Brugada Syndrome Cases Research Articles

RRAD mutation causes electrical and cytoskeletal defects in cardiomyocytes derived from a familial case of Brugada syndrome

The Brugada syndrome (BrS) is an inherited cardiac disorder predisposing to ventricular arrhythmias and sudden death. In the present day, only 30% of BrS cases have known genetic causes. Using whole-exome sequencing in a large pedigree with affected members, we identified a rare variant (p.R211H) in RRAD, the gene encoding Rad GTPase. The aim of this work was to elucidate the mechanisms by which the RRAD p.R211H variant leads to BrS. The study was performed in two cell models, i.e., cardiomyocytes derived from induced pluripotent stem cells (iPSC-CM) reprogrammed from the proband carrying the familial mutation and his healthy brother (non-carrier) and neonatal mouse cardiomyocytes (NMC) infected with adenoviruses encoding wildtype human RAD (ad_WT-RAD) or GFP (ad_GFP), and knock-in mouse mo del carrying the equivalent p.R210H Rad mutation (KI mice). iPSC-CMs from the proband displayed a severe decrease of INa and a moderate decrease of ICaL. Overexpression of WT-RAD in NMC triggered similar impact on both currents. The iPSC-CMs carrying the variant exhibited reduced action potential upstroke velocity, prolonged action potentials and increased incidence of early afterdepolarizations. Combined with the electrical phenotype, these cells showed cortical distribution of actin, cell rounding and reduced focal adhesion count. In mice, Rad was predominantly expressed in the right ventricle outflow tract compared to the other cardiac compartments. This pattern of expression was not altered by the variant. KI mice displayed ventricular conduction disorders under ajmaline challenge and histological anomalies, including fibrosis development, in the right ventricular wall. Mutation in the RAD GTPase recapitulate the typical electrophysiological signature of Brugada syndrome coupled with cytoskeleton disturbances in cardiomyocytes derived from the patient. KI mice showed both cardiac electrical and structural disturbances.

Neuroleptic-Induced Brugada Syndrome - A Case Report

Brugada syndrome is a rare genetic disease, of autosomal dominant inheritance with low penetrance, manifested by ST-segment elevation at right precordial V1, V2, and V3, and right branch block aspect. to the electrocardiogram. It exposes to a high risk of ventricular arrhythmia that can cause syncope and even sudden death, on a structurally healthy heart.We report here the case of a young patient of 25 years who has a syndrome of Brugada induced by a neuroleptic. To our knowledge, this is the first reported case of Brugada syndrome induced by a neuroleptic Morocco. Therapeutic management is based on Amiodarone and beta-blockers. Regular monitoring of the ECG should, however, be performed on patients taking psychotropic drugs and also on associations.

Critical Roles of Xirp Proteins in Cardiac Conduction and Their Rare Variants Identified in Sudden Unexplained Nocturnal Death Syndrome and Brugada Syndrome in Chinese Han Population.

BackgroundSudden unexplained nocturnal death syndrome (SUNDS) remains an autopsy negative entity with unclear etiology. Arrhythmia has been implicated in SUNDS. Mutations/deficiencies in intercalated disc components have been shown to cause arrhythmias. Human cardiomyopathy‐associated 1 (XIRP1) and 3 (XIRP2) are intercalated disc–associated, Xin repeats‐containing proteins. Mouse Xirp1 is necessary for the integrity of intercalated disc and for the surface expression of transient outward and delayed rectifier K+ channels, whereas mouse Xirp2 is required for Xirp1 intercalated disc localization. Thus, XIRP1 and XIRP2 may be potentially causal genes for SUNDS.Methods and ResultsWe genetically screened XIRP genes in 134 sporadic SUNDS victims and 22 Brugada syndrome (BrS) cases in a Chinese Han population. We identified 16 rare variants (6 were in silico predicted as deleterious) in SUNDS victims, including a novel variant, XIRP2‐E215K. There were also four rare variants (2 were in silico predicted as deleterious) detected in BrS cases, including a novel variant, XIRP2‐L2718P. Interestingly, among these 20 variants, we detected 2 likely pathogenic variants: a nonsense variant (XIRP2‐Q2875*) and a frameshift variant (XIRP2‐T2238QfsX7). Analyzing available Xirp2 knockout mice, we further found that mouse hearts without Xirp2 exhibited prolonged PR and QT intervals, slow conduction velocity, atrioventricular conduction block, and an abnormal infranodal ventricular conduction system. Whole‐cell patch‐clamp detected altered ionic currents in Xirp2 −/− cardiomyocytes, consistent with the observed association between Xirp2 and Nav1.5/Kv1.5 in co‐immunoprecipitation.ConclusionsThis is the first report identifying likely pathogenic XIRP rare variants in arrhythmogenic disorders such as SUNDS and Brugada syndrome, and showing critical roles of Xirp2 in cardiac conduction.

