Read your latest personalised notifications
No account yet? Start here
Don't miss out
Ok, got it
Prof. Josep Brugada
Although the estimated prevalence of the Brugada syndrome makes it a rare disease - it ranges from 1-5/10,000 in Europe to 12/10,000 inhabitants in Southeast Asia – the implied risk of a tragic and preventable sudden death in young and otherwise healthy individuals has attracted great interest from scientists all over the world. The correct recognition and management of these patients should be considered an essential skill for any cardiologist. Learn to recognise and treat these patients in six steps.
Brugada syndrome (BS), first described in 1992, is an inherited arrhythmogenic disease characterised by coved-type ST-segment elevation in right precordial leads and an increased risk of sudden cardiac death (SCD) due to ventricular fibrillation (VF). (1) In all series, approximately 80% of the affected individuals are men (2, 3) and the onset of symptoms typically occurs at a mean age of 40.
1) There is one true diagnostic of the Brugada pattern; two others may suggest the disease. Three repolarisation patterns are associated with BS4 (Figure 1) when found in more than one right precordial leads (V1 to V3):
2) Drug challenge to help with diagnosis. Several studies have informed about the dynamic character of the ECG in BS6, 13, 14. That fact, and the finding that Class I AAD were able to reproduce the diagnostic pattern when administered to those patients in whom the ECG spontaneously normalised (based on the results of basic research on subject 15) led to the use of Class I antiarrhythmic drugs (AAD) as a diagnostic test for the disease. (6) A drug challenge for the diagnosis of BS is indicated in cases in which the disease is suspected, but in which the basal ECG is normal (e.g. familial screening) or suspicious, but not diagnostic (types 2 or 3). Flecainide, ajmaline, procainamide, dispyramide, propafenone and pilsicainide have been used to unmask BS16-18. The current recommendations on drugs, doses, routes and times of administration are outlined in Table 15. A drug challenge is only considered positive when a conversion to the diagnostic type 1 occurs. It is recommended to place the right precordial leads up to the second intercostals space because it may increase the sensitivity of the ECG (basal and during drug challenge with Class I AAD) for detecting the diagnostic BS pattern 19-21.
Many conditions may develop ST-segment elevation, mimicking the BS ECG pattern (Table 2). In order to attain the diagnosis of BS, they should be carefully excluded. It is also important to be aware that some drugs (listed in Table 3) may also produce a Brugada-like ST-segment elevation.
Once we have observed a type 1 ECG in more than one precordial lead and have excluded other conditions that may account for it, we should search for clinical data that support the diagnosis of BS. There are three kinds of clinical criteria for the disease:
BS is definitely diagnosed when the patient presents: 1) a type 1 ECG (either spontaneously or elicited by Class I AADs) and 2) at least one of the above-mentioned clinical criteria. If a type 1 ECG is observed in the absence of any clinical criteria, this should be referred to as 'idiopathic Brugada ECG pattern' and not as BS4. Figure 2 shows a proposed diagnostic algorithm.
Once the diagnosis of BS is made, the next step is risk stratification for which the main objective is the accurate identification and treatment of individuals at high risk of SCD (25% of the total population with BS will experience SCD or VF during their lifetimes, according to our data. (22) To date, some markers of high risk in BS patients have been clearly identified, but other issues still remain controversial: (23, 24)
Current recommendations on risk stratification are summarised in Figure , based on the conclusions of the second consensus conference on BS. (5)
a) ICD To date, the only proven effective therapeutic strategy for the prevention of SCD in BS patients is the ICD. (28-30) It is important to remark that these patients present a considerably high rate of inappropriate shocks (20%-36% at 21-47 months follow-up), mostly due to sinus tachycardia, supraventricular tachyarrhythmias and lead complications; emphasising the importance of a careful ICD programming.
