Brugada syndrome

Brugada syndrome (BrS) is, along with the long QT syndrome, one of the most frequently diagnosed inherited arrhythmogenic syndromes. It is a primary electric heart disease manifested by ST segment elevations in the right precordial leads. BrS is responsible for more than 4% of all sudden deaths and at least 20% of sudden deaths in patients with structurally normal hearts. In 1998, the first mutations in the gene coding the structure of the cardiac sodium channel were identified in patients with BrS. Nowadays, several hundreds of mutations in at least 8 genes have been already associated with BrS. Functional consequences of many of these mutations on the molecular level have been revealed and, in some of them, even the consequences for the overall cardiac electrophysiology were suggested thank to the mathematical modelling. However, despite intense study of many scientific teams and formulation of several hypotheses, arrhythmogenic mechanisms in BrS have not been fully elucidated yet. This review provides a contemporary view of clinical symptoms, pathophysiology, diagnostics and therapy in BrS.     

A New Approach for the Comparison of Conduction Abnormality between Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia and Brugada Syndrome

Background: Right ventricular outflow tract ventricular tachycardia (RVOT‐VT), arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/ARVD), and Brugada syndrome (BrS) were characterized by arrhythmias originating in the right ventricle, and the pathophysiologic mechanism underlying these arrhythmias has not been fully understood. Methods: This study consisted of 40 subjects, including 20 patients with RVOT‐VT, 10 patients with BrS, and 10 ARVD patients. The parameters on the signal‐averaged electrocardiography (ECG) and the frequency components recorded from the wavelet‐transformed ECG were compared between the three groups. Late potentials were positive in none of the patients with RVOT‐VT, seven of the patients with BrS, and all of ARVD patients. Results: In Brugada and ARVD patients, the power of high‐frequency components (80–150 Hz) was developed to a greater extent than in RVOT‐VT patients. In the power analysis of the high‐frequency components between BrS and ARVD, the frequency showing the greatest power was significantly higher in ARVD patients than that in BrS patients (145.4 ± 27.9 Hz vs 81.7 ± 19.9 Hz, P < 0.01). Conclusions: High‐frequency components were developed in ARVD and BrS, but not in RVOT‐VT. The frequency levels showing high power by wavelet analysis obviously differ between ARVD and BrS. Wavelet analysis may provide new insight into unsolved mechanisms in arrhythmogenic right heart disease. Ann Noninvasive Electrocardiol 2011;16(3):263–269     

Dormant conduction in the right ventricular outflow tract unmasked by adenosine in a patient with Brugada syndrome

Recent data of electrophysiological mapping in patients with Brugada syndrome (BrS) suggest that the presence of an abnormal arrhythmogenic substrate in the epicardial right ventricular outflow tract is responsible for ST-segment elevation and ventricular fibrillation (VF). Complete elimination of the epicardial abnormal potentials normalizes Brugada-pattern electrocardiogram and suppresses VF recurrence. We herein report the first case of BrS in which an injection of adenosine unmasked dormant conduction in the epicardial RVOT after the disappearance of the epicardial potentials.     

What is new in Brugada syndrome?

The Brugada syndrome (BrS) and the long QT syndrome are the most frequently diagnosed genetically-conditioned arrhythmogenic syndromes. It is a primary disorder of electric cardiac activity which is demonstrated by elevation of the ST segment in the right precordial leads connected to an increased risk of sudden death in patients without a structural damage of the heart. In this article, an overview of genetic heterogeneity, pathophysiology, ECG diagnostics and therapy possibilities are discussed, including the innovations of the recent years. A brief case report of a patient presenting with syncope and ST segment elevation is described.     

Coexisting early repolarization pattern and Brugada syndrome: recognition of potentially overlapping entities

The Brugada type 1 electrocardiographic (ECG) pattern and the early repolarization pattern (ERP) are 2 ECG patterns characterized by the appearance of J waves. Although Brugada type 1 ECG pattern in the context of the Brugada syndrome (BrS) is well known for predisposing to life-threatening ventricular arrhythmias, it has only recently come to light that ERP, which was previously believed to be benign, may also be a marker for arrhythmogenic potential. ERP and BrS share many remarkable cellular, ionic, and ECG similarities and behave comparably in terms of their response to heart rate, pharmacologic agents, and neuromodulation. The extent to which ERP and BrS may overlap remains unclear. Here, we present an illustrated case of a symptomatic patient whose ECG signature evolved spontaneously from ERP alone to ERP with a concomitant Brugada type 1 ECG pattern over a short number of days. This case lends further strength to the notion that these 2 ECG patterns may be more closely related than had been initially thought.     

