Spontaneous type 1 pattern, ventricular arrhythmias and sudden cardiac death in Brugada Syndrome： an updated systematic review and meta-analysis

Brugada syndrome （BrS） is primary electrical disorder characterized by ST segment elevation with right bundle branch block morphology in patients with apparent structurally normal hearts, It predisposes affected individuals to ventricular tachycardia/fibrillation （VT/VF） and sudden cardiac death （SCD）.A number of studies have identified risk factors that are associated with a more malignant course of disease. These include male gender, syncope, a spontaneous type 1 ECG pattern, family history of SCD, family history of Brugada syndrome,

Tpeak-Tend interval as a new risk factor for arrhythmic event in pa-tient with Brugada syndrome

Objective：To evaluate Tpeak-Tend （Tp-e） interval in surface standard ECG as a new risk factor for arrhythmic event in patient with Brugada syndrome. Methods： 23 male patients with Brugada syndrome and 20 male patients with paroxysmal supraventricular tachycardia （PSVT） as the control group were investigated in this study. Tp-e interval in surface standard ECG was compared between BrS and PSVT patients. Results： Tp-e interval in BrS patients was significantly longer than that in PSVT patients （109.57±22.86 ms vs. 88.50±13.08ms, P〈0.05）. There was significant difference in Tp-e interval between 16 BrS patients with arrhythmic events （including syncope, clinical ventricular fibrillation [VF] and programmed electrica/ stimulation [PES]-induced VF） and 7 BrS patients without arrhythmic events and PSVT patients （118.12±20.40ms vs. 90.00±15.27ms, P〈0.05; 118.12±20.40ms vs. 88.50±13.08ms, P〈0.05）. However, Tp-e interval was similar in BrS patients without arrhythmic events and PSVT patients （90.00±15.27ms vs 88.50±13.08ms, P〉0.05）. Conclusion： The prolongation of Tp-e interval could serve as a new noninvasive event predictor for arrhythmic events in patients with Brugada syndrome.

Pathogenesis and drug response of iPSC-derived cardiomyocytes from two Brugada syndrome patients with different Nav1.5-subunit mutations

Brugada syndrome(BrS)is a complex genetic cardiac ion channel disease that causes a high predisposition to sudden cardiac death.Considering that its heterogeneity in clinical manifestations may result from genetic background,the application of patient-specific induced pluripotent stem cell-derived cardiomyocytes(iPSC-CMs)may help to reveal cell phenotype characteristics underlying different genetic variations.Here,to verify and compare the pathogenicity of mutations(SCN5A c.4213G>A and SCN1B c.590C>T)identified from two BrS patients,we generated two novel BrS iPS cell lines that carried missense mutations in SCN5A or SCN1B,compared their structures and electrophysiology,and evaluated the safety of quinidine in patient-specific iPSC-derived CMs.Compared to the control group,BrS-CMs showed a significant reduction in sodium current,prolonged action potential duration,and varying degrees of decreased Vmax,but no structural difference.After applying different concentrations of quinidine,drug-induced cardiotoxicity was not observed within 3-fold unbound effective therapeutic plasma concentration(ETPC).The data presented proved that iPSC-CMs with variants in SCN5A c.4213G>A or SCN1B c.590C>T are able to recapitulate single-cell phenotype features of BrS and respond appropriately to quinidine without increasing incidence of arrhythmic events.

