Brugada Syndrome: The Enigma

Johnson Francis, MD, DM*; C.G. Sajeev, MD, DM**; K. Venugopal MD, DM***.
* Associate Professor ** Assistant Professor *** Professor & Head,
Department of Cardiology, Medical College Calicut.

Address for Correspondence: Dr. Johnson Francis, Associate Professor of Cardiology, Medical College Calicut -673008, Kerala, India. Email: beenajon@eth.net  



Abstract

The initial description of this entity by Brugada brothers was in 1992.[1] This new syndrome is characterised by syncopal episodes and/or sudden death in patients with a structurally normal heart and a characteristic electrocardiogram (ECG) with a pattern of right bundle branch block (RBBB) with ST segment elevation in leads V1 to V3. The incidence of sudden death in this syndrome is very high and, at present, sudden death can only be prevented by implanting a cardioverter-defibrillator. Patients with the syndrome who do not receive an implantable defibrillator has a poor prognosis.[2] The genetic nature of the disease and its association to a mutation in the cardiac sodium channel gene was described in 1998[3]. Since the diagnosis is easily made by means of the ECG, an increasing number of patients with the ECG pattern are being identified worldwide. Recently, Riera et al has proposed that this entity should be promoted to the category of disease, since it has a characteristic set of signs and symptoms, and an identified genetic defect[4].



Key Words: ventricular tachycardia ,ventricular fibrillation , arrhythmia ,sudden death 



Introduction

In 1986, Prof. Pedro Brugada observed his first patient with RBBB pattern and persistent ST segment elevation in leads V1 to V3, a Polish Caucasian child, who suffered several episodes of syncope. The boy's sister had a sudden cardiac death (SCD), even though she had been treated with a combination of amiodarone and pacemaker implantation. Pedro and Josep Brugada, presented as an abstract in the North American Society of Pacing and Electrophysiology (NASPE) meeting, three cases of a new clinical and electrocardiographic syndrome, characterised by the association of RBBB, persistent ST segment elevation, normal QT interval and SCD in 1991[5]. Yan and Antzelevitch highlighted the importance of the ST-segment elevation and apparent RBBB as the basis for a substrate capable of giving rise to malignant arrhythmias and named it the Brugada syndrome in 1996[6]. Subsequently the literature on Brugada Syndrome has grown so much that over 400 papers have been published on this topic worldwide. First Virtual Symposium about the Brugada Syndrome (http://www.brugada-symposium.org/) was held in 2002 to commemorate the 10th anniversary of its description. During this symposium it was proposed that this entity should be promoted to the category of disease, since it has a characteristic set of signs and symptoms, and an identified genetic defect.



Clinical and Electrocardiographic Features

The typical electrocardiographic features of the Brugada Syndrome are illustrated in Figure [1]. It consists of an rSr' pattern suggestive of RBBB with ST segment elevation in leads V1 to V3 and inverted T waves. The clinical syndrome is characterised by a history of recurrent syncope due to malignant ventricular arrhythmias and a positive family history of SCD. Some patients may present with recurrent ventricular fibrillation (“electrical storm”). Brugada Syndrome differs from other conditions producing similar ECG changes in the total absence of structural changes in the heart. Instead there is a defect in the alpha subunit of the cardiac sodium channel gene SCN5A.[3]

In several individuals, the characteristic ECG changes occur without the clinical syndrome. Sometimes the ECG changes are noted while screening the family of an index case. The ECG changes in Brugada Syndrome are dynamic and may be absent in an ECG taken after an episode of syncope. The ECG changes may occasionally be unmasked by drugs given for other arrhytmias like atrial fibrillation[7]. The electrocardiographic pattern of Brugada syndrome may also be disclosed by a febrile illness[8,9]. 


Brugada – like ECG Pattern

Several cases of Brugada-like ECG pattern has been reported in literature. These conditions have to be carefully excluded while making a diagnosis of Brugada Syndrome. Nakazato et al described compression of the right ventricular outflow tract by an abnormal infective mass as the mechanism of Brugada-like ST elevation in a patient [10]. After treatment with antibiotics, the mass lesion gradually shrunk and the ST elevation disappeared. The ability of local pressure to give rise to an ST segment elevation has also been demonstrated experimentally in the arterially perfused right ventricular wedge preparation [11]. Tarin et al reported a patient with a mediastinal tumor and ECG findings similar to those described in the Brugada syndrome. This ECG pattern disappeared after tumor removal, thus suggesting that it was probably caused by compression of the right ventricular outflow tract by the mass[12]. Another case of pericardial fluid and “tumour” compressing the right ventricle with Brugada-like ECG pattern in a patient with rheumatoid arthritis has also been reported[13]. During surgery the “tumour” was found to be organised haemopericardium. After the surgery the patient was well and had a normal ECG. The author had reviewed the other causes of Brugada-like ECG pattern elsewhere[14].

Risk Stratification

Priori et al[15], in a prospective study of 52 families, noted that asymptomatic individuals with Brugada-type ECG pattern have a very low risk of SCD. Symptomatic individuals with aborted SCD have the highest mortality rate of 23% in a mean follow-up of 33 months. The genetic mutation can be identified in 15% of cases. A positive electrophysiologic study has an accuracy of 50% while pharmacological tests have an accuracy of only 35% in asymptomatic carriers.

Treatment

Though a lot of progress has been made in the diagnostic evaluation of Brugada Syndrome, very little progress has been made in the treatment. The only established effective treatment is implantation of a cardioverter-defibrillator (ICD). This is not a feasible option for developing countries like ours. Moreover, even in developed countries, limited battery life of the ICD and logistics of implantation make it a difficult mode of treatment in infants and children. Drugs like quinidine, tedisamil and isoproterenol have been shown to normalize the ST elevation in Brugada Syndrome[16-18]. Phosphodiesterase III inhibitor cilostazol has also been reported to be useful recently[19]. But long term efficacy in preventing sudden death is yet to be demonstrated.

