Search

Background: Brugada syndrome is a rare inherited arrhythmic syndrome with a coved type 1 ST-segment elevation on ECG and an increased risk of sudden death. Many studies have evaluated risk stratification performance based on ECG-derived parameters. However, since historical Brugada patient cohorts included mostly paper ECGs, most studies have been based on manual ECG parameter measurements. We hypothesized that it would be possible to run automated algorithm-based analysis of paper ECGs. We aimed: 1) to validate the digitization process for paper ECGs in Brugada patients; and 2) to quantify the acute class I antiarrhythmic drug effect on relevant ECG parameters in Brugada syndrome., Methods: A total of 176 patients (30% female, 43 ± 13 years old) with induced type 1 Brugada syndrome ECG were included in the study. All of the patients had paper ECGs before and during class I antiarrhythmic drug challenge. Twenty patients also had a digital ECG, in whom printouts were used to validate the digitization process. Paper ECGs were scanned and then digitized using ECGScan software, version 3.4.0 (AMPS, LLC, New York, NY, USA) to obtain FDA HL7 XML format ECGs. Measurements were automatically performed using the Bravo (AMPS, LLC, New York, NY, USA) and Glasgow algorithms., Results: ECG parameters obtained from digital and digitized ECGs were closely correlated (r = 0.96 ± 0.07, R 2  = 0.93 ± 0.12). Class I antiarrhythmic drugs significantly increased the global QRS duration (from 113 ± 20 to 138 ± 23, p < 0.0001). On lead V2, class I antiarrhythmic drugs increased ST-segment elevation (from 110 ± 84 to 338 ± 227 μV, p < 0.0001), decreased the ST slope (from 14.9 ± 23.3 to -27.4 ± 28.5, p < 0.0001) and increased the TpTe interval (from 88 ± 18 to 104 ± 33, p < 0.0001)., Conclusions: Automated algorithm-based measurements of depolarization and repolarization parameters from digitized paper ECGs are reliable and could quantify the acute effects of class 1 antiarrhythmic drug challenge in Brugada patients. Our results support using computerized automated algorithm-based analyses from digitized paper ECGs to establish risk stratification decision trees in Brugada syndrome., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Brugada syndrome (BrS) is associated with mutations in the cardiac sodium channel gene, SCN5A. However, genetic studies of patients with BrS with arrhythmic events have been limited. We sought to compare various clinical, ECG, and electrophysiological parameters according to SCN5A genotype in a large cohort of BrS probands with first arrhythmic event., Methods: Survey on Arrhythmic Events in Brugada Syndrome is a survey of 10 Western and 4 Asian countries, gathering 678 patients with BrS with first arrhythmic event. Only probands were included, and SCN5A genotype adjudicated. Patients without appropriate genetic data were excluded. Associations of genotype with clinical features were analyzed., Results: The study group comprised 392 probands: 92 (23.5%) SCN5A+ (44 pathogenic/likely pathogenic [P/LP] and 48 variants of unknown significance) and 300 (76.5%) SCN5A-. SCN5A missense variants and the patients hosting them were similar regardless of adjudication. A higher proportion of patients with P/LP were pediatric (<16 years) compared with SCN5A- (11.4% versus 3%, P =0.023). The proportion of females was higher among patients with P/LP compared with SCN5A - (18.2% versus 6.3%, P =0.013). P/LP probands were more likely to have a family history of sudden cardiac death compared with SCN5A - (41.9% versus 16.8%, P <0.001). A higher proportion of patients with P/LP were White compared with SCN5A- (87.5% versus 47%, P <0.001). Ethnicity (odds ratio, 5.41 [2.8-11.19], P <0.001) and family history of sudden cardiac death (odds ratio, 2.73 [1.28-5.82], P =0.009) were independent variables associated with P/LP genotype following logistic regression., Conclusions: The genetic basis of BrS has a complex relationship with gender, ethnicity, and age. Probands hosting a P/LP variant tended to experience their first arrhythmic event at a younger age and to have events triggered by fever compared with patients with SCN5A- . In addition, they were more likely to be White and to have family history of sudden cardiac death. Among females, a P/LP variant suggests an increased risk of being symptomatic. This association should be further studied on an ethnically specific basis in large prospectively collected international cohorts.