Brugada syndrome associated with out-of-hospital cardiac arrest: A case report

BACKGROUND Brugada syndrome(BrS)is an inherited disease characterized by an electrocardiogram(ECG)with a coved-type ST-segment elevation in the right precordial leads(V1-V3),which predisposes to sudden cardiac death(SCD)due to polymorphic ventricular tachycardia or ventricular fibrillation in the absence of structural heart disease.We report the case of a 29-year-old man with out-ofhospital cardiac arrest.BrS is associated with a high incidence of SCD in adults,and increasing the awareness of BrS and prompt recognition of the Brugada ECG pattern can be lifesaving.CASE SUMMARY A 29-year-old man suffered from out-of-hospital cardiac arrest,and after defibrillation,his ECG demonstrated a coved-type elevated ST segment in V1 and V2.These findings were compatible with type 1 Brugada pattern,and ECG of his brother showed a type 2 Brugada pattern.The diagnosis was BrS,NYHF IV,multiple organ dysfunction syndrome,sepsis,and hypoxic ischemic encephalopathy.The patient had no arrhythmia episodes after discharge throughout a follow-up period of 36 mo.CONCLUSION Increasing awareness of BrS and prompt recognition of the Brugada ECG pattern can be lifesaving.

Brugada Syndrome: Anesthesia Management

Brugada’s Syndrome (BrS) is a rare but highly risky medical condition. It is a genetic disorder that may result in Ventricular Fibrillations (VF) that can lead to sudden cardiac arrest. The highest possible standards of safety in anesthetic medications must be followed and adequate measures must be taken with sufficient monitorization in patients with BrS. We wanted to mention the importance of monitorization in the early detection of possible complications and a careful follow-up even though no administration of anesthetic medication is present.

Brugada Syndrome Type 1 Electrocardiogram Pattern Induced by Fever in a Black African: A Case Report

Brugada syndrome is a channelopathy that can be familial or sporadic. It is a major cause of sudden death in young people with no obvious heart structural abnormality. The electrocardiogram can be dynamic over time with sometimes normalization. Several pathophysiological conditions are known to induce the electrocardiographic expression of the syndrome. We report here the case of a 65-year-old hypertensive man, without syncope or family sudden death history who was hospitalized for shigella gastroenteritis. Electrocardiogram during fever showed an incomplete block and ST segment elevation with negative T waves in V1 and V2 suggested type 1 Brugada syndrome. Troponin was negative. Electrocardiogram after fever recovered an incomplete right block and normalization of the ST segment. Electrocardiogram should be performed in patients admitted to the emergency unit for infectious syndrome in our countries. This may reveal a number of patients with Brugada syndrome abnormalities.

Brugada syndrome:A new mutation found in Norway

Brugada syndrome is increasingly recognized as a clinical syndrome world wide. We report a case with a new SCN5A mutation. As the awareness of this disease entity increases more cases will probably be found.

Single nucleotide polymorphisms of the SCN5A gene in Han Chinese and their relation with Brugada syndrome

Background Mutations in the cardiac sodium channel gene (SCN5A) may lead to a broad spectrum of familial arrhythmias, including long QT syndrome (LQTS), idiopathic ventricular fibrillation (IVF), and isolated cardiac conduction diseases Recent studies have shown that polymorphisms in the SCN5A gene also play an important role in the manifestation of disorders involving cardiac excitability In this study, we investigated the polymorphisms of the SCN5A gene in Han Chinese and its relation to Brugada syndrome (BS) Methods Genomic DNA was isolated from 120 unrelated healthy volunteers and 48 unrelated Brugada syndrome patients by means of standard procedures All exons including the putative splicing sites of the SCN5A gene were amplified by PCR and sequenced directly or after subcloning using an ABI Prism 377 DNA sequencer Results A total of 5 single nucleotide polymorphisms (SNPs) were identified in the Han Chinese population, including 3 novel ones: G87A(A29A), 4245+82A>G, and G6174A The allele frequencies of each SNP in the Han Chinese population were as follows: G87A (A29A) 27 5%, A1673G (H558R) 10 4%, 4245+82A>G 32 8%, C5457T (D1819D) 41 3%, and G6174A 44 9% S1102Y and 10 other SNPs identified in other ethnic populations were not detected in this study There was no significant difference in the allele frequency of A1673G (H558R) between different ethnic populations (all P >0 5) On the other hand, the allele frequency of C5457T (D1819D) among Han Chinese was similar to its frequency among Japanese ( P >0 5), but higher than that among Americans ( P <0 005) The allele G1673 (R558) was over-represented in BS patients compared to controls ( P <0 005), but there was no significant difference in genotype frequencies at this locus There were also no differences in either the allele or genotype frequencies of the 4 other identified SNPs when comparing BS patients with healthy controls Conclusions The distribution of SCN5A SNPs may vary between different ethnicities The polymorphism of A1673G might be associated with BS and may contribute to a susceptibility to BS in Han Chinese

