Drug-induced Brugada Syndrome

Yee Guan Yap; Elijah R. Behr; A. John Camm


Europace. 2009;11(8):989-994. 

In This Article

Abstract and Introduction


Brugada syndrome is an inherited cardiac arrhythmia condition characterized by (i) coved ST-elevation and J point elevation of at least 2 mm in at least two of the right precordial ECG leads (V1–V3) and (ii) ventricular arrhythmias, syncope, and sudden death. Patients with Brugada syndrome or suspected mutation carriers can have normal ECG recordings at other times. In these cases, a diagnostic challenge with a sodium channel blocker such as ajmaline, flecainide, or pilsicainide may induce the full-blown type 1 ECG pattern and support the diagnosis. However, recently, many other pharmacological agents not related to class I anti-arrhythmic agents have been reported to induce Brugada ECG patterns including tricyclic antidepressants, fluoxetine, lithium, trifluoperazine, antihistamines, and cocaine. As published reports of the drug-induced Brugada sign have become increasingly prevalent, there is growing interest in the mechanisms responsible for this acquired ECG pattern and its clinical significance. It is possible that drug-induced Brugada syndrome may be due to an individual susceptibility that favours drug-induced ECG abnormalities, possibly as a result of an increase in a latent ion channel dysfunction similar to that in drug-induced long QT syndrome. However, further evidence is needed to confirm this postulation. In this paper, we will review the cases and evidence of drug-induced Brugada syndrome reported in the literature.


Brugada syndrome is an inherited cardiac arrhythmia condition, characterized by coved ST elevation and J point elevation of at least 2 mm in at least two of the right precordial ECG leads (V1–V3) that are unrelated to ischaemia, electrolyte disturbances, or obvious structural heart disease. It is also characterized by ventricular arrhythmias, atrial arrhythmias, syncope, and sudden death. The diagnosis in an individual requires the presence of the Brugada ECG pattern as described above (type 1) with at least one of the recognized diagnostic criteria: syncope, prior cardiac arrest, documented or inducible polymorphic ventricular tachycardia or ventricular fibrillation, a family history of sudden death <45 years old, or type 1 Brugada pattern and/or nocturnal agonal respiration.[1] It is a familial condition that displays an autosomal dominant mode of transmission, with incomplete penetrance and an incidence ranging between 5 and 66 per 10 000.[2,3] The majority of patients with Brugada syndrome are caused by mutations in the cardiac sodium channel gene SCN5A, the gene encoding for the α-subunit of the sodium channel.[4] Recently, however, a subgroup of familial sudden cardiac death syndrome in which a Brugada syndrome phenotype is combined with short QT intervals (rate corrected QT interval ≤360 ms) has been identified. In these patients, loss-of-function missense mutations in CACNA1C (A39V and G490R) and CACNB2 (S481L) encoding the α1- and β2b-subunits of the L-type calcium channel have been found to be the underlying cause.[5] Similarly, a mutation in the glycerol-3-phosphate dehydrogenase 1-like (GPD1-L) gene has also been identified as a less common cause of Brugada syndrome.[6,7] In these patients, the mutation in GPD1-L gene causes a decrease in the SCN5A surface membrane expression and a subsequent reduction in the inward sodium current across the cell membrane by as much as 50%, resulting in the phenotypical appearance of Brugada syndrome. The mechanism by which GPD1-L mutations alter the sodium channel membrane expression is currently unknown, although alteration in the cellular oxidative state has been suggested.[6]

Brugada phenotype is more prevalent in males and is a result of the presence of a more prominent Ito channels in males than females.[8] Carriers of the condition are at high risk of ventricular tachycardia, ventricular fibrillation, and sudden cardiac death. Syncopal episodes and paroxysmal palpitations are the only symptoms the patient may have before sudden arrhythmic death occurs. Brugada syndrome is estimated to be responsible for at least 20% of sudden deaths in patients with structurally normal hearts.[1] In regions of Southeast Asia where it is endemic, the clinical presentation of Brugada syndrome is distinguished by a male predominance (8:1 ratio of male:female) and the appearance of arrhythmic events at an average age of 40 years (range: 1–77 years).[9]


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