Prevalence of Supraventricular Tachyarrhythmias in a Cohort of 115 Patients with Brugada Syndrome

Background : The Brugada syndrome is characterized by ST segment elevation in leads V₁ to V₃ and a right bundle branch block like pattern. It is associated with an increased risk of syncope and sudden cardiac death. Initial reports in small numbers of patients suggest an association between supraventricular tachycardias and Brugada syndrome with a prevalence varying between 13% and 40%. Objective : Aim of this study was to evaluate the prevalence of AV nodal reentrant tachycardia, AV reentry tachycardia, and/or atrial fibrillation in a large cohort of patients diagnosed as Brugada syndrome. Methods and Results : From three different European centers 115 consecutive patients with a Brugada syndrome were evaluated noninvasively and invasively (mean age 45 ± 12 years, n = 82 men, n = 33 women). Nineteen of 115 patients (17%) had a history of previous cardiac arrest. Syncope was reported by 58 patients (50%), 33 patients had a positive family history of sudden cardiac death (29%). Supraventricular tachycardias were documented in 26 of the patients (23%): Eight patients (7%) had AV‐nodal reentrant tachycardias and two patients had AV‐reentry tachycardias; atrial tachycardias were documented in three patients, and another 13 patients (11%) suffered from atrial fibrillation/atrial flutter. Additionally, atrial fibrillation was inducible by programmed atrial stimulation in nine patients (8%). Conclusions : Supraventricular tachycardias occur in 23% of patients with Brugada syndrome. Documentation of atrial fibrillation especially in the young or supraventricular tachycardias associated with syncope should give reason to screen for Brugada syndrome.     

Brugada Syndrome: Current Clinical Aspects and Risk Stratification

Brugada syndrome is a primary electrical disease of the heart that causes sudden cardiac death or life‐threatening ventricular arrhythmias, especially in younger men. Genetic analysis supports that this syndrome is a cardiac ion channel disease. A typical electrocardiographic finding consists of a right bundle branch block pattern and ST‐segment elevation in the right precordial leads. The higher intercostal space V₁ to V₃ lead electrocardiogram could be helpful in detecting Brugada patients. Although two types of the ST‐segment elevation are present, the coved type is more relevant to the syndrome than the saddle‐back type. These patterns can be present permanently or intermittently. Recent data suggest that the Brugada‐type electrocardiogram is more prevalent than the manifest Brugada syndrome. Asymptomatic individuals have a much lower incidence of future cardiac events than the symptomatic patients. Although risk stratification for the Brugada syndrome is still incomplete, the inducibility of sustained ventricular arrhythmias has been proposed as a good outcome predictor in this syndrome. In noninvasive techniques, some clinical evidence supports that late potentials detected by signal‐averaged electrocardiography are a useful index for identifying patients at risk. The available data recommend prophylactic implantation of an imptantabie cardioverter defibrillator to prevent sudden cardiac death. This review summarizes recent information of the syndrome by reviewing most of new clinical reports and speculates on its risk stratification. A.N.E. 2002;7(3):251–262     

J‐Wave Disappearance Immediately After an Episode of Ventricular Fibrillation in a Patient With Resuscitated Sudden Cardiac Death and Brugada Syndrome

J‐Wave Disaapearance After an Episode of Ventricular Fibrillation . Early repolarization (ER) abnormalities in the inferior‐lateral leads are a matter of intense scientific debate because of their demonstrated association with Brugada syndrome (BS) and idiopathic ventricular fibrillation (VF). To add fuel to the fire, we present a case in which ER abnormalities are associated with BS but in which, more importantly, they were shown to be transient and strictly correlated with an episode of VF. (J Cardiovasc Electrophysiol, Vol. 21, pp. 1413‐1415, December 2010)     

Prevalence of the Brugada sign in idiopathic ventricular fibrillation and healthy controls