A case of anomalous aortic origin of coronary artery associated with a coved-type electrocardiogram

Brugada syndrome (BrS) is a sudden cardiac death syndrome characterized by a coved-type electrocardiogram (ECG). Different disorders, such as ischemia, can emulate a Brugada-pattern ECG (Brugada phenocopy). We report herein, the first case of surgical epicardial electrophysiological mapping in a successfully resuscitated patient with an anomalous aortic origin of the coronary artery (AAOCA) associated with a coved-type ECG. It was debatable whether the coved-type ECG and the abnormal arrhythmogenic substrate in the epicardial right ventricular outflow tract were derived from BrS or from repetitive ischemia due to AAOCA; however, the epicardial electrophysiological mapping helped in deciding the treatment strategy.     

Catheter ablation for electrical storm in Brugada syndrome: Results of substrate based ablation

BackgroundBrugada syndrome (BrS) is known to cause malignant ventricular arrhythmia (VA) and sudden cardiac death (SCD). Patients with implantable cardioverter defibrillator (ICD) may experience recurrent shocks from ICD. Recent reports indicate that radiofrequency ablation (RFA) in BrS is feasible, and effective. Catheter ablation of premature ventricular complexes (PVCs) triggering VA and substrate modification of right ventricular outflow tract (RVOT) has been described.Methods and resultsFive patients (4 males, age-23 to 32 years) with BrS and electrical storm (ES) despite being on isoprenaline infusion and cilostazol (phosphodiestrase-3 inhibitor) underwent 3 dimensional electroanatomic mapping and RFA. Ventricular fibrillation was easily inducible in two patients. Voltage map of right ventricle was created in sinus rhythm in all patients. Substrate modification of RVOT was performed endocardially in one patient, both endocardial and epicardial in three and only epicardially in one patient. Brugada pattern gradually resolved over one week in all patients post procedure. These patients completed follow up of median 40 months (1.5–70). One patient had inappropriate shock due to atrial fibrillation, one had an episode of VF and appropriate shock 24 months after the RFA. The remaining four patients had no device therapy or VA in device log on follow up.ConclusionAbnormal myocardial substrate is observed in RVOT among patients with BrS. Substrate modification in these patients may abolish Brugada pattern on the ECG and prevents spontaneous VAs on long term follow up.     

Ionic and cellular mechanisms underlying the development of acquired Brugada syndrome in patients treated with antidepressants

Antidepressant‐Induced Brugada Syndrome. Introduction: Tricyclic antidepressants are known to induce cardiac arrhythmias at therapeutic or supratherapeutic doses. The tricyclic antidepressant, amitriptyline, is reported to induce ST segment elevation in the right precordial electrocardiogram (ECG) leads, thus unmasking Brugada syndrome (BrS). The mechanism by which antidepressants induce the BrS phenotype and associated sudden death is not well established. Methods and Results: Action potentials (AP) were simultaneously recorded from epicardial and endocardial sites of isolated coronary‐perfused canine right ventricular wedge preparations, together with a transmural pseudo‐ECG. Amitriptyline alone (0.2 μM–1 mM) failed to induce a BrS phenotype. NS5806 (8 μM), a transient outward potassium channel current (I_to) agonist, was used to produce an outward shift of current mimicking a genetic predisposition to BrS. In the presence of NS5806, a therapeutic concentration of amitriptyline (0.2 μM) accentuated the epicardial AP notch leading to ST‐segment elevation of the ECG. All‐or‐none repolarization at some epicardial sites but not others gave rise to phase‐2‐reentry and polymorphic ventricular tachycardia (VT) in 6 of 9 preparations. Isoproterenol (100 nM) or quinidine (10 μM) reversed the effects of amitriptyline aborting phase 2 reentry and VT (4/4). Using voltage‐clamp techniques applied to isolated canine ventricular myocytes, 0.2 μM amitriptyline was shown to produce use‐dependent inhibition of sodium channel current (I_Na), without significantly affecting I_to (n = 5). Conclusions: Our data suggest that amitriptyline‐induced inhibition of I_Na unmasks the Brugada ECG phenotype and facilitates development of an arrhythmogenic substrate only in the setting of a genetic predisposition by creating repolarization heterogeneities that give rise to phase 2 reentry and VT.     