Interventricular septum motion abnormalities:unexpected echocardiographic changes of Brugada syndrome

Background There remains controversy about whether Brugada syndrome （BS） has structural heart changes. We occasionally noted that a patient with BS had a quite unusual regional wall motion abnormality at the basal segment of the interventricular septum （IVS） during echocardiographic examination. The unexpected finding promoted us to reexamine our patients with BS by echocardiographic interrogation in the present study. Methods Patients with BS （n=11）, patients with complete right bundle branch block （RBBB） （n=11）, and control subjects （n=11） were enrolled in this study. Two-dimensional echocardiography （2DE） was performed to obtain parasternal left ventricular long axis view on which M-mode scanning line was adjusted to be perpendicular to the basal segment of IVS for delineation of the segmental motion curve, with a simultaneously electrocardiographic tracing. Results 2DE revealed a rapid swing motion shifting toward the right ventricle of the IVS basal segment at early systole in 73% （8/11） patients with BS, which was further confirmed on the M-mode curve evidenced by an early systolic notch toward the right ventricle. The position of the notch corresponded to C-point on the mitral motion curve, lasting for （53±5） ms. There were no similar changes both in patients with RBBB and in the control subjects. Conclusion IVS basal motion abnormalities at early-systolic phase may be the novel finding of BS.

Brugada syndrome:a fatal disease with complex genetic etiologies–still a long way to go

Brugada syndrome(BrS)is an arrhythmogenic disorder which was first described in 1992.This disease is a channelopathy characterized by ST-segment elevations in the right precordial leads and is susceptible to sudden death.BrS is a fatal disease with gender and age preferences.It occurs mainly in young male subjects with a structurally normal heart and silently progresses to sudden death with no significant symptoms.The prevalence of BrS has been reported in the ranges of 5-20 per 10000 people.The disease is more prevalent in Asia.Nowadays,numerous variations in 23 genes have been linked to BrS since the first gene SCN5A has been associated with BrS in 1998.Not only can clinical specialists apply these discoveries in risk assessment,diagnosis and personal medicine,but also forensic pathologists can make full use of these variations to conduct death cause identification.However,despite the progress in genetics,these associated genes can only account for approximately 35%of the BrS cases while the etiology of the remaining BrS cases is still unexplained.In this review,we discussed the prevalence,the genes associated with BrS and the application of molecular autopsy in forensic pathology.We also summarized the present obstacles,and provided a new insight into the genetic basis of BrS.

Molecular genetics of Brugada syndrome

Brugada syndrome(BrS)is a life-threatening cardiac rhythm disorder characterized by persistent STsegment elevation in leads V1–V3 and right bundle branch block on electrocardiograms(ECG),and by syncope and sudden death from ventricular tachycardia(VT)and ventricular fibrillation(VF).BrS is responsible for nearly 4%of sudden cardiac deaths and considered to be the most common cause of natural death in males younger than 50 years in some Asian countries.Since the first diseasecausing gene for BrS(the cardiac sodium channel gene SCN5A)was identified in 1998,extensive investigations on both clinical and basic aspects of BrS have occurred rapidly.SCN5A mutations remain the most common cause of BrS;nearly 300 SCN5A mutations have been identified and are responsible for 20%–30%of BrS cases.Commercial genetic testing is available for SCN5A.Recently,seven other disease-causing genes for BrS have been identified and include GPD1L(BrS2),CACNA1C(Cav1.2,BrS3),CACNB2(Cavβ2,BrS4),SCN1B(Navβ1,BrS5),KCNE3(MiRP2,BrS6),SCN3B(Navβ3,BrS7),and HCN4(BrS8).This article will briefly review the progress made over the past decade in our understanding of the clinical,genetic and molecular aspects of BrS.

