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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 event - 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 men2, 3, and the onset of symptoms typically occurs at a mean age of 40 years.
1 ) One true diagnostic 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 the subject15), let to the use of class I antiarrhythmic drugs (AAD) as a diagnostic test for the disease6. Drug challenge for 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, route and time of administration are outlined in table 15. 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 2nd 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 pattern19-21.
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 1 precordial leads, and exclude other conditions that may account for it, we should search for clinical data that support the diagnosis of BS. There are three kind 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 lifetime, according to our data22). To date, some markers of high risk in BS patients have been clearly identified, but other issues still remain controversial23, 24:
Current recommendations on risk stratification are summarised on figure 3, based on the conclusions of the second consensus conference on BS5.
a) ICD To date, the only proven effective therapeutic strategy for the prevention of SCD in BS patients is the ICD28-30. 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 4 genes have been linked to BS: SCN5A, encoding for the α-subunit of the cardiac sodium (Na+) channel31 , and resulting in loss of function of the mentioned channel by different mechanisms32 (being responsible for up to 30% of BS cases5) ; 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 surface33, 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 syndrome35 (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), which expression levels varies 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, and 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, has shown to prevent induction of VF and suppress spontaneous ventricular arrhythmias in a clinical setting36, 37, being currently used in patients with ICD and multiple shocks, cases in which ICD implantation is contraindicated, or for the treatment of supraventricular arrhythmias38. It has been suggested that it could be also useful in children with BS, as a bridge to ICD or as an alternative to it39. However, it has also presented a high rate of secondary effects36.-Isoproterenol (which increases the ICaL current), in combination with quinidine, has proved to be useful for the treatment of electrical storms in BS40, 41. -Other drugs being evaluated for BS are tedisamile, phosphodiesterase III inhibitors (cilostazol) and dimethyl lithospermate B.
Figure 1 - The three ECG patterns associated to 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 from (16)).
Table 1 - Drugs used to unmask Brugada syndrome. Abbreviations: IV, intravenous; PO: per os, orally. (modified from (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 from (10)) I Antiarrhythmic drugs:1. Sodium channel blockers:
2. Calcium channel blockers:
II Beta -blockers:
III-Antianginal drugs:1. Calcium channel blockers:
3. Potasium channel openers:
III-Psychotropic drugs:1. Tricyclic antidepressants:
2- Tetracyclic antidepressants:
4- Selective serotonine reuptake inhibitors:
IV- 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 JPP 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 MJ, Raatikainen MJP, Karjalainen J, Kauma H, Kesaniemi YA, Huikuri HV. 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 JS, Lemoine JL, Bou Aoun F, Jarry G, Rey JL, Quiret JC. Prevalence of the Brugada Syndrome in an Apparently Healthy Population. Eur Heart J 2000 January 7;86(1):91-4. (12) Gallagher MM, Forleo GB, Behr ER 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 GX, 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 SG, 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 SG, 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 GE, 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 January;30(1):9-54. (33) 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 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 November 13;116(20):2260-8. (35) Antzelevitch C, Pollevick GD, Cordeiro JM 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 January 30;115(4):442-9. (36) Belhassen B, Glick A, Viskin S. Efficacy of quinidine in high-risk patients with Brugada syndrome. Circulation 2004 September 28;110(13):1731-7. (37) Hermida JS, 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 GB, Richter S, Brugada P. The Brugada syndrome: facts and controversies. Herz 2007 May;32(3):192-200. (39) Probst V, Denjoy I, Meregalli PG 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 JM, Hernandez MA, Garcia A, Garcia dC, Mejias A, Moro C. [Recurrent ventricular fibrillation during a febrile illness in a patient with the Brugada syndrome]. Rev Esp Cardiol 2000 May;53(5):755-7.You may send an e-mail here should you wish to receive pubmed links to articles listed in reference.
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