Impact of premature activation of the right ventricle with programmed stimulation in Brugada syndrome.

In Brugada syndrome (BrS), it has been reported that delayed activation in the RV is related to the development of type-1 ECG, which is more critical than type-2. On the other hand, the coexistence of complete right bundle-branch block (CRBBB), which also causes delayed activation in the RV, sometimes makes typical BrS ECG misleading. We hypothesized that premature stimulation of the RV can unmask the influence of delayed activation in the RV and convert the morphology of ECG in BrS patients. In 35 BrS patients with type-1 ECG including 8 patients with concomitant CRBBB and 6 control subjects with CRBBB, progressively premature single stimulations were delivered from the RV apex on electrophysiological study. Then we evaluated QRS morphology of fusion beats created by single premature stimulation in each patient. In 29 (83%) of 35 of the BrS patients, conversion from type-1 to type-2 ECG was observed during the process of single premature stimulation. Additionally, in all 8 BrS patients with concomitant CRBBB, type-1 or type-2 BrS ECG was revealed by premature stimulation with relief of CRBBB. These findings were not observed in any of the control subjects with CRBBB. Single premature stimulation of the RV converts ECG from type-1 to type-2 in most BrS cases and unmasks type-1 ECG in all BrS cases with CRBBB. Our results could suggest that type-1 ECG is associated with delayed activation of the RV compared with type-2 ECG.

Brugada Syndrome: Current Practices in Diagnosis, Prognosis, and Treatment

<p>Brugada syndrome (BrS) is a hereditable syndrome, first reported in 1992, characterized by right bundle branch block and an uncommon form of ST-T wave elevation in the V1 and V2 leads and associated with risk of sudden cardiac death (SCD) arising from polymorphic ventricular tachyarrhythmias. BrS is an autosomal dominant inherited condition; however, more than 50% of BrS cases may be sporadic. Approximately 20% to 25% of BrS cases originate from loss of function mutations in the SCN5A cardiac sodium channel.</p><p>The diagnosis of BrS is mainly based on electrocardiogram. SCD due to ventricular fibrillation can be the first clinical presentation of BrS. The insertion of an implantable cardioverter-defibrillator remains the only approved effective measure to prevent SCD in BrS patients. Risk stratification in BrS is still challenging. Because the role of electrophysiological study (EPS) for estimating prognosis in BrS patients has been controversial, but the expert consensus published in 2013 (Priori et al, 2013) considered the performance of EPS, class IIb. Future randomized studies focused on risk stratification and the value of radiofrequency ablation in BrS patients are needed.</p><p>This review provides a succinct general overview of BrS focusing on<strong> </strong>current practices in diagnosis, prognosis, and treatment.</p>

A woman case of Brugada Syndrome with a recurrent syncope.

A woman case of Brugada Syndrome with a recurrent syncope.

健康診断時の心電図自動診断で見逃したブルガダ症候群の一例

健康診断時の心電図自動診断で見逃したブルガダ症候群の一例

An Autopsy Case of Brugada Syndrome with Prominent J Wave in the Inferior Leads Presenting Headache and Chest Pain

An Autopsy Case of Brugada Syndrome with Prominent J Wave in the Inferior Leads Presenting Headache and Chest Pain

Bundle Branch Re-Entrant VentricularTachycardia: Novel Genetic Mechanisms in a Life-Threatening Arrhythmia.

