Brugada Syndrome: Progress in Genetics, Risk Stratification and Management.
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SUBMITTER: Romero J
PROVIDER: S-EPMC6434506 | biostudies-literature | 2019 Mar
REPOSITORIES: biostudies-literature
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Brugada Syndrome: Progress in Genetics, Risk Stratification and Management.
Romero Jorge J Li Dan L DL Avendano Ricardo R Diaz Juan Carlos JC Tung Roderick R Di Biase Luigi L
Arrhythmia & electrophysiology review 20190301 1
Brugada syndrome (BrS) is one of the most common causes of sudden cardiac death in normal structural heart individuals. First characterised in 1992, the global prevalence of BrS is unclear, with estimates placing it at around 0.05% and presenting most frequently in southeast Asian countries. This review aims to summarise the development in the understanding of BrS and, importantly, progress in its management, underpinned by knowledge regarding its genetics and molecular mechanisms. It also provi ...[more]
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Project description:Brugada syndrome is an inherited arrhythmogenic disorder leading to sudden death predominantly in the 3-4 decade. To date the only reliable treatment is the implantation of a cardioverter defibrillator; however, better criteria for risk stratification are needed, especially for asymptomatic subjects. Brugada syndrome genetic bases have been only partially understood, accounting for <30% of patients, and have been poorly correlated with prognosis, preventing inclusion of genetic data in current guidelines. We designed an observational study to identify genetic markers for risk stratification of Brugada patients by exploratory statistical analysis. The presence of genetic variants, identified by SCN5A gene analysis and genotyping of 73 candidate polymorphisms, was correlated with the occurrence of major arrhythmic events in a cohort of 92 Brugada patients by allelic association and survival analysis. In all, 18 mutations were identified in the SCN5A gene, including 5 novel, and statistical analysis indicated that mutation carriers had a significantly increased risk of major arrhythmic events (P=0.024). In addition, we established association of five polymorphisms with major arrhythmic events occurrence and consequently elaborated a pilot risk stratification algorithm by calculating a weighted genetic risk score, including the associated polymorphisms and the presence of SCN5A mutation as function of their odds ratio. This study correlates for the first time the presence of genetic variants with increased arrhythmic risk in Brugada patients, representing a first step towards the design of a new risk stratification model.
| S-EPMC3746265 | biostudies-literature
Project description:In 1992, the Brugada syndrome (BrS) was recognized as a disease responsible for sudden cardiac death, characterized by a right bundle-branch block with ST segment elevation in the leads V1 and V2. This syndrome is highly associated with sudden cardiac death, especially in young males. BrS is currently diagnosed in patients with ST-segment elevation showing type 1 morphology ≥ 2 mm in ≥1 leads among the right precordial leads V1 or V2 positioned in the 2nd, 3rd, or 4th intercostal space, and occurring either spontaneously or after a provocative drug test by the intravenous administration of Class I antiarrhythmic drugs. With accumulated findings, the BrS inheritance model is believed to be an autosomal dominant inheritable model with incomplete penetrance, although most patients with BrS were sporadic cases. SCN5A, which was identified as the first BrS-associated gene in 1998, has emerged as the most common gene associated with BrS, and more than 10 BrS-associated genes have been identified thereafter. Mutation-specific genetic testing is recommended for the family members and appropriate relatives following the identification of BrS-causative mutations in an index patient. In addition, comprehensive or BrS1 (SCN5A) targeted genetic testing could be useful for patients in whom a cardiologist has established a clinical index of suspicion for BrS based on the patient׳s clinical history, family history, and the expressed electrocardiographic (resting 12-lead ECGs and/or provocative drug challenge testing) phenotype. Over the past 20 years, extensive research in this field has allowed better understanding of the pathophysiology, genetic background, and management of BrS even though controversies still exist. In this review article, a background of genetics, the genetic background of BrS, the genotype and phenotype relationship, the role of genetic screening in clinical practice, and the interpretation of the identified genetic variants have been addressed based on this understanding.
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Project description:Brugada syndrome (BrS) is one of the most common inherited channelopathies associated with an increased risk of sudden cardiac death. Appropriate use of an ICD in high-risk patients is life-saving. However, there remains a lack of consensus on risk stratification, and even on the diagnosis of BrS itself. Some argue that people with a type 1 Brugada ECG pattern but no symptoms should not be diagnosed with BrS, and guidelines recommend observation without therapy in these patients. Others argue that the presence of a spontaneous (rather than drug-induced) type 1 ECG pattern alone is enough to label them as high-risk for arrhythmic events, particularly if syncope is also present. Syncope and a spontaneous type 1 ECG pattern are the only factors that have consistently been shown to predict ventricular arrhythmic events and sudden cardiac death. Other markers have yielded conflicting data. However, in combination they may have roles in risk scoring models. Epicardial catheter ablation in the right ventricular outflow tract has shown promise in studies as an alternative management option to an ICD, but longer follow-up is required to ensure that the ablation effect is permanent.
