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The case of a 26-year-old male with sudden cardiac arrest due to ventricular fibrillation and the final diagnosis of arrhythmogenic right ventricular dysplasia-cardiomyopathy (ARVD/C) and initial early repolarization phenomenon is presented in detail. An additional analysis of early repolarization in additional 359 patients with ISFC/ESC diagnostic criteria of ARVD/C revealed a frequency within the threshold in healthy volunteers with 3% in isolated lateral leads and 7% in inferolateral leads. The high frequency of electrocardiographic early repolarization limited to inferior leads (22%) is probably due to late depolarization and represents an already reported typical feature of ARVD/C.

Aims: Provocable coved-type ST-segment elevation in right precordial leads is an observation in approximately 16% of patients with typical arrhythmogenic right ventricular cardiomyopathy (ARVC). The value of this observation should be analysed in a long-term follow-up of 17 patients identified by systematic ajmaline challenge., Methods and Results: At first evaluation, one female had an aborted sudden cardiac death and eight patients suffered from recurrent syncopes. Intrathoracic cardioverter defibrillator (ICD) implantation was done in the patient with aborted sudden cardiac death and in six patients with recurrent syncopes. One of these six patients had intermittant 2-3 degrees AV block. Another patient had inducible ventricular tachycardia (VT) at electrophysiological study. Follow-up over more than 3 years in all but one patient was characterized by documented monomorphic VT in the patient with inducible VT and ICD implantation (6%). The patient with aborted sudden cardiac death had only non-sustained VT's shortly after ICD implantation. From the eight patients without syncopes two more patients developed AV block and SA block 3 degrees (18%). Lead-associated complications appeared in three of eight patients with ICDs (38%). Repeated ajmaline challenge was positive in four of eight cases (50%). One patient had a new mutation encoding for SCN5A gene., Conclusion: Ajmaline challenge in typical ARVC characterizes a subgroup of elderly, predominantly female patients with the risk of developing conduction disease. Tachycardia-related events are rare. The indication of ICD implantation in recurrent syncopes is critical as the rate of lead-associated complications in a more than 3 years follow-up is high.

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.

Background: The diagnostic dilemma in arrhythmogenic right ventricular dysplasia-cardiomyopathy (ARVD/C) is that a single diagnostic test does not exist and that there is a need for broadening diagnostic criteria. As standard ECG contributes significantly to clinical diagnosis and represents a tool for screening in family studies ECG data should be revisited., Methods and Results: In a cohort of 265 patients (159 males, mean age 46.8 years) with ISFC/ESC criteria of ARVD/C ECG features were reevaluated. QRS duration in (V1 + V2 + V3)/(V4 + V5 + V6) > or = 1.2-called localized right precordial QRS prolongation-was present in 261/265 patients (98%) and represents the essential finding. Right precordial epsilon potentials were found in 23% in standard and in 75% in highly amplified and modified recording technique. Right precordial T wave inversions were present in 143 cases (54%) and ST-segment elevation of different types in 66 patients (25%). Localized prolongation of inferior QRS complexes could be found in 58 cases (22%), complete right bundle branch block with T inversions beyond V2 in most cases in 17 patients (6%), incomplete right bundle branch block in 38 cases (14%), pseudo-incomplete right bundle branch block in 8 patients (3%), and right precordial R wave reduction in 14 cases (5%)., Conclusion: With regard to sensitivity and already known specificity an ECG score for the diagnosis of ARVD/C was developed with high probability of ARVD/C in cases with > or =4 points, possibly without the need for an additional imaging technique. Standard ECG with additional highly amplified and modified recording technique represents a single diagnostic test with high value in the clinical diagnosis of ARVD/C and should be used as a first line tool in noninvasive family screening.

The so-called Brugada syndrome (BS), first called precordial early repolarization syndrome (PERS), is characterized by the association of a fascinating electrocardiographic pattern, namely an aspect resembling right bundle branch block with a coved and sometime upsloping ST segment elevation in the precordial leads, and major ventricular arrhythmic events that could rarely lead to sudden death. Its electrogenesis has been related to a conduction delay mostly, but not only, located on the right ventricular outflow tract (RVOT), probably due to a progressive fibrosis of the conduction system. Many tests have been proposed to identify people at risk of sudden death and, among all, ajmaline challenge, thanks to its ability to enhance latent conduction defects, became so popular, even if its role is still controversial as it is neither specific nor sensitive enough to guide further invasive investigations and managements. Interestingly, a type 1 pattern has also been induced in many other cardiac diseases or systemic diseases with a cardiac involvement, such as long QT syndrome (LQTS), arrhythmogenic right ventricular cardiomyopathy (ARVC), hypertrophic cardiomyopathy (HCM) and myotonic dystrophy, without any clear arrhythmic risk profile. Evidence-based studies clearly showed that a positive ajmaline test does not provide any additional information on the risk stratification for major ventricular arrhythmic events on asymptomatic individuals with a non-diagnostic Brugada ECG pattern. [ABSTRACT FROM AUTHOR]

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]