This study sought to investigate for an underlying genetic etiology in cases of apparent idiopathic bundlebranch re-entrant ventricular tachycardia (BBRVT). BBRVT is a life-threatening arrhythmia occurring secondary to macro-re-entry within the His-Purkinje system. Although classically associated with dilated cardiomyopathy, BBRVT may also occur in the setting of isolated,unexplained conduction system disease. Cases of BBRVT with normal biventricular size and function were recruited from 6 North American centers. Enrollment required a clinically documented wide complex tachycardia and BBRVT proven during invasive electrophysiology study. Study participants were screened for mutations within genes associated with cardiac conductionsystem disease. Pathogenicity of identified mutations was evaluated using in silico phylogenetic and physicochemical analyses and invitro biophysical studies. Among 6 cases of idiopathic BBRVT, each presented with hemodynamic compromise and 2 suffered cardiac arrests requiring resuscitation. Putative culprit mutations were identified in 3 of 6 cases, including 2 in SCN5A (Ala1905Gly [novel] and c.4719C>T [splice site mutation]) and 1 in LMNA (Leu327Val [novel]). Biophysical analysis of mutant Ala1905Gly Nav1.5 channels in tsA201 cells revealed significantly reduced peak current density and positive shiftsin the voltage-dependence of activation, consistent with a loss-of-function. The SCN5A c.4719C>T splice sitemutation has previously been reported as disease-causing in 3 cases of Brugada syndrome, whereas the novel LMNA Leu327Val mutation was associated with a classic laminopathy phenotype. Following catheter ablation, BBRVT was noninducible in all cases and none experienced a clinical recurrence during follow-up. Our investigation into apparent idiopathic BBRVT has identified the first genetic culprits for this life-threatening arrhythmia, providing further insight into its underlying pathophysiology and emphasizing a potentialrole for genetic testing in this condition. Our findings also highlight BBRVT as a novel genetic etiology ofunexplainedsudden cardiac death that can be cured with catheter ablation.

Abstract 12229: Bundle Branch Reentrant Ventricular Tachycardia: Novel Genetic Mechanisms in a Life-Threatening Arrhythmia

Introduction: Bundle branch reentrant ventricular tachycardia (BBRVT) is a life-threatening ventricular arrhythmia occurring secondary to macroreentry within the His-Purkinje system. Although classically associated with dilated cardiomyopathy, BBRVT may also occur in the setting of isolated, unexplained conduction system disease. Hypothesis: Idiopathic BBRVT may be secondary to genetic mutations associated with conduction system disease. Methods & Results: We identified 6 cases of BBRVT associated with normal biventricular size and function from 6 centers across North America. Study participants were screened for mutations within pre-specified genes linked to cardiac conduction system disease. Putative culprit mutations were identified in 3 of 6 cases, including 2 in SCN5A (Ala1905Gly [novel] and c.4719C>T [splice site mutation]) and 1 in LMNA (Leu327Val [novel]). Biophysical analysis of mutant Ala1905Gly Na v 1.5 channels in tsA201 cells revealed significantly reduced peak current density and positive shifts in the voltage-dependence of activation consistent with a loss-of-function. The SCN5A c.4719C>T splice-site mutation has previously been reported as disease causing in 3 cases of Brugada syndrome, while the novel LMNA Leu327Val mutation was associated with a classic laminopathy phenotype. Following catheter ablation, BBRVT was non-inducible in all cases and no clinical recurrences were observed during follow-up. Conclusions: Our investigation into apparent idiopathic BBRVT has identified the first genetic culprits for this life-threatening ventricular arrhythmia. This provides further insight into its underlying pathophysiology and emphasizes that conduction system disease, in the absence of ventricular dilation, serves as a sufficient substrate for BBRVT. Our findings also highlight BBRVT as a novel genetic etiology of unexplained sudden cardiac death that can be cured with catheter ablation.

Management of Brugada Syndrome 2016: Should All High Risk Patients Receive an ICD? Alternatives to Implantable Cardiac Defibrillator Therapy for Brugada Syndrome.

