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Abstract: Latest advances in the diagnostic management of arrhythmogenic right ventricular dysplasia–cardiomyopathy (ARVD/C) confirm that ARVD/C is not a rare disease (one affected in 1000–1250 inhabitants) and is of familial origin in 50–80% of cases. Diagnostic criteria defined in 1994 lead to low rates in the diagnosis of ARVD/C. Progress was made in the definition of diagnostic markers. New criteria of localised right precordial QRS prolongation could be identified. The detection of epsilon potentials could be enhanced by highly amplified and modified recording techniques. Vectorcardiography, signal averaging per lead and electroanatomic voltage mapping might become more important in the future. Cardiac MRI does not represent the single diagnostic test to make the diagnosis of ARVD/C. It remains a promising noninvasive imaging technique with advantages in the evaluation of the right ventricle. After the characterisation of mutations in the plakophilin-2 gene, molecular genetics is going to become an important diagnostic tool. Up to now, unsolved problems exist in the differentiation of ARVD/C and other conditions with ventricular arrhythmias evolving from the right ventricle such as Brugada syndrome and right ventricular outflow tract tachycardia. These problems can be overcome by distinct ECG analysis and the use of imaging techniques. With the help of corrected and modified diagnostic criteria it seems to be possible to identify symptomatic and asymptomatic affected by ARVD/C with predominantly major criteria and only in a minority of cases minor criteria. [Copyright &y& Elsevier]

An association between arrhythmogenic right ventricular dysplasia–cardiomyopathy (ARVD/C) and Brugada syndrome can be supposed according to several case reports.In order to examine a possible link between ARVD/C and Brugada syndrome, systematic ajmaline testing with 1 mg/kg body weight intravenously, was done in 55 patients (32 males, mean age 46.7±12.3 years) with ISFC/ESC criteria of ARVD/C. In nine patients ajmaline testing could demonstrate coved ST segment elevation of at least 2 mm in at least two right precordial leads. Three of these patients had recurrent syncopes. Electrophysiological study revealed non-sustained ventricular tachycardia with left bundle branch block configuration and inferior axis in only one case. Systematic ajmaline testing could demonstrate a definite link between ARVD/C and Brugada syndrome. [Copyright &y& Elsevier]

Cardiomyopathies are an essential component in clinical cardiology. The number of different cardiomyopathies have increased a lot due to genetics and newer insights in pathomechanism. The current treatment and future options are demonstrated in advance. [ABSTRACT FROM AUTHOR]

Abstract: Syncopes appear in 10–20% in arrhythmogenic right ventricular dysplasia–cardiomyopathy (ARVD/C). In the majority of cases sustained or non-sustained monomorphic ventricular tachycardias represent the underlying mechanism of syncope. In other cases the mechanism remains unclear. In 37 patients (23 females, mean age 43.6±12.8 years) without detectable and inducible monomorphic ventricular tachycardia, a diagnostic algorithm including repeat ECG, holter monitoring, telemetry, electrophysiological examination, ajmaline challenge, tilt table testing and neurological work-up (EEG, cranial computer tomography) was used in order to identify the mechanism of syncopes. Constant AV block 3° could be found in 3 patients (2 males). Intermittant AV block 2° or 3° could be identified in 3 females. Four males had abnormal Wenckebach point during rapid atrial stimulation, 3 males demonstrate isolated HV interval prolongation. Rapid polymorphic VT and VF could be induced in a young female with ARVD/C. Eight patients (7 females) presented with recurrent syncopes and provocable right precordial ST elevation and right bundle branch block during ajmaline challenge. Three patients had abnormal tilt table testing as the only pathological finding. In one female with intermittent AV block 2° tilt table testing and ajmaline challenge was positive. One female had the diagnosis of focal epilepsia after neurological work-up. In 11 cases the mechanism of syncopes remained unclear. In patients with ARVD/C and syncopes beyond detectable or inducible monomorphic VT, several mechanisms of syncopes could be identified with conduction disease as the predominant finding. These results may help in identifying rare mechanisms of syncopes in ARVD/C. [Copyright &y& Elsevier]

In a cardiological department of a non-referral hospital responsible for 80,000 inhabitants with 2500 in-hospital patients and 1500 out-hospital patients per year, the prevalence, symptoms and prognosis of arrhythmogenic right ventricular dysplasia-cardiomyopathy (ARVD/C) were examined retrospectively.From 1997 to 2002, ARVD/C was diagnosed in 35 females and 45 males (overall prevalence 1 in 1000 inhabitants) with a mean age of 45.6 years. Symptoms were chest pain (80%), palpitations (60%) and syncopes (30%), and clinical findings were repetitive ventricular premature beats (50%), supraventricular arrhythmias (30%), ventricular tachycardia (20%), aborted sudden death due to ventricular fibrillation (1%), right heart failure (4%), biventricular heart failure (1%) and high grade AV nodal block (4%). Endomyocardial biopsies were not performed.Aborted sudden death occurred in only one patient (0.3%) before the diagnosis was made, annual heart failure rate was 1%. No deaths appeared in a follow-up of 1–5 (mean 2.4) years with clinical assessment as the basis of diagnosis.The prevalence of ARVD/C is much higher and the prognosis better than expected from results of reference centers. [Copyright &y& Elsevier]