b) Pharmacological treatment is under study. : Genetic basis and pathophysiology of BS-Rationale for pharmacological treatment. As a result of exhaustive investigation on the subject, some of the genetic basis and pathophysiologic substrate of arrhythmias in BS have been unravelled. Mutations in four genes have been linked to BS: SCN5A, encoding for the α-subunit of the cardiac sodium (Na+) channel, (31) and resulting in loss of function of the mentioned channel by different mechanisms (32) (being responsible for up to 30% of BS cases; (5) glycerol-3-phosphate dehydrogenase 1-like gene (GPD1L), which reduce the inward Na+ current by affecting the trafficking of the cardiac Na+ channel to the cell surface; (33, 34) finally, mutations in genes encoding the α1-(CACNA1C) and β- (CACNB2b) subunits of the L-type cardiac calcium (Ca+2) channel result in a combined Brugada/short QT syndrome. (35) (It has not been established yet which percentage of BS patients present these three last types of mutations). To date, the most accepted theory to explain the ECG changes and the arrhythmogenic basis of BS is based on the effect of the decrease of the inward positive currents (Na+, Ca+2) on the potassium transient outward current (Ito), whose expression levels vary across the myocardium layers (epicardium>endocardium). These changes in the ionic imbalance are responsible for the modification of the morphology of the cardiac action potential (presenting a remarked notch during the Phase 1, otherwise called 'loss of dome'), the typical ECG changes. These changes constitute the electrophysiological basis of the increased susceptibility of these patients to present episodes of polymorphic VT and/or VF (by a mechanism of Phase-2 reentry). With the objective of rebalancing the ionic currents during the cardiac action potential, drugs that inhibit the Ito current or increase the Na+ and Ca+2 currents have been tested in BS:-Quinidine and Ito and I-Kr inhibitor have shown to prevent induction of VF and suppress spontaneous ventricular arrhythmias in a clinical setting, (36, 37), currently being used on patients with ICD and multiple shocks – cases in which ICD implantation is contraindicated, or for the treatment of supraventricular arrhythmias, (38) It has been suggested that it could also be useful in children with BS as a bridge to an ICD or as an alternative to it39. However, it has also presented a high rate of secondary effects. (36)-Isoproterenol (which increases the ICaL current) in combination with quinidine has proved to be useful for the treatment of electrical storms in BS. (40, 41) -Other drugs being evaluated for BS are tedisamile, phosphodiesterase III inhibitors (cilostazol) and dimethyl lithospermate B.
Figure 1 - The Three ECG Patterns Associated with Brugada Syndrome: Only Type 1 (first from the left) Is Diagnostic of the Disease
Figure 2 - Diagnostic Algorithm for Brugada Syndrome Abbreviations: BS – Brugada syndrome; SCD – sudden cardiac death; PVT – polymorphic ventricular tachycardia; VF – ventricular fibrillation; AAD – antiarrhythmic drugs.
Figure 3 - Current Risk Stratification Scheme and Recommendations of ICD in BS Patients Abbreviations: ICD – implantable cardioverter-defibrillator; BS – Brugada syndrome; SCD – sudden cardiac death; NAR – nocturnal agonal respiration; AAD – antiarrhythmic drugs; PVT – polymorphic ventricular tachycardia; VF – ventricular fibrillation (modified, see Reference 16).
Table 1 - Drugs Used to Unmask Brugada Syndrome. Abbreviations: IV – intravenous; PO – per os, orally (modified, see Reference 5).
Table 2- Abnormalities Which May Account for ST-Segment Elevation in Right Precordial Leads
Acute myocarditisAcute pericarditisHemopericardiumRight ventricular ischemia/infarctionDissecting aortic aneurysmAcute pulmonary thromboemboliCentral and autonomic nervous system abnormalitiesDuchenne muscular dystrophyFriedreich´s ataxiaThiamine deficiencyHypercalcemiaHyperkalemiaMediastinal tumor compresing right ventricular outflow tractArrhythmogenic right ventricular cardiomyopathyLong QT syndrome type 3Right bundle branch blockLeft bundle branch blockLeft ventricular hypertrophyEarly repolarization syndromeHypothermia
Table 3 - Drug-induced Brugada-Like ECG Patterns (reproduced, see Reference 10). I Antiarrhythmic drugs:1. Sodium channel blockers:
2. Calcium channel blockers:
III-Antianginal drugs:1. Calcium channel blockers:
3. Potasium channel openers:
IV-Psychotropic drugs:1. Tricyclic antidepressants:
