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.     

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.

     

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.     

Conduction Delay in Right Ventricle as a Marker for Identifying High‐Risk Patients With Brugada Syndrome

Conduction Delay as a Marker for Brugada Syndrome. Objectives: To evaluate the significance of conduction delay (CD) in the right ventricle (RV) in Brugada syndrome (BS) as a marker for risk stratification of sudden death. Methods: Twenty‐five patients with BS (7 with documented ventricular fibrillation (VF), 8 with syncope, and 10 without symptoms) and 10 control subjects were paced from the RV apex using 8 beats of drive pacing and a single extra‐stimulus. CDs in the right ventricular outflow tract (RVOT) (CD‐RV) and in the lateral left ventricle (L‐LV) (CD‐LV), and the local electrogram durations at a single extra‐stimulus in RVOT (D‐RV) and L‐LV (D‐LV) were calculated. We also evaluated changes in 12‐lead ECG parameters in 16 patients with BS after pilsicainide challenge test (Pilsicainide‐test). Results: Maximal CD‐RV and maximal D‐RV were significantly larger than maximal CD‐LV and maximal D‐LV in BS (26 ± 10 and 105 ± 15 vs 20 ± 6 and 92 ± 15 ms, P < 0.05, respectively). Maximal CD‐RV and maximal D‐RV in patients with documented VF were the largest among the 3 groups. There was a significant positive correlation between maximal CD‐RV or maximal D‐RV and changes in QRS duration in leads V2 and V5 and in S wave duration in lead II and V5 after Pilsicainide‐test (CD‐RV; r = 0.54, 0.51, 0.56, and 0.53: D‐RV; r = 0.55, 0.5, 0.57, and 0.53, P < 0.05, respectively). In control subjects, there were no significant differences. Conclusions: CD in RV was a useful marker for identifying high‐risk patients with BS. CD in the RV, especially in the RVOT epicardium, may be related to arrhythmias in BS. (J Cardiovasc Electrophysiol, Vol. 21, pp. 688‐696, June 2010)     

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.     

Two-year case collection of the Brugada syndrome electrocardiogram pattern at a large teaching hospital

BACKGROUND: Recommendations have recently emerged suggesting that the presence of the Brugada electrocardiographic (ECG) pattern in an otherwise asymptomatic individual warrants electrophysiologic testing for inducible ventricular arrhythmias. However, the prevalence of this pattern in the general population and its specificity for identifying those likely to develop the true Brugada syndrome are not known. HYPOTHESIS: The purpose of this study was to collect ECGs that displayed the Brugada pattern from unselected, noncardiac patients at a single institution to determine whether the implied prevalence in the literature may represent a significant underestimation of the true prevalence. METHODS: We performed a prospective case collection of Brugada-patterned ECGs over a 2-year time period from unselected, noncardiac patients at a large urban teaching hospital. RESULTS: Of approximately 12,000 noncardiac patients, 52 were found to have an ECG pattern fully consistent with the Brugada sign. CONCLUSIONS: The Brugada type ECG pattern is much more prevalent than previously reported when rigorously searched for in a prospective manner. More data are needed on its specificity for predicting future arrhythmic events in asymptomatic individuals before recommendations are made for extensive evaluation in this group.     

Novel pore mutation in SCN5A manifests as a spectrum of phenotypes ranging from atrial flutter, conduction disease, and Brugada syndrome to sudden cardiac death