OBJECTIVE—To determine the prevalence of the Brugada sign (right bundle branch block with ST elevation in V1-V3) in idiopathic ventricular fibrillation and in an age matched healthy population.DESIGN—ECGs from 39 consecutive patients with idiopathic ventricular fibrillation and 592 healthy controls were reviewed. They were classified as definite, questionable, and no Brugada sign (according to predetermined criteria) by four investigators blinded to the subjects'' status.RESULTS—Eight patients (21%) with idiopathic ventricular fibrillation but none of the 592 controls had a definite Brugada sign (p < 0.005). Thus the estimated 95% confidence limits for the prevalence of a definite Brugada sign among healthy controls was less than 0.5%. A questionable Brugada sign was seen in two patients with idiopathic ventricular fibrillation (5%) but also in five controls (1%) (p < 0.05). Normal ECGs were found following resuscitation and during long term follow up in 31 patients with idiopathic ventricular fibrillation (79%). Patients with idiopathic ventricular fibrillation and a normal ECG and those with the Brugada syndrome were of similar age and had similar spontaneous and inducible arrhythmias. However, the two groups differed in terms of sex, family history, and the incidence of sleep related ventricular fibrillation.CONCLUSIONS—A definite Brugada sign is a specific marker of arrhythmic risk. However, less than obvious ECG abnormalities have little diagnostic value, as a "questionable" Brugada sign was observed in 1% of healthy controls. In this series of consecutive patients with idiopathic ventricular fibrillation, most had normal ECGs.     

Mutations in SCN10A Are Responsible for a Large Fraction of Cases of Brugada Syndrome

Background

BrS is an inherited sudden cardiac death syndrome. Less than 35% of BrS probands have genetically identified pathogenic variants. Recent evidence has implicated SCN10A, a neuronal sodium channel gene encoding Na_v1.8, in the electrical function of the heart.

Objectives

The purpose of this study was to test the hypothesis that SCN10A variants contribute to the development of Brugada syndrome (BrS).

Methods

Clinical analysis and direct sequencing of BrS susceptibility genes were performed for 150 probands and family members as well as >200 healthy controls. Expression and coimmunoprecipitation studies were performed to functionally characterize the putative pathogenic mutations.

Results

We identified 17 SCN10A mutations in 25 probands (20 male and 5 female); 23 of the 25 probands (92.0%) displayed overlapping phenotypes. SCN10A mutations were found in 16.7% of BrS probands, approaching our yield for SCN5A mutations (20.1%). Patients with BrS who had SCN10A mutations were more symptomatic and displayed significantly longer PR and QRS intervals compared with SCN10A-negative BrS probands. The majority of mutations localized to the transmembrane-spanning regions. Heterologous coexpression of wild-type (WT) SCN10A with WT-SCN5A in HEK cells caused a near doubling of sodium channel current compared with WT-SCN5A alone. In contrast, coexpression of SCN10A mutants (R14L and R1268Q) with WT-SCN5A caused a 79.4% and 84.4% reduction in sodium channel current, respectively. The coimmunoprecipitation studies provided evidence for the coassociation of Na_v1.8 and Na_v1.5 in the plasma membrane.

Conclusions

Our study identified SCN10A as a major susceptibility gene for BrS, thus greatly enhancing our ability to genotype and risk stratify probands and family members.     

Spontaneous Fluctuations between Diagnostic and Nondiagnostic ECGs in Brugada Syndrome Screening: Portuguese Family with Brugada Syndrome

Background: All family members of patients with Brugada syndrome (BS) should be screened. Fluctuations between diagnostic and nondiagnostic electrocardiogram (ECG) patterns in patients with BS are recognized, but systematic studies are lacking. The objective of this work was to prospectively evaluate the spontaneous changes between diagnostic and nondiagnostic ECG patterns in a family screened for BS. Methods: One hundred twenty‐nine family members were possibly affected plus the index case were screened with two ECGs with an interval of 6 months. Only coved‐type ECG pattern was defined as diagnostic; type 2 and 3 ECGs were considered suggestive. Results: The first ECG series made six diagnostics and the second 11, but only three patients maintained the diagnostic ECG. Patients with basal diagnostic ECG were older and more frequently symptomatic. Body mass index (BMI) was significantly lower in adults with diagnostic plus suggestive ECG when compared with the others. No significant gender difference was found among relatives with or without diagnostic ECG. Conclusion: Spontaneous phenotypic manifestation of BS was more frequent in older symptomatic patients, absent in children, and related with low BMI. ECG manifestations were intermittent in more than 3/4 of the affected patients. Fluctuations between diagnostic and nondiagnostic ECGs may have an implication on the correct phenotyping in family screening so several ECGs with drug challenging are mandatory. Ann Noninvasive Electrocardiol 2010;15(4):337‐343     

Beta‐Blocker Efficacy in High‐Risk Patients with the Congenital Long‐QT Syndrome Types 1 and 2: Implications for Patient Management

