Brugada Syndrome

Brugada syndrome results from mutations that:

• Decrease inward sodium or calcium currents OR

• Increase early outward potassium currents

These abnormalities lead to early loss of the action potential plateau, particularly in the epicardial cells of the right ventricular outflow tract that produce characteristic right precordial ECG changes and a propensity to ventricular tachyarrhythmias. Although different mutations have been reported, most are in the SCN5A gene, producing a loss-of-function of the inward sodium current (1).

Typically, patients have no clinical evidence of structural heart disease, although most have microscopic structural abnormalities in the epicardial region of the right ventricular outflow tract. Relationships with other genetic and acquired structural heart diseases are increasingly being recognized, as are overlap syndromes with long QT syndrome type 3, early repolarization syndrome, and arrhythmogenic right ventricular cardiomyopathy (ARVC) (1, 2, 3).

The majority of patients diagnosed with Brugada syndrome are asymptomatic (1). However, in some patients it leads to syncope or sudden cardiac death due to polymorphic ventricular tachycardia and ventricular fibrillation. Ventricular arrhythmias can cause sudden death during sleep. Approximately 10 to 20% of patients develop atrial tachyarrhythmias, predominantly atrial fibrillation (2, 3), and some present with atrial fibrillation as the first clinical manifestation of disease (4).

Events occur more often at night and are not usually related to exercise. Events may also be brought on by fever and by certain medications, including sodium channel blockers, beta-blockers, certain antidepressants and antipsychotics, lithium, alcohol, and cocaine (5).

• Electrocardiography (ECG)

• Family history

• Provocative testing to induce characteristic ECG changes

• Genetic testing

Diagnosis should be considered in patients with unexplained cardiac arrest or syncope or a family history of such when the affected people do not have structural heart disease.

Initial diagnosis of Brugada syndrome is based on a characteristic ECG pattern, the type 1 Brugada ECG pattern (see figure Type 1 Brugada ECG Pattern). The type 1 Brugada ECG pattern has prominent J-point and ST elevation in V1 and V2 (sometimes involving V3) that causes the QRS complex in these leads to resemble right bundle branch block. The ST segment is coved and descends to an inverted T-wave. These characteristics may be more evident in V1 and V2 leads recorded from the second or third intercostal spaces rather than the usual fourth intercostal space. Only a spontaneous type 1 pattern is considered diagnostic for Brugada syndrome according to the Shanghai Brugada syndrome score (1).

Lesser degrees of these patterns (type 2 and type 3 Brugada ECG patterns) are not considered diagnostic. The type 2 and type 3 patterns may change to a type 1 pattern spontaneously, with fever, or in response to medications. The latter is the basis of a provocative challenge usually using IV ajmaline, procainamide, flecainide or pilsicainide. Scores have been developed to aid in diagnosing Brugada syndrome, with a diagnosis of "possible" Brugada syndrome defined for borderline cases (1). Application of clinical, family history, and genetic criteria is the required to establish the diagnosis (1).

Genetic testing is usually recommended and has a yield of approximately 20% (2).

The diagnosis of Brugada syndrome includes considering, and excluding, other disorders that produce similar cardiac findings, including hypothermia, hypocalcemia, right bundle branch block, arrhythmogenic right ventricular cardiomyopathy, acute pulmonary embolism, and left anterior descending coronary artery of conus branch of the right coronary artery occlusion (1).

Type 1 Brugada ECG Pattern

Prominent J-point elevation to a coved ST segment, leading to an inverted T-wave in leads V1 and V2.

• Sometimes an implantable cardioverter-defibrillator (ICD)

• Quinidine

• Catheter ablation

• Screening of family members

It is important to avoid factors that can trigger arrhythmias. Patients should monitor their temperature during infectious illness and take antipyretic therapy for fever. When possible, clinicians should stop any predisposing medications and prescribe alternatives. Patients should avoid substances, particularly cocaine and excessive alcohol, that are arrhythmogenic in Brugada syndrome (for an up-to-date list, see www.brugadadrugs.org).

Patients with a spontaneous or provoked type 1 Brugada syndrome ECG pattern and sustained VT, cardiac arrest, and in some cases syncope presumed to be due to ventricular arrhythmia, should typically have an implantable cardioverter-defibrillator (ICD) (1, 2).

Optimal treatment of Brugada syndrome in patients diagnosed based on ECG pattern and family history but who do not have syncope or arrhythmia is unclear, although they do have increased risk of sudden death. Multiple scoring systems have been developed to aid in determining if an ICD is appropriate therapy in such patients (3, 4, 5).

The role of electrophysiologic testing for risk stratification in patients with type 1 Brugada ECG but no arrhythmia symptoms is currently debated. In asymptomatic patients with a spontaneous type 1 Brugada ECG, inducible ventricular tachycardia or ventricular fibrillation with programmed ventricular stimulation limited to 2 extra stimuli is associated with an increased risk of future serious arrhythmic events (6). Thus, electrophysiology study may be considered in asymptomatic patients with a spontaneous type 1 Brugada ECG, particularly if the result would influence the decision to place an ICD (eg, if inducible ventricular arrhythmia is demonstrated) (1, 2).

When frequent ICD discharges need to be suppressed, or when the patient qualifies for an ICD but declines, quinidine, which blocks the transient outward potassium current that may be increased in Brugada syndrome, should be used, or considered (1, 2). IV isoproterenol has also been used for frequently recurrent ventricular tachyarrhythmias (7). In patients refractory to such therapy, catheter ablation of the arrhythmogenic substrate may be considered (8).

• Brugada syndrome is a genetic disorder causing characteristic ECG changes and an increased risk of ventricular arrhythmias, which can cause syncope and sometimes sudden cardiac death at a relatively young age.

• Risk factors for symptomatic arrhythmias include fever and numerous medications and other substances (eg, alcohol, cocaine).

• Diagnosis is by ECG, sometimes with provocative testing.

• An implantable cardioverter-defibrillator may be required.