I. Brugada Syndrome: What every physician needs to know.
Brugada syndrome is characterized by a coved-type ST segment elevation in the right precordial leads of the electrocardiogram (ECG) and isassociated with a relatively high risk of sudden cardiac death due to ventricular fibrillation (VF) without major structural heart disease.
The syndrome was first reported in 1992 as a distinct clinical entity associated with sudden cardiac death. Since its introduction, the Brugada syndrome has attracted great interest because of its high incidence in many parts of the world and its association with high risk of sudden death in young and otherwise healthy adults, and less frequently in infants and children.
II. Diagnostic Confirmation: Are you sure your patient has Brugada Syndrome?
Three types of ST segment elevation patterns in the right precordial leads of the ECG are recognized (Figure 1). Type 1 or coved-type ST segment elevation, characterized by a J point elevation of ≥2 mm (0.2 mV) followed by a negative or isoelectric T wave, is diagnostic of Brugada syndrome.
Type 2 has a saddleback appearance with a J point elevation of >2 mm followed by a trough displaying ≥1 mm ST elevation with either a positive or biphasic T wave and type-3 ST segment elevation has a saddleback appearance with an J point elevation of <1 mm. These three patterns may be observed spontaneously in serial ECGs from the same patient or after the administration of sodium channel blockers.
The Brugada syndrome is definitively diagnosed when a type 1 ST segment elevation is observed in one or more right precordial leads (V1 to V3) in the presence or absence of a sodium channel blocking agent, and in conjunction with one of the following: documented VF, polymorphic ventricular tachycardia VT), a family history of sudden cardiac death at <45 years old, coved-type ECGs in family members, inducibility of VT with programmed electrical stimulation, syncope, or nocturnal agonal respiration.
The ECG manifestations of Brugada syndrome are often dynamic or concealed, and may be unmasked or modulated by sodium channel blockers, such as ajmaline, flecainide, pilsicainide or procainamide, a febrile state, vagotonic agents, alpha-adrenergic agonists, beta-adrenergic blockers, tricyclic or tetracyclic antidepressants, a combination of glucose and insulin, hypokalemia and hyperkalemia, hypercalcemia, and alcohol and cocaine toxicity. Because of the dynamic nature of the ECG phenotype, ECGs should be recorded several times on different days.
A comprehensive and up-to-date list of agents to avoid in Brugada syndrome can be found at www.BrugadaDrugs.org
Placement of the right precordial leads (V1 and V2) in a superior position (up to the second intercostal space) can increase the sensitivity of the ECG for detecting the Brugada phenotype in some patients,both in the presence or absence of a sodium block drug challenge.
Differential diagnosis of the Brugada syndrome must be approached with care since ST segment elevation is associated with a wide variety of conditions. Confounding factor(s) that could account for the ECG abnormality need to be carefully excluded. Exaggerated ST segment elevation is sometimes observed for a brief period following DC cardioversion, and this must be factored in when evaluating a patient following defibrillation.
A. Part I: Pattern Recognition:
Clinical Characteristics Part I: Symptoms
Symptoms associated with Brugada syndrome include:
VF or aborted sudden cardiac death (at night >> day time)
Noctural agonal respiration
These symptoms often occur during rest or sleep (Figure 2), during a febrile state or with vagotonic conditions, but rarely during exercise. The syndrome typically first manifests during adulthood, with a mean age of sudden death of 41 ±15 years (Figure 3). Many subjects displaying a type 1 ECG are asymptomatic.
B. History Part 2: Prevalence:
Clinical Characteristics Part 2: Prevalence
Prevalence of Brugada-ECG
Because the ECG is so dynamic and often concealed, it is difficult to estimate the true prevalence of the disease in the general population. Worldwide prevalence of Brugada syndrome is estimated to be 1 in 10,000, but is much higher in Asian and Southeast Asian countries, reaching 5 to 10 in 10,000 and much lower in some Eastern European countries like Denmark, with an estimated prevalence of 1.1 in 100,000.
The frequency is higher (≥5 per 10,000) in Southeast Asia, especially Thailand and the Philippines where the Brugada syndrome is considered to be the major cause of sudden death in young individuals. In Japan, type-1 ST segment elevation diagnostic of Brugada syndrome was observed in 12 per 10,000 inhabitants, whereas type-2 and type-3 ECG were much more prevalent, appearing in 58 per 10,000 inhabitants.
In parts of Asia (e.g., the Philippines, Thailand, Japan), Brugada syndrome seems to be the most common cause of natural death in men younger than 50 years old. It is known as Lai Tai (Thailand), Bangungot (Philippines), and Pokkuri (Japan). The reason for this higher prevalence in Asia is not yet fully understood but may be in part related to an Asian-specific sequence in the promoter region of SCN5A.
