Brugada syndrome

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Brugada syndrome
Synonyms Sudden unexplained nocturnal death syndrome, bangungut[1]
Brugada EKG Schema.jpg
(A) Normal electrocardiogram of the precordial leads V1-3, (B) changes in Brugada syndrome (type B)
Specialty Cardiology
Symptoms Passing out, sudden cardiac death[2]
Usual onset Adulthood[2]
Causes Genetics, certain medication[2]
Risk factors Family history, Asian descent, male[2][1]
Diagnostic method Electrocardiogram (ECG), genetic testing[2][3]
Similar conditions Romano-Ward syndrome, arrhythmogenic cardiomyopathy, Duchenne muscular dystrophy[3]
Treatment Watchful waiting, implantable cardioverter defibrillator (ICD)[4][3]
Frequency 5 per 10,000[1]
Deaths 8% of sudden cardiac death[2]

Brugada syndrome (BrS) is a genetic condition that results in abnormal electrical activity within the heart, increasing the risk of sudden cardiac death.[2] Those affected may have episodes of passing out.[2] Typically this occurs when a person is at rest.[1]

It is often inherited from a person's parent with about a quarter of people having a family history.[2] Some cases may be due to a new mutation or certain medications.[1] The abnormal heart rhythms can be triggered by a fever or increased vagal tone.[2] Diagnosis is typically by electrocardiogram (ECG), however, the abnormalities may not be consistently present.[2]

Treatment may be with an implantable cardioverter defibrillator (ICD).[4] Isoproterenol may be used in those who are acutely unstable.[3] In those without symptoms the risk of death is much lower, and how to treat this group is unclear.[4][3] Testing people's family members may be recommended.[3]

Between 1 and 30 per 10,000 people are affected.[2] Onset of symptoms is usually in adulthood.[2] It is more common in people of Asian descent.[2] Males are more commonly affected than females.[1] It is named after the Spanish cardiologists Pedro and Josep Brugada who described the condition in 1992.[5][3] Their brother Ramon Brugada described the underlying genetics in 1998.[3]

Signs and symptoms[edit]

Brugada syndrome causes a tendency to serious abnormal heart rhythms. These may be abnormally rapid heart rhythms such as ventricular fibrillation or polymorphic ventricular tachycardia, but patients with Brugada syndrome are also more likely to experience abnormally slow heart rhythms such as sinus node dysfunction. The condition is frequently not associated with any symptoms, and is frequently diagnosed following a cardiac arrest or incidentally on an electrocardiogram performed for another reason. When symptoms are seen, these usually take the form of blackouts or fainting. These episodes may be caused by abnormal heart rhythms that revert to a normal rhythm spontaneously, although blackouts in these patients are also frequently caused by a drop in blood pressure despite a normal heart rhythm, known as vasovagal syncope. [2]

The abnormal heart rhythms seen in Brugada syndrome often occur at rest, following a heavy meal, or even during sleep. These situations are linked to periods when the vagus nerve is activated, referred to as periods of high vagal tone. Abnormal heart rhythms may also occur during fever or following excessive alcohol. Certain medications may also worsen the tendency to abnormal heart rhythms in patients with Brugada syndrome and should be avoided by these patients.[6]


Approximately 20% of the cases of Brugada syndrome have been shown to be associated with mutations in a gene that encodes for a sodium ion channel in the cell membranes of the muscle cells of the heart (the myocytes); this is often referred to as a sodium channelopathy. The majority of patients affected by Brugada syndrome are not found to have known genetic mutations to explain the disease, as of 2015.[7] The gene, named SCN5A, is located on the short arm of the third chromosome (3p21). Loss-of-function mutations in this gene lead to a loss of the action potential dome of some epicardial areas of the right ventricle. This results in transmural and epicardial dispersion of repolarization. The transmural dispersion underlies ST-segment elevation and the development of a vulnerable window across the ventricular wall, whereas the epicardial dispersion of repolarization facilitates the development of phase 2 reentry, which generates a phase 2 reentrant extrasystole that captures the vulnerable window to precipitate ventricular tachycardia and/or ventricular fibrillation that often results in sudden cardiac death. At present time however, all the reported patients who died because of the disease and were submitted to detailed autopsy study have shown a structural right ventricular pathology underlying the syndrome.

