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Brugada Syndrome (BS) is a genetic cause of sudden cardiac arrest (SCA) which occurs due to the development of either polymorphic ventricular tachycardia (VT) or ventricular fibrillation (VF). These are lethal arrhythmias that prevent the ventricle 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 VT or VF 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. The risk of SCA in asymptomatic patients with “true” Brugada type ECG pattern ranges from 0.5 to 14 percent. Because of this risk, it is important to identify and appropriately manage BS patients at high risk according to best available evidence.

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. It codes for the α subunit of the cardiac sodium channel. 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. In patients with BS, we know that there is altered depolarization of the right ventricle making a person vulnerable to fatal ventricular arrhythmias. Genetic counseling about BS is available through our center, as is the commercially available test for SCN5A.

The mutant sodium channel leads to decrease in the sodium (INA) current due to either failure of expression of the sodium channel, accelerated inactivation, or prolonged recovery from inactivation. This causes a shortening of the action potential duration by blunting phase 0 depolarization. Furthermore, in the right ventricular (RV) epicardium, there is an increased number of transient outward potassium current channels, Ito. This mismatch in potassium and sodium currents leads to decreased activation of the L-type calcium channels that maintain the depolarized state during phase 2 of the action potential. The net effect is loss of the action potential dome causing a short refractory period of the RV epicardium and heterogeneity of refractory periods between the RV endo- and epicardium (Figure 2).  Since these mutant sodium channels fail to activate properly there is unidirectional block. The unidirectional block coupled with the short refractory period makes this substrate ideal for reentry; the reentrant circuit leads to continuous depolarization of the ventricular myocardium causing ventricular tachycardia and fibrillation. This form of reentry tends to occur in phase 2 of the action potential, thus is termed phase 2 reentry.

 Other Arrhythmias

Patients with BS are also at increased risk for developing atrial fibrillation, an irregularly irregular rhythm originating from the upper chambers of the heart. Atrial fibrillation is observed clinically in up to 20% of these patients. Other arrhythmias include AV nodal reentrant tachycardia and Wolf-Parkinson-White syndrome. The increased incidence of these arrhythmias may reflect the diffuse nature of the sodium channel abnormality. These arrhythmias may lead to inappropriate firing from implanted cardioverter-defibrillator (ICD) highlighting the importance of appropriate device programming in the management of supraventricular arrhythmias in BS. 

 Precipitating Factors

The ECG manifestations of Brugada syndrome are often concealed, but can be unmasked by various clinical conditions, such as being febrile, or administration of certain drugs, sodium channel blockers. These precipitating factors and lead to changes in ion currents that occur in the myocardial cells during depolarization, leading to the abnormal ECG pattern typical of BS (Figure 3).

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.

Diagnosis

Three ECG patterns in the right precordial (chest) leads are recognized as being associated with BS (Figure 2.1). Type 1 is diagnostic of Brugada pattern and is characterized by a coved ST-segment elevation 2 mm followed by a negative T wave. A definitive diagnoses of BS can be made when a type 1 ST-segment elevation pattern is observed in >1 right precordial lead (V1 to V3) along with one of the following: documented polymorphic VT or VF; a family history of sudden cardiac death at < 45 years of age; similar type ECGs in family members, inducibility of VT/VF during an electrophysiology study; unexplained syncope; or history of nocturnal agonal respiration.

The type 2 ST-segment elevation pattern has a saddleback appearance with a ST-segment elevation of > 2 mm, a trough displaying >1 mm ST elevation, and then either a positive or biphasic T wave. The type 3 pattern has either a saddleback or coved appearance with an ST-segment elevation of <1 mm. Unlike the type 1 pattern, type 2 and 3 pattern ECGs are not diagnostic of the Brugada pattern.  In order for a diagnosis of BS to be made in patients with either a type 2 or 3 pattern, conversion to a more diagnostic type 1 pattern must be observed  either spontaneously or after administration of a sodium channel blocker e.g. procainamide. (ST-segment elevation should be >2 mm) in conjunction with one or more of the clinical criteria described above. Placement of the right precordial leads in a superior position (up to the second intercostal space above normal) can increase the sensitivity of the ECG for detecting the BS.

 Treatment

The pharmacological approach to therapy is based on rebalancing of currents during the action potential. Antiarrhythmic drugs, that affect the transient outward potassium current (Ito), have shown promise because they reestablish the action potential dome. Unfortunately medications that specifically target Ito are not available.  Instead, quinidine, which has some Ito blocking properties, is used most commonly. Quinidine has been used in some patients to reestablish a normal contour to the action potential and normalize the ECG pattern in patients with BS. The recommended dosing of quinidine is 1200 to 1500 mg/ day given in divided doses.  However, clinical trials demonstrating the long-term efficacy of quinidine are limited; thus quinidine cannot be recommended as sole first-line therapy for patients with BS.

Other agents that boost the L-type calcium current, such as isoproterenol, may be also useful in patients with BS. The phosphodiesterase III inhibitor, cilostazol, normalizes the ST segment by augmenting the calcium current (ICa), as well as by reducing Ito secondary to an increase in heart rate. Tedisamil, an experimental antiarrhythmic agent, with Ito blocking properties may be more potent than quinidine because it lacks the relatively strong inward Na current–blocking actions of quinidine. Nevertheless, appropriate clinical trials are needed to establish the effectiveness of all of the above pharmacological agents. Currently, these medications are reserved for controlling "electrical storms" (incessant episodes of VT/VF) 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 4).  These patients include those with the type 1 ECG pattern (either spontaneous or induced by administration of a sodium channel blocker) who have been successfully resuscitated from SCA or have had unexplained syncope, seizures, or nocturnal agonal respirations.

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.