Purpose: Stringent variant interpretation guidelines can lead to high rates of variants of uncertain significance (VUS) for genetically heterogeneous disease like long QT syndrome (LQTS) and Brugada syndrome (BrS). Quantitative and disease-specific customization of American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines can address this false negative rate., Methods: We compared rare variant frequencies from 1847 LQTS (KCNQ1/KCNH2/SCN5A) and 3335 BrS (SCN5A) cases from the International LQTS/BrS Genetics Consortia to population-specific gnomAD data and developed disease-specific criteria for ACMG/AMP evidence classes-rarity (PM2/BS1 rules) and case enrichment of individual (PS4) and domain-specific (PM1) variants., Results: Rare SCN5A variant prevalence differed between European (20.8%) and Japanese (8.9%) BrS patients (p = 5.7 × 10 -18 ) and diagnosis with spontaneous (28.7%) versus induced (15.8%) Brugada type 1 electrocardiogram (ECG) (p = 1.3 × 10 -13 ). Ion channel transmembrane regions and specific N-terminus (KCNH2) and C-terminus (KCNQ1/KCNH2) domains were characterized by high enrichment of case variants and >95% probability of pathogenicity. Applying the customized rules, 17.4% of European BrS and 74.8% of European LQTS cases had (likely) pathogenic variants, compared with estimated diagnostic yields (case excess over gnomAD) of 19.2%/82.1%, reducing VUS prevalence to close to background rare variant frequency., Conclusion: Large case-control data sets enable quantitative implementation of ACMG/AMP guidelines and increased sensitivity for inherited arrhythmia genetic testing.

Background: Brugada syndrome (BrS) is characterized by the type 1 Brugada ECG pattern. Pathogenic rare variants in SCN5A (mutations) are identified in 20% of BrS families in whom incomplete penetrance and genotype-negative phenotype-positive individuals are observed. E1784K- SCN5A is the most common SCN5A mutation identified. We determined the association of a BrS genetic risk score (BrS-GRS) and SCN5A mutation type on BrS phenotype in BrS families with SCN5A mutations., Methods: Subjects with a spontaneous type 1 pattern or positive/negative drug challenge from cohorts harboring SCN5A mutations were recruited from 16 centers (n=312). Single nucleotide polymorphisms previously associated with BrS at genome-wide significance were studied in both cohorts: rs11708996, rs10428132, and rs9388451. An additive linear genetic model for the BrS-GRS was assumed (6 single nucleotide polymorphism risk alleles)., Results: In the total population (n=312), BrS-GRS ≥4 risk alleles yielded an odds ratio of 4.15 for BrS phenotype ([95% CI, 1.45-11.85]; P =0.0078). Among SCN5A -positive individuals (n=258), BrS-GRS ≥4 risk alleles yielded an odds ratio of 2.35 ([95% CI, 0.89-6.22]; P =0.0846). In SCN5A -negative relatives (n=54), BrS-GRS ≥4 alleles yielded an odds ratio of 22.29 ([95% CI, 1.84-269.30]; P =0.0146). Among E1784K- SCN5A positive family members (n=79), hosting ≥4 risk alleles gave an odds ratio=5.12 ([95% CI, 1.93-13.62]; P =0.0011)., Conclusions: Common genetic variation is associated with variable expressivity of BrS phenotype in SCN5A families, explaining in part incomplete penetrance and genotype-negative phenotype-positive individuals. SCN5A mutation genotype and a BrS-GRS associate with BrS phenotype, but the strength of association varies according to presence of a SCN5A mutation and severity of loss of function.