Over 160 mutations in the SCN5A gene have been discovered to date, each having varying mechanisms and effects on function, thereby explaining the varying degrees of likelihood of the genetic mutation leading to the disease (that is to say, penetrance) and expression of this disorder.[8]

An example of one of the mechanisms in which a loss of function of the sodium channel occurs is a mutation in the gene that disrupts the sodium channel's ability to bind properly to ankyrin-G, an important protein mediating interaction between ion channels and cytoskeletal elements. Very recently a mutation in a second gene, Glycerol-3-phosphate dehydrogenase 1-like gene (GPD1L) has been shown to result in Brugada syndrome in a large multigenerational family (London, 2006). This gene acts as an ion channel modulator in the heart, although the exact mechanism is not yet understood.

Recently Antzelevitch has identified mutations in the L-type calcium channel subunits (CACNA1C (A39V and G490R) and CACNB2 (S481L)) leading to ST elevation and a relatively short QT interval (below 360 ms).[9] For a comprehensive list of all mutations see [8] In 2013, Bezzina et al. showed that common variants at SCN5A-SCN10A and HEY2 are associated with Brugada syndrome.[10]

This condition is inherited in an autosomal dominant pattern and manifests itself more commonly in males, due to a higher penetrance. In addition it has a higher prevalence in most Asian populations.

Type OMIM Mutation Notes
B1 601144 SCN5A alpha subunit of the sodium channel. Current through this channel is commonly referred to as INa. Loss of function in this channel leads to an unopposed Ito current (KCND2)
B2 611778 GPD1L Glycerol-3-phosphate dehydrogenase like peptide
B3 114205 CACNA1C Alpha subunit of cardiac L-type calcium channel.[11]
B4 600003 CACNB2 Beta-2 subunit of the voltage dependent L-type calcium channel.[11]
B5 600235 SCN1B Beta-1 subunit of the sodium channel SCN5A[12]
B6 604433 KCNE3 which coassembles with KCND3 Beta subunit to KCND3. Modulates the Ito potassium outward current[13]
SCN10A [10]
HEY2 [10]


Genetic testing for Brugada syndrome is clinically available and may help confirm a diagnosis, as well as differentiate between relatives who are at risk for the disease and those who are not. Some symptoms when pinpointing this disease include fainting, irregular heartbeats, and chaotic heartbeats. However, just detecting the irregular heartbeat may be a sign of another disease, so the doctor must detect another symptom as well.[14]


ECG pattern in Brugada syndrome. According to a recent consensus document, type 1 ST segment elevation, either spontaneously present or induced with the sodium channel-blocker challenge test, is considered diagnostic. Type 2 and 3 may lead to suspicion, but the drug challenge is required for diagnosis. The ECGs in the right and left panels are from the same patient before (right panel, type 3) and after (left panel, type 1) endovenous administration of 1 mg/kg of Ajmaline during 10 minutes.

In some cases, the disease can be detected by observing characteristic patterns on an electrocardiogram. These patterns may be present all the time, they might be elicited by the administration of particular drugs (e.g., Class IA, such as ajmaline or procainamide, or class 1C, such as flecainide or pilsicainide, antiarrhythmic drugs that block sodium channels and cause appearance of ECG abnormalities), or they might resurface spontaneously due to as-yet unclarified triggers.

Brugada syndrome has three different ECG patterns:[15]

  • Type 1 has a coved type ST elevation with at least 2 mm (0.2 mV) J-point elevation and a gradually descending ST segment followed by a negative T-wave.
  • Type 2 has a saddle-back pattern with a least 2 mm J-point elevation and at least 1 mm ST elevation with a positive or biphasic T-wave. Type 2 pattern can occasionally be seen in healthy subjects.
  • Type 3 has either a coved (type 1 like) or a saddle-back (type 2 like) pattern, with less than 2 mm J-point elevation and less than 1 mm ST elevation. Type 3 pattern is not rare in healthy subjects.