More than 20 years ago, the Brugada brothers reported 8 patients with recurrent episodes of aborted sudden death and no demonstrable heart disease having a peculiar ECG pattern of ST elevation in right precordial leads.1 The Brugada syndrome (BrS), one of the most devastating causes of sudden cardiac death (SCD) in relatively young patients with apparently normal heart, was born. In fact, it is likely that the first case of BrS was reported a few years before by Martini et al.2 The syndrome was recognized although not fully characterized even earlier in various southeastern Asian countries as responsible for mysterious cases of unexpected nocturnal SCD.3 Over the following 2 decades, extensive research on the clinical and ECG aspects, electrophysiological (EP) mechanism, genetic background, and management of the syndrome has been accomplished. Two consensus reports on the diagnostic criteria, risk stratification, and management of BrS were published in 20054 and 2013.5 Recent publication of several works dealing with various modes of management of BrS has raised questions about the optimal treatment that should be offered to these patients. Hereunder, I review these updated results and give my own viewpoint on the issue of management of BrS. See Response by Sieira and Brugada ### Importance of ECG Phenotype Ascertainment Although there has been general initial consensus about the ECG definition of Brugada ECG pattern into 3 types (type 1, type 2, and type 3),4 there has been a recent effort to establish a more simplified mode of classification, including only 2 ECG patterns6: pattern 1 identical to the classic type 1 of other consensus (coved pattern) and pattern 2 that joins patterns 2 and 3 of previous consensus (saddle-back pattern). This is in agreement with the classification presently adopted by most specialists that differentiates Brugada ECG type 1 versus non-type …

Association of common and rare variants of SCN10A gene with sudden unexplained nocturnal death syndrome in Chinese Han population.

Sudden unexplained nocturnal death syndrome (SUNDS) remains an autopsy negative entity with unknown etiology to both forensic pathologists and physicians. The electrocardiogram (ECG) characteristics and clinical phenotype of SUNDS survivors strongly suggest that SUNDS shares some similarities with Brugada syndrome (BrS). Recently, the variants of sodium channel Nav 1.8 coding gene SCN10A were identified to be associated with BrS. Here, we investigated the association of SCN10A gene variants with 105 sporadic SUNDS victims and 22 BrS cases in the Chinese Han population. A total of 6 rare mutations and 16 polymorphisms were detected in SUNDS victims. Of the six rare mutations, two were putative pathogenic mutations (F386C and R1263*), one was a likely pathogenic mutation (R14H), and the other three were predicted as benign (R817Q, T1181M, and P1683S). As for the 16 polymorphisms, 1 was a novel polymorphism (c.4144-84G>A) located in intron 24, and the rest were reported previously including one polymorphism (c.2884A>G [I962V]) which showed a statistically significant difference in allele frequency (p=0.044) between SUNDS and the control group. There were also 5 rare mutations and 15 polymorphisms detected in BrS cases. This is the first report of common and rare variants of SCN10A gene in SUNDS and BrS in the Chinese Han population, which provides the genetic epidemiological evidence that SCN10A may be a novel susceptibility gene for SUNDS and account for approximately 3% of SUNDS in China.

A Zebra Among Horses: A Case of Brugada Syndrome and Coronary Artery Disease.

A Zebra Among Horses: A Case of Brugada Syndrome and Coronary Artery Disease.

A case of brugada syndrome presenting with ventricular fibrillation storm and prominent early repolarization

A 21-year-old man developed ventricular fibrillation (VF) while drinking alcohol and was admitted to our hospital. An electrocardiogram (ECG) on admission revealed remarkably prominent slurs on the terminal part of QRS complexes in the left precordial leads and a coved type ST elevation at higher intercostal spaces. After hypothermia therapy, he underwent implantation of an implantable cardioverter-defibrillator (ICD). Standard twelve-lead follow-up ECGs revealed early repolarization pattern and an intermittent coved type ST elevation. When the coved type ST elevation appeared, the early repolarization pattern in the inferior and left precordial leads was attenuated. Prominent early repolarization pattern was the most likely trigger of the VF storm in this Brugada patient.