Aims: Data on predictors of time-to-first appropriate implantable cardioverter-defibrillator (ICD) therapy in patients with Brugada Syndrome (BrS) and prophylactically implanted ICD's are scarce., Methods and Results: SABRUS (Survey on Arrhythmic Events in BRUgada Syndrome) is an international survey on 678 BrS patients who experienced arrhythmic event (AE) including 252 patients in whom AE occurred after prophylactic ICD implantation. Analysis was performed on time-to-first appropriate ICD discharge regarding patients' characteristics. Multivariate logistic regression models were utilized to identify which parameters predicted time to arrhythmia ≤5 years. The median time-to-first appropriate ICD therapy was 24.8 ± 2.8 months. A shorter time was observed in patients from Asian ethnicity (P < 0.05), those with syncope (P = 0.001), and those with Class IIa indication for ICD (P = 0.001). A longer time was associated with a positive family history of sudden cardiac death (P < 0.05). Multivariate Cox regression revealed shorter time-to-ICD therapy in patients with syncope [odds ratio (OR) 1.65, P = 0.001]. In 193 patients (76.6%), therapy was delivered during the first 5 years. Factors associated with this time were syncope (OR 0.36, P = 0.001), spontaneous Type 1 Brugada electrocardiogram (ECG) (OR 0.5, P < 0.05), and Class IIa indication (OR 0.38, P < 0.01) as opposed to Class IIb (OR 2.41, P < 0.01). A near-significant trend for female gender was also noted (OR 0.13, P = 0.052). Two score models for prediction of <5 years to shock were built., Conclusion: First appropriate therapy in BrS patients with prophylactic ICD's occurred during the first 5 years in 76.6% of patients. Syncope and spontaneous Type 1 Brugada ECG correlated with a shorter time to ICD therapy., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2018. For permissions, please email: journals.permissions@oup.com.)

Background: Information on young patients with Brugada syndrome (BrS) and arrhythmic events (AEs) is limited., Objectives: The purpose of this study was to describe their characteristics and management as well as risk factors for AE recurrence., Methods: A total of 57 patients (age ≤20 years), all with BrS and AEs, were divided into pediatric (age ≤12 years; n = 26) and adolescents (age 13 to 20 years; n = 31)., Results: Patients' median age at time of first AE was 14 years, with a majority of males (74%), Caucasians (70%), and probands (79%) who presented as aborted cardiac arrest (84%). A significant proportion of patients (28%) exhibited fever-related AE. Family history of sudden cardiac death (SCD), prior syncope, spontaneous type 1 Brugada electrocardiogram (ECG), inducible ventricular fibrillation at electrophysiological study, and SCN5A mutations were present in 26%, 49%, 65%, 28%, and 58% of patients, respectively. The pediatric group differed from the adolescents, with a greater proportion of females, Caucasians, fever-related AEs, and spontaneous type-1 ECG. During follow-up, 68% of pediatric and 64% of adolescents had recurrent AE, with median time of 9.9 and 27.0 months, respectively. Approximately one-third of recurrent AEs occurred on quinidine therapy, and among the pediatric group, 60% of recurrent AEs were fever-related. Risk factors for recurrent AE included sinus node dysfunction, atrial arrhythmias, intraventricular conduction delay, or large S-wave on ECG lead I in the pediatric group and the presence of SCN5A mutation among adolescents., Conclusions: Young BrS patients with AE represent a very arrhythmogenic group. Current management after first arrhythmia episode is associated with high recurrence rate. Alternative therapies, besides defibrillator implantation, should be considered., (Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: There is limited information on gender differences in patients with Brugada syndrome (BrS) who experienced arrhythmic events (AEs)., Objective: The purpose of this study was to compare clinical, electrocardiographic (ECG), electrophysiological, and genetic characteristics between males and females in patients with BrS with their first AE., Methods: The multicenter Survey on Arrhythmic Events in BRUgada Syndrome collected data on the first AE in 678 patients with BrS including 619 males (91.3%) and 59 females (8.7%) aged 0.27-84 years (mean age 42.5 ± 14.1 years) at the time of AE occurrence., Results: After excluding pediatric patients, it was found that females were older than males (49.5 ± 14.4 years vs 43 ± 12.7 years, respectively; P = .001). Higher proportions of females were observed in the pediatric and elderly populations. In Asians, the male to female ratio for AEs was ≈9-fold higher than that in White. Spontaneous type 1 BrS ECG was associated with an earlier onset of AEs in pediatric females. A similar prevalence (≈65%) of spontaneous type 1 BrS ECG was present in males and females above the age of 60 years. Females less frequently showed spontaneous type 1 BrS ECG (41% vs 69%; P < .001) or arrhythmia inducibility at electrophysiology study (36% vs 66%; P < .001). An SCN5A mutation was more frequently found in females (48% vs 28% in males; P = .007)., Conclusion: This study confirms that female patients with BrS are much rarer, display less type 1 Brugada ECG, and exhibit lower inducibility rates than do males. It shows for the first time that female patients with BrS with AE have higher SCN5A mutation rates as well as the relationship between gender vs age at the onset of AEs and ethnicity., (Copyright © 2018 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Background: The literature on fever-related arrhythmic events (AEs) in Brugada syndrome (BrS) is currently limited to few case reports and small series., Objective: The present study aimed to describe the characteristics of fever-related AE in a large cohort of patients with BrS., Methods: The Survey on Arrhythmic Events in Brugada Syndrome is a multicenter study on 678 patients with BrS with first AE documented at the time of aborted cardiac arrest (n = 426) or after prophylactic implantable cardioverter-defibrillator implantation (n = 252)., Results: In 35 of 588 patients (6%) with available information, the AE occurred during a febrile illness. Most of the 35 patients were male (80%), Caucasian (83%), and proband (70%). The mean age at the time of AE was 29 ± 24 years (range 0.3-76 years). Most patients (80%) presented with aborted cardiac arrest and 6 (17%) with arrhythmic storm. Family history of sudden death, history of syncope, and spontaneous type 1 Brugada electrocardiogram were noted in 17%, 40%, and 71% of patients, respectively. Ventricular fibrillation was induced at electrophysiology study in 9 of 19 patients (47%). An SCN5A mutation was found in 14 of 28 patients (50%). The highest proportion of fever-related AE was observed in the pediatric population (age <16 years), with a disproportionally higher event rate in the very young (age 0-5 years) (65%). Males were involved in all age groups and females only in the pediatric and elderly groups. Fever-related AE affected 17 Caucasians aged <24 years, but no Asians aged <24 years., Conclusion: The risk of fever-related AE in BrS markedly varies according to age group, sex, and ethnicity. Taking these factors into account could help the clinical management of patients with BrS with fever., (Copyright © 2018 Heart Rhythm Society. All rights reserved.)