Risk stratification in patients with Brugada syndrome

Brugada syndrome (BrS), one of the most frequently diagnosed inherited arrhythmogenic syndromes, is responsible for more than 4% of all sudden deaths and at least 20% of sudden deaths in patients with structurally normal hearts. The sudden death is often the first symptom of BrS and appears most often already during the fourth decade of life of BrS patients. Implantation of cardioverter--defibrillator was proved to be the only effective treatment, i.e. prevention of the sudden death, in BrS. Thus, it is uniquely determined to be used in case of symptomatic BrS patients. On the contrary, the individual risk of life-threatening arrhythmias has to be thoroughly considered in case of asymptomatic BrS patients due to substantial side effects of implantation of cardioverter-defibrillator. This review first provides a summary of factors recommended for the risk stratification in BrS patients in 2005 including their support or rejection in the following studies. Subsequently, we focused on the most important risk factors newly suggested after 2005.     

Differences in 12-lead electrocardiogram between symptomatic and asymptomatic Brugada syndrome patients

Introduction: Brugada syndrome (BrS) is an inherited disorder that predisposes some subjects to sudden cardiac death (SCD). It is not well established which BrS patients are at risk of severe arrhythmias. Our aim was to study whether standard 12-lead electrocardiogram (ECG) would give useful information for this purpose.
Methods: This study included 200 BrS probands (142 male, 62%; mean age 42 ± 16 years). Symptoms related to BrS were defined as syncope, documented ventricular tachyarrhythmia, or SCD. We determined PR, QRS, QTc, T_peak, and T_end interval from leads II and V₂ and QRS from lead V₅, R'/S ratio from lead aVR (aVR sign), QRS axis, and J-point elevation amplitude from right precordial leads from the baseline ECGs.
Results: Sixty-six subjects (33%) had experienced symptoms related to BrS. The only significant difference between the symptomatic and asymptomatic BrS subjects was the QRS duration measured from lead II or lead V₂, for example, the mean QRS in V₂ was 115 ± 26 ms in symptomatic versus 104 ± 19 ms in asymptomatic patients (P < 0.001). The optimized cut-off point of V₂ QRS ≥120 ms gave an odds ratio (OR) of 2.5 (95% CI: 1.4–4.6, P = 0.003) for being symptomatic. In a multivariate analysis adjusted with gender, age, and SCN5A mutation, the OR was 2.6 (95% CI: 1.4–4.8, P = 0.004).
Conclusion: Prolonged QRS duration, measured from standard 12-lead ECG, is associated with symptoms and could serve as a simple noninvasive risk marker of vulnerability to life-threatening ventricular arrhythmias in BrS.     

Desmosomes and the sodium channel complex: Implications for arrhythmogenic cardiomyopathy and Brugada syndrome

Mutations in proteins of the desmosome are associated with arrhythmogenic cardiomyopathy (AC; also referred to as “ARVC” or “ARVD”). Life-threatening ventricular arrhythmias often occur in the concealed phase of the disease before the onset of structural changes. Among the various potential mechanisms for arrhythmogenesis in AC, in this article, we concentrate on the relation between desmosomes and sodium channel function. We review evidence indicating that (1) loss of desmosomal integrity (including mutations or loss of expression of plakophilin-2; PKP2) leads to reduced sodium current (I_Na), (2) the PKP2–I_Na relation could be partly consequent to the fact that PKP2 facilitates proper trafficking of proteins to the intercalated disc, and (3) PKP2 mutations can be present in patients diagnosed with Brugada syndrome (BrS), thus supporting the previously proposed notion that AC and BrS are not two completely separate entities, but “bookends” in a continuum of variable sodium current deficiency and structural disease.     