Brugada type 1 electrocardiogram:Should we treat the electrocardiogram or the patient?

Patients with a Brugada type 1 electrocardiogram(ECG) pattern may suffer sudden cardiac death(SCD). Recognized risk factors are spontaneous type 1 ECG and syncope of presumed arrhythmic origin. Familial sudden cardiac death(f-SCD) is not a recognized independent risk factor. Finally, positive electrophysiologic study(+EPS) has a controversial prognostic value. Current ESC guidelines recommend implantable cardioverter defibrillator(ICD) implantation in patients with a Brugada type 1 ECG pattern if they have suffered a previous resuscitated cardiac arrest(class Ⅰrecommendation) or if they have syncope of presumed cardiac origin(class Ⅱa recommendation). In clinical practice, however, many other patients undergo ICD implantation despite the suggestions of the guidelines. In a 2014 cumulative analysis of the largest available studies(including over 2000 patients), we found that 1/3 of patients received an ICD in primary prevention. Interestingly, 55% of these latter were asymptomatic, while 80% had a + EPS. This means that over 30% of subjects with a Brugada type 1 ECG pattern were considered at high risk of SCD mainly on the basis of EPS, to which a class Ⅱb indication for ICD is assigned by the current ESC guidelines. Follow-up data confirm that in clinical practice single, and often frail, risk factors overestimate the real risk in subjects with the Brugada type 1 ECG pattern. We can argue that, in clinical practice, many cardiology centers adopt an aggressive treatment in subjects with a Brugada type 1 ECG pattern who are not at high risk. As a result, many healthy persons may be treated in order to save a few patients with a true Brugada Syndrome. Better risk stratification is needed. A multi-parametric approach that considers the contemporary presence of multiple risk factors is a promising one.

MODELING AND SIMULATION OF E1784K MUTATION AND SODIUM IONIC CHANNEL DISEASES

In the clinical reports, the E1784K mutation in SCN5A is recognized as a phenotypic overlap between the long QT syndrome （LQT3） and the Brugada syndrome （BrS） in the characteristics of electrocardiograms （ECGs） since the mutation can influence sodium channel functions. However it is still unclear if the E1784K mutation-induced sodium ionic channel alterations account for the overlap at tissue level. Thsu, a detailed computational model is developed to underpin the functional impacts of the E1784K mutation on the action potential （AP）, the effective refractory period （ERP） and the abnormal ECG. Simulation results stlggest＇that the E1784K mutation-induced sodium channel alterations are insufficient to produce the phenotypic overlap between LQT3 and BrS, and the overlap may arise from the complicated effects of the E1784K mutation-induced changes in sodium channel currents with an increase of the transient outward current ITo or a decrease of the L-type calcium current ICaL .

Gender-based differences in cardiac diseases

It has been observed that the incidence of heart failure and Brugada syndrome are higher in men, while women are more likely to have QT interval prolongation and develop torsades de pointes （TdP）. Over the past decade, new studies have improved our understanding of the mechanisms of abnormal repolarization and the relationship between gender differences in cardiac repolarization and presentation of clinical syndromes. Nevertheless, the causes of gender-based differences in cardiac disease are still not completely clear. This review paper briefly summarized what is currently known about gender differences in heart failure, Brugada syndrome and long QT syndrome from molecular mechanisms to clinical presentations.

