Impact of clinical and genetic findings on the management of young patients with Brugada syndrome.

BACKGROUND: Brugada syndrome (BrS) is an arrhythmogenic disease associated with sudden cardiac death (SCD) that seldom manifests or is recognized in childhood. OBJECTIVES: The objectives of this study were to describe the clinical presentation of pediatric BrS to identify prognostic factors for risk stratification and to propose a data-based approach management. METHODS: We studied 106 patients younger than 19 years at diagnosis of BrS enrolled from 16 European hospitals. RESULTS: At diagnosis, BrS was spontaneous (n = 36, 34%) or drug-induced (n = 70, 66%). The mean age was 11.1 ± 5.7 years, and most patients were asymptomatic (family screening, (n = 67, 63%; incidental, n = 13, 12%), while 15 (14%) experienced syncope, 6(6%) aborted SCD or symptomatic ventricular tachycardia, and 5 (5%) other symptoms. During follow-up (median 54 months), 10 (9%) patients had life-threatening arrhythmias (LTA), including 3 (3%) deaths. Six (6%) experienced syncope and 4 (4%) supraventricular tachycardia. Fever triggered 27% of LTA events. An implantable cardioverter-defibrillator was implanted in 22 (21%), with major adverse events in 41%. Of the 11 (10%) patients treated with hydroquinidine, 8 remained asymptomatic. Genetic testing was performed in 75 (71%) patients, and SCN5A rare variants were identified in 58 (55%); 15 of 32 tested probands (47%) were genotype positive. Nine of 10 patients with LTA underwent genetic testing, and all were genotype positive, whereas the 17 SCN5A-negative patients remained asymptomatic. Spontaneous Brugada type 1 electrocardiographic (ECG) pattern (P = .005) and symptoms at diagnosis (P = .001) were predictors of LTA. Time to the first LTA event was shorter in patients with both symptoms at diagnosis and spontaneous Brugada type 1 ECG pattern (P = .006). CONCLUSION: Spontaneous Brugada type 1 ECG pattern and symptoms at diagnosis are predictors of LTA events in the young affected by BrS. The management of BrS should become age-specific, and prevention of SCD may involve genetic testing and aggressive use of antipyretics and quinidine, with risk-specific consideration for the implantable cardioverter-defibrillator

Evaluation de l'alternance de l'onde T par la méthode de la variabilité (à propos de 48 cas)

POITIERS-BU Médecine pharmacie (861942103) / SudocSudocFranceF

Analyse de la variabilité de l'onde T chez l'athlète (étude de 18 sportifs de haut niveau comparés à des témoins)

POITIERS-BU Médecine pharmacie (861942103) / SudocSudocFranceF

Intérêt pronostique de la fraction d'éjection et du volume de l'oreillette gauche, évalués par scanner multi-coupe, après ablation de fibrillation auriculaire par radiofréquence

POITIERS-BU Médecine pharmacie (861942103) / SudocSudocFranceF

Valeur pronostique de la variabilité de l'onde T chez des insuffisants cardiaques à fonction systolique altérée porteurs d'un défribillateur

POITIERS-BU Médecine pharmacie (861942103) / SudocSudocFranceF

Comparaison des dispersions des délais électro-mécaniques et électro-systoliques en Doppler tissulaire pulsé chez l'insuffisant cardiaque dans le cadre du diagnostic de désynchronisation intra-ventriculaire gauche

POITIERS-BU Médecine pharmacie (861942103) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Intein-Mediated Cyclization of Randomized Peptides in the Periplasm of Escherichia coli and Their Extracellular Secretion

Split-inteins can be used to generate backbone cyclized peptide as a source of new bioactive molecules. In this work we show that cysteine-mediated splicing can be performed in the oxidative environment of the periplasm of Escherichia coli. Cyclization of the TEM-1 beta-lactamase and of small randomized peptides was demonstrated using an artificially permuted version of the DnaB mini-intein from Synechocystis sp. PCC6803 strain fused to a signal sequence. For small peptides, a signal sequence that promotes cotranslational translocation had to be used. Efficient backbone cyclization was observed for more than 50% of combinatorial peptides featuring a fully randomized sequence inserted between a serine and glycine that are necessary for fast splicing. Furthermore, by coexpressing a mutant of the ply outer membrane pore protein of fd bacteriophage, we showed that peptides can diffuse in the extracellular medium. These results open new routes for searching compounds acting on new targets such as exported and membrane proteins or pathogen microorganisms

Myotonic dystrophy type 1 mimics and exacerbates Brugada phenotype induced by Nav1.5 sodium channel loss of function mutation.

International audienceBACKGROUND: Myotonic dystrophy type 1 (DM1), a muscular dystrophy due to CTG-expansion in the DMPK gene, can cause cardiac conduction disorders and sudden death. These cardiac manifestations are similar to those observed in loss-of-function SCN5A mutations, which are also responsible for Brugada syndrome (BrS). OBJECTIVE: To investigate DM1 effects on the clinical expression of a loss-of-function SCN5A mutation causing BrS. METHODS: We performed complete clinical evaluation, including ajmaline test, in one family combining DM1 and BrS. We screened the known BrS susceptibility genes. We characterized an SCN5A mutation using whole-cell patch-clamp experiments associated to cell surface biotinylation. RESULTS: The proband, a 15-year old female, was a survivor of out-of-hospital cardiac arrest with ventricular fibrillation. She combined a DMPK CTG-expansion from the father's side and an SCN5A mutation (S910L) from the mother's side. S910L is a trafficking defective mutant inducing a dominant negative effect when transfected with wild-type Nav1.5. This loss-of-function SCN5A mutation caused a Brugada phenotype during the mother's ajmaline test. Surprisingly in the father, a DM1 patient without SCN5A mutation, ajmaline also unmasked a Brugada phenotype. Furthermore, association of both genetic abnormalities in the proband exacerbated the response to ajmaline with a massive conduction defect. CONCLUSIONS: Our study is the first to describe the deleterious effect of DM1 on the clinical expression of a loss-of-function SCN5A mutation and to show a provoked BrS phenotype in a DM1 patient. The modification of the electrocardiographic pattern by ajmaline supports the hypothesis of a link between DM1 and Nav1.5 loss-of-function