Ferri – Brugada Syndrome

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Brugada Syndrome

  • John Wylie, M.D.

 Basic Information

Definition

Brugada syndrome (BRS) is an inherited disorder involving cardiac sodium channels characterized by typical electrocardiographic abnormalities. Patients with a Brugada pattern on ECG and symptoms such as palpitations, syncope, or sudden death are deemed to have BRS. BRS predisposes one to sudden cardiac death (SCD) secondary to polymorphic ventricular tachycardia (PVT)/ventricular fibrillation (VF) in the absence of structural heart disease.

Synonyms

  1. Sudden unexpected nocturnal death syndrome (SUNDS)

ICD-10CM CODES
I49.9 Cardiac arrhythmia, unspecified
I47.2 Ventricular tachycardia

Epidemiology & Demographics

Incidence

The incidence ranges from 1 to 5:10,000 people in Europe and 12:10,000 in Southeast Asia.

Prevalence

It comprises 4% of SCD and 20% of SCD in structurally normal hearts. Although found in every population, the prevalence is much higher in Asian and Southeast Asian countries; in fact in some Southeast Asian countries, such as Laos and Thailand, it may be the most common form of natural death in younger males.

Predominant Sex and Age

BRS is more common in males (58% to 80% of patients). Mean age at presentation is 40 to 45.

Genetics

The disease is autosomal dominant with variable expression (Table 1).

  1. •

    SCN5A, the gene that encodes for the alpha subunit of the cardiac sodium channel, accounts for about 20% to 30% of cases of BRS.

  2. •

    SCN10a, the gene that encodes the Nav1.8 subunit of the sodium channel, has been found in 17% of BRS patients, making it the second most common known mutation.

  3. •

    Known genetic abnormalities are only found in half of patients; thus the impact of genetic testing is limited. When available, it may be useful in identifying silent carriers.

  4. •

    In all genotypes, the basic abnormality is either a decrease in the inward sodium or calcium current or an increase in the outward potassium current.

TABLE1 Molecular Basis of the Brugada SyndromeFrom Issa ZF, et al.: Clinical arrhythmology and electrophysiology: a companion to Braunwald’s heart disease, ed 2, Philadelphia, 2012, Saunders.
Disease Gene Protein Ionic Current Function Inheritance
BrS type 1 SCN5A Nav1.5 Subunit alpha INa Loss Autosomal dominant
BrS type 2 GPD1L G3PD1L Interaction subunit alpha INa Loss Autosomal dominant
BrS type 3 CACNA1C Cav1.2 Subunit alpha ICaL Loss Autosomal dominant
BrS type 4 CACNB2B Cavβ2 Subunit beta ICaL Loss Autosomal dominant
BrS type 5 SCN1B Navβ1/β1b Subunit beta INa Loss Autosomal dominant
BrS type 6 KCNE3 MiRP2 Subunit beta IKs/Ito Gain Autosomal dominant
BrS type 7 SCN3B Navβ3 Subunit beta INa Loss Autosomal dominant

Risk Factors

  1. •

    First-degree relatives with sudden death or known BRS

Physical Findings & Clinical Presentation

  1. •

    Physical exam is usually benign.

  2. •

    Classic ECG finding is a pattern of atypical right bundle branch block (RBBB) with persistent ST elevation of cove-like morphology and T-wave inversion in the anterior leads (V1-V2)

  3. •

    Often an incidental finding diagnosed from a typical ECG pattern

  4. •

    Palpitations

  5. •

    Nocturnal agonal respirations

  6. •

    Syncope

  7. •

    Sudden cardiac arrest (SCA)/SCD secondary to rapid PVT that frequently degenerates into VF more often at night

  8. •

    Fig. 1 illustrates Brugada ECG patterns. Type 1 is the most common and characteristic (Fig. 2).

    FIG.1 

    Brugada ECG patterns.
    A type 1 ECG pattern supports diagnosis of Brugada syndrome. Brugada syndrome can be considered for type 2 or 3 ECG patterns if ECG pattern converts to a type 1 pattern after challenge with a sodium channel blocker.
    From Olshansky B, et al.: Arrhythmia essentials, ed 2, Philadelphia, 2017, Elsevier.
    FIG.2 

    ECG changes in Brugada syndrome.
    ST elevation occurs in the anterior precordial leads, leads V1 and V2. Type 1 (coved) ECGs with 1 mV of ST elevation have the most prognostic significance.
    From Strickberger SA, et al.: AHA/ACCF scientific statement on the evaluation of syncope, J Am Coll Cardiol 47:473–484, 2006.
  9. •

    Type 1 ECG pattern is defined as an elevated ST segment ≥2 mm that descends in a coved pattern to an inverted T wave. This finding can be transient and may be provoked (sodium channel blockers, vagal maneuvers, increased alpha-adrenergic tone, beta-blockers, tricyclic or tetracyclic antidepressants, fever, hypokalemia, hyperkalemia, hypercalcemia, and alcohol and cocaine toxicity).

