Brugada syndrome (BrS; OMIM 601144), or "Idiopathic ventricular fibrillation" as defined by some authors 1, is an autosomal dominant form of cardiac arrhythmia, presenting with a typical electrocardiographic (ECG) pattern of ST segment elevation in leads V1 to V3, and incomplete or complete right bundle branch block 2. Syncope, typically occurring at rest or during sleep, is a common presentation of BrS 3, and it is caused by fast polymorphic ventricular tachycardia. In some cases, tachycardia does not terminate spontaneously. It may degenerate into ventricular fibrillation and lead to sudden death.

The incomplete information concerning the genetic bases of BrS prevents a prevalence assessment among the general population. The current estimate is based upon ECG surveys among healthy subjects. These studies have been mostly done in the Asian population and only one has been carried out among Caucasians. The suggested prevalence ranges from 5/1,000 (Caucasians) to 14/1,000 (Japanese) 456. The higher prevalence of the BrS ECG pattern in far eastern countries has been recently confirmed in a large clinical study 7 (see paragraph Genetic bases and pathophysiology). In this region the disease is thought to represent a frequent cause of sudden death among young individuals and is named as: lai-tai, pokkuri, sudden unexplained death syndrome, sudden unexplained nocturnal death syndrome.

BrS manifests with syncope and cardiac arrest, typically occurring in the third and fourth decade of life, and usually at rest or during sleep. In 1998 Brugada et al. presented data on 63 patients in whom, after a mean follow up of 34 ± 32 months, 34% of previously symptomatic (syncope and/or cardiac arrest) patients had recurrence, while a first cardiac event occurred in 27% of the asymptomatic individuals. These results called 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 implantable cardioverter defibrillator (ICD) implants in several young asymptomatic individuals. However, a different picture is emerging from more recent epidemiological surveys. In 2000, Priori et al. showed an incidence of 16% for the recurrence of a cardiac arrest in symptomatic patients, while none of the asymptomatic individuals at enrolment had a cardiac event after three years of follow up 8. The low incidence of events at follow up in the subgroup of patients who are asymptomatic at diagnosis has been subsequently confirmed by several authors 79101112. It is important to stress the concept that this figure might be biased by the fact that it is currently not known whether a Brugada-like ECG always indicates the presence of the disease or whether it is a non-specific finding in some cases.

At the present time, only one BrS-related gene is known. Mutations in the cardiac sodium channel gene, SCN5A, on chromosome 3p21-23, were identified by Chen in 1998 14. Interestingly, BrS is not the only phenotype linked to mutations in this gene. Known allelic disorders are: the LQT3 variant of Long QT syndrome 15 (OMIM 603830), the progressive cardiac conduction defect (PFHB, OMIM 113900) and the Sick sinus syndrome (SSS1; OMIM 608567) 161718. In vitro expression of mutant SCN5A proteins showed that BrS, PFHB and SSS1 are characterized by a loss of sodium channel function, whereas in LQT3 there is an excess of sodium inward current 14. To add to the complexity of the SCN5A-related phenotypes, overlapping syndromes have been also described in association with some specific SCN5A mutations that may cause the coexistence of LQT3 and BrS 192021 or LQT3, BrS and PFHB in the same individuals 1722.

Unfortunately, SCN5A mutations account for approximately 20% of BrS cases 23. Only one additional locus (on chromosome 3p22-25 24) has been identified by linkage analysis in a single large family, but, despite screening of several candidates in the region, the corresponding gene has not been found.

A possible explanation of the race-specific differential prevalence of the BrS phenotype has been suggested by Bezzina et al. 25. Resequencing of the SCN5A promoter region allowed these authors to identify an Asian-specific haplotype: a six single nucleotide polymorphism (SNP) block not present among Caucasians, that is associated with lower transcription activity of the gene. The haplotype has an impressively high frequency of 0.22 in the Asian population and it is clinically associated with a reduced intraventricular conduction velocity. Thus, a constitutively reduced inward sodium current (I_Na) may be present and favor the high rate of occurrence of the BrS ECG pattern in far east countries.

SCN5A has a 6.048 Kb coding sequence spanning 28 exons. As of January 2006, approximately 160 SCN5A mutations had been reported33, and approximately 65% of them are associated with a BrS phenotype, but no specific clustering within the coding region is demonstrable. No hot spots have been reported.

As a result of this genetic heterogeneity, the screening for known mutations is not feasible. Therefore, most of the molecular analysis laboratories usually screen the SCN5A coding region by performing single strand conformational polymorphism (SSCP) or denaturing high performance liquid chromatography (DHPLC), and DNA sequencing.

