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Brugada Syndrome (BS) is a genetic cause of sudden cardiac arrest (SCA). In this condition, SCA occurs due to the development of a fatal arrhythmia (irregularity of the heart rhythm) arising from the ventricles (lower chambers of the heart). This arrhythmia prevents the ventricles from contracting effectively. Without prompt defibrillation (electrical shock), death ensues within a few minutes due to lack of blood flow to the body’s vital organs. 

In approximately 30% of patients, SCA is the initial clinical manifestation of BS. When the arrhythmia occurs, it tends to be in the evening hours.  This is thought to be due to increased nocturnal parasympathetic activity as part of the body’s natural circadian rhythm.

Patients with BS do not have structural heart disease on conventional cardiac tests such as an echocardiogram, a stress test, or cardiac catheterization. However, a standard electrocardiogram (ECG) usually shows the characteristic abnormality: right bundle branch block type morphology of the QRS complex with ST segment elevation in the right precordial leads (V1 – V3; Figure1). The differential diagnosis for the ECG pattern seen in BS is extensive (Table 1) so not all patients with this sort of ECG abnormality actually have the BS and thus will not be at risk for SCA.  However because of this risk for sudden death, it is important to identify and appropriately manage BS patients.

 

Epidemiology

BS typically presents during adulthood. Although most patients are in their 30’s to 40’s, BS has been reported in patients as young as 2 years of age and as old as 84 years. Men are affected more commonly than women with a ratio of 8-9:1. The reason for this male preponderance is possibly related to underlying differences in hormonal status. It is estimated that BS is responsible for at least 4% of all sudden deaths and at least 20% of all sudden deaths occurring in patients without structural heart disease. The syndrome occurs more commonly in Southeast Asians, with the highest incidence occurring in the peoples of Northern Thailand.

Genetics and Pathophysiology

BS is a genetic disorder. In the inherited form, the mutant genes are passed down from parents to offspring and the syndrome runs in families. Since BS is an autosomal dominant disorder, offspring of people with the mutant gene have a 50% chance of inheriting it from their affected parent. A sporadic form is also seen due to spontaneous mutations in the germ cells (ova or sperm) of the patient’s parents affecting the segments of DNA that code for the specific Brugada proteins.

To date, the only gene linked with this condition, SCN5A, occurs on chromosome 3. Only 18 to 30 percent of families with BS have been found to have this mutant gene, making it likely that additional genes, yet to be identified, are responsible for this syndrome. The SCN5A gene codes for a defective sodium channel protein. A normally functioning sodium channel is required for the normal electrical activity of the heart. In patients with BS, the defective sodium channel leads to development of chaotic electrical activity which manifests itself as an arrhythmia. As described above, this arrhythmia prevents proper ventricular contraction and leads to sudden cardiac death. Genetic counseling about BS is available through our center, as is the commercially available test for SCN5A.

 Other Arrhythmias

Since the normal electrical activity of the heart is altered, patients with BS are also at increased risk for developing non-lethal arrhythmias including an irregularly irregular rhythm originating from the upper chambers of the heart called atrial fibrillation (AF). Atrial fibrillation is observed clinically in up to 20% of patients with BS. Other arrhythmias include AV nodal reentrant tachycardia and Wolf-Parkinson-White syndrome. While these arrhythmias tend not to be lethal they may lead to complications in patients with BS such as inappropriate firing from implanted cardioverter-defibrillator (ICD).

 Precipitating Factors

The ECG manifestations of Brugada syndrome are often concealed, but can be unmasked by various clinical conditions (such as fever), maneuvers or administration of certain drugs (sodium channel blockers). These precipitating factors and conditions cause changes in the electrical currents of the heart leading to the abnormal ECG pattern typical of BS (Figure 2). 

Diagnosis

The diagnosis of BS is made by recording the electrical activity of the patient’s heart. This is known as an ECG. Three ECG patterns are recognized as being associated with BS (Figure 1). Type 1 is the only type diagnostic of a Brugada pattern ECG. Type 2 and 3 pattern ECGs are not diagnostic of Brugada and require further evaluation. Diagnosis of BS is not always simple and may require administration of medications or performing specialized studies on the heart’s electrical system. Data from these studies are combined with the medical history of the patient or the patient’s family to determine if the patient: 1) has BS and 2) the risk of SCA associated with the disorder.

Treatment

The pharmacological approach to therapy is based on rebalancing the abnormal electrical currents of the heart. Several medications exist in the treatment of BS. However none of these are associated with complete prevention of SCA. Therefore these medications are reserved for controlling "electrical storms" (incessant episodes of arrthymias) in BS.

Currently, ICDs are the only proven treatment for BS. Furthermore, since SCA may be the initial manifestation of the disease, it is critically important to identify patients who many benefit from ICD implantation (Figure 3).  These patients include those with the type 1 ECG pattern who have been successfully resuscitated from SCA or have had unexplained syncope (loss of consciousness), seizures, or nocturnal agonal respirations.

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. Circulation111;659-670, 2005.

The indications for ICD become less clear in asymptomatic patients with the Brugada pattern on ECG, and unfortunately, there is no consensus among physicians. One method for risk stratifying asymptomatic patients is with an electrophysiology study. Patients in whom a sustained ventricular arrhythmia (ventricular fibrillation, polymorphic ventricular tachycardia, or monomorphic ventricular tachycardia lasting >30 seconds) is inducible are felt to be at high risk and may warrant ICD implantation. However, the specificity of this test in this patient population has been questioned. Thus, the management of asymptomatic patients still remains to be definitively defined.