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Brugada Syndrome

The disease

Brugada syndrome (BS) is a disease characterized by characteristic ECG derangements in conjunction with an increased risk of sudden cardiac death. The first 8 patients were reported in 1992 by the brothers Pedro and Josep Brugada.1

The ECG abnormalities are right precordial ST-segment elevations and (discrete) signs of conduction slowing in all cardiac compartments. The typical clinical manifestation is nocturnal sudden death of males at the age of around.2,3 Hyperthermia may be a precipitating factor. In Southeast Asia and Japan, this entity is known by various names, reflecting its endemic nature in these regions.4

The gene(s)

At present, one causal gene has been identified. This gene (SCN5A) encodes the cardiac fast sodium channel and is located on the short arm of chromosome 3 (3p21-23).5 In approximately 30% of BS patients can SCN5A mutations be identified.3 It is believed that a second gene lies in close proximity of SCN5A, because linkage analysis in a large American family has indicated its locus here. However, the causative gene awaits identification.6 The mode of inheritance is autosomal dominant and involves inheritance of a mutation in one gene on one allele.

The protein

SCN5A encodes a protein that constitutes the fast sodium channel within the cell mebrane (a discussion of the function of ion channel is provided in the section on Long QT syndrome). SCN5A mutations that result in BS cause ‘loss of function’, while those that result in Long QT syndrome (type 3) cause ‘gain of function’.7 Loss of function means that the sodium channels conducts less net sodium current (see below).

The cell

Mutant sodium channels may not reach the cell membrane after their synthesis in the endoplasmic reticulum, resulting in fewer functional ion channels. Allternatively, mutant sodium channels may be integrated into the cell membrane, but conduct less net sodium current due to altered functional properties.7

The result of reduced sodium current is slower propagation of the cardiac action potential, i.e., reduced conduction velocity in all cardiac compartments.

The right precordial ST-segment elevation is explained by inhomogeneities in action potential shape and duration between epicardial en endocardial action potentials. Normally, the epicardial action potential has a ‘spike en dome’ morfology, i.e., a fast ‘spike’ is followed by transient repolarisation (phase 1) carried by the transient outward current, Ito. Upon activation of the L-type calcium current, the ‘dome’ ensues, i.e., the action potential plateau phase. This calcium current can only activate if the mebrane potential during phase 1 repolarisation does not become more negative than –30 mV.

However, reduction in sodium current allows the transient outward current to predominate and drive the membrane potential during phase 1 to more negative values than –30 mV. Because the transient outward current is most strongly expressed in right ventricular myocytes, this mechanism is particularly relevant in right epicardial layers.  Here, repolarization inhomogeneity ensues, with short action potentials in epicardium and normal action potentials in endocardium, giving rise to electrotonic current passing from endocardium to epicardium during phases 2 and 3 of the cardiac action potential. Surface electrodes (leads V1 and V2) record this current as ST-segment elevation. An alternative explanation for these ECG characteristics is progressive (severe) local conduction slowing in the right ventricular outflow tract.

Particular sodium channel mutations may cause reduced function during phase 0 (‘loss of function’) and increased function during the repolarisation phase (‘gain of function’). The clinical manifestation here is a combination of BS and Long QT syndrome. The first report of such a family came from the Netherlands.8  BS associated conduction disturbances are more severe with more severe loss of sodium channel function. In general, conduction slowing is most prominent in those BS forms that are caused by sodium channel mutations.9

The population

The prevalence of BS is estimated at 1:1.000 in Southeast Asia and Japan, and much lower in Western populations. BS has been reported worldwide. Also, there is an increasing number of case reports of drug-induced ST-segment changes (see list of drugs to be avoided). This group of drugs include cocaine, tricyclic antidepressants and class 1 antiarrhytmic drugs. 

The latter group of drugs is used to unmask the ECG-pattern in individuals suspected of being afflicted with BS (e.g., after cardiac arrest or syncope) or in relatives of BS patients (see below).

Diagnosis

In BS, DNA-diagnosis reveals a SCN5A mutation in 30% of patients at most.3 This proportion is probably larger when conduction slowing is also present.9

We believe that cardiological analysis aimed at BS should be performed in resuscitated patients with no clear substrate, in families with sudden cardiac death at a young age (with or without typical featyres, see above), and in patients who suffered from collaps with no clear explanation (particularly in those with a family history of sudden cardiac death). A conventional ECG may provide sufficient evidence; its diagnostic yield may be increased by recording right precordial ECGs from one intercostal space cranial from the conventional leads. In a recent consensus meeting, three types of ECG abnormalities have been recognized. Only type 1 (coved type) may be regarded as diagnostic.3 Type 2 (saddle back type) should raise the suspicion of BS. An example of a ‘classic’ BS ECG is found under this ECG-link.