β‐Blockers for LQTS Types 1 and 2. Background: Beta‐blockers are the mainstay therapy in patients with the congenital long‐QT syndrome (LQTS) types 1 and 2. However, limited data exist regarding the efficacy and limitations of this form of medical management within high‐risk subsets of these populations. Methods and Results: Multivariate analysis was carried out to identify age‐related gender‐ and genotype‐specific risk factors for cardiac events (comprising syncope, aborted cardiac arrest [ACA] or sudden cardiac death [SCD]) from birth through age 40 years among 971 LQT1 (n = 549) and LQT2 (n = 422) patients from the International LQTS Registry. Risk factors for cardiac events included the LQT1 genotype (HR = 1.49, P = 0.003) and male gender (HR = 1.31, P = 0.04) in the 0–14 years age group; and the LQT2 genotype (HR = 1.67, P < 0.001) and female gender (HR = 2.58, P < 0.001) in the 15–40 years age group. Gender–genotype subset analysis showed enhanced risk among LQT1 males (HR = 1.93, P < 0.001) and LQT2 females (HR = 3.28, P < 0.001) in the 2 respective age groups. Beta‐blocker therapy was associated with a significant risk‐reduction in high‐risk patients, including a 67% reduction (P = 0.02) in LQT1 males and a 71% reduction (P < 0.001) in LQT2 females. Life‐threatening events (ACA/SCD) rarely occurred as a presenting symptom among beta‐blocker‐treated patients. However, high‐risk patients who experienced syncope during beta‐blocker therapy had a relatively high rate of subsequent ACA/SCD (>1 event per 100 patient‐years). Conclusions: The present findings suggest that beta‐blocker therapy should be routinely administered to all high‐risk LQT1 and LQT2 patients without contraindications as a first line measure, whereas primary defibrillator therapy should be recommended for those who experience syncope during medical therapy. (J Cardiovasc Electrophysiol, Vol. 21, pp. 893‐901, August 2010)     

Neurally Mediated Syncope as a Cause of Syncope in Patients with Brugada Electrocardiogram

Neurally Mediated Syncope in Brugada Syndrome. Introduction: Patients with type 1 Brugada electrocardiogram (ECG) and an episode of syncope are diagnosed as symptomatic Brugada syndrome; however, all episodes of syncope may not be due to ventricular tachyarrhythmia. Methods and Results: Forty‐six patients with type 1 Brugada ECG (all males, 51 ± 13 years, 29 spontaneous, 17 Ic‐drug induced), 20 healthy control subjects (all males, 35 ± 11 years), and 15 patients with suspected neurally mediated syncope (NMS; 9 males, 54 ± 22 years) underwent the head‐up tilt (HUT) test. During the HUT test, 12‐lead ECGs were recorded in all patients, and the heart rate variability was investigated in some patients. Sixteen (35%) of 46 patients with Brugada ECG, 2 (10%) of 20 control subjects, and 10 (67%) of 15 patients with suspected NMS showed positive responses to the HUT test. Although no significant differences were observed in HUT‐positive rate among Brugada patients with documented VT (7/14; 50%), syncope (5/19; 26%) and asymptomatic patients (4/13; 31%), the HUT‐positive rate was significantly higher in patients with documented VT (50%) and those with VT or no symptoms (11/27, 41%) compared to that in control subjects (10%) (P < 0.05). Augmentation of ST‐segment amplitude (≥0.05 mV) in leads V1‐V3 was observed in 11 (69%) of 16 HUT‐positive patients with Brugada ECG during vasovagal responses, and was associated with augmentation of parasympathetic tone following sympathetic withdrawal. Conclusion: Thirty‐five percent of patients with Brugada ECG showed vasovagal responses during the HUT test, suggesting that some Brugada patients have impaired balance of autonomic nervous system, which may relate to their syncopal episodes. (J Cardiovasc Electrophysiol, Vol. 21, pp. 186‐192, February 2010)     

Assessing the Malignant Ventricular Arrhythmic Substrate in Patients With Brugada Syndrome

Background

Guidelines recommend the use of implanted cardioverter-defibrillators in patients with Brugada syndrome and induced ventricular tachyarrhythmias, but there is no evidence supporting it.

