Brugada syndrome

Creation date: December 2002

Definition
In 1992 Brugada et al.(1) described a novel clinical entity, which  is now frequently called "Brugada syndrome" (BrS) (BrS;OMIM 601144). BrS or “Idiopathic Ventricular Fibrillation” as improperly defined by some authors (2), is an inherited form of cardiac arrhythmia, presenting with a typical electrocardiographic pattern of ST segment elevation in leads V1 to V3, and incomplete or complete right bundle branch block (1.)  In approximately 20% of cases,  the underlying cause of BrS is a genetic defect in the SCN5A gene, which encodes the sodium channel controlling the depolarization phase of the cardiac action potential.
Since no cardiac structural abnormalities are usually found in BrS patients, the disease may be defined as a “pure” electrical abnormality of myocardial cells within an otherwise normal heart. Syncope, typically occurring at rest or during sleep is a common presentation of BrS (3), and it is caused by fast polymorphic ventricular tachycardia. When tachycardia does not terminate spontaneously or if resuscitation maneuvers are not promptly carried out, it may degenerate into ventricular fibrillation and lead to sudden death.

Genetic bases and pathophysiology
To date, only one BrS-related gene is known. Mutations in the cardiac sodium channel gene, SCN5A, on chromosome 3p21-23, have been identified for the first time by Chen in 1998 (4). Since then, an increasing number of mutations have been reported (for a list of published mutations see: http://pc4.fsm.it:81/cardmoc). Interestingly, SCN5A mutations may also cause the LQT3 variant of Long QT syndrome (5) (another form of inherited arrhythmias and sudden death in the normal heart; OMIM 603830). Thus, BrS and LQT3 are allelic disorders. In vitro expression of BrS and LQT3 mutant channels show substantial differences as to the cellular phenotypes, with BrS mutations causing a loss of sodium channel function, whereas LQT3 defects are associated with, an excess of sodium inward current (4). However, overlapping phenotypes between BrS and LQT3 have been reported in some families, both at clinical and cellular level (6-8). Finally, a third phenotype, the progressive cardiac conduction defect, or Lenegre syndrome (OMIM: 113900) (9-12), has been associated with SCN5A mutations
Overall, SCN5A mutations account for only a minority of BrS. In molecular screening of this gene a mutation is identified in only 20-25% of families (13). Few data are currently available concerning the BrS genes that remain to be identified. Only an additional locus on chromosome 3p22-25 (14), has been recently identified by linkage analysis in a single large family. However the corresponding gene has not been found despite the screening of several candidates in this chromosomal region.

Prevalence of BrS
Due to the limited amount of information on the genetic bases of BrS, the disease prevalence among the general population cannot be firmly assessed. The current prevalence estimate is 1-5/10.000 in the Western countries. Higher frequency (1/2500) may be found in eastern countries, especially Thailand, where BrS is considered the major cause of sudden death in young individuals. In these countries BrS is often defined as SUNDS, Sudden Unexplained Nocturnal Death Syndrome (15). SCN5A mutations have been identified in patients diagnosed with this disorder, thus confirming that SUNDS and BrS are the same clinical entity (16).

Role of molecular diagnosis in Brs
The molecular screening of the SCN5A gene is usually performed by SSCP (Single Strand Conformational Polymorphism) or DHPLC (Denaturating High Performance Liquid Chromatography), and DNA sequencing. using genomic DNA, which has been extracted from 3-5 ml of peripheral blood lymphocytes.
Establishing a diagnosis of BrS in an asymptomatic individual on the basis of the electrocardiographic phenotype involves an important part of responsibility for the clinician, as it implies informing a young “healthy” subject about the risks of sudden death and transmission to the offspring. Molecular genetics may help the cardiologist in defining diagnosis in difficult cases, and  should be of particular interest in conditions such as BrS that may present incomplete penetrance (17,18). In this case, the detection of a genetic defect within a family may represents the only tool for the identification of all subjects that may be at risk of developing cardiac events and transmitting the disease to the offspring.  This information has a direct relevant impact for clinical management. Nonetheless, genetic testing of BrS is currently limited as only a minority of patients has been successfully genotyped. Therefore a negative result does not exclude BrS diagnosis.

Diagnosis and clinical features
BrS is characterized by a typical electrocardiogram (ECG ) pattern of incomplete or complete right bundle branch block and ST segment elevation (> 2mm) in leads V1 through V3. In their initial report on 8 patients, Brugada et al. also emphasized the lack of structural cardiac abnormalities and the high recurrence rate of life threatening cardiac events (1). BrS manifests with syncope and cardiac arrest, typically occurring in the third and fourth decade of life, and usually at rest or during sleep. Data on 63 patients collected after a mean follow up of 34±32 months (Brugada et al., 1998), showed that 34% of previously symptomatic (syncope and/or cardiac arrest) patients relapsed, while a first cardiac event occurred in 27% of the asymptomatic individuals. These results highlighted the need for an aggressive therapeutic strategy in all patients with BrS and, since no pharmacological treatment of proven efficacy was (and still is) available, it led to the use of ICD (Implantable Cardioverter Defibrillator) implant in several young asymptomatic individuals. However, a different picture is emerging from more recent epidemiological surveys. In 2000, Priori et al found that the recurrence incidence of a cardiac arrest in symptomatic patients was 16%, while none of the asymptomatic individuals at enrollment had a cardiac event after a three years follow up (19). The low incidence of events in asymptomatic patients has been subsequently confirmed by Atarashi et al. (20)(1.5%), Takenaka et al. (21), (0%), and Brugada et al. (22), who reported an incidence of 1.5%, 0% and 8%, respectively. These studies suggest that the majority of BrS patients are likely to remain asymptomatic and are at relatively low risk of relapsing. Nonetheless, life-threatening events may seldom occur, thus prompting the need for an effective risk stratification algorithm.

