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Genetics can contribute to the prognosis of Brugada syndrome: a pilot model for risk stratification.

ABSTRACT: 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.

SUBMITTER: Sommariva E

PROVIDER: S-EPMC3746265 | biostudies-literature | 2013 Sep

REPOSITORIES: biostudies-literature

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Genetics can contribute to the prognosis of Brugada syndrome: a pilot model for risk stratification.

Sommariva Elena E Pappone Carlo C Martinelli Boneschi Filippo F Di Resta Chiara C Rosaria Carbone Maria M Salvi Erika E Vergara Pasquale P Sala Simone S Cusi Daniele D Ferrari Maurizio M Benedetti Sara S

European journal of human genetics : EJHG 20130116 9

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 g ...[more]

PMID: 23321620

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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.

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.

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Genetics can contribute to the prognosis of Brugada syndrome: a pilot model for risk stratification.

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Genetics can contribute to the prognosis of Brugada syndrome: a pilot model for risk stratification.

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