Study of the Extent of the Information of Cardiologists from São Paulo City,Brazil, Regarding a Low‐Prevalence Entity: Brugada Syndrome

Objective: To determine the degree of knowledge that cardiologists from São Paulo, Brazil, have regarding a low‐prevalent entity associated with a high rate of sudden death—Brugada syndrome. Methods: Two hundred forty‐four cardiologists were interviewed by an instrument divided in two parts: in the first, we recorded gender, age, and data related to academic profile. The second—answered only by the professionals that manifested having some degree of knowledge on the syndrome—had 28 questions that evaluated their knowledge. The answers were spontaneous and they did not have a chance to consult. We used uni‐ and multivariate analysis on the average percentage of right and wrong answers, and the influence of the academic profile. Results: The predominant gender was the male gender (61.1%), the average age was 44.32 ± 10.83 years, 40% with more than 20 years after obtaining their degree, 44% were educated in public institutions, 69% had a residency in cardiology, 20% had overseas practice, 12% had postdegree, 41% were linked to an educational institution, 24% with publication(s) in an indexed journal, 17.2% were authors of chapters in books, 2.5% had edited books, and 10% were linked to the Brazilian Society of Cardiac Arrhythmias. The average percentage of right answers was 45.7%. Conclusion: The sample studied revealed a little knowledge on the entity. A residency in cardiology was the factor of greater significance in the percentage of right answers. Other significant factors were the link of the interviewed person to an educational institution, or the Brazilian Society of Cardiac Arrhythmias, and having a specialist degree.     

Assessment of Microvolt T‐Wave Alternans in High‐Risk Patients with the Congenital Long‐QT Syndrome

Background: Microvolt T‐wave alternans (MTWA) has been used for arrhythmogenic risk stratification in cardiac disease conditions associated with increased risk of sudden cardiac death. Macroscopic T‐wave alternans has been observed in patients with congenital long‐QT syndrome (LQTS). The role of MTWA testing in patients with LQTS has not been established. Objective: To determine the diagnostic value of MTWA testing in high‐risk patients with LQTS. Methods and results: We assessed MTWA in 10 consecutive LQTS index patients who survived cardiac arrest or had documented torsade de pointes tachycardia and 6 first‐degree family members with congenital LQTS which had been genotyped in 13 of 16 subjects (7 index patients, 6 family members). No LQTS‐causing mutation was identified in 3 index patients with overt QT prolongation. MTWA was assessed during standardized bicycle exercise testing using the spectral method and yielded negative (n = 8) or indeterminate (n = 2) results in index patients, respectively. Similarly, all first‐degree family members tested MTWA negative except for one indeterminate result. Two genotype positive family members could not be tested (two children—4 and 9 years of age). Conclusion: In patients with congenital LQTS, free from structural heart disease and with a history of life‐threatening cardiac arrhythmias, assessment of MTWA does not yield diagnostic value. Hence, determination of MTWA in lower risk LQTS patients without spontaneous arrhythmic events is likely not to be useful for arrhythmia risk stratification.     

右室相关心律失常的临床和基础

冠心病或心肌病所致左室结构和电重构是室性心律失常和心源性猝死发生的主要原因.近20年来,右室相关心律失常已受到工作者重视,其好发于青壮年患者,易导致心源性猝死,基础研究尤其是分子遗传学的发展推动了人们对右室相关心律失常发病机制、诊断和预后的认识和理解.右室相关心律失常多见于致心律失常型右室心肌病、Brugada综合征、...     

Baseline fragmented QRS increases the risk of major arrhythmic events in Brugada syndrome: Systematic review and meta‐analysis

Background

Fragmented QRS reflects disturbances in the myocardium predisposing the heart to ventricular tachyarrhythmias. Recent studies suggest that fragmented QRS (fQRS) is associated with major arrhythmic events in Brugada syndrome. However, a systematic review and meta‐analysis of the literature has not been done. We assessed the association between fQRS and major arrhythmic events in Brugada syndrome by a systematic review of the literature and a meta‐analysis.

Methods

We comprehensively searched the databases of MEDLINE and EMBASE from inception to May 2017. Included studies were published prospective or retrospective cohort studies that compared major arrhythmic events (ventricular fibrillation, sustained ventricular tachycardia, sudden cardiac arrest, or sudden cardiac death) in Brugada syndrome with fQRS versus normal QRS. Data from each study were combined using the random‐effects, generic inverse variance method of DerSimonian and Laird to calculate risk ratios and 95% confidence intervals.