The Brugada Syndrome Unmasked by Fever in a Two-Year-Old Child: Case Report

The Brugada Syndrome Unmasked by Fever in a Two-Year-Old Child: Case Report ________________________________________ Yazdan Ghandi 1, * ; Parsa Yousefi Chaichi 1 ; Mehrzad Sharifi 2 ; and Najmeh Bolandnazar 3 1 Amirkabir Hospital, Arak University of Medical Sciences, Arak, IR Iran 2 Amiralmomenin Hospital, Arak University of Medical Sciences, Arak, IR Iran 3 Mafi Military Hospital, Shush, IR Iran Abstract Introduction: Brugada syndrome (BrS) is an autosomal-dominant inherited cardiac arrhythmia that occurs due to sodium channelopathy and increases sudden cardiac death due to episodes of polymorphic ventricular tachyarrhythmia. It is characterized by ST-segment elevation in the right precordial leads and right bundle branch block (RBBB) pattern. We herewith present a case of Brugada syndrome with an unusual presentation. Case Presentation: A 2.5-year-old girl with a history of quadriplegic cerebral palsy was admitted due to aspiration pneumonia. Cardiovascular examination and echocardiography was normal. She had a history of surgery for gastro esophageal reflux disease and was under treatment with pantoprazole. Electrocardiogram revealed ST-segment elevation in the right precordial leads (V1 - V3). The patient died during hospitalization due to cardiac arrest before any intervention. Conclusions: The most important feature of Brugada syndrome is clinically suspicion. Therefore it should be considered in cases with uncontrolled seizures, stroke, refractory seizures, recurrent syncope, repeated attacks VT and conduct disorders like RBBB in the absence of structural cardiac and metabolic disorders. Keywords: Brugada Syndrome; Fever; Pediatric; Sudden Cardiac Death; Ventricular Arrhythmia

A case of Brugada syndrome, initially diagnosed as idiopathic ventricular fibrillation, whose asymptomatic identical twin presented Brugada type ST segment elevation

A case of Brugada syndrome, initially diagnosed as idiopathic ventricular fibrillation, whose asymptomatic identical twin presented Brugada type ST segment elevation

New methodologies for measuring Brugada ECG patterns cannot differentiate the ECG pattern of Brugada syndrome from Brugada phenocopy

BackgroundBrugada phenocopies (BrP) are clinical entities characterized by ECG patterns that are identical to true Brugada syndrome (BrS), but are elicited by various clinical circumstances. A recent study demonstrated that the patterns of BrP and BrS are indistinguishable under the naked eye, thereby validating the concept that the patterns are identical. ObjectiveThe aim of our study was to determine whether recently developed ECG criteria would allow for discrimination between type-2 BrS ECG pattern and type-2 BrP ECG pattern. MethodsTen ECGs from confirmed BrS (aborted sudden death, transformation into type 1 upon sodium channel blocking test and/or ventricular arrhythmias, positive genetics) cases and 9 ECGs from confirmed BrP were included in the study. Surface 12-lead ECGs were scanned, saved in JPEG format for blind measurement of two values: (i) β-angle; and (ii) the base of the triangle. Cut-off values of ≥58° for the β-angle and ≥4mm for the base of the triangle were used to determine the BrS ECG pattern. ResultsMean values for the β-angle in leads V1 and V2 were 66.7±25.5 and 55.4±28.1 for BrS and 54.1±26.5 and 43.1±16.1 for BrP respectively (p=NS). Mean values for the base of the triangle in V1 and V2 were 7.5±3.9 and 5.7±3.9 for BrS and 5.6±3.2 and 4.7±2.7 for BrP respectively (p=NS). The β-angle had a sensitivity of 60%, specificity of 78% (LR+ 2.7, LR− 0.5). The base of the triangle had a sensitivity of 80%, specificity of 40% (LR+ 1.4, LR− 0.5). ConclusionsNew ECG criteria presented relatively low sensitivity and specificity, positive and negative predictive values to discriminate between BrS and BrP ECG patterns, providing further evidence that the two patterns are identical.