Avoiding sports-related sudden cardiac death in children with congenital channelopathy

For the past few years, children affected by an inherited channelopathy have been counseled to avoid (recreational) sports activities and all competitive sports so as to prevent exercise-induced arrhythmia and sudden cardiac death. An increased understanding of the pathophysiological mechanisms, better anti-arrhythmic strategies, and, in particular, more epidemiological data on exercise-induced arrhythmia in active athletes with channelopathies have changed the universal recommendation of “no sports,” leading to revised, less strict, and more differentiated guidelines (published by the American Heart Association/American College of Cardiology in 2015). In this review, we outline the disease- and genotype-specific mechanisms of exercise-induced arrhythmia; give an overview of trigger-, symptom-, and genotype-dependent guidance in sports activities for children with long QT syndrome (LQTS), Brugada syndrome (BrS), catecholaminergic polymorphic ventricular tachycardia (CPVT), or short QT syndrome (SQTS); and highlight the novelties in the current guidelines compared with previous versions. While it is still recommended for patients with LQT1 and CPVT (even when asymptomatic) and all symptomatic LQTS patients (independent of genotype) to avoid any competitive and high-intensity sports, other LQTS patients successfully treated with anti-arrhythmic therapies and phenotype-negative genotype-positive patients may be allowed to perform sports at different activity levels – provided they undergo regular, sophisticated evaluations to detect any changes in arrhythmogenic risk.

     

Electroanatomic Mapping of the Endocardium

The electroanatomic mapping system Carto((R)) with its combination of anatomic and electrophysiologic information has substantially improved our understanding of arrhythmia mechanisms and substrates in patients with ventricular tachycardia (VT) and structural heart disease. Identification of the individual arrhythmogenic substrate and successful ablation guided by the combination of sinus rhythm voltage mapping and conventional electrophysiologic techniques like pace and activation/entrainment mapping are best described for patients with recurrent VT in remote myocardial infarction. In about 75-90% of the patients, the target VT can be ablated with acute success and the patients remain free of any VT recurrence in up to 75%. First results of electroanatomically guided ablation in patients with arrhythmogenic right ventricular dysplasia are promising. Data on ablation of VT in other structural heart diseases are very limited, since the arrhythmogenic substrate is very diffuse, e. g., in dilated cardiomyopathy, or there are only small patient numbers, e. g., for cardiac sarcoidosis or monomorphic VT after repair of congenital heart disease. In this article, the current status of electroanatomically guided endocardial mapping and ablation of VT in patients with structural heart disease is described.     

Electrocardiographic characteristics of premature ventricular contractions in subjects with type 1 pattern of Brugada syndrome

Background

The ECG characteristics of premature ventricular contractions (PVCs) in subjects with Brugada syndrome (BrS) phenotype were investigated.

Methods and results

A total of 96 patients with type 1 ECG pattern of BrS were screened for PVCs. The study population consisted of 10 male individuals (mean age 41.9 ± 5.6 years) with spontaneous (n = 2) or drug-induced (n = 8) type 1 ECG phenotype of BrS and PVCs. Twenty patients (11 males, age 44.6 ± 15.1 years) with idiopathic right ventricular outflow tract (RVOT) PVCs (LBBB/inferior axis morphology with a negative QRS complex in lead aVL) successfully ablated from an endocardial site were also included in the study, and served as comparative controls. Six subjects with BrS phenotype (five during drug challenge) displayed PVCs with LBBB/inferior axis morphology and negative QRS complex in aVL lead which indicates an RVOT origin. The ECG characteristics of PVCs with LBBB/inferior axis in subjects with BrS and idiopathic RVOT arrhythmia were subsequently compared. QRS duration in inferior (p = 0.001) and right precordial leads (p < 0.001) was significantly longer in subjects with BrS phenotype. The RS interval in lead V2 was also significantly prolonged in individuals with BrS phenotype (p = 0.016). Subjects with BrS phenotype exhibited an increased intrinsicoid deflection time measured in right precordial leads compared to those with idiopathic RVOT PVCs (46.0 ± 7.6 vs. 27.2 ± 9.5 ms, p < 0.001). Finally, a pseudo-delta wave in precordial leads was more commonly observed in subjects with BrS ECG pattern (p = 0.029).