OBJECTIVES: The purpose of this study was to determine the clinical and biophysical characteristics of a novel SCN5A mutation. BACKGROUND: Brugada syndrome and isolated cardiac conduction defect have been linked to SCN5A mutations. METHODS: Eleven members of a western European family underwent electrophysiologic investigations and mutation analysis of the SCN5A gene. Wild-type and mutant SCN5A channels were expressed in HEK293 cells, and whole cell currents were studied using patch clamp procedures. RESULTS: A novel mutation, R376H, in the first pore segment of SCN5A variably causes Brugada syndrome and/or conduction disease in a single family. Biophysical analysis demonstrated a significant current reduction for the mutant, a pathophysiologic profile consistent with Brugada syndrome and isolated cardiac conduction defect. Among 11 family members, 9 were carriers of the mutation. The proband's initial presentation was a saddleback Brugada ECG, atrial flutter, and diffuse conduction disturbances. He had no inducible ventricular arrhythmias but experienced sudden cardiac death. His brother was affected by atrial flutter and had a clear conduction disorder, but he did not display baseline or evocable ECG signs of Brugada syndrome. He received an implantable cardioverter-defibrillator that delivered one appropriate shock after 1 year of follow-up. The phenotype in the family members was highly variable and ranged from noninducible and inducible asymptomatic carriers of the mutations to isolated conduction disease and to symptomatic Brugada syndrome. CONCLUSIONS: We describe the functional characterization of a novel SCN5A pore mutation, R376H, with variable clinical expression in the same family. Differentiating between electrophysiologic entities (Brugada syndrome-isolated cardiac conduction defect) is more challenging. Recognition of factors modifying the clinical presentation may be important for clinical decision making.     

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.     

Risk stratification of individuals with the Brugada electrocardiogram: a meta-analysis

OBJECTIVES: We performed a meta-analysis of prognostic studies of patients with a Brugada ECG to assess predictors of events. BACKGROUND: The Brugada syndrome is an increasingly recognized cause of idiopathic ventricular fibrillation; however, there is wide variation in the prognosis of patients with the Brugada ECG. METHODS AND RESULTS: We retrieved 30 prospective studies of patients with the Brugada ECG, accumulating data on 1,545 patients. Summary estimates of the relative risk (RR) of events (sudden cardiac death [SCD], syncope, or internal defibrillator shock) for a variety of potential predictors were made using a random-effects model. The overall event rate at an average of 32 months follow-up was 10.0% (95% CI 8.5%, 11.5%). The RR of an event was increased (P < 0.001) among patients with a history of syncope or SCD (RR 3.24 [95% CI 2.13, 4.93]), men compared with women (RR 3.47 [95% CI 1.58, 7.63]), and patients with a spontaneous compared with sodium-channel blocker induced Type I Brugada ECG (RR 4.65 [95% CI 2.25, 9.58]). The RR of events was not significantly increased in patients with a family history of SCD (P = 0.97) or a mutation of the SCN5A gene (P = 0.18). The RR of events was also not significantly increased in patients inducible compared with noninducible by electrophysiologic study (EPS) (RR 1.88 [95% CI 0.62, 5.73], P = 0.27); however, there was significant heterogeneity of the studies included. CONCLUSIONS: Our findings suggest that a history of syncope or SCD, the presence of a spontaneous Type I Brugada ECG, and male gender predict a more malignant natural history. Our findings do not support the use of a family history of SCD, the presence of an SCN5A gene mutation, or EPS to guide the management of patients with a Brugada ECG.     

Brugada and Long QT‐3 Syndromes: Two Phenotypes of the Sodium Channel Disease

Brugada and long QT‐3 syndromes are two allelic diseases caused by different mutations in SCN5A gene inherited by an autosomal dominant pattern with variable penetrance. Both of these syndromes are ion channel diseases of the heart manifest on surface electrocardiogram by ST‐segment elevation in the right precordial leads and prolonged QT_c interval, respectively, with predilection for polymorphic ventricular tachycardia and sudden death, which may be the first manifestation of the disease. Brugada syndrome usually manifests during adulthood with male preponderance, whereas long QT3 syndrome usually manifests in teenage years, although it can also manifest in adulthood. Class IA and IC antiarrhythmic drugs increase ST‐segment elevation and predilection for polymorphic ventricular tachycardia and ventricular fibrillation in Brugada syndrome, whereas these agents shorten the repolarization and QT_c interval, and thus may be beneficial in long QT‐3 syndrome. Beta‐blockade also increases the ST‐segment elevation in Brugada syndrome but decreases the dispersion of repolarization in long QT‐3 syndrome. Mexiletine, a class IB sodium channel blocker decreases QT_c interval as well as dispersion of repolarization in long QT‐3 syndrome but has no effect on Brugada syndrome. The only effective treatment available at this time for Brugada syndrome is implantable cardioverter defibrillator, although repeated episodes of polymorphic ventricular tachycardia can be treated with isoproterenol. In symptomatic patients of long QT‐3 syndrome in whom the torsade de pointes is bradycardia‐dependent or pause‐dependent, a pacemaker could be used to avoid bradycardia and pauses and an implantable cardioverter defibrillator is indicated where arrhythmia is not controlled with pacemaker and beta‐blockade. However, the combination of new devices with pacemaker and cardioverter‐defibrillator capabilities appear promising in these patients warranting further study.     

Variability of the Diagnostic ECG Pattern in an ICD Patient Population with Brugada Syndrome

Introduction: The spontaneous presence of a coved-type ECG is considered as an important risk factor in Brugada syndrome. However, diagnosis making and risk stratification may be hampered by the dynamic nature of the ECG abnormalities. The objective of this study was to determine the variability and predictive value of the electrocardiogram in Brugada patients implanted with a cardioverter-defibrillator (ICD).
Methods and Results: We analyzed consecutive 12-lead ECGs from 89 ICD patients (44 ± 14 years, 69 males) with Brugada syndrome. A total of 1,161 ECGs were included for analysis (13 ± 8 ECGs/patient). Twenty-four percent of the ECGs/patient were coved-type I, 25% saddleback-type II or III, and 51% normal. Fifty-seven patients had a diagnostic coved-type ECG spontaneously (group A), 32 patients only after drug challenge (group B). In group A, 38% of the ECGs/patient were diagnostic, 25% saddleback-type, and 37% normal. Fifty-five group A patients (96%) had transient normalization and/or conversion to saddleback-type ECGs. During a mean follow-up of 48 ± 35 months, 16 patients (18%) experienced appropriate shocks. All patients with appropriate shocks had spontaneous diagnostic ECGs. They tended to have more coved-type ECGs (36 vs 22%, respectively, P = 0.05) than patients without appropriate shocks.
Conclusions: Analysis of serial ECG recordings in an ICD patient population shows that the Brugada-ECG pattern is highly variable over time. In patients with spontaneous coved-type ECG, only every third ECG is diagnostic and every third ECG normal. Patients with spontaneous coved-type ST-segment elevation have a high incidence of appropriate shocks. Spontaneous saddleback-type electrocardiograms are not helpful for risk stratification.     

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)     

Genotype‐Specific Risk Stratification and Management of Patients with Long QT Syndrome

Long QT syndrome (LQTS) is an inherited disorder associated with life‐threatening ventricular arrhythmias. An understanding of the relationship between the genotype and phenotype characteristics of LQTS can lead to improved risk stratification and management of this hereditary arrhythmogenic disorder. Risk stratification in LQTS relies on combined assessment of clinical, electrocardiographic, and mutations‐specific factors. Studies have shown that there are genotype‐specific risk factors for arrhythmic events including age, gender, resting heart rate, QT corrected for heart rate, prior syncope, the postpartum period, menopause, mutation location, type of mutation, the biophysical function of the mutation, and response to beta‐blockers. Importantly, genotype‐specific therapeutic options have been suggested. Lifestyle changes are recommended according to the prevalent trigger for cardiac events. Beta‐blockers confer greater benefit among patients with LQT1 with the greatest benefit among those with cytoplasmic loops mutations; specific beta‐blocker agents may provide greater protection than other agents in specific LQTS genotypes. Potassium supplementation and sex hormone–based therapy may protect patients with LQT2. Sodium channel blockers such as mexiletine, flecainide, and ranolazine could be treatment options in LQT3.