Results

Nine studies from January 2012 to May 2017 were included in this meta‐analysis involving 2,360 subjects with Brugada syndrome (550 fQRS and 1,810 non‐fQRS). Fragmented QRS was associated with major arrhythmic events (pooled risk ratio =3.36, 95% confidence interval: 2.09‐5.38, p < .001, I² = 50.9%) as well as fatal arrhythmia (pooled risk ratio =3.09, 95% confidence interval: 1.40‐6.86, p = .005, I² = 69.7%).

Conclusions

Baseline fQRS increased major arrhythmic events up to 3‐fold. Our study suggests that fQRS could be an important tool for risk assessment in patients with Brugada syndrome.

     

Increased Right Ventricular Repolarization Gradients Promote Arrhythmogenesis in a Murine Model of Brugada Syndrome

Repolarization Gradients in Brugada Syndrome. Introduction: Brugada syndrome (BrS) is associated with loss of Na⁺ channel function and increased risks of a ventricular tachycardia exacerbated by flecainide but reduced by quinidine. Previous studies in nongenetic models have implicated both altered conduction times and repolarization gradients in this arrhythmogenicity. We compared activation latencies and spatial differences in action potential recovery between different ventricular regions in a murine Scn5a+/? BrS model, and investigated the effect of flecainide and quinidine upon these. Methods and Results: Langendorff‐perfused wild‐type and Scn5a+/? hearts were subjected to regular pacing and a combination of programmed electrical stimulation techniques. Monophasic action potentials were recorded from the right (RV) and left ventricular (LV) epicardium and endocardium before and following flecainide (10 μM) or quinidine (5 μM) treatment, and activation latencies measured. Transmural repolarization gradients were then calculated from the difference between neighboring endocardial and epicardial action potential durations (APDs). Scn5a+/? hearts showed decreased RV epicardial APDs, accentuating RV, but not LV, transmural gradients. This correlated with increased arrhythmic tendencies compared with wild‐type. Flecainide increased RV transmural gradients, while quinidine decreased them, in line with their respective pro‐ and antiarrhythmic effects. In contrast, Scna5+/? hearts showed slowed conduction times in both RV and LV, exacerbated not only by flecainide but also by quinidine, in contrast to their differing effects on arrhythmogenesis. Conclusion: We use a murine genetic model of BrS to systematically analyze LV and RV action potential kinetics for the first time. This establishes a key role for accentuated transmural gradients, specifically in the RV, in its arrhythmogenicity. (J Cardiovasc Electrophysiol, Vol. 21, pp. 1153‐1159)     

Long‐term prognosis in patients with non‐type 1 Brugada electrocardiogram: Results from a large Japanese cohort of idiopathic ventricular fibrillation

BackgroundBrugada syndrome (BrS) is diagnosed in patients with ST‐segment elevation with spontaneous, drug‐induced, or fever‐induced type 1 morphology. Prognosis in type 2 or 3 Brugada electrocardiogram (Br‐ECG) patients remains unknown. The purpose of this study is to evaluate long‐term prognosis in non‐type 1 Br‐ECG patients in a large Japanese cohort of idiopathic ventricular fibrillation (The Japan Idiopathic Ventricular Fibrillation Study [J‐IVFS]).MethodsFrom 567 patients with Br‐ECG in J‐IVFS, a total of 28 consecutive non‐type 1 patients who underwent programmed electrical stimulation (PES) (median age: 58 years, all male, previous sustained ventricular tachyarrhythmias [VTs] 1, syncope 11, asymptomatic 16) were enrolled. Cardiac events (CEs: sudden cardiac death or sustained VT/ventricular fibrillation) during the follow‐up period were examined.ResultsDuring a median follow‐up of 136 months, four patients (14%) had CEs. None of patients with PES‐ have experienced CEs. There was no statistically significant clinical risk factor for the development of CEs. Using the Kaplan–Meier method, the event‐free rate significantly decreased in a group with all 3 risk factors (symptom, wide QRS complex in lead V₂, and positive PES) (p = .01).ConclusionsOur study revealed long‐term prognosis in patients with non‐type 1 Br‐ECG. The combination analysis of these risk factors may be useful for the risk stratification of CEs in non‐type 1 Br‐ECG patients. The present study suggests that the patients with all these parameters showed high risk for CEs and need to be carefully followed.