J Wave Syndromes： A Decade of Progress

Objective： The objective was to provide a brief history of J wave molecular, ionic, cellular mechanisms, and clinical features. We will clinical research for J wave syndromes. syndromes and to summarize our current understanding of their also discuss the existing debates and further direction in basic and Data Sources： The publications on key words of＂J wave syndromes＂, ＂early repolarization syndrome （ERS）＂, ＂Brugada syndrome （BrS）＂ and ＂ST-segment elevation myocardial infarction （STEMI）＂ were comprehensively reviewed through search of the PubMed literatures without restriction on the publication date. Study Selection： Original articles, reviews and other literatures concerning J wave syndromes, ERS, BrS and STEMI were selected. Results： J wave syndromes were firstly defined by Yah et al. in a Chinese journal a decade ago, which represent a spectrum of variable phenotypes characterized by appearance of prominent electrocardiographic J wave including ERS, BrS and ventricular fibrillation （VF） associated with hypothermia and acute STEMI. J wave syndromes can be inherited or acquired and are mechanistically linked to amplification of the transient outward current （I ）-mediated J waves that can lead to phase 2 reentry capable of initiating VF. Conclusions： J wave syndromes are a group of newly highlighted clinical entities that share similar molecular, ionic and cellular mechanism and marked by amplified J wave on the electrocardiogram and a risk of VF. The clinical challenge ahead is to identify the patients with J wave syndromes who are at risk for sudden cardiac death and determine the alternative therapeutic strategies to reduce mortality.

Does anti-neoplastic drug lead to Brugada-like wave

Background We have discovered an unexpected phenomenon that patients with malignant tumor （MT） were commonly associated with type I Brugada-like wave on electrocardiogram（ECG）. Methods For a retro- spective study, we collected the clinical history, demographic data, laboratory examinations, imaging docu- ments and medication information of 22 patients with type I Brugada-like wave. Results Of 22 patients with type I Brugada-like wave, five suffered from MT, accounting for 22.7%. Of the 5 MT patients, two had nor- mal ECG when diagnosis was made, displayed Brugada-like wave during the chemotherapy of anti-neoplastic drug. After appearing, Brugada-like wave would continuously exist during the course of chemotherapy. The longest existing time of Brugada-like wave lasted over five years. The two patients had no compression of right ventricular outflow tract（RVOT）, no electrolyte abnormality and no use of the known drugs being able to in- duce Brugada-like wave, such as class I anti-arrhythmic drugs. Conclusion Anti-neoplastic drug is a new factor being able to induce Brugada-like wave.

Clinical variability in onset of influenza A （H7N9） infection

Clinical information of infections with the novel avian influenza A （H7N9） have been described elsewhere,but clinical variability, especially changes ot mental status in the onset of infection, has rarely been reported in patients infected with H7N9. In this report, the initial clinical manifestations of three confirmed cases are summarized. Two of the patients were in critical condition. In addition,

T-wave oversensing and inappropriate shocks in implantable cardioverter defibrillators

The implantable cardioverter defibrillator （ICD） represents today the treatment and prophylaxis of choice for patients at risk for sustained ventricular tachyarrhythmias.1-6 Accurate sensing of ventricular tachyarrhythmias is a critical aspect of the function of ICD. All currently available models include algorithms with variable sensitivity, allowing adjustments which optimize the detection of low amplitude signals during ventricular tachyarrhythmia. However,

Sudden Cardiac Death and Cardiac Sodium Channel Diseases

Sudden cardiac death(SCD),accounting for a substantial part of the forensic autopsy,is a leading cause of mortality worldwide.Lethal arrhythmia due to sodium channel diseases is recognized as one of the most prevalent etiologies of SCD.In these disorders,defective cardiomyocytes,including the pacemaker and the working cardiomyocytes,would manifest as abnormal electrical activity and morphology,thereby predisposing individuals to SCD.It is always a problem for forensic pathologists to adjudicate a sudden death caused by sodium channel diseases since structural changes in those cases are often inconspicuous.With the advent of the molecular autopsy,forensic pathologists can conduct targeted gene testing to identify the risk of SCD for family members of the probands.This review aims to discuss the relationship between SCD and sodium channel diseases,clarify the underlying mechanisms,and provide prophylactic suggestions for the relatives of SCD patients at risk.