Background: Detailed information on the profile of patients with Brugada syndrome (BrS) presenting their first arrhythmic event (AE) after prophylactic implantation of an implantable cardioverter-defibrillator (ICD) is limited., Objectives: The objectives of this study were (1) to compare clinical, electrocardiographic, electrophysiologic, and genetic profiles of patients who exhibited their first documented AE as aborted cardiac arrest (group A) with profiles of those in whom the AE was documented after prophylactic ICD implantation (group B) and (2) to characterize group B patients' profile using the class II indications for ICD implantation established by HRS/EHRA/APHRS expert consensus statement in 2013., Methods: A survey of 23 centers from 10 Western and 4 Asian countries enabled data collection of 678 patients with BrS who exhibited their AE (group A, n = 426; group B, n = 252)., Results: The first AE occurred in group B patients 6.7 years later than in group A (mean age 46.1 ± 13.3 years vs 39.4 ± 15.1 years; P < .001). Group B patients had a higher incidence of family history of sudden cardiac death and SCN5A mutations. Of the 252 group B patients, 189 (75%) complied with the HRS/EHRA/APHRS indications whereas the remaining 63 (25%) did not., Conclusion: Patients with BrS with the first AE documented after prophylactic ICD implantation exhibited their AE at a later age with a higher incidence of positive family history of sudden cardiac death and SCN5A mutations as compared with those presenting with aborted cardiac arrest. Only 75% of patients who exhibited an AE after receiving a prophylactic ICD complied with the 2013 class II indications, suggesting that efforts are still required for improving risk stratification., (Copyright © 2018 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Background: Data on the age at first arrhythmic event (AE) in Brugada syndrome are from limited patient cohorts. The aim of this study is 2-fold: (1) to define the age at first AE in a large cohort of patients with Brugada syndrome, and (2) to assess the influence of the mode of AE documentation, sex, and ethnicity on the age at first AE., Methods and Results: A survey of 23 centers from 10 Western and 4 Asian countries gathered data from 678 patients with Brugada syndrome (91.3% men) with first AE documented at time of aborted cardiac arrest (group A, n=426) or after prophylactic implantable cardioverter-defibrillator implantation (group B, n=252). The vast majority (94.2%) of the patients were 16 to 70 years old at the time of AE, whereas pediatric (<16 years) and elderly patients (>70 years) comprised 4.3% and 1.5%, respectively. Peak AE rate occurred between 38 and 48 years (mean, 41.9±14.8; range, 0.27-84 years). Group A patients were younger than in Group B by a mean of 6.7 years (46.1±13.2 versus 39.4±15.0 years; P <0.001). In adult patients (≥16 years), women experienced AE 6.5 years later than men ( P =0.003). Whites and Asians exhibited their AE at the same median age (43 years)., Conclusions: SABRUS (Survey on Arrhythmic Events in Brugada Syndrome) presents the first analysis on the age distribution of AE in Brugada syndrome, suggesting 2 age cutoffs (16 and 70 years) that might be important for decision-making. It also allows gaining insights on the influence of mode of arrhythmia documentation, patient sex, and ethnic origin on the age at AE., (© 2017 American Heart Association, Inc.)