Conclusion

Brugada Syndrome is a clinical entity which has been described in the last decade of the 20th century. In countries where it is endemic, it is one of the important causes of sudden cardiac death in individuals below the age of 50 years. The familial occurrence and absence of effective pharmacological treatment are of concern. The only treatment of proven efficacy is implantation of a cardioverter-defibrillator. For readers interested in further reading, an exhaustive review is available elsewhere[20].

References


[1]. Brugada P, Brugada J. Right bundle branch block, persistent ST segment elevation and sudden cardiac death: A distinct clinical and electrocardiographic syndrome. J Am Coll Cardiol 1992;20:1391-1396.


[2]. Brugada J, Brugada R, Brugada P. Right bundle branch block and ST segment elevation in leads V1-V3: A marker for sudden death in patients with no demonstrable structural heart disease. Circulation 1998;97:457-460.

[3]. Chen Q, Kirsch GE, Zhang D, Brugada R, Brugada J, Brugada P, et al. Genetic basis and molecular mechanisms for idiopathic ventricular fibrillation. Nature; 1998;392:293-296.

[4]. Andrés Ricardo Pérez Riera, Edgardo Schapachnik and Celso Ferreira. Brugada Disease: Chronology Of Discovery And Paternity - Preliminary Observations And Historical Aspects. Indian Pacing Electrophysiol. J. 2003;3(4):253-260. Free Full Text at: http://www.ipej.org/0304/riera.htm  

[5]. Brugada P, Brugada J. A distinct clinical and electrocardiographic syndrome: right bundle branch block, persistent ST segment elevation with normal QT interval and sudden cardiac death (abstr). PACE 1991;14:746.

[6]. Yan GX, Antzelevitch C. Cellular basis for the electrocardiographic J wave. Circulation. 1996; 93: 372–379.

[7]. Josep Brugada, Pedro Brugada, Ramon Brugada. Brugada Syndrome: The Syndrome of Right Bundle Branch Block, ST segment Elevation in V1 to V3 and Sudden Death. Indian Pacing Electrophysiol. J. 2001;1(1):6 Free Full Text at: http://www.ipej.org/0101/brugada.htm  

[8].Patruno N, Pontillo D, Achilli A, Ruggeri G, Critelli G.. Electrocardiographic pattern of Brugada syndrome disclosed by a febrile illness: clinical and therapeutic implications. Europace. 2003;5(3):251-5

[9]. Mok NS, Priori SG, Napolitano C, Chan NY, Chahine M, Baroudi G. A newly characterized SCN5A mutation underlying Brugada syndrome unmasked by hyperthermia.J Cardiovasc Electrophysiol. 2003 Apr;14(4):407-11. 

[10]. Nakazato Y, Ohmura T, Shimada I, Daida H. Brugada-like Precordial ST Elevation on ECG by Anterior Mediastinal Infective Mass Lesion. Indian Pacing Electrophysiol. J. 2003;3(3):184 Free Full Text at: http://www.ipej.org/0303/nakazato2.htm  

[11]. Antzelevitch, C. & Dumaine, R. (2002). Electrical heterogeneity in the heart: Physiological, pharmacological and clinical implications. In Handbook of Physiology. The Heart., eds. Page, E., Fozzard, H. A., & Solaro, R. J., pp. 654-692. Oxford University Press, New York.

[12]. Tarin N, Farre J, Rubio JM, et al. Brugada-like electrocardiographic pattern in a patient with a mediastinal tumor. PACE 1999; 22:1264–1266.

[13]. Tomcsányi J, Simor T and Papp L. Haemopericardium and Brugada-like ECG pattern in rheumatoid arthritis. Heart 2002;87:234.

[14]. Francis J, Antzelevitch C. Brugada-Like Electrocardiographic Pattern. Indian Pacing Electrophysiol. J. 2003;3(3):91 Free Full Text at: http://www.ipej.org/0303/francis3.htm  

[15]. Priori SG, Gasparini M, Napolitano C, et al. Clinical and genetic heterogeneity of the right bundle branch block and ST segment elevation syndrome. A prospective evaluation of 52 families. Circulation 2000;102:2509-2515.

[16]. Alings M, Dekker L, Sadee A, Wilde A. Quinidine induced electrocardiographic normalization in two patients with Brugada syndrome. Pacing Clin Electrophysiol. 2001; 24: 1420–1422.

[17]. Shimizu W, Matsuo K, Takagi M, Tanabe Y, Aiba T, Taguchi A, Suyama K, Kurita T, Aihara N, Kamakura S. 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; 11: 396–404.

[18]. Tanaka H, Kinoshita O, Uchikawa S, Kasai H, Nakamura M, Izawa A, Yokoseki O, Kitabayashi H, Takahashi W, Yazaki Y, Watanabe N, Imamura H, Kubo K. Successful prevention of recurrent ventricular fibrillation by intravenous isoproterenol in a patient with Brugada syndrome. Pacing Clin Electrophysiol. 2001; 24: 1293–1294.

[19]. Tsuchiya T, Ashikaga K, Honda T, Arita M. Prevention of ventricular fibrillation by cilostazol, an oral phosphodiesterase inhibitor, in a patient with Brugada syndrome. J Cardiovasc Electrophysiol. 2002; 13: 698–701.

[20]. Charles Antzelevitch, Pedro Brugada, Josep Brugada, Ramon Brugada, Jeffrey A. Towbin, Kolawanee Nademanee. Brugada Syndrome: 1992–2002, A Historical Perspective. J Am Coll Cardiol 2003;41:1665-71.

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