Brugada Syndrome

Alternative names

• Also known as sudden unexplained nocturnal death syndrome (SUNDS) and idiopathic ventricular fibrillation.
• SUNDS has been described in Southeast Asia under regional terms:
  • Bangungut (Philippines)
  • Lai tai (Thailand)
  • Pokkuri (Japan)
• SUNDS and Brugada syndrome are now recognised as the same clinical and genetic entity.

Electrocardiographic hallmark

• Type 1 Brugada pattern: coved ST-segment elevation (≥2 mm) with a negative T wave in leads V1–V2, recorded in the second to fourth intercostal spaces.

Genetics

• Brugada syndrome is inherited in an autosomal dominant pattern with variable expressivity and reduced penetrance.
• The first genetic association described was a loss-of-function mutation in the SCN5A gene, which encodes the cardiac sodium channel NaV1.5.
• SCN5A variants are the only mutations consistently considered definitely disease-causing, and are found in approximately 20–30% of patients. Nearly 300 distinct SCN5A mutations have been reported.
• Other implicated genes account for 2–5% of cases, including:
  • CACNA1C and CACNB2, encoding L-type calcium channel subunits, associated with Brugada syndrome and short QT interval.
  • GPD1-L, which influences trafficking of sodium channels.
  • SCN1B, encoding a sodium channel β-subunit.
  • Other less well-established genes and variants, some of which may be rare or population-specific.
• Genetic heterogeneity and reduced penetrance mean that not all carriers manifest disease, and additional genetic or environmental modifiers influence phenotype.

Environmental and acquired triggers

• Features of Brugada syndrome may be unmasked or exacerbated in genetically predisposed individuals by:
  • Febrile illness, which can induce type 1 ECG changes and precipitate arrhythmias. Prevalence of Brugada syndrome has been reported to be significantly higher among febrile patients in endemic regions compared with controls.
  • Medications such as sodium channel blockers (e.g., flecainide, procainamide), psychotropic agents (e.g., tricyclic/tetracyclic antidepressants, lithium), and local anaesthetics.
  • Illicit substances including alcohol and cocaine.
  • Electrolyte disturbances, particularly hyperkalaemia, hypokalaemia, and hypercalcaemia.
  • Other physiological conditions, such as increased vagal tone or insulin/glucose administration.

Genetic and ionic mechanisms

• In approximately 20–30% of cases, mutations in the SCN5A gene (encoding the cardiac sodium channel NaV1.5) are identified. These loss-of-function variants reduce inward sodium current (INa), slowing the upstroke of the cardiac action potential (phase 0) and shortening its duration. Over 300 distinct SCN5A mutations have been described.
• Other implicated genes include SCN10A, sodium channel β-subunits (such as SCN1B), and genes involved in NaV1.5 trafficking or expression, as well as calcium (CACNA1C, CACNB2) and potassium channel genes. However, only SCN5A mutations are consistently considered definitively pathogenic.
• Experimental data show that temperature influences sodium channel function, with higher temperatures further reducing current, which explains the frequent arrhythmic events seen during fever.

Repolarisation and depolarisation hypotheses

• Two main mechanistic models have been proposed:
  • Repolarisation disorder hypothesis: enhanced transient outward potassium current (Ito) in right ventricular epicardial cells leads to a prominent action potential notch compared with endocardial cells. This transmural voltage gradient generates the characteristic ST-segment elevation and may predispose to phase 2 re-entry and malignant arrhythmias.
  • Depolarisation disorder hypothesis: slow conduction through the right ventricular outflow tract results in activation delays, producing the Brugada ECG pattern and creating a substrate for reentrant arrhythmias.
• Some clinical and experimental findings support a combined mechanism, where conduction abnormalities (depolarisation disorder) give rise to secondary repolarisation changes. Ajmaline provocation studies, for example, have demonstrated concordant repolarisation and conduction abnormalities.

Histological and structural abnormalities

• Although traditionally regarded as a purely electrical disease, structural changes in the right ventricular outflow tract have been described in some patients. These include:
  • Fibrosis and increased collagen deposition
  • Fatty infiltration and inflammatory changes
  • Reduced expression of connexin-43, impairing intercellular coupling
• These abnormalities may contribute to areas of delayed conduction, fractionated electrograms, and localised arrhythmogenic substrate. Catheter ablation targeting these sites can abolish Brugada ECG changes and prevent recurrent ventricular arrhythmias.