The clinical phenotype is 8 to 10 times more prevalent in males than in females in patients with Brugada syndrome. The transient outward current (Ito), responsible for phase-1 of the action potential and theaction potential notch in the right ventricular epicardium, is thought to play a key role in the manifestation of the accentuated J wave or ST segment elevation in Brugada syndrome. The presence of a more prominent Ito in males may contribute to the male predominance of the syndrome. Higher testosterone levels associated with lower visceral fat may have a significant role in the Brugada phenotype and male predominance in Brugada syndrome.
C. History Part 3: Diagnoses that can mimic the Brugada syndrome
Clinical Characteristics Part 3: Competing diagnoses that can mimic Brugada Syndrome
Arrhythmogenic right ventricular cardiomyopathy (ARVC)
A subpopulation of arrhythmogenic right ventricular cardiomyopathy (ARVC) patients have been found to display an ST segment elevation and polymorphic VT characteristic of Brugada syndrome. The ECG patterns of the two syndromes may be similar with respect to the presence of right bundle branch block (RBBB), fragmented QRS, and positive late potentials.
However, imaging techniques such as ECG, angiography, magnetic resonance imaging (MRI), and radionuclide scintigraphy show no evidence of overt structural heart disease in patients with Brugada syndrome, whereas ARVC patients characteristically display morphologic and functional changes (e.g., global dilatation, bulgings/aneurysms, and wall motion abnormalities) particularly in the RV.
Two-dimensional echocardiography focusing on the right ventricular function and wall motion abnormalities is one of the ways used to screen for ARVC. The recent finding that plakophilin mutations associated with ARVC can lead to a reduction in sodium channel current may provide the link between ARVC and BrS.
Ventricular arrhythmias in ARVC are most commonly monomorphic VT (left bundle branch block (LBBB) type), often precipitated by catecholamines or exercise. In contrast, ST segment elevation and arrhythmias in patients with Brugada syndrome are enhanced by vagotonic agents or beta-adrenergic blockers, and polymorphic VT occurs most commonly during rest or sleep. In contrast, the ECG abnormalities in ARVC are not dynamic and display a constant T-wave inversion, epsilon waves, and, in progressively later stages, reduction of the R wave amplitude.
Patients with a type 1 Brugada ECG and an episode of syncope may be diagnosed as having symptomatic Brugada syndrome; however, not all episodes of syncope may be due to ventricular tachyarrhythmia. A positive head-up tilt (HUT) test can help identify neurally mediated episodes of syncope. Nearly 35% of patients with Brugada ECG show vasovagal responses during the HUT test, suggesting that some Brugada patients have impaired autonomic nervous system balance, which may relate to their syncopal episodes.
A number of confounding factors that could account for the ECG abnormality or syncope should be carefully excluded, including atypical right bundle branch block, left ventricular hypertrophy, early repolarization, acute pericarditis, acute myocardial ischemia or infarction, pulmonary embolism, Prinzmetal angina, dissecting aortic aneurysm, various central and autonomic nervous system abnormalities, Duchenne muscular dystrophy, thiamine deficiency, hyperkalemia, hypercalcemia, arrhythmogenic right ventricular dysplasia/cardiomyopathy, pectus excavatum, hypothermia, and mechanical compression of the right ventricular outflow tract (RVOT) as occurs in mediastinal tumor or hemopericardium.
D. Physical Examination Findings.
There are no specific physical examination findings in the Brugada syndrome because of no structural heart disease and normal LV function.
E. What diagnostic tests should be performed?
The following tests are helpful in diagnosing Brugada syndrome:
ECG (including superior position of the right precordial leads: V1-V2).
To rule out ischemic heart disease and ARVC: Imaging (Exercise radioisotope (RI) scintigraphy using Thallium-201 or Technetium-99m, computed tomography (CT), MRI, or echography).
Sodium channel block challenge using ajmaline, flecainide, pilsicainide, or procainamide to unmask the Brugada ECG ST-segment elevation.
Exercise test; ST elevation normalizes during the peak exercise but further elevated soon after the recovery periods.
Signal averaged ECG designed to look for late potentials.
Holter monitoring ECG to detect ST segment elevation, spontaneous premature ventricular contrast (PVC), AF.
1. What laboratory studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?
Electrophysiologic study (EPS): inducibility of VT/VF
There is currently a great deal of controversy as to whether electrophysiologic (EP) testing is helpful in risk stratification of patients with Brugada syndrome.
Several large registry studies agree that Brugada syndrome patients at higher risk for the development of subsequent events are those presenting with a spontaneous type 1 ST segment elevation and/or those with a previous VT/VF or sudden cardiac death (SCD). The registries also agree that EPS inducibility is greatest among patients with previous VT/VF or syncope. Approximately 1/3 of asymptomatic patients are inducible.