The pattern seen on the ECG is persistent ST elevations in the electrocardiographic leads V1-V3 with a right bundle branch block (RBBB) appearance, with or without the terminal S waves in the lateral leads that are associated with a typical RBBB. A prolongation of the PR interval (a conduction disturbance in the heart) is also frequently seen. The ECG can fluctuate over time, depending on the autonomic balance and the administration of antiarrhythmic drugs. Adrenergic stimulation decreases the ST segment elevation, while vagal stimulation worsens it. (There is a case report of a patient who died while shaving, presumed due to the vagal stimulation of the carotid sinus massage.)

The administration of class Ia, Ic, and III drugs increases the ST segment elevation, as does fever.[16] Exercise decreases ST segment elevation in some people, but increases it in others (after exercise, when the body temperature has risen). The changes in heart rate induced by atrial pacing are accompanied by changes in the degree of ST segment elevation. When the heart rate decreases, the ST segment elevation increases, and when the heart rate increases, the ST segment elevation decreases. However, the contrary can also be observed.


Labelled sketch of an already-implanted cardioverter-defibrillator

The cause of sudden death in Brugada syndrome is ventricular fibrillation (VF). The average age of death is 41. According to clinical reports, sudden death in people with Brugada syndrome most often happens during sleep. The episodes of syncope (fainting) and sudden death (aborted or not) are caused by fast polymorphic ventricular tachycardias or ventricular fibrillation. These arrhythmias appear with no warning. While there is no exact treatment modality that reliably and totally prevents ventricular fibrillation from occurring in this syndrome, treatment lies in termination of this lethal arrhythmia before it causes death. This is done via insertion of an implantable cardioverter-defibrillator (ICD), which continuously monitors the heart rhythm and will shock the wearer if ventricular fibrillation is sensed.

Studies have evaluated the role of quinidine, a Class Ia antiarrhythmic drug, for decreasing VF episodes occurring in this syndrome. Quinidine has been found to both decrease the number of VF episodes and correct spontaneous ECG changes, possibly via inhibiting Ito channels.[17] Some drugs have been reported to induce the type-1 ECG and/or (fatal) arrhythmias in Brugada syndrome patients. Patients with Brugada syndrome can prevent arrhythmias by avoiding these drugs or using them only in controlled conditions.[6] Those with risk factors for coronary artery disease may require an angiogram before ICD implantation.


Between 1 and 30 per 10,000 people are affected by Brugada syndrome.[2][1] Although those affected are born with the condition, the onset of symptoms is usually in adulthood and symptoms are only rarely seen in childhood. While the rare cases in childhood are equally likely to be male or female, in adulthood the condition is more frequently seen in males than females, potentially due to testosterone levels. [2][18] Brugada syndrome is more common in people of Asian descent and is the most common cause of sudden death in young men without known underlying cardiac disease in Thailand and Laos.[2][19] Type 1 Brugada ECG patterns are seen more frequently in Asian populations (0%–0.36%) than those in Europe (0%–0.25%) and the United States (0.03%). Similarly, Type 2 and Type 3 ECG patterns are more prevalent in Asia (0.12%–2.23%) than in Europe (0.0%–0.6%) or the United States (0.02%).[20]


Brugada syndrome is named after the Spanish cardiologists Pedro and Josep Brugada who first described the condition in 1992.[21][3] Their brother Ramon Brugada described the underlying genetics in 1998.[3]

Society and culture[edit]

  • A 1992 segment of the television series Unsolved Mysteries profiled a family that had lost various members due to heart issues. Surviving members of the family were ultimately diagnosed with Brugada syndrome.[22]
  • The British television soap opera Eastenders featured a storyline in which one of the characters suffered a cardiac arrest due to Brugada syndrome. [23]