Functional consequences

• When repolarisation remains balanced, a saddleback ST elevation (type 2 or 3 ECG pattern) is observed.
• When repolarisation gradients are sufficiently altered, inversion of the T wave with a coved ST elevation occurs, corresponding to the diagnostic type 1 Brugada pattern.
• Heterogeneous depolarisation and repolarisation abnormalities predispose to re-entrant arrhythmias such as polymorphic ventricular tachycardia and ventricular fibrillation.

Prevalence

• The overall prevalence of Brugada syndrome is estimated at 3–5 per 10,000 individuals worldwide.
• When considering only type 1 Brugada ECG patterns (diagnostic of the syndrome), prevalence is approximately 1 in 2000.
• Type 2 or type 3 ECG patterns, which are not diagnostic but require further investigation, occur in about 1 in 500 individuals.
• Prevalence estimates vary widely due to the intermittent nature of the ECG findings and the fact that many individuals remain asymptomatic.

Age distribution

• Brugada syndrome is most frequently diagnosed in young to middle-aged adults, typically between 30 and 50 years of age.
• The mean age at sudden cardiac death in Brugada syndrome is around 41 years.
• The condition is rare in children, with an estimated prevalence of approximately 1 in 20,000, but it is implicated in 4–12% of sudden cardiac deaths in children and young athletes.

Sex distribution

• Brugada syndrome is 8–10 times more common in men than in women.
• This difference is not observed in childhood, suggesting that hormonal factors, particularly testosterone, and sex-related variations in ionic currents influence disease expression after puberty.
• Although the likelihood of carrying a pathogenic mutation is similar between sexes, penetrance is markedly higher in men.

Geographic distribution

• Brugada syndrome occurs more commonly in Asia than in Europe or North America.
• Southeast Asia reports the highest prevalence, where it has long been recognised under local terms such as bangungut (Philippines), lai tai (Thailand), pokkuri (Japan), and bei gui ya (China).
• In Northeast Thailand, Lai Tai is responsible for a mortality rate of approximately 30 cases per 100,000 population per year.
• It is the leading cause of natural death in men under 40 years of age in parts of Southeast Asia.
• By contrast, the lowest prevalence is reported in North Africa.

Contribution to sudden cardiac death

• Brugada syndrome is responsible for about 4% of all sudden cardiac deaths globally.
• It accounts for approximately 20% of sudden unexplained deaths in young people with structurally normal hearts.

Symptom spectrum

• Patients with Brugada syndrome may present with a wide range of symptoms, from complete absence of complaints to sudden cardiac death.
• Syncope is one of the most common presentations, occurring in up to one third of patients and often due to ventricular tachycardia (VT) or ventricular fibrillation (VF).
• Cardiac arrest frequently occurs during sleep or rest, thought to be related to increased vagal tone.
• Palpitations, dizziness, nightmares, or nocturnal thrashing movements may precede syncope or cardiac arrest.
• Many patients remain asymptomatic and are only identified following incidental ECG findings.

Triggers and inducible features

• Fever is a well-recognised trigger that can unmask the type 1 Brugada ECG pattern and precipitate arrhythmic events. Prevalence of Brugada syndrome among febrile patients has been reported up to 20-fold higher than in non-febrile controls in endemic regions.
• Certain medications, particularly sodium channel blockers (e.g., flecainide, procainamide), tricyclic/tetracyclic antidepressants, lithium, and local anaesthetics, can precipitate diagnostic ECG changes or trigger arrhythmias.
• Illicit drugs such as cocaine, as well as alcohol, have been associated with arrhythmic events and unmasking of Brugada ECG patterns.

Atrial arrhythmias

• Atrial fibrillation or flutter may be the initial presenting feature, particularly in younger patients (<30 years).
• Concomitant atrial arrhythmias occur in approximately 10% of cases and may signal higher arrhythmic risk.

Nocturnal agonal respirations

• Nocturnal gasping or agonal respirations during sleep have been described in up to 14% of patients and may represent aborted arrhythmias.
• These symptoms are considered significant, especially as they overlap with early descriptions of sudden unexplained nocturnal death syndrome (SUNDS) in Southeast Asia, now understood to be phenotypically and genetically linked to Brugada syndrome.