Brugada et al have consistently shown that a positive EP test is associated with a much higher level of risk for development of VT/VF whether or not a type 1 ST segment elevation was spontaneously present or whether or not the patient was symptomatic.
In sharp contrast, others have reported that inducibility of VT/VF in asymptomatic patients is not associated with risk. Gehi et al reported the results of a meta-analysis of 30 prospective studies that included 1,545 patients with a Brugada ECG to assess predictors of events. The meta-analysis suggested 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.
The findings, however, did not support the use of a family history of SCD, the presence of a SCN5A gene mutation, or electrophysiologic study to guide the management of patients with a Brugada ECG. A similar meta-analysis by Paul et al also concluded that the inducibility of VF in asymptomatic patients is of no prognostic value.
Two large multicenter studies from Japan and from Europe (the France, Italy, Netherlands, Germany (FINGER) study) were recently published. The Japanese study is important because it included only probands (330 probands of whom 154 were asymptomatic) and the FINGER study is important because the number of asymptomatic patients included (n = 654) was significantly larger than the number of asymptomatic patients included in the last published series by Brugada (n = 263) and even larger than the 457 patients compiled from 15 studies in the meta-analysis by Paul.
Both studies used an EPS protocol that included two sites of stimulation (right ventricular apex [RVA] and outflow tract [RVOT]) with up to three extrastimuli, with the FINGER protocol using a minimal coupling interval of 200 msec, whereas the Japanese investigators limited the coupling interval of the extrastimulus only by ventricular refractoriness. This difference in the EPS protocol probably explains why the percentage of asymptomatic individuals with inducible VF was higher in the Japanese study than in FINGER (57% vs. 37%). The latter figure is very close to the 34% inducibility rate reported by Brugada among their asymptomatic individuals.
Makimoto and Shimizu recently reported that inducibility of VF was of prognostic value only when VF was induced with one or two extrastimuli and suggested that triple extrastimulation should be avoided to prevent false-positive results. These results, however, were not confirmed by the prospective PRELUDE study; the induction of VF was of no prognostic value regardless of the protocol of extrastimulation used.
Inheritance of Brugada syndrome occurs via an autosomal dominant mode of transmission. The first gene to be linked to Brugada syndrome is SCN5A, the gene that encodes the alpha subunit of the cardiac sodium channel. Over 300 mutations in SCN5A have been linked to BrS.
BrS has in recent years been linked to mutations in 18 other genes (Table I). SCN5A mutations have been identified in 10% to 28% of BrS probands among 9 international sites surveyed.
SCN5A mutations associated with Brugada syndrome cause a loss-of-function, an effect also associated with: familial atrial fibrillation, progressive cardiac conduction defect, sick sinus syndrome, early repolarization syndrome, dilated cardiomyopathy, and sudden infant death syndrome. Hu et al. (PUBMED:24998131) recently presented evidence that mutations in SCN10A encoding the neuronal sodium channel, Nav1.8, account for 16.7% of Brugada syndrome probands.
Calcium channel genes mutations, including those in CACNA1C (Cav1.2), CACNB2b (Cavß2b), and CACNA2D1 (Cava2δ1) are found in approximately 6-12% of probands. Mutations in glycerol-3-phosphate dehydrogenase 1-like enzyme gene (GPD1L), SCN1B (β1-subunit of Na channel), KCNE3 (MiRP2), SCN3B (β3-subunit of Na channel), KCNJ8 (Kir6.1), and KCND3 (Ky4.3), RANGRF (MOG1), SLMAP, ABCC9 (SUR2A), SCN2B (Navß2), PKP2 (Plakophillin-2), FGF12 (FHAF1), HEY2, and SEMA3A (Semaphorin) are more rare.
A genotype can be identified in greater than 50% of BrS probands.
Interpretation of genetic study
It is generally accepted that identification of specific mutations may not be very helpful in formulating a diagnosis or providing a prognosis. Recent data suggest that nonsense mutations leading to truncation of the Nav1.5 protein responsible for the sodium channel is associated with a more severe phenotype than missense mutations of the SCN5A gene. Mutations have been reported throughout the SCN5A gene and no hotspots have been identified.
Genetic testing is therefore of limited prognostic value, but is recommended for support of the clinical diagnosis, for early detection of relatives at potential risk, and particularly for the purpose of advancing research and our understanding of genotype-phenotype correlation.
2. What imaging studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?
MRI and echocardiography are useful for differential diagnosis of ARVC.
Implantable cardioverter-defibrillator (ICD): Only clearly established therapy for prevention of sudden death in the Brugada syndrome (Table II).
1. Symptomatic Brugada syndrome patients
Symptomatic patients displaying the type 1 Brugada ECG (either spontaneously or after sodium channel blockade) who present with aborted sudden death should receive an ICD.