A pharmacologic test with flecainide or ajmaline may be required.

The recommended protocol is found under this protocol-link.

Until recently, an ICD was regarded the only reliable treatment of BS. Recently, evidence has emerged to suggest that quinidine may be effective.10 For resuscitated and symptomatic patients, ICD therapy is still considered the therapy of choice. The best course in asymptomatic patients is a matter of debate. In series of Brugada et al., arrhythmia inducibility during elektrophysiologic study was predictive of advertent ICD shocks or sudden death.11,12 However, Priori et al, and we have published disparate results, i.e., a much lower risk in asymptomatic patients and a lack of prognostic value of an elektrophysiologic study.13,14 At present, it is unknown how these disparities must be explained.

Literature

  1. Brugada P, Brugada J: Right bundle branch block, persistent ST segment elevation and sudden cardiac death: a distinct clinical and electrocardiographic syndrome: a multicenter report.  J Am Coll Cardiol  1992;20:1391-1396.
  2. Alings M, Wilde A: "Brugada" syndrome: clinical data and suggested pathophysiological mechanism [see comments]. Circulation 1999;99:666-673.
  3. Wilde AA, Antzelevitch C, Borggrefe M, et al: Proposed diagnostic criteria for the Brugada syndrome.  Eur Heart J 2002;23:1648-1654
  4. Vatta M, Dumaine R, Varghese G, et al: Genetic and biophysical basis of sudden unexplained nocturnal death syndrome (SUNDS), a disease allelic to Brugada syndrome.  Hum Mol Genet  2002;11:337-345.
  5. Chen Q, Kirsch GE, Zhang D, et al: Genetic basis and molecular mechanisms for idiopathic ventricular fibrillation. Nature 1998;392:293-296.
  6. Weiss R, Barmada MM, Nguyen T, et al: Clinical and molecular heterogeneity in the Brugada syndrome. A novel gene locus on chromosome 3.  Circulation 2002;105:707-713
  7. Tan HL, Bezzina CR, Smits JP, et al: Genetic control of sodium channel function.  Cardiovasc Res  2003;57:961-973
  8. Bezzina CR, Veldkamp MW, van den Berg MP, Postma AV, Rook MB, Viersma JW, van Langen IM, Tan-Sindhunata MB, Bink-Boelkens MThE, Van der Hout AH, Mannens MMAM, Wilde AAM. A single sodium channel mutation causing both long QT- and Brugada syndrome. Circ Res1999;85:1206-1213 1999.
  9. Smits JPP, Eckardt L, Probst V, Bezzina CR, Schott JJ, Remme CA, Haverkamp W,  Breithardt G, Escande D, schulze-Bahr E, le Marec H, Wilde AAM. Genotype-phenotype relationship in Brugada syndrome; Electrocardiographic features differentiate SCN5A-related patients from non SCN5A related patients.  J Am Coll Cardiol 40, 350-356, 2002.
  10. Belhassen B, Glick A, Viskin S. Efficacy of Quinidine in high risk patients with Brugada Syndrome. Circulation 2004;110:1731-1737.
  11. Brugada J, Brugada R, Antzelevitch C, et al. Long-term follow-up of individuals with the electrocardiographic pattern of right bundle-branch block and ST-segment elevation in precordial leads V(1) to V(3).  Circulation 2002;105:73-78
  12. Brugada P, Brugada R, Mont L, Rivero M, Geelen P, Brugada J. Natural history of Brugada syndrome: the prognostic value of programmed electrical stimulation of the heart. J Cardiovasc Electrophysiol 2003;14:455-457
  13. Priori SG, Napolitano C, Gasparini M, et al. Natural history of Brugada syndrome: insights for risk stratification and management.  Circulation 2002;105:1342-1347
  14. Eckardt L, Probst V, Smits JPP, Schulze-Bahr E, Wolpert C, Schimpf R, Wichter T, Boisseau P, Breithardt G, Borggrefe M, leMarec H, Bocker D, Wilde AAM. Long-term prognosis of individuals with right precordial ST-elevation. Brugada syndrome. Circulation 2005;111: 257-263

 
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