Clinical management and risk stratification
Being affected by a genetically determined disease, BrS patients are exposed to a life-long risk of events. However, the disease is usually characterized by very long intervals (years) of complete well-being between the cardiac events. The implant of an ICD may remarkably impair quality of life.  Therefore, it  is of outmost importance to identify precisely, among BrS patients, the subgroup of individuals for whom this aggressive therapeutic approach is mandatory, due to their high risk of cardiac events.
Programmed electrical stimulation (PES) has been initially considered as a rational approach to risk stratification in BrS (23), however these data have not been subsequently confirmed  (13,19,24). Low reproducibility of PES in these patients (25) and lack of uniformity of stimulation protocols may be confounding factors. Furthermore, PES inducibility could also vary depending on the same “transitory” factors, like autonomic tone (26-28), thus being intrinsically poorly related with the life-long risk of cardiac events.
Therefore, alternative guidelines for risk stratification are strongly needed to optimize the clinical management of the affected patients. A recent study (13) analyzed the natural history of BrS in a large cohort of patients by means of multivariate survivorship analyses. Interestingly, BrS patients presenting with history of syncope and a spontaneously abnormal ECG (i.e. independently from the provocative test with intravenous sodium channel blockers) showed a significantly increased risk of cardiac arrest (Heart Rate HR 6.1). In these patients, the implant of an ICD may be indicated. The presence of spontaneous ST segment elevation alone was associated with a moderate risk of life-threatening events (HR 2.1), while the history of syncope alone was not an independent predicting factor of the disease outcome. These latter patients (i.e patients presenting with either history of syncope or a spontaneously abnormal ECG), as well as carriers  of the silent gene, belong to the group at low risk. On the basis of these findings, these patients do not appear to require treatment and may be reassured.
These results still await confirmation in prospective surveys; nonetheless, they indicate that a risk stratification based on simple clinical parameters is feasible, and may significantly improve the clinical management of BrS.
 

Differential diagnosis
ST segment elevation in leads V1-V3 may be found during acute anterior myocardial infarction. In such instances, angina pectoris and myocardial necrosis markers (CK, CPK-MB, Troponin I, LDH) are common findings and the differential diagnosis is easily established. However, even in the absence of these latter signs, myocardial ischemia should be carefully excluded.
ST segment elevation in right precordial leads and right bundle branch block has rarely been reported in Arrhythmogenic Right Ventricular Dysplasia (ARVD) (29). Therefore morphological analysis of the right ventricle should be carried out by echocardiography and NMR in order to exclude the presence of a structural cardiac abnormality.
 

References
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 2.  Priori SG. Foretelling the future in Brugada syndrome: do we have the crystal ball? J Cardiovasc Electrophysiol 2001; 12:1008-1009.
 3.  Wilde AA, Priori SG. Brugada syndrome and sudden death. Eur Heart J 2000; 21:1483.
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 5.  Wang Q, Shen J, Splawski I, Atkinson D, Li Z, Robinson JL, Moss AJ, Towbin JA, Keating MT. SCN5A mutations associated with an inherited cardiac arrhythmia, long QT syndrome. Cell 1995; 80:805-811.
 6.  Rivolta I, Abriel H, Tateyama M, Liu H, Memmi M, Vardas P,  Napolitano C, Priori SG, Kass RS. Inherited brugada and LQT-3 syndrome mutations of a single residue of the cardiac sodium channel confer distinct channel and clinical phenotypes. J Biol Chem 2001.
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 17. Priori SG, Napolitano C, Grillo M. Concealed arrhythmogenic syndromes: the hidden substrate of idiopathic ventricular fibrillation? Cardiovasc Res 2001; 50:218-223.
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 21.  Takenaka S, Kusano KF, Hisamatsu K, Nagase S, Nakamura K, Morita H, Matsubara H, Emori T, Ohe T. Relatively benign clinical course in asymptomatic patients with brugada-type electrocardiogram without family history of sudden death. J Cardiovasc Electrophysiol 2001; 12:2-6.
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 23.  Brugada P, Geelen P, Brugada R, Mont L , Brugada J. Prognostic value of electrophysiologic investigations in Brugada syndrome. J Cardiovasc Electrophysiol 2001; 12:1004-1007.
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 28.  Tanaka H, Kinoshita O, Uchikawa S, Kasai H, Nakamura M, Izawa A, Yokoseki O, Kitabayashi H, Takahashi W, Yazaki Y, Watanabe N, Imamura H, Kubo K. Successful prevention of recurrent ventricular fibrillation by intravenous isoproterenol in a patient with Brugada syndrome. Pacing Clin Electrophysiol 2001; 24 :1293-1294.
 29.  Corrado D, Nava A, Buja G, Martini B, Fasoli G, Oselladore L, Turrini P, Thiene G. Familial cardiomyopathy underlies syndrome of right bundle branch block, ST segment elevation and sudden death. J Am Coll Cardiol 1996; 27:443-448.