Patients with spontaneous type-1 ECG and history of syncope are recommend for ICD.
2. Asymptomatic Brugada patients:
In patients with spontaneous type-1 ECG who are asymptomatic, close follow-up is recommended
Quinidine (900 mg/day) can be useful in this setting.
Haissaguerre et al reported a focal radiofrequency ablation at the RV endocardium for the ventricular premature beats that trigger VT/VF in Brugada syndrome was potentially valuable in controlling arrhythmogenesis. More recently, Nademanee et al reported that catheter ablation of the anterior aspect of the RVOT epicardium results in normalization of the Brugada ECG pattern and prevents VT/VF in patients with Brugada syndrome. However, the study included a small number of cases and the long-term efficacy is unknown. It is considered a Class IIb indication by the recent HRS/EHRA/APHRS Expert Consensus Statement on the Diagnosis and Management of Patients with Inherited Primary Arrhythmia Syndromes (Table II).
Antiarrhythmic agents such as amiodarone and beta-blockers have been shown to be ineffective. Class Ic antiarrhythmic drugs (eg, flecainide and propafenone) and the class Ia agent procainamide are contraindicated. The class Ia agent quinidine exerts a therapeutic action due to its Ito-blocking properties.
Because the presence of a prominent transient outward current (Ito) in the RV is at the heart of the mechanism underlying Brugada syndrome, any agent that inhibits this current may be protective. Quinidine is the only agent on the market with significant Ito-blocking properties.
A number of reports have demonstrated the effectiveness of quinidine in normalizing ST segment elevation in patients with Brugada syndrome, although clinical trials designed to assess the efficacy of this agent are limited.
In cases in which quinidine is contraindicated, cilostazol can be used to suppress arrhythmogenesis in Brugada syndrome. Cilostazol is a phosphodiesterase III inhibitor that acts by boosting calcium channel current. Experimental studies have recently shown another phosphodiesterase III inhibitor, milrinone, to be more potent than cilostazol.
A. Immediate management.
VF or cardiac arrest; CPR and DC
If no ICD is implanted, educating the patient and his or her family members and coworkers about basic cardiopulmonary resuscitation (CPR) and use of an automatic external defibrillator (AED) is important.
Isoproterenol, beta-adrenergic receptor agonist, infusion increases inward Ca current and restores the action potential dome, thus normalizing ST elevation and suppressing “phase-2 reentry” and polymorphic VT or VF. This drug is very effective in Brugada patients with frequent VF episodes referred to as “VF or electrical storm.” The phosphodiesterase inhibitor, cilostazol, is also useful in this setting.
B. Physical Examination Tips to Guide Management.
No evidence-based recommendations are available relative to physical examination parameters to monitor response to therapy.
C. Laboratory Tests to Monitor Response To, and Adjustments in, Management
No laboratory test is now useful for monitoring the risk of SCD in the Brugada syndrome. In the case of quinidine therapy, quinidine plasma levels and ST segment elevation could be monitored to assess drug compliance.
D. Long-term management.
ECG and its dynamic changes are the best way to monitor long-term management.
Appearance of the following should raise a red flag:
Accentuation of coved-type (type I) ST elevation
Beat-by-beat T wave alternans
Short-coupled spontaneous PVC arising from the right ventricle
Increased duration or fragmentation of QRS and late potentials
J point elevation in inferior and/or lateral leads in addition to anterior leads
E. Common Pitfalls and Side-Effects of Management
ICD-mediated VF storm: isoproterenol infusion normalizes the ST elevation and suppress frequent VF development and cilostazol and quinidine can help reduce appropriate shock long term.
Inappropriate ICD shocks may occur in cases of sinus tachycardia, atrial fibrillation, or atrial flutter. Severe diarrhea often accompanies high-dose quinidine. This may necessitate reduction of dose or termination of drug.
IV. Management with Co-Morbidities
Fever should be avoided in patients with BrS. A list of drugs to be avoided can be found at www.BrugadaDrugs.org
What's the Evidence for specific management and treatment recommendations?
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- I. Brugada Syndrome: What every physician needs to know.
- II. Diagnostic Confirmation: Are you sure your patient has Brugada Syndrome?
- A. Part I: Pattern Recognition:
- B. History Part 2: Prevalence:
- C. History Part 3: Diagnoses that can mimic the Brugada syndrome
- D. Physical Examination Findings.
- E. What diagnostic tests should be performed?
- 1. What laboratory studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?
- 2. What imaging studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?
- III. Management.
- A. Immediate management.
- B. Physical Examination Tips to Guide Management.
- C. Laboratory Tests to Monitor Response To, and Adjustments in, Management
- D. Long-term management.
- E. Common Pitfalls and Side-Effects of Management
- IV. Management with Co-Morbidities
- What's the Evidence for specific management and treatment recommendations?