See also[edit]


  1. ^ a b c d e f g "Brugada syndrome". Genetics Home Reference. March 2015. Archived from the original on 28 October 2017. Retrieved 28 October 2017. 
  2. ^ a b c d e f g h i j k l m n o p q r Polovina, Marija M.; Vukicevic, Milica; Banko, Bojan; Lip, Gregory Y. H.; Potpara, Tatjana S. (2017). "Brugada syndrome: A general cardiologist's perspective". European Journal of Internal Medicine. pp. 19–27. doi:10.1016/j.ejim.2017.06.019. PMID 28645806. 
  3. ^ a b c d e f g h i j "Brugada Syndrome". NORD (National Organization for Rare Disorders). 2016. Archived from the original on 11 February 2017. Retrieved 28 October 2017. 
  4. ^ a b c "Brugada syndrome". Genetic and Rare Diseases Information Center (GARD) – an NCATS Program. 2017. Archived from the original on 17 October 2017. Retrieved 28 October 2017. 
  5. ^ Brugada P, Brugada J (November 1992). "Right bundle branch block, persistent ST segment elevation and sudden cardiac death: a distinct clinical and electrocardiographic syndrome. A multicenter report". Journal of the American College of Cardiology. 20 (6): 1391–6. doi:10.1016/0735-1097(92)90253-J. PMID 1309182. 
  6. ^ a b Postema PG, Wolpert C, Amin AS, Probst V, Borggrefe M, Roden DM, Priori SG, Tan HL, Hiraoka M, Brugada J, Wilde AA (September 2009). "Drugs and Brugada syndrome patients: review of the literature, recommendations, and an up-to-date website (". Heart Rhythm. 6 (9): 1335–41. doi:10.1016/j.hrthm.2009.07.002. PMC 2779019Freely accessible. PMID 19716089. 
  7. ^ Genet Med. 2015 Apr 23. doi: 10.1038/gim.2015.35. Brugada syndrome: clinical and genetic findings. Sarquella-Brugada G1, Campuzano O2, Arbelo E3, Brugada J4, Brugada R5.
  8. ^ a b Hedley PL, Jørgensen P, Schlamowitz S, Moolman-Smook J, Kanters JK, Corfield VA, Christiansen M (September 2009). "The genetic basis of Brugada syndrome: a mutation update". Human Mutation. 30 (9): 1256–66. doi:10.1002/humu.21066. PMID 19606473. 
  9. ^ Antzelevitch C (June 2007). "Genetic basis of Brugada syndrome". Heart Rhythm. 4 (6): 756–7. doi:10.1016/j.hrthm.2007.03.015. PMC 1989771Freely accessible. PMID 17556198. 
  10. ^ a b c Bezzina CR, Barc J, Mizusawa Y, Remme CA, Gourraud JB, Simonet F, et al. (September 2013). "Common variants at SCN5A-SCN10A and HEY2 are associated with Brugada syndrome, a rare disease with high risk of sudden cardiac death". Nature Genetics. 45 (9): 1044–9. doi:10.1038/ng.2712. PMC 3869788Freely accessible. PMID 23872634. 
  11. ^ a b Antzelevitch C, Pollevick GD, Cordeiro JM, Casis O, Sanguinetti MC, Aizawa Y, Guerchicoff A, Pfeiffer R, Oliva A, Wollnik B, Gelber P, Bonaros EP, Burashnikov E, Wu Y, Sargent JD, Schickel S, Oberheiden R, Bhatia A, Hsu LF, Haïssaguerre M, Schimpf R, Borggrefe M, Wolpert C (January 2007). "Loss-of-function mutations in the cardiac calcium channel underlie a new clinical entity characterized by ST-segment elevation, short QT intervals, and sudden cardiac death". Circulation. 115 (4): 442–9. doi:10.1161/CIRCULATIONAHA.106.668392. PMC 1952683Freely accessible. PMID 17224476. 