In 19 patients (14 females, mean age 49.1 ± 11.3 years) with typical arrhythmogenic cardiomyopathy and provocable type I Brugada ECG pattern by ajmaline administration were analysed by novel electrocardiographic features as having "true" or "false" Brugada syndrome. Three patients turned out as having false Brugada syndrome, the diagnosis is pure arrhythmogenic cardiomyopathy. In 16 patients, however, true Brugada syndrome could be provoked. In these patients the diagnosis was arrhythmogenic cardiomyopathy associated by provocable Brugada syndrome. [ABSTRACT FROM AUTHOR]

Abstract: We searched for special features in patients with complete and incomplete right bundle branch block diagnosed as having arrhythmogenic right ventricular cardiomyopathy/dysplasia. Whether right bundle branch block is a frequent finding in arrhythmogenic right ventricular cardiomyopathy should be studied. The question is whether special features exist such as T-wave inversions, localized right precordial QRS prolongation and r’/s ratio<1. Results: ARVC could be diagnosed according to ISFC/ESC criteria in 374 patients. CRBBB was found in 22 cases (6%) and iCRBBB was present in 47 cases (12.5%). In CRBBB T wave inversions≥V4 was found in 10 cases (n.s.) and r’/s ratio<1 was present in 12 cases (p<0.001). In iCRBBB T wave inversions≥V4 was found in 10 cases (n.s.) and ST segment elevation in right precordial leads was present in 19 cases (p<0.005). In all patients with ARVC localized right precordial QRS prolongation was found. Patients with CRBBB have a bad prognosis: 17 of 22 patients developed biventricular heart failure requiring heart transplantation and diuretic therapy. Conclusions: CRBBB and iCRBBB are infrequent findings in arrhythmogenic right ventricular cardiomyopathy. Complete right bundle branch block is characterized by r’/s ratio<1. There are no significant T wave inversions≥V4. Incomplete right bundle branch block is characterized by ST segment elevation in right precordial leads but not by T wave inversions≥V4. [Copyright &y& Elsevier]

Over the past decades, there has been tremendous progress in understanding genetic alterations that can result in different phenotypes of human cardiomyopathies. More than a thousand mutations in various genes have been identified, indicating that distinct genetic alterations, or combinations of genetic alterations, can cause either hypertrophic (HCM), dilated (DCM), restrictive (RCM), or arrhythmogenic cardiomyopathies (ARVC). Translation of these results from "bench to bedside" can potentially group affected patients according to their molecular etiology and identify subclinical individuals at high risk for developing cardiomyopathy or patients with overt phenotypes at high risk for cardiac deterioration or sudden cardiac death. These advances provide not only mechanistic insights into the earliest manifestations of cardiomyopathy, but such efforts also hold the promise that mutation-specific pathophysiology might result in novel "personalized" therapeutic possibilities. Recently, the FLNC gene encoding the sarcomeric protein filamin C has gained special interest since FLNC mutations were found in several distinct and possibly overlapping cardiomyopathy phenotypes. Specifically, mutations in FLNC were initially only linked to myofibrillar myopathy (MFM), but are now increasingly found in various forms of human cardiomyopathy. FLNC thereby represents another example for the complex genetic and phenotypic continuum of these diseases. [ABSTRACT FROM AUTHOR]

Abstract: Objective: Mutations in the cardiac ryanodine receptor (RYR2) gene have been reported to cause arrhythmogenic right ventricular cardiomyopathy (ARVC). The molecular mechanisms by which genetic modifications lead to ARVC are still not well understood. Methods: ARVC patients were screened for mutations in the RYR2 gene by denaturing HPLC and DNA sequencing. Single channel measurements were carried out with RyR2 channels purified from explanted hearts of ARVC patients. Results: None of the published RYR2 mutations were found in our ARVC-cohort. However, we identified two single nucleotide polymorphisms (SNPs) in exon 37 of the human RYR2 gene which lead to the amino acid exchanges G1885E and G1886S, respectively. Both SNPs together were found exclusively in 3 out of 85 ARVC patients in a composite heterozygous fashion (genotype T4). This genotype was associated with ARVC (p <0.05) but not with dilated cardiomyopathy (DCM, 79 patients) or none-failing controls (463 blood donors). However, either one of the two SNPs were identified in further 7 ARVC patients, in 11 DCM patients, and in 64 blood donors. The SNP leading to G1886S may create a protein kinase C phosphorylation site in the human RyR2. Single channel recordings at pCa4.3 revealed four conductance states for the RyR2 of genotype T4 and a single open state for the wild type RyR2. At pCa7.7, the lowest subconductance state of the RyR2 channel of genotype T4 persisted with a greatly enhanced open probability indicating a leaky channel. Conclusion: The RyR2 channel leak under diastolic conditions could cause SR-Ca2+ depletion, concomitantly arrhythmogenesis and heart failure in a subgroup of ARVC patients of genotype T4. A change in the RyR2 subunit composition due to the combined expression of both SNPs alters the behaviour of the tetrameric channel complex. [Copyright &y& Elsevier]

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is associated with fibrofatty replacement of cardiac myocytes, ventricular tachyarrhythmias and sudden cardiac death. In 32 of 120 unrelated individuals with ARVC, we identified heterozygous mutations in PKP2, which encodes plakophilin-2, an essential armadillo-repeat protein of the cardiac desmosome. In two kindreds with ARVC, disease was incompletely penetrant in most carriers of PKP2 mutations. [ABSTRACT FROM AUTHOR]