2- Tetracyclic antidepressants:
4- Selective serotonine reuptake inhibitors:
V- Other drugs:
(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 Cardioll, 1992. 20 (6): 1391-6. (2) Benito B., Sarkozy A., Mont L. et al. Gender differences in clinical manifestations of Brugada syndrome. J Am Coll Cardiol, 2008, November 4. 52 (19): 1567-73. (3) Eckardt L., Probst V., Smits J. P. P. et al. Long-Term Prognosis of Individuals With Right Precordial ST-Segment-Elevation Brugada Syndrome. Circulation, 2005, January 25. 111 (3): 257-63. (4) Wilde A., Antzelevitch C., Borggrefe M. et al. Proposed Diagnostic Criteria for the Brugada Syndrome: Consensus Report. Circulation, 2002. 106: 2514-9. (5) Antzelevitch C., Brugada P., Borggrefe M. et al. Brugada Syndrome: Report of the Second Consensus Conference: Endorsed by the Heart Rhythm Society and the European Heart Rhythm Association. Circulation, 2005, February 8. 111 (5): 659-70. (6) Brugada J., & Brugada P. Further characterization of the syndrome of right bundle branch block, ST segment elevation, and sudden cardiac death. J Cardiovasc Electrophysiol, 1997, March 8. (3): 325-31. (7) Viskin S., Fish R., Eldar M. et al. Prevalence of the Brugada sign in idiopathic ventricular fibrillation and healthy controls. Heart, 2000, July 1. 84 (1): 31-6. (8) Miyasaka Y., Tsuji H., Yamada K. et al. Prevalence and mortality of the Brugada-type electrocardiogram in one city in Japan. J Am Coll Cardiol, 2001, September 1. 38( 3): 771-4. (9) Matsuo K., Akahoshi M., Nakashima E. et al. The prevalence, incidence and prognostic value of the Brugada-type electrocardiogram : A population-based study of four decades. J Am Coll Cardiol, 2001, September. 38 (3): 765-70. (10) Junttila M. J., Raatikainen M. J. P., Karjalainen J., Kauma H., Kesaniemi Y. A., & Huikuri H. V. Prevalence and prognosis of subjects with Brugada-type ECG pattern in a young and middle-aged Finnish population. Eur Heart J, 2004, May 2. 25 (10): 874-8. (11) Hermida J. S., Lemoine J. L., Bou Aoun F., Jarry G., Rey J. L., & Quiret J. C. Prevalence of the Brugada Syndrome in an Apparently Healthy Population. Eur Heart J, 2000, January 7. 86 (1): 91-4. (12) Gallagher M. M., Forleo G. B., Behr E. R. et al. Prevalence and significance of Brugada-type ECG in 12,012 apparently healthy European subjects. International Journal of Cardiology, 2008, October 30. 130 (1): 44-8. (13) Brugada J., & Brugada P. What to do in patients with no structural heart disease and sudden arrhythmic death? Am J Cardiol, 1996, September 12. 78 (5A): 69-75. (14) Veltmann C., Schimpf R., Echternach C. et al. A prospective study on spontaneous fluctuations between diagnostic and non-diagnostic ECGs in Brugada syndrome: implications for correct phenotyping and risk stratification. Eur Heart J, 2006, November 1. 27 (21): 2544-52. (15) Yan G. X., & Antzelevitch C. Cellular basis for the Brugada syndrome and other mechanisms of arrhythmogenesis associated with ST-segment elevation. Circulation, 1999, October 12. 100 (15): 1660-6. (16) Brugada R., Brugada J. Antzelevitch C. et al. Sodium Channel Blockers Identify Risk for Sudden Death in Patients With ST-Segment Elevation and Right Bundle Branch Block but Structurally Normal Hearts. Circulation, 2000, February 8. 101 (5): 510-5. (17) Shimizu W., Antzelevitch C., Suyama K. et al. Effect of sodium channel blockers on ST segment, QRS duration, and corrected QT interval in patients with Brugada syndrome. J Cardiovasc Electrophysiol, 2000, December 11. (12): 1320-9. (18) Morita H., Takenaka-Morita S., Fukushima-Kusano K. et al. Risk stratification for asymptomatic patients with Brugada syndrome. Circ J, 2003, April. 67 (4): 312-6. (19) Sangwatanaroj S., Prechawat S., Sunsaneewitayakul B., Sitthisook S., Tosukhowong P., & Tungsanga K. New electrocardiographic leads and the procainamide test for the detection of the Brugada sign in sudden unexplained death syndrome survivors and their relatives. Eur Heart J, 2001, December 22. (24): 2290-6. (20) Sangwatanaroj S., Prechawat S., Sunsaneewitayakul B., Sitthisook S., Tosukhowong P., & Tungsanga K. Right ventricular electrocardiographic leads for detection of Brugada syndrome in sudden unexplained death syndrome survivors and their relatives. Clin Cardiol, 2001, December 24. (12): 776-81. (21) Shimizu W., Matsuo K., Takagi M. et al. Body surface distribution and response to drugs of ST segment elevation in Brugada syndrome: clinical implication of eighty-seven-lead body surface potential mapping and its application to twelve-lead electrocardiograms. J Cardiovasc Electrophysiol, 2000, April 11 (4): 396-404. (22) Benito B., Brugada R, Brugada J, Brugada P. Brugada syndrome. Prog Cardiovasc Dis 2008 July;51(1):1-22. (23) Priori S. G., & Napolitano C. Should patients with an asymptomatic Brugada electrocardiogram undergo pharmacological and electrophysiological testing? Circulation, 2005, July 12. 