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., (Copyright © 2016 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Aims: To evaluate the long-term efficacy and safety of an electrophysiologically guided therapy, based on a strategy of treatment using hydroquinidine (HQ) among asymptomatic Brugada patients with inducible ventricular fibrillation (VF)., Methods and Results: In two French reference centres, consecutive asymptomatic type 1 Brugada patients with inducible VF were treated with HQ (600 mg/day, targeting a therapeutic range between 3 and 6 µmol/L) and enroled in a specific follow-up (mean 6.6 ± 3 years), including a second programmed ventricular stimulation (PVS) under HQ. An implantable cardioverter defibrillator (ICD) was eventually implanted in patients inducible under HQ, or during follow-up in case of HQ intolerance, as well as occurrence of arrhythmic events. From a total of 397 Brugada patients, 44 were enroled (47 ± 10 years, 95% male). Of these, 34 (77%) were no more inducible (Group PVS-), and were maintained under HQ alone during a mean follow-up of 6.2 ± 3 years. In this group, an ICD was eventually implanted in four patients (12%), with occurrence of appropriate ICD therapies in one. Among the 10 other patients (22%), who remained inducible and received ICD (Group PVS+), none of them received appropriate therapy during a mean follow-up of 7.7 ± 2 years. The overall annual rate of arrhythmic events was 1.04% (95% confidence interval 0.00-2.21), without any significant difference according to the result of PVS under HQ. One-third of patients experienced device-related complications., Conclusion: Our long-term follow-up results emphasize that the rate of arrhythmic events among asymptomatic Brugada patients with inducible VF remains low over time. Our results also suggest that residual inducibility under HQ is of limited value to predict events during follow-up.

Brugada syndrome (BrS) is characterized by ST-segment elevation in the right precordial leads and is associated with increased risk of sudden cardiac death. We have recently reported families with BrS and SCN5A mutations where some affected members do not carry the familial mutation. We evaluated the involvement of additional genetic determinants for BrS in an affected family. We identified three distinct gene variants within a family presenting BrS (5 individuals), cardiac conduction defects (CCD, 3 individuals) and shortened QT interval (4 individuals). The first mutation is nonsense, p.Q1695*, lying within the SCN5A gene, which encodes for NaV1.5, the α-subunit of the cardiac Na(+) channel. The second mutation is missense, p.N300D, and alters the CACNA1C gene, which encodes the α-subunit CaV1.2 of the L-type cardiac Ca(2+) channel. The SCN5A mutation strictly segregates with CCD. Four out of the 5 BrS patients carry the CACNA1C variant, and three of them present shortened QT interval. One of the BrS patients carries none of these mutations but a rare variant located in the ABCC9 gene as well as his asymptomatic mother. Patch-clamp studies identified a loss-of-function of the mutated CaV1.2 channel. Western-blot experiments showed a global expression defect while increased mobility of CaV1.2 channels on cell surface was revealed by FRAP experiments. Finally, computer simulations of the two mutations recapitulated patient phenotypes. We report a rare CACNA1C mutation as causing BrS and/or shortened QT interval in a family also carrying a SCN5A stop mutation, but which does not segregate with BrS. This study underlies the complexity of BrS inheritance and its pre-symptomatic genetic screening interpretation.