| S-EPMC6020188 | biostudies-literature
Project description:The role of programmed ventricular stimulation in identifying patients with Brugada syndrome at the highest risk for sudden death is uncertain.We performed a systematic review and pooled analysis of prospective, observational studies of patients with Brugada syndrome without a history of sudden cardiac arrest who underwent programmed ventricular stimulation. We estimated incidence rates and relative hazards of cardiac arrest or implantable cardioverter-defibrillator shock. We analyzed individual-level data from 8 studies comprising 1312 patients who experienced 65 cardiac events (median follow-up, 38.3 months). A total of 527 patients were induced into arrhythmias with up to triple extrastimuli. Induction was associated with cardiac events during follow-up (hazard ratio, 2.66; 95% confidence interval [CI], 1.44-4.92, P<0.001), with the greatest risk observed among those induced with single or double extrastimuli. Annual event rates varied substantially by syncope history, presence of spontaneous type 1 ECG pattern, and arrhythmia induction. The lowest risk occurred in individuals without syncope and with drug-induced type 1 patterns (0.23%, 95% CI, 0.05-0.68 for no induced arrhythmia with up to double extrastimuli; 0.45%, 95% CI, 0.01-2.49 for induced arrhythmia), and the highest risk occurred in individuals with syncope and spontaneous type 1 patterns (2.55%, 95% CI, 1.58-3.89 for no induced arrhythmia; 5.60%, 95% CI, 2.98-9.58 for induced arrhythmia).In patients with Brugada syndrome, arrhythmias induced with programmed ventricular stimulation are associated with future ventricular arrhythmia risk. Induction with fewer extrastimuli is associated with higher risk. However, clinical risk factors are important determinants of arrhythmia risk, and lack of induction does not necessarily portend low ventricular arrhythmia risk, particularly in patients with high-risk clinical features.
| S-EPMC4758872 | biostudies-literature
Project description:Background A combination of clinical and electrocardiographic risk factors is used for risk stratification in Brugada syndrome. In this study, we tested the hypothesis that the incorporation of latent variables between variables using nonnegative matrix factorization can improve risk stratification compared with logistic regression. Methods and Results This was a retrospective cohort study of patients presented with Brugada electrocardiographic patterns between 2000 and 2016 from Hong Kong, China. The primary outcome was spontaneous ventricular tachycardia/ventricular fibrillation. The external validation cohort included patients from 3 countries. A total of 149 patients with Brugada syndrome (84% males, median age of presentation 50 [38-61] years) were included. Compared with the nonarrhythmic group (n=117, 79%), the spontaneous ventricular tachycardia/ ventricular fibrillation group (n=32, 21%) were more likely to suffer from syncope (69% versus 37%, P=0.001) and atrial fibrillation (16% versus 4%, P=0.023) as well as displayed longer QTc intervals (424 [399-449] versus 408 [386-425]; P=0.020). No difference in QRS interval was observed (108 [98-114] versus 102 [95-110], P=0.104). Logistic regression found that syncope (odds ratio, 3.79; 95% CI, 1.64-8.74; P=0.002), atrial fibrillation (odds ratio, 4.15; 95% CI, 1.12-15.36; P=0.033), QRS duration (odds ratio, 1.03; 95% CI, 1.002-1.06; P=0.037) and QTc interval (odds ratio, 1.02; 95% CI, 1.01-1.03; P=0.009) were significant predictors of spontaneous ventricular tachycardia/ventricular fibrillation. Increasing the number of latent variables of these electrocardiographic indices incorporated from n=0 (logistic regression) to n=6 by nonnegative matrix factorization improved the area under the curve of the receiving operating characteristics curve from 0.71 to 0.80. The model improves area under the curve of external validation cohort (n=227) from 0.64 to 0.71. Conclusions Nonnegative matrix factorization improves the predictive performance of arrhythmic outcomes by extracting latent features between different variables.
| S-EPMC7763720 | biostudies-literature
Project description:Our group began investigating the cause of sudden unexplained death syndrome in Thailand in 1994 and found that among sudden unexplained death syndrome patients, the Brugada phenotype was ubiquitous. Following this important observation, Brugada syndrome (BrS) became our main research focus and has galvanized our collaboration with several global prominent scientists over the past 30 years. Through this collaborative research, we made major progress toward better understanding of the syndrome and gained knowledge in genetic background, pathophysiology, and new management. Two consensus reports were published to help define diagnostic criteria, risk stratification, and management of BrS patients. In this review, we share our experiences and progress of our research and development of our program that was designed to identify the cause of sudden death, understand pathophysiology of the syndrome, and develop effective and safe management and therapy of BrS patients. Although our work in Thailand was challenging at the beginning, it later blossomed into a multicollaborative research enterprise that has produced several important findings that have shed light on the pathophysiology of BrS and development of a new effective treatment modality, catheter ablation.
