in immunoreactive signal levels for plakoglobin (also known as gamma-catenin), a protein that links adhesion molecules at the intercalated disk to the cytoskeleton. Other desmosomal proteins showed variable changes, but signal levels for the nondesmosomal adhesion molecule N-cadherin were normal in all subjects with ARVC. To determine whether a diminished plakoglobin signal level was specific for ARVC, we analyzed myocardium from 15 subjects with hypertrophic, dilated, or ischemic cardiomyopathies. In every sample, levels of N-cadherin and plakoglobin signals at junctions were indistinguishable from those in control samples. Finally, we performed blinded immunohistochemical analysis of heart-biopsy samples from the Johns Hopkins ARVC registry. We made the correct diagnosis in 10 of 11 subjects with definite ARVC on the basis of clinical criteria and correctly ruled out ARVC in 10 of 11 subjects without ARVC, for a sensitivity of 91%, a specificity of 82%, a positive predictive value of 83%, and a negative predictive value of 90%. The plakoglobin signal level was reduced diffusely in ARVC samples, including those obtained in the left ventricle and the interventricular septum. CONCLUSIONS: Routine immunohistochemical analysis of a conventional endomyocardial-biopsy sample appears to be a highly sensitive and specific diagnostic test for ARVC.

Naxos disease presenting with ventricular tachycardia and troponin elevation.

Naxos disease is a recessively inherited stereotype association of arrhythmogenic cardiomyopathy with a cutaneous phenotype, characterized by peculiar woolly hair and palmoplantar keratoderma. The cardiomyopathy clinically manifests by adolescence and the symptomatic presentation is usually with syncope and/or sustained ventricular tachycardia of left bundle branch block configuration. We report the case of a 43-year-old man without any history of heart disease who was admitted to the hospital because of an episode of sustained ventricular tachycardia and troponin I elevation, in the absence of coronary artery disease. Diagnostic workup, including genetic assessment, revealed Naxos disease as the underlying cause. In this case, acute myocarditis seems to be the most plausible explanation for the nonischemic myocardial injury.

Arrhythmogenic right ventricular cardiomyopathy caused by deletions in plakophilin-2 and plakoglobin (Naxos disease) in families from Greece and Cyprus: genotype-phenotype relations, diagnostic features and prognosis.

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.