Aims: Brugada syndrome (BrS) is an inherited cardiac disease characterized by ST segment elevation in V1-V3 ECG leads. Mutations SCN5A gene encoding for the cardiac voltage-gated Na(+) channel are found in some BrS patients, but also in family members with isolated conduction disturbances. However, some patients show coved ST elevation in the inferior or lateral leads whose association with SCN5A and familial conduction disturbances are poorly known., Methods and Results: Two novel SCN5A mutations, D1430N and Q1476X, were identified in two unrelated families comprising patients with Brugada-like ST elevation located in the inferior leads or isolated conduction disturbances. Wild-type (WT) and D1430N mutant channels were expressed in tsA201 cells. Patch clamp electrophysiological experiments revealed total absence of Na(+) current resulting from Nav1.5 mutant when compared to WT channels. Treatments known to restore trafficking defect (incubation at low temperature, with mexiletine or lidocaine) did not restore Na(+) current supporting that Nav1.5 mutation is not a defective trafficking mutation. Furthermore, immunocytolabelling indicates the membrane localisation of both WT and mutant channels confirming what we observed in our patch clamp experiments. This suggests that the mutation may induce a complete block of Na(+) permeation. The nonsense mutation Q1476X was leading to a premature stop codon and was not expressed., Conclusion: Brugada-like ST elevation in the inferior ECG leads or isolated conduction disturbances were found in two unrelated families and associated with two novel SCN5A mutations. The missense and nonsense mutations are both resulting in a complete loss of ventricular Na(+) current explaining the phenotypes.

Aims: Brugada syndrome (BrS) is an autosomal-inherited cardiac arrhythmia characterized by an ST-segment elevation in the right precordial leads of the electrocardiogram and an increased risk of syncope and sudden death. SCN5A, encoding the cardiac sodium channel Na(v)1.5, is the main gene involved in BrS. Despite the fact that several mutations have been reported in the N-terminus of Na(v)1.5, the functional role of this region remains unknown. We aimed to characterize two BrS N-terminal mutations, R104W and R121W, a construct where this region was deleted, ΔNter, and a construct where only this region was present, Nter., Methods and Results: Patch-clamp recordings in HEK293 cells demonstrated that R104W, R121W, and ΔNter abolished the sodium current I(Na). Moreover, R104W and R121W mutations exerted a strong dominant-negative effect on wild-type (WT) channels. Immunocytochemistry of rat neonatal cardiomyocytes revealed that both mutants were mostly retained in the endoplasmic reticulum and that their co-expression with WT channels led to WT channel retention. Furthermore, co-immunoprecipitation experiments showed that Na(v)1.5-subunits were interacting with each other, even when mutated, deciphering the mutation dominant-negative effect. Both mutants were mostly degraded by the ubiquitin-proteasome system, while ΔNter was addressed to the membrane, and Nter expression induced a two-fold increase in I(Na). In addition, the co-expression of N-terminal mutants with the gating-defective but trafficking-competent R878C-Na(v)1.5 mutant gave rise to a small I(Na)., Conclusion: This study reports for the first time the critical role of the Na(v)1.5 N-terminal region in channel function and the dominant-negative effect of trafficking-defective channels occurring through α-subunit interaction.

Background: Brugada syndrome (BrS) is caused mainly by mutations in the SCN5A gene, which encodes the α-subunit of the cardiac sodium channel Na(v)1.5. However, ≈ 20% of probands have SCN5A mutations, suggesting the implication of other genes. MOG1 recently was described as a new partner of Na(v)1.5, playing a potential role in the regulation of its expression and trafficking. We investigated whether mutations in MOG1 could cause BrS., Methods and Results: MOG1 was screened by direct sequencing in patients with BrS and idiopathic ventricular fibrillation. A missense mutation p.Glu83Asp (E83D) was detected in a symptomatic female patient with a type-1 BrS ECG but not in 281 controls. Wild type (WT)- and mutant E83D-MOG1 were expressed in HEK Na(v)1.5 stable cells and studied using patch-clamp assays. Overexpression of WT-MOG1 alone doubled sodium current (I(Na)) density compared to control conditions (P<0.01). In contrast, overexpression of mutant E83D alone or E83D+WT failed to increase I(Na) (P<0.05), demonstrating the dominant-negative effect of the mutant. Microscopy revealed that Na(v)1.5 channels failed to properly traffic to the cell membrane in the presence of the mutant. Silencing endogenous MOG1 demonstrated a 54% decrease in I(Na) density., Conclusions: Our results support the hypothesis that dominant-negative mutations in MOG1 can impair the trafficking of Na(v)1.5 to the membrane, leading to I(Na) reduction and clinical manifestation of BrS. Moreover, silencing MOG1 reduced I(Na), demonstrating that MOG1 is likely to be important in the surface expression of Na(v)1.5 channels. All together, our data support MOG1 as a new susceptibility gene for BrS.