| S-EPMC9795288 | biostudies-literature
Project description:Brugada syndrome (BrS) is a primary electrical disease associated with life-threatening arrhythmias. It is estimated to cause at least 20% of sudden cardiac deaths (SCDs) in patients with normal cardiac anatomy. In this review paper, we discuss recent advances in complex BrS pathogenesis, diagnostics, and current standard approaches to major arrhythmic events (MAEs) risk stratification. Additionally, we describe a protocol for umbrella reviews to systematically investigate clinical, electrocardiographic, electrophysiological study, programmed ventricular stimulation, and genetic factors associated with BrS, and the risk of MAEs. Our evaluation will include MAEs such as sustained ventricular tachycardia, ventricular fibrillation, appropriate implantable cardioverter-defibrillator therapy, sudden cardiac arrest, and SCDs from previous meta-analytical studies. The protocol was written following the Preferred Reporting Items for Systematic review and Meta-Analysis Protocols (PRISMA-P) guidelines. We plan to extensively search PubMed, Embase, and Scopus databases for meta-analyses concerning risk-stratification in BrS. Data will be synthesized integratively with transparency and accuracy. Heterogeneity patterns across studies will be reported. The Joanna Briggs Institute (JBI) methodology, A MeaSurement Tool to Assess systematic Reviews 2 (AMSTAR 2), and the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) are planned to be applied for design and execution of our evidence-based research. To the best of our knowledge, these will be the first umbrella reviews to critically evaluate the current state of knowledge in BrS risk stratification for life-threatening ventricular arrhythmias, and will potentially contribute towards evidence-based guidance to enhance clinical decisions.
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Project description:AimsBrugada syndrome (BrS) is associated with an increased risk of sudden cardiac death due to ventricular tachycardia/fibrillation (VT/VF) in young, otherwise healthy individuals. Despite SCN5A being the most commonly known mutated gene to date, the genotype-phenotype relationship is poorly understood and remains uncertain. This study aimed to elucidate the genotype-phenotype correlation in BrS.Methods and resultsBrugada syndrome probands deemed at high risk of future arrhythmic events underwent genetic testing and phenotype characterization by the means of epicardial arrhythmogenic substrate (AS) mapping, and were divided into two groups according to the presence or absence of SCN5A mutation. Two-hundred probands (160 males, 80%; mean age 42.6 ± 12.2 years) were included in this study. Patients harbouring SCN5A mutations exhibited a spontaneous type 1 pattern and experienced aborted cardiac arrest or spontaneous VT/VF more frequently than the other subjects. SCN5A-positive patients exhibited a larger epicardial AS area, more prolonged electrograms and more frequently observed non-invasive late potentials. The presence of an SCN5A mutation explained >26% of the variation in the epicardial AS area and was the strongest predictor of a large epicardial area.ConclusionIn BrS, the genetic background is the main determinant for the extent of the electrophysiological abnormalities. SCN5A mutation carriers exhibit more pronounced epicardial electrical abnormalities and a more aggressive clinical presentation. These results contribute to the understanding of the genetic determinants of the BrS phenotypic expression and provide possible explanations for the varying degrees of disease expression.
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Project description: Not available
| S-EPMC10715984 | biostudies-literature
Project description:Background: SCN5A with Brugada syndrome (BrS) is not commonly considered as an independent risk marker for subsequent cardiac events. However, the risk of SCN5A combined with other clinical characteristics has not been fully investigated. Objectives: The aim of this study is to investigate and evaluate risk stratification and related risk factors of SCN5A in BrS. Methods: The databases of PubMed, EMBASE, Cochrane Library, MEDLINE, Chinese National Knowledge Infrastructure (CNKI) and Wanfang Data were searched for related studies published from January 2002 to May 2018 followed by meta-analysis. The BrS patients who underwent SCN5A gene tests were included. The prognosis and risk stratification of SCN5A combined with symptoms and asymptoms diagnosis in BrS, electrophysiology study (EPS) were then investigated and evaluated. Outcomes were defined as ventricular tachycardia/fibrillation (VT/VF), sudden cardiac death (SCD). Results: Eleven suitable studies involving 1892 BrS patients who underwent SCN5A gene tests were identified. SCN5A (+) was not considered to be a significant predictor of future cardiac events (95% CI: 0.89-2.11; P = 0.15; I 2 = 0%). However, SCN5A (+) patients with symptoms at diagnosis revealed a higher prevalence of future VT/VF, SCD compared to SCN5A (-) patients with symptoms at diagnosis. (95% CI: 1.06-3.70; P = 0.03 I 2 = 0%) Among asymptomatic patients, the risk did not significantly differ between SCN5A (+) patients and SCN5A (-) patients. (95% CI: 0.51-4.72; P = 0.45 I 2 = 0 %). In an investigation involving patients in EPS (-) BrS electrocardiogram (ECG), the risk of SCN5A (+) is higher than that of SCN5A (-) (P < 0.001). Conclusions: In BrS patients with symptoms at diagnosis or EPS (-), the meta-analysis suggests that SCN5A (+) are at a higher risk of arrhythmic events than SCN5A (-).
| S-EPMC6389868 | biostudies-literature