Family history

• A family history of Brugada syndrome or unexplained sudden cardiac death, particularly before the age of 45, should be sought.
• Although not universally present (28% of patients lack a positive family history), this remains an important diagnostic clue.
• The Shanghai diagnostic score assigns weight to a history of Brugada syndrome, suspicious sudden cardiac death (e.g., nocturnal, febrile, or drug-related), or unexplained sudden cardiac death in young relatives.

Risk-related historical features

• Male sex and age between 30 and 50 years are commonly associated with higher arrhythmic risk.
• Younger patients, including infants, may rarely present with life-threatening arrhythmias; in women, serious arrhythmic events may occur more frequently during childhood or later in life.
• Asian ancestry, particularly Southeast Asian populations, carries increased prevalence and risk, consistent with epidemiological data.
• A history of cardiogenic syncope increases risk for malignant arrhythmias, with studies showing a 2.5–5-fold higher risk of serious events compared to patients with non-cardiogenic syncope.

General examination

• Most patients with Brugada syndrome have a normal physical examination.
• The primary role of the clinical exam is to exclude other structural or functional cardiac abnormalities that could explain syncope or cardiac arrest.
• Heart murmurs suggesting hypertrophic cardiomyopathy, valvular heart disease, or septal defects should be sought, as these represent alternative causes.

Arrhythmic events

• In patients presenting after unexplained cardiac arrest or documented polymorphic ventricular tachycardia (PMVT) or ventricular fibrillation (VF), Brugada syndrome should be considered, particularly if the ECG demonstrates a Brugada pattern.
• Monomorphic VT may occasionally occur but is rare; this finding should prompt evaluation for other arrhythmogenic cardiomyopathies.

Inducible features

• Febrile illness can trigger type 1 Brugada ECG changes and provoke arrhythmias; therefore, clinical signs of fever may have diagnostic and prognostic relevance.
• Certain medications, psychotropic drugs, local anaesthetics, and sodium-channel blockers may precipitate Brugada ECG patterns; clinicians should be alert to patients under treatment with these agents.
• Evidence of alcohol intoxication or substance use, including cocaine, may be relevant if examination coincides with arrhythmic risk.

Atrial arrhythmias

• Atrial fibrillation or flutter is not usually detected on general examination unless coinciding with presentation, but may manifest as an irregular pulse.
• Identification of atrial arrhythmia in younger patients should prompt consideration of Brugada syndrome, especially when associated with type 1 ECG findings.

Nocturnal features

• Witnessed nocturnal agonal respirations or abnormal breathing patterns during sleep may be reported by relatives and should be carefully documented.
• Such findings are clinically significant as they overlap with sudden unexplained nocturnal death syndrome (SUNDS), considered phenotypically and genetically the same as Brugada syndrome.

Risk-related physical findings

• Although examination is typically normal, clinical context is important:
  • Patients aged 30–50 years are more likely to present with their first serious arrhythmic event.
  • Patients over 50 years tend to have a lower incidence of malignant events, and their mortality risk approaches that of the general population.
  • Male sex and Asian ancestry correlate with higher prevalence and risk, though these are determined by epidemiological background rather than physical exam findings.
• Family history may not be evident on physical exam but should be actively sought during assessment; unexplained sudden cardiac death in young relatives increases suspicion.

Initial approach

• Many patients with Brugada syndrome are young, otherwise healthy, and present with syncope. Syncope should not be assumed to be benign, and a 12-lead ECG is essential in all such patients.
• If the ECG shows a Brugada pattern, further diagnostic evaluation should follow.
• When the ECG is equivocal, additional tests including drug challenge, imaging, or genetic testing may be required.

Electrocardiography

• A 12-lead ECG is the cornerstone of diagnosis.
• Three Brugada ECG patterns are recognised:
  • Type 1: coved ST-segment elevation ≥2 mm with a negative T wave in V1–V2 (diagnostic).
  • Type 2: saddleback ST elevation ≥1 mm.
  • Type 3: saddleback ST elevation <1 mm.
• Moving right precordial leads to higher intercostal spaces (second or third) can increase diagnostic sensitivity.
• Exercise stress testing may suppress typical ECG changes and arrhythmias.
• Additional ECG markers under study include prolonged QRS duration, inferolateral repolarisation abnormalities, and a terminal S wave in lead I.