Background: Spontaneous type 1 electrocardiographic (ECG) is a risk factor for arrhythmic events in Brugada patients but the importance of the proportion of time with a type 1 ECG is unknown., Patients and Methods: Thirty-four Brugada patients (15 symptomatic) underwent a 24-hour 12-lead ECG recording. One-minute averaged waveforms displaying ST-segment elevation above 200 microV, with descending ST-segment and negative T-wave polarity on leads V(1)-V(3) were considered as type 1 Brugada ECG. The burden was defined as the percentage of type 1 Brugada waveforms., Results: Type 1 ECG on lead V2 was more frequent in symptomatic patients (median 80.6% [15.7-96.7] vs 12.4% [0.0-69.7], P = .05). Patients with a permanent type 1 pattern on lead V(2) were more likely to be symptomatic (5/6) than patients without type 1 ECG during a 24-hour period (2/9) (P < .05)., Conclusion: Type 1 pattern is more prevalent across a 24-hour period in symptomatic Brugada patients., (Copyright 2010 Elsevier Inc. All rights reserved.)

Aims: The distinct cardiac arrhythmia diseases, Brugada syndrome (BS) and isolated cardiac conduction disease (ICCD) are caused by heterozygous mutations in the SCN5A gene. Previous studies have demonstrated an intriguing association between ICCD and BS with the same mutation in the SCN5A gene., Methods and Results: The proband of a multigenerational family presented BS and a familial history of sudden death. We performed clinical evaluations in family members including drug testing and screening for SCN5A mutations. Based on electrocardiogram features, we identified four individuals with BS, two with ICCD and one compatible with both. For five individuals, one with BS and ICCD, three with BS and one with ICCD, we characterized a heterozygous C- to T- mutation at position 4313 (P1438L) in the SCN5A gene. Expression studies of the P1438L mutation showed non-functional channels. The proband's father with the BS phenotype was not a carrier of the new SCN5A mutation., Conclusion: We report the case of a family with BS and/or ICCD and describe a novel mutation, the P1438L SCN5A mutation. In this family, the occurrence of BS and ICCD could be due to this single mutation but also to the accidental association of both diseases.

Brugada syndrome is characterized clinically by the onset of syncopes or sudden death related to ventricular tachyarrhythmias in patients with a structurally normal heart. Its electrocardiographic features include right bundle branch bloc and ST-segment elevations in the precordial leads V1-V3. The estimated prevalence is 1 per 1000 in Asian countries and probably lower elsewhere: Asia is probably a birthplace of the syndrome. Its transmission is autosomal dominant with variable penetrance. Mutations have been identified in a gene coding for the alpha subunit of the sodium channel (SCN5A) in only 25% of cases. These genetic abnormalities cause a reduction of the density of the sodium current and explain the aggravation of electrocardiographic abnormalities caused by antiarrhythmic sodium channel blockers. Prognosis is very serious in symptomatic patients: prevention of sudden death requires implantation of an automatic defibrillator. The treatment decision is much more difficult for asymptomatic subjects with no family history.

Background: Brugada syndrome is an arrhythmogenic disease characterized by an ECG pattern of ST-segment elevation in the right precordial leads and augmented risk of sudden cardiac death. Little is known about the clinical presentation and prognosis of this disease in children., Methods and Results: Thirty children affected by Brugada syndrome who were <16 years of age (mean, 8+/-4 years) were included. All patients displayed a type I ECG pattern before or after drug provocation challenge. Diagnosis of Brugada syndrome was made under the following circumstances: aborted sudden death (n=1), syncope of unexplained origin (n=10), symptomatic supraventricular tachycardia (n=1), suspicious ECG (n=1), and family screening for Brugada syndrome (n=17). Syncope was precipitated by fever in 5 cases. Ten of 11 symptomatic patients displayed a spontaneous type I ECG. An implantable cardioverter-defibrillator was implanted in 5 children; 4 children were treated with hydroquinidine; and 1 child received a pacemaker because of symptomatic sick sinus syndrome. During a mean follow-up of 37+/-23 months, 1 child experienced sudden cardiac death, and 2 children received an appropriate implantable cardioverter-defibrillator shock; all of them were symptomatic and had manifested a type I ECG spontaneously. One child had a cardioverter-defibrillator infection that required explantation of the defibrillator., Conclusions: In the largest population of children affected by Brugada syndrome described to date, fever represented the most important precipitating factor for arrhythmic events, and as in the adult population, the risk of arrhythmic events was higher in previously symptomatic patients and in those displaying a spontaneous type I ECG.