  12. ^ Watanabe H, Koopmann TT, Le Scouarnec S, Yang T, Ingram CR, Schott JJ, Demolombe S, Probst V, Anselme F, Escande D, Wiesfeld AC, Pfeufer A, Kääb S, Wichmann HE, Hasdemir C, Aizawa Y, Wilde AA, Roden DM, Bezzina CR (June 2008). "Sodium channel β1 subunit mutations associated with Brugada syndrome and cardiac conduction disease in humans". The Journal of Clinical Investigation. 118 (6): 2260–8. doi:10.1172/JCI33891. PMC 2373423Freely accessible. PMID 18464934. 
  13. ^ Delpón E, Cordeiro JM, Núñez L, Thomsen PE, Guerchicoff A, Pollevick GD, Wu Y, Kanters JK, Larsen CT, Hofman-Bang J, Burashnikov E, Christiansen M, Antzelevitch C (August 2008). "Functional effects of KCNE3 mutation and its role in the development of Brugada syndrome". Circulation. Arrhythmia and Electrophysiology. 1 (3): 209–18. doi:10.1161/CIRCEP.107.748103. PMC 2585750Freely accessible. PMID 19122847. 
  14. ^ "Brugada syndrome Symptoms - Mayo Clinic". Archived from the original on 2015-11-09. Retrieved 2015-11-09. 
  15. ^ Antzelevitch C, Brugada P, Borggrefe M, Brugada J, Brugada R, Corrado D, Gussak I, LeMarec H, Nademanee K, Perez Riera AR, Shimizu W, Schulze-Bahr E, Tan H, Wilde A (April 2005). "Brugada syndrome: report of the second consensus conference". Heart Rhythm. 2 (4): 429–40. doi:10.1016/j.hrthm.2005.01.005. PMID 15898165. 
  16. ^ Kalavakunta JK, Bantu V, Tokala H, Kodenchery M (2010-01-01). "Sudden cause of cardiac death-be aware of me: a case report and short review on brugada syndrome". Case Reports in Medicine. 2010: 823490. doi:10.1155/2010/823490. PMC 3014853Freely accessible. PMID 21209740. 
  17. ^ Belhassen B, Glick A, Viskin S (September 2004). "Efficacy of quinidine in high-risk patients with Brugada syndrome". Circulation. 110 (13): 1731–7. doi:10.1161/01.CIR.0000143159.30585.90. PMID 15381640. 
  18. ^ Behere SP, Weindling SN (September 2017). "Brugada syndrome in children - Stepping into unchartered territory". Annals of Pediatric Cardiology. 10 (3): 248–258. doi:10.4103/apc.APC_49_17. PMC 5594936Freely accessible. PMID 28928611. 
  19. ^ Brugada J, Brugada P, Brugada R (July 1999). "The syndrome of right bundle branch block ST segment elevation in V1 to V3 and sudden death--the Brugada syndrome". Europace. 1 (3): 156–66. doi:10.1053/eupc.1999.0033. PMID 11225790. 
  20. ^ Mizusawa Y, Wilde AA (June 2012). "Brugada syndrome". Circulation. Arrhythmia and Electrophysiology. 5 (3): 606–16. doi:10.1161/CIRCEP.111.964577. PMID 22715240. 
  21. ^ Brugada P, Brugada J (November 1992). "Right bundle branch block, persistent ST segment elevation and sudden cardiac death: a distinct clinical and electrocardiographic syndrome. A multicenter report". Journal of the American College of Cardiology. 20 (6): 1391–6. doi:10.1016/0735-1097(92)90253-J. PMID 1309182. 
  22. ^ "Season 4, Episode: 24." Unsolved Mysteries: Original Robert Stack Episodes. Cosgrove/Meurer Productions, Apr. 2017. Web. 14 Apr. 2017.
  23. ^ "EastEnders: does Stacey's son Arthur have Brugada syndrome?". Radio Times. Retrieved 2018-01-16. 

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