Provocative drug testing

• Indicated for patients with type 2 or type 3 ECG patterns, or equivocal findings but high clinical suspicion.
• Sodium channel blockers (flecainide, procainamide, ajmaline, pilsicainide) may unmask a type 1 Brugada pattern.
• Continuous cardiac monitoring is essential, as drug testing can precipitate ventricular arrhythmias.
• Test is positive if a diagnostic type 1 pattern emerges (coved ST elevation ≥2 mm with a negative T wave in V1–V2)
• Not indicated in patients with spontaneous type 1 Brugada pattern, as this already establishes diagnosis.
• Reported sensitivity varies; arrhythmia induction occurs in approximately 1–2% of challenges.

Laboratory studies

• Serum potassium and calcium should be checked, as hyperkalaemia and hypercalcaemia can mimic Brugada-like ST changes.
• Cardiac enzymes (CK-MB, troponin) help exclude acute coronary syndromes in patients with chest pain or suggestive features.

Genetic testing

• Testing for SCN5A mutations may be considered when clinical suspicion is high or when type 1 Brugada pattern is confirmed.
• Supports diagnosis and is particularly important for family screening.
• Pathogenic variants are identified in only 20–30% of patients, and the absence of a mutation does not exclude the diagnosis.

Imaging

• Echocardiography and cardiac MRI are performed to exclude structural heart disease (e.g., arrhythmogenic right ventricular cardiomyopathy, hypertrophic cardiomyopathy, myocarditis, coronary anomalies).
• In some patients, MRI may show subtle right ventricular outflow tract dilation or fibrosis, but Brugada syndrome is generally considered an electrical disease rather than a structural cardiomyopathy.

Signal-averaged ECG

• May help differentiate Brugada syndrome from arrhythmogenic right ventricular cardiomyopathy by detecting late potentials associated with fibrofatty replacement.

Electrophysiological (EP) study

• Used in some centres to assess arrhythmia inducibility.
• The prognostic value is debated: some studies suggested inducibility predicts adverse outcomes, while others found no correlation.
• Current evidence suggests that clinical features (e.g., spontaneous type 1 ECG, history of syncope) are more predictive than EP study findings.

Additional considerations

• Nocturnal agonal respirations, history of fever, or family history of sudden cardiac death should be integrated with investigation findings for risk stratification.
• Referral to a cardiologist or electrophysiologist is recommended for any patient with a type 1 pattern, whether spontaneous or drug-induced.

Arrhythmogenic cardiomyopathy

• Inherited condition caused by defective desmosomal proteins, leading to fibrofatty replacement of myocardium.
• Commonly presents in the young with ventricular arrhythmias.
• Cardiac MRI often reveals right ventricular or outflow tract abnormalities, contrasting with Brugada syndrome, where imaging is usually normal
• ECG shows T-wave inversion in right precordial leads, sometimes with epsilon waves. Unlike Brugada syndrome, changes are fixed rather than dynamic.

Hypokalaemia

• Frequently results from gastrointestinal losses, diuretic therapy, or renal tubular acidosis, and can mimic Brugada-like ECG changes.
• ECG features include ST-segment depression, flattened T waves, and prominent U waves, particularly in lateral precordial leads.
• Serum potassium <3.5 mmol/L confirms diagnosis.
• Arrhythmias may include atrial or ventricular ectopy, atrioventricular block, or ventricular fibrillation.

Acute coronary syndrome

• Ischaemia, especially in the right coronary or left anterior descending artery, may produce precordial ST-segment elevation that resembles Brugada ECG changes.
• Differentiated by clinical features such as chest pain, sweating, and nausea, together with cardiovascular risk factors.
• Raised cardiac biomarkers (troponin, CK-MB) support myocardial infarction.

Athlete’s heart

• Physiological remodelling in male endurance athletes.
• ECG shows early repolarisation with upsloping ST elevation, in contrast to the coved morphology of Brugada syndrome.
• The Corrado index (STJ/ST80 ratio) is <1 in athletes but >1 in Brugada syndrome.
• Echocardiography demonstrates chamber enlargement and symmetric hypertrophy, which regress on detraining.

Incomplete right bundle branch block (RBBB)

• Distinguished from Brugada syndrome by ECG findings:
  • Terminal R wave in V1 is sharp and narrow, not