2015 AHA Late-Breaking Basic Science Abstracts.

### 23060 ### Validation Of Circulating MicroRnas As Biomarkers In Heart Failure In Two Large Independent Cohorts Antoni Bayes-Genis1, David Lanfear2, Maurice de Ronde3, Josep Lupon1, Joost Leenders4, Elisabet Zamora1, L. Keoki Williams2, De Antonio Marta5, Zhen Liu4, Koos Zwinderman3, Sara-Joan Pinto-Sietsma3, Yigal Pinto3; 1Universitat Autonoma de Barcelona, Barcelona, Spain; 2Henry Ford Hospital, Detroit, MI; 3Academic Med Cntr, Univ of Amsterdam, Amsterdam, Netherlands; 4Mirnext BV, Amsterdam, Netherlands; 5Germans Trias i Pujol Hosp, Badalona, Spain Background: Small studies suggested circulating microRNAs (circmiRs) as biomarkers for Heart Failure (HF). However, standardized approaches and quality assessment are not established, and results have been inconsistent, with little replication between studies. We aimed to implement quality standards to enable comparison between cohorts and assess which circmiRs may add prognostic information in HF. Methods: We measured 15 circmiRs in two independent cohorts totaling >2000 subjects. Cohort I (Barcelona) comprised of n=843 chronic HFrEF patients. Cohort II from Detroit comprised n= 1384 chronic HF patients (892 HFrEF, 492 HFpEF). Each sample was measured in duplicate, and normalized to an abundant and stable circmiR (miR-486-5p). Algorithms were installed to define each circmiR measurement as “valid”, “unmeasurable” or “invalid”. This allowed inclusion of valid low-level circmiR measurements while reducing noise from false amplification signals. Results: In general, between 20–40% of measurements were “invalid”, while miR-499a\_5p and -208a were “unmeasurable” in the majority of patients in both cohorts. Higher levels of circmiRs-133b, -1254, -622, -208a and -499a\_5p were significantly associated with risk of death in both cohorts, with hazard ratios ranging from 1.103 to 1.365 per log increase (p-values 0.001 to 0.05). However, adding these circmiRs to established predictors (age, renal function and NTproBNP) did not further augment the c-stat beyond 0.71 (cohort I) or 0.78 (cohort II). …

Expert cardiologists cannot distinguish between Brugada phenocopy and Brugada syndrome electrocardiogram patterns.

Brugada phenocopies (BrPs) are electrocardiogram (ECG) patterns that are identical to true Brugada syndrome (BrS) but are induced by various clinical conditions. The concept that both ECG patterns are visually identical has not been formally demonstrated. The aim of our study was to determine if experts on BrS were able to accurately distinguish between the BrS and BrP ECG patterns. Six ECGs from confirmed cases of BrS and six ECGs from previously published cases of BrP were included in the study. Surface 12-lead ECGs were scanned, saved in JPEG format, and sent to 10 international experts on BrS for evaluation (no clinical history provided). Evaluators were asked to label each case as a Brugada ECG pattern or non-Brugada ECG pattern by visual interpretation alone. The overall accuracy was 53 ± 33% for all cases. Within the BrS cases, the mean accuracy was 63 ± 34% and within the BrP cases, the mean accuracy was 43 ± 33%. Intra-observer repeatability was moderate (κ = 0.56) and inter-observer agreement was fair (κ = 0.36) while evaluator accuracy vs. the true diagnosis was only marginally better than chance (κ = 0.05). Similarly, diagnostic operating characteristics were poor (sensitivity 62%, specificity 43%, +LR 1.1, -LR 0.9). Our results provide strong evidence that BrP and BrS ECG patterns are visually identical and indistinguishable. These findings support the use of systematic diagnostic criteria for differentiating BrP vs. BrS as an erroneous diagnosis may have a negative impact on patient morbidity and mortality.

Mutational analysis of mitochondrial DNA in Brugada syndrome.

Brugada syndrome (BrS) is a primary electrical disease associated with an increased risk of sudden cardiac death due to ventricular fibrillation. This pathology has nuclear heterogeneous genetic origins, and at present, molecular diagnostic tests on nuclear DNA cover only 30% of BrS patients. The aim of this study was to assess the possible involvement of mitochondrial (mt) DNA variants in BrS since their etiological role in several cardiomyopathies has already been described. The whole mt genome of BrS patients was sequenced and analyzed. A specific mtDNA mutation responsible for BrS can be excluded, but BrS patient d-loop was found to be more polymorphic than that of control cases (P=0.003). Moreover, there appears to be an association between patients with the highest number of variants (n>20) and four mt Single Nucleotide Polymorphism (SNPs) (T4216C, A11251G, C15452A, T16126C) and the most severe BrS phenotype (P=0.002). The high substitution rate found in BrS patient mtDNA is unlikely to be the primary cause of the disease, but it could represent an important cofactor in the manifestation of the BrS phenotype. Evidence suggesting that a specific mtDNA allelic combination and a high number of mtDNA SNPs may be associated with more severe cases of BrS represents the starting point for further cohort studies aiming to test whether this mt genetic condition could be a genetic modulator of the BrS clinical phenotype.