Establishing a diagnosis of BrS in an asymptomatic individual based on the ECG phenotype is a big responsibility for the clinician, as it implies informing a young "healthy" subject that they are at risk of sudden death and are at risk of generating affected offspring.

Molecular genetics may free the cardiologist from the burden of defining the diagnosis in difficult cases. This may be particularly important in conditions such as BrS that may present incomplete penetrance 3435. In this case, the detection of a genetic defect within a family may represent the only tool for the identification of all those who are at risk of cardiac events and transmitting the disease to their offspring. This information has a direct impact on clinical management. Obviously, the limited yield of genetic testing in BrS does not allow diagnosis to be excluded in negative patients.

Furthermore, with the exception of a tendency for a more severe conduction delay among patients carrying a mutation in SCN5A 36, clinical manifestations do not differ between genotyped and not-genotyped patients, thus making genotyping an inappropriate method for risk stratification 23.

ST segment elevation in leads V1-V3 may be found during acute anterior myocardial infarction. In such instances, angina pectoris and myocardial necrosis markers – creatine kinase (CK), creatine phosphokinase-MB (CPK-MB), Troponin I and lactate dehydrogenase (LDH) – are common findings and the differential diagnosis is easily established. Furthermore, there are several other disorders in which, although not constantly observed, ECG abnormalities resembling BrS may develop: arrhythmogenic right ventricular dysplasia/cardiomyopathy, Prinzmetal's variant angina, acute pericarditis/myocarditis, Friedreich's ataxia, Duchenne muscular dystrophy, hypercalcemia/vitamin D intoxication, hyperkalemia, acute pulmonary thromboembolism, acute cholecystitis, transthoracic cardioversion, myotonic dystrophy type 1, Chagas disease, hypothermia, vomiting. Obviously, all of the above mentioned disorders should be considered in patients with suspected BrS.

Besides specific diseases, before BrS diagnosis can be definitely established, it is important to exclude drug-related causes of BrS-like ECG patterns. All antiarrhythmic drugs with a sodium channel blocking effect, especially class Ia and Ic drugs, must be avoided (asymptomatic BrS patients are often diagnosed incidentally after administration of one of these compounds to treat supraventricular arrhythmias). Other drugs reported to be potentially pro-arrhythmic in Brugada syndrome patients are:

• Local anesthetics (non antiarrhythmic): bupivacaine 37;

• Cocaine38;

• Alpha adrenergic agonists: methoxamine, noradrenaline 39;

• Beta-blockers: propranolol 39;

• Potassium channel activators: pinacidil 40;

• Parasympathetic agonists: acetylcholine 41;

• Ergot alkaloids: ergonovine 41;

• Tricyclic antidepressants 42;

• Opioid analgesics: propoxyphene 43;

• Lithium 44;

• First-generation antihistamines: dimenhydrinate 45;

• Propofol 46.

Being affected by a genetically determined disease, BrS patients are exposed to a life-long risk of events, but the disease is usually characterized by very long (years) intervals of complete well-being between the cardiac events. Therefore, the implant of an ICD may remarkably impair quality of life and it is of utmost importance to precisely identify the subgroup of individuals in whom this aggressive therapeutic approach is mandatory because of their high-risk of cardiac events.

Treatment guidelines for Brugada syndrome clearly emphasize that patients who have already experienced a cardiac arrest should receive an ICD 47. However, these patients are in the minority, since most BrS patients are either asymptomatic or are referred with one or few syncopal spells in their clinical history. Risk stratification in these latter subgroups requires careful evaluation of the clinical presentation. Observational studies 2348. on the natural history of BrS in large cohorts concordantly suggest that patients with a history of syncope plus a spontaneously abnormal ECG (i.e. independent of the provocative test with intravenous sodium channel blockers) have an approximately 6-fold higher risk of cardiac events (syncope and cardiac arrest) as compared with asymptomatic patients and patients in whom the diagnosis is established only after a provocative test. The presence of only spontaneous ST segment elevation was associated with a moderate risk of life-threatening events (Hazard Ratio 2.1) 49, while a history of syncope alone was not an independent predictor of outcome. These patients, as well as the silent gene carriers, belong to a low risk group. Although rare instances of life-threatening events may occur among this latter category, the most effective strategies for their identification remain to be established and the wide-spread use of ICD is not indicated, since device-related complications outweigh the benefits.

The role of programmed electrical stimulation (PES) as a risk stratification tool in Brugada syndrome is still a matter of debate. While some authors support it 1350, others have provided experimental evidence suggesting a poor predictive value and low reproducibility 2351 Several factors have been advocated to explain this discrepancy 52 and two prospective studies (that are likely to provide a definitive answer to this issue) are now ongoing, one in the USA and one in Italy.