  10. •

    Type 2 ECG pattern (Fig. 3) is not diagnostic of BRS but may be suggestive and warrant further testing. This pattern is a “saddle back” ST-T wave morphology with an upright or biphasic T wave. Type 2 (formerly known as types 2 and 3) can change to a type 1 pattern with the triggers noted above. Table 2 describes drugs used to unmask Brugada ECG pattern.

    FIG.3 

    Type II Brugada pattern ECG.
    This 12-lead ECG shows a type II Brugada pattern in leads V1 and V2. Whereas a type I ECG pattern supports a diagnosis of Brugada syndrome, Brugada syndrome can be considered for type 2 or 3 ECG patterns (see Fig. 1) if the ECG pattern converts to a type 1 pattern after challenge with a sodium channel blocker.
    From Olshansky B, Chung MK, Pogwizd SM, et al.: Arrhythmia essentials, ed 2, Philadelphia, 2017, Elsevier.
    TABLE2 Drugs Used to Unmask Brugada ECG Pattern
    Drug Dose
    Ajmaline 1-mg/kg IV infusion over 5 min
    Flecainide 2-mg/kg IV infusion over 10 min, maximum 150 mg; or 400 mg PO
    Procainamide 10-mg/kg IV infusion over 10 min
    Pilsicainide 1-mg/kg IV infusion over 10 min

Etiology

  1. •

    Autosomal dominant inheritance with variable penetration.

Diagnosis

Diagnosis is made by the presence of a type 1 ECG and symptoms.

  1. •

    ST segment elevation with type 1 morphology ≥2 mm in one or more right-sided leads (V1-V2), occurring either spontaneously or after provocative drug testing

  2. •

    Type 2 ECG that converts into type 1 following sodium channel blocker (procainamide/flecainide/ajmaline) challenge (Fig. 2)

Differential Diagnosis

A number of diseases can lead to a BRS-like abnormality on the surface ECG, including the following:

  1. •

    Atypical RBBB

  2. •

    Early repolarization

  3. •

    Acute pericarditis

  4. •

    Acute myocardial infarction or ischemia

  5. •

    Pulmonary embolism

  6. •

    Various central and autonomic system abnormalities

  7. •

    Duchenne’s muscular dystrophy

  8. •

    Electrolyte abnormalities such as hyperkalemia and hypercalcemia

  9. •

    Arrhythmogenic right ventricular cardiomyopathy

  10. •

    Pectus excavatum

Workup

  1. •

    Clinical history with special emphasis on syncope, palpitations, nocturnal agonal respirations, and family history.

  2. •

    Echocardiography to rule out structural heart disease. While no structural heart disease is usually apparent, there are some recent reports indicating mild abnormalities in the right ventricle (RV) and left ventricle (LV).

  3. •

    MRI, especially to rule out ARVC (arrhythmogenic right ventricular cardiomyopathy).

  4. •

    Electrophysiology study. No consensus exists on the value of arrhythmia induction in predicting future clinical events in individual patients. However, findings such as HV (His ventricular) conduction interval >60 ms and VERP (ventricular effective refractory period) <200 ms during electrophysiology study can help in supporting a diagnosis. Repeated trials have failed to show a predictive power of electrophysiology study, and although it still exists as a IIb recommendation in the most recent consensus statement, the data supporting this practice are extremely limited, so it remains a matter of controversy.

  5. •

    Laboratory tests are unhelpful. Genetic testing may be helpful for prognosis and family evaluation, but it is not necessary for diagnostic purposes.

  6. •

    First-degree relatives should obtain ECG and be evaluated for symptoms.

  7. •

    Risk stratification in the asymptomatic patient

  8. •

    The following are considered indicators of high risk:

    1. 1.

      Spontaneous type 1 ECG at baseline

    2. 2.

      Presence of fragmented QRS on ECG

    3. 3.

      RVERP (right ventricular effective refractory period) <200 ms on EPS

    4. 4.

      Male sex

    5. 5.

      Spontaneous atrial fibrillation

Note that family history of sudden death is not considered a high-risk feature in BRS.

Treatment

Nonpharmacologic Therapy

  1. •

    The only effective strategy that prevents sudden cardiac death in BRS is implantable cardioverter-defibrillator (ICD). Currently there are no class I recommendations for primary prevention because clinical events are extremely rare, even in high-risk patients. Fig. E4 depicts the algorithm for clinical decision making regarding recommendation of an ICD.