112 (2): 279-92. (24) Brugada P., Brugada R., & Brugada J. Should patients with an asymptomatic Brugada electrocardiogram undergo pharmacological and electrophysiological testing? Circulation, 2005, July 12. 112 (2):279-92. (25) Brugada J., Brugada R., Antzelevitch C., Towbin J., Nademanee K., & Brugada P. Long-term follow-up of individuals with the electrocardiographic pattern of right bundle-branch block and ST-segment elevation in precordial leads V1 to V3. Circulation, 2002, January 1. 105 (1):73-8. (26) Brugada J., Brugada R., & Brugada P. Determinants of sudden cardiac death in individuals with the electrocardiographic pattern of Brugada syndrome and no previous cardiac arrest. Circulation, 2003, December 23. 108 (25): 3092-6. (27) Priori S. G., Napolitano C., Gasparini M. et al. Natural History of Brugada Syndrome: Insights for Risk Stratification and Management. Circulation, 2002, March 19. 105 (11): 1342-7. (28) Sacher F., Probst V., Iesaka Y. et al. Outcome After Implantation of a Cardioverter-Defibrillator in Patients With Brugada Syndrome: A Multicenter Study. Circulation, 2006, November 28. 114 (22): 2317-24. (29) Sarkozy A., Boussy T., Kourgiannides G. et al. Long-term follow-up of primary prophylactic implantable cardioverter-defibrillator therapy in Brugada syndrome. Eur Heart J, 2007, February 1. 28 (3): 334-44. (30) Rosso R., Glick A., Glikson M. et al. Outcome after implantation of cardioverter defibrillator [corrected] in patients with Brugada syndrome: a multicenter Israeli study (ISRABRU). Isr Med Assoc J, 2008, June 10. (6): 435-9. (31) Chen Q., Kirsch G. E., Zhang D. et al. Genetic basis and molecular mechanism for idiopathic ventricular fibrillation. Nature, 1998, March 19. 392 (6673): 293-6. (32) Antzelevitch C., Brugada P., Brugada J., & Brugada R. Brugada syndrome: From cell to bedside. Current Problems in Cardiology, 2005, Jan 30. (1): 9-54. (33) Weiss R., Barmada M. M., Nguyen T. et al. Clinical and Molecular Heterogeneity in the Brugada Syndrome: A Novel Gene Locus on Chromosome 3. Circulation, 2002, February 12. 105 (6): 707-13. (34) London B, Michalec M., Mehdi H. et al. Mutation in Glycerol-3-Phosphate Dehydrogenase 1-Like Gene (GPD1-L) Decreases Cardiac Na+ Current and Causes Inherited Arrhythmias. Circulation, 2007, Nov 13. 116 (20): 2260-8. (35) Antzelevitch C., Pollevick G. D., Cordeiro J. M. et al. 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, 2007, Jan 30. 115 (4): 442-9. (36) Belhassen B., Glick A., & Viskin S. Efficacy of quinidine in high-risk patients with Brugada syndrome. Circulation, 2004, Sept 28. 110 (13): 1731-7. (37) Hermida J. S., Denjoy I., Clerc J. et al. Hydroquinidine therapy in Brugada syndrome. J Am Coll Cardiol, 2004, May 19. 43 (10): 1853-60. (38) Boussy T., Sarkozy A., Chierchia G. B., Richter S., & Brugada P. The Brugada syndrome: facts and controversies. Herz, 2007, May. 32 (3): 192-200. (39) Probst V., Denjoy I., Meregalli P. G. et al. Clinical aspects and prognosis of Brugada syndrome in children. Circulation, 2007, April 17. 115 (15): 2042-8. (40) Maury P., Couderc P., Delay M., Boveda S., & Brugada J. Electrical storm in Brugada syndrome successfully treated using isoprenaline. Europace, 2004, March 6 (2): 130-3. (41) Maury P., Hocini M., & Haissaguerre M. Electrical storms in Brugada syndrome: review of pharmacologic and ablative therapeutic options. Indian Pacing Electrophysiol J, 2005. 5 (1): 25-34. (42) Antzelevitch C., & Brugada R. Fever and Brugada syndrome. Pacing Clin Electrophysiol, 2002, November 25 (11): 1537-9. (43) Gonzalez Rebollo J. M., Hernandez M. A., Garcia A., Garcia D. C., Mejias A., & Moro C. [Recurrent ventricular fibrillation during a febrile illness in a patient with the Brugada syndrome]. Rev Esp Cardiol, 2000, May 5. 3 (5): 755-7.You may send an email here should you wish to receive pubmed links to articles listed in reference.
Vol 7, N° 24
Our mission: To reduce the burden of cardiovascular disease.
© 2020 European Society of Cardiology. All rights reserved.