Conclusions

PVCs in BrS usually originate from the RVOT and display specific ECG characteristics that might be indicative of an epicardial origin. The prolonged interval criteria may be related to a localized epicardial conduction delay.     

Epsilon‐Like Electrocardiographic Pattern in a Patient with Brugada Syndrome

Both Brugada syndrome (BrS) and arrhythmogenic right ventricle dysplasia/cardiomyopathy (ARVD/C) can cause repolarization abnormalities in right precordial leads and predispose to sudden cardiac death (SCD) due to ventricular arrhythmias. Although there is controversy over whether BrS is distinct from ARVD/C, it is believed that both are different clinical entities with respect to both the clinical presentation and the genetic predisposition. The coexistence of these two relatively rare clinical entities is also reported, but, some hypothesized that it is more possible that disease of the right ventricular muscle might accentuate the Brugada electrocardiographic pattern. In clinic practice, there may be cases where the dividing line is not so clear. We report a 33‐year‐old male presenting with recurrent syncope, who has a peculiar pattern of coved‐type ST‐segment elevation (ST‐SE) with epsilon‐like wave in right precordial leads.     

Illicit drugs and cardiac arrhythmias in athletes.

The current management of athletes with cardiac arrhythmias has become complicated by the widespread use of illicit drugs, which can be arrhythmogenic. The World Anti-Doping Agency annually updates a list of prohibited substances and methods banned by the International Olympic Committee that includes different classes of substances namely, anabolic androgenic steroids, hormones and related substances, beta2-agonists, diuretics, stimulants, narcotics, cannabinoids, glucocorticosteroids, alcohol, beta-blockers and others. Almost all illicit drugs may cause, through a direct or indirect arrhythmogenic effect, a wide range of cardiac arrhythmias (focal or reentry type, supraventricular and/or ventricular) that can even be lethal and which are frequently sport activity related. A large use of illicit drugs has been documented in competitive athletes, but the arrhythmogenic effect of specific substances is not precisely known. Precipitation of cardiac arrhythmias, particularly in the presence of a latent electrophysiologic substrate including some inherited cardiomyopathies, at risk of sudden death or due to long-term consumption of the substances, should raise the suspicion that illicit drugs may be a possible cause and lead cardiologists to investigate carefully this relationship and appropriately prevent the clinical consequences.     

J wave syndromes: Molecular and cellular mechanisms

An early repolarization (ER) pattern in the ECG, consisting of J point elevation, distinct J wave with or without ST segment elevation or slurring of the terminal part of the QRS, was long considered a benign electrocardiographic manifestation. Experimental studies a dozen years ago suggested that an ER is not always benign, but may be associated with malignant arrhythmias. Validation of this hypothesis derives from recent case–control and population-based studies showing that an ER pattern in inferior or infero-lateral leads is associated with increased risk for life-threatening arrhythmias, termed early repolarization syndrome (ERS). Because accentuated J waves characterize both Brugada syndrome (BrS) and ERS, these syndromes have been grouped under the heading of J wave syndromes. BrS and ERS appear to share common ECG characteristics, clinical outcomes, risk factors as well as a common arrhythmic platform related to amplification of I_to-mediated J waves. However, they differ with respect to the magnitude and lead location of abnormal J waves and can be considered to represent a continuous spectrum of phenotypic expression. Recent studies support the hypothesis that BrS and ERS are caused by a preferential accentuation of the AP notch in right or left ventricular epicardium, respectively, and that this repolarization defect is accentuated by cholinergic agonists. Quinidine, cilostazol and isoproterenol exert ameliorative effects by reversing these repolarization abnormalities. Identifying subjects truly at risk is the challenge ahead. Our goal here is to review the clinical and genetic aspects as well as the cellular and molecular mechanisms underlying the J wave syndromes.     

Hydroquinidine therapy in Brugada syndrome

OBJECTIVES: We sought to assess hydroquinidine (HQ) efficacy in selected patients with Brugada syndrome (BrS). BACKGROUND: Management of asymptomatic patients with BrS and inducible arrhythmias remains a key issue. Effectiveness of class Ia antiarrhythmic drugs, which inhibit the potassium transient outward current of the action potential, has been suggested in BrS. METHODS: From a cohort of 106 BrS patients, we studied 35 who received HQ (32 men; mean age 48 +/- 11 years). Patients had asymptomatic BrS and inducible arrhythmia (n = 31) or multiple appropriate shocks from an implantable cardioverter-defibrillator (ICD) (n = 4). Asymptomatic patients with inducible arrhythmia underwent electrophysiologic (EP)-guided therapy. When ventricular tachycardia (VT)/ventricular fibrillation (VF) inducibility was not prevented, or in case of HQ intolerance, an ICD was placed. RESULTS: Hydroquinidine prevented VT/VF inducibility in 76% of asymptomatic patients who underwent EP-guided therapy. Syncope occurred in two of the 21 patients who received long-term (17 +/- 13 months) HQ therapy (1 syncope associated with QT interval prolongation and 1 unexplained syncope associated with probable noncompliance). In asymptomatic patients who received an ICD (n = 10), one appropriate shock occurred during a follow-up period of 13 +/- 8 months. In patients with multiple ICD shocks, HQ prevented VT/VF recurrence in all cases during a mean follow-up of 14 +/- 8 months. CONCLUSIONS: Hydroquinidine therapy prevented VT/VF inducibility in 76% of asymptomatic patients with BrS and inducible arrhythmia, as well as VT/VF recurrence in all BrS patients with multiple ICD shocks. These preliminary data suggest that preventive treatment by HQ may be an alternative strategy to ICD placement in asymptomatic patients with BrS and inducible arrhythmia.     

Predicting Sudden Cardiac Death in Genetic Heart Disease

Genetic heart diseases are common causes of sudden cardiac death (SCD) in the young and are typically divided into inherited cardiomyopathies and primary electrical heart diseases. Cardiomyopathies associated with risk of SCD include hypertrophic cardiomyopathy (HCM) and arrhythmogenic cardiomyopathy (ACM). The latter includes arrhythmogenic right ventricular cardiomyopathy (ARVC) as well as ACM primarily affecting the left ventricle, such as lamin cardiomyopathy. Primary electrical diseases more commonly seen in clinical practice include Brugada syndrome (BrS) and long QT syndrome (LQTS). Risk stratification of SCD is a central component of the management of patients with these genetic heart diseases. Numerous risk factors have been identified with variable degrees of scientific evidence. More recently, risk prediction models have been developed to estimate the absolute risk of sustained arrhythmias and SCD, to support clinicians and patients in decision making regarding prophylactic implantable cardioverter-defibrillators (ICDs). This paper provides a practical review of the current literature on risk stratification in ARVC and other ACMs, HCM, BrS, and LQTS, and summarises current recommendations for ICD use.     

Brugada syndrome: A general cardiologist's perspective

Brugada syndrome (BrS) is one of the commonest inherited primary arrhythmia syndromes typically presenting with arrhythmic syncope or sudden cardiac death (SCD) due to polymorphic ventricular tachycardia and ventricular fibrillation precipitated by vagotonia or fever in apparently healthy adults, less frequently in children. The prevalence of the syndrome (0.01%–0.3%) varies among regions and ethnicities, being the highest in Southeast Asia.BrS is diagnosed by the “coved type” ST-segment elevation ≥ 2 mm followed by a negative T-wave in ≥ 1 of the right precordial leads V₁–V₂. The typical electrocardiogram in BrS is often concealed by fluctuations between normal, non-diagnostic and diagnostic ST-segment pattern in the same patient, thus hindering the diagnosis.Presently, the majority of BrS patients is incidentally diagnosed, and may remain asymptomatic for their lifetime. However, BrS is responsible for 4–12% of all SCDs and for ~ 20% of SCDs in patients with structurally normal hearts. Arrhythmic risk is the highest in SCD survivors and in patients with spontaneous BrS electrocardiogram and arrhythmic syncope, but risk stratification for SCD in asymptomatic subjects has not yet been fully defined. Recent achievements have expanded our understanding of the genetics and electrophysiological mechanisms underlying BrS, while radiofrequency catheter ablation may be an effective new approach to treat ventricular tachyarrhythmias in BrS patients with arrhythmic storms.The present review summarizes our contemporary understanding and recent advances in the inheritance, pathophysiology, clinical assessment and treatment of BrS patients.