    FIG.E4 

    Consensus recommendations for ICDs in patients diagnosed with Brugada syndrome.
    Priori SG, et al.: HRS/EHRA/APHRS expert consensus statement on the diagnosis and management of patients with inherited primary arrhythmia syndromes, Heart Rhythm 10:1932–1963, 2013.
  2. •

    Definitive candidates for ICD (class I) are patients who survived SCD or have had sustained VT (secondary prevention).

  3. •

    ICD can be useful (class IIa) for patients who have type 1 ECG pattern in the absence of class IC drug test associated with history of syncope.

  4. •

    ICD may be considered (class IIb) if there is inducible VF on electrophysiologic (EP) study, but the literature on EP study in patients with BRS does not support this practice.

  5. •

    Patients with spontaneous type 1 ECG without syncope or inducible VF on EP study or asymptomatic patients with drug-induced type 1 ECG pattern are considered a lower risk group for SCD, and ICD is not indicated in these patients.

Acute General Rx

  1. •

    Isoproterenol (class IIa) may be used for electrical storm.

  2. •

    Quinidine, which blocks both Ito and IKr currents in the RV epicardium, is used in patients with a history of multiple appropriate ICD shocks, as well as for electrical storms and treatment of supraventricular tachycardia (SVT) in these patients. It is also useful in cases where the patient refuses an ICD implant or when an ICD implant is contraindicated.

  3. •

    Radiofrequency ablation: There are a few published case reports of radiofrequency ablation of premature ventricular contractions (PVCs) leading to reduced clinical events. These have been performed in patients already implanted with an ICD. In addition, epicardial substrate ablation in the right ventricular outflow tract (RVOT) has been shown to prevent VF inducibility.

Referral

Consultation with cardiology is strongly recommended if BRS is suspected.

Pearls & Considerations

Comments

  1. •

    The clinical manifestations, such as syncope and SCD, are rare in the pediatric group, but fever can acutely predispose to cardiac arrest. Mean age of presentation is 40 to 45 years.

  2. •

    Cardiac events may occur during sleep, at rest, or after a large meal.

BRS patients should be advised to avoid all drugs that may induce a type 1 ECG pattern and/or be known to trigger ventricular arrhythmias and avoid unnecessary use of drugs (a drug that is not yet identified as potentially dangerous for these patients does not make its use safe). For up-to-date information on this matter, a full list can be found at www.brugadadrugs.org.

  1. •

    Fever may induce the appearance of a type 1 BRS ECG pattern and may trigger episodes of PVT/VF in BRS patients. In the case of fever, close ECG monitoring is appropriate in combination with lowering of the body temperature.

  2. •

    The classic ECG changes in BRS can be transient with patients having normal ECGs in between highly abnormal ones.

  3. •

    The appearance of syncope, seizures, or nocturnal agonal respiration must lead to prompt medical evaluation.

  4. •

    Family screening for BRS in first-degree relatives is strongly recommended.

  5. •

    Although participation in sports is not strictly prohibited, competitive training can lead to development of strong vagal tone and subsequent higher risk of clinical events. Hence, participation in sports at a competitive or professional level is not advised.

  6. •

    Once diagnosed initially by an ECG pattern, all patients must be followed up on a regular basis by an electrophysiologist.

Prevention

Identification of patients with BRS, risk stratification, and appropriate screening of family members are paramount to the prevention of SCD. Patients with known BRS should have fevers aggressively treated with antipyretics and avoid drugs associated with drugs that induce a type 1 pattern.

Patient/Family Education

Immediate family members should be notified and be screened for BRS.

Suggested Readings

  • P. Berne, J. Brugada: Brugada syndrome. Circ J. 76:1563–1571 2012 22789973

  • A.E. Epstein, et al.: ACC/AHA/HRS 2008 Guidelines for device-based therapy of cardiac rhythm abnormalities: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (writing committee to revise the ACC/AHA/NASPE 2002 guideline update for implantation of cardiac pacemakers and antiarrhythmia devices): developed in collaboration with the American Association for Thoracic Surgery and Society of Thoracic Surgeons. Circulation. 117:e350 2008 18483207

  • A.B. Luna, et al.: Current electrocardiographic criteria for diagnosis of Brugada pattern: a consensus report. J Electrocardiol. 45:433–442 2012 22920782

  • S.G. Priori, et al.: HRS/EHRA/APHRS expert consensus statement on the diagnosis and management of patients with inherited primary arrhythmia syndromes. Heart Rhythm. 10:1932–1963 2013 24011539

  • J. Sroubek, et al.: Programmed ventricular stimulation for risk stratification in the Brugada syndrome: a pooled analysis. Circulation. 133:622–630 2016 26797467

  • D.P. Zipes, et al.: ACC/AHA/ESC 2006 Guidelines for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death—executive summary. A report of the American College of Cardiology/American Heart Association Task Force and the European Society of Cardiology Committee for Practice Guidelines (writing committee to develop guidelines for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death). J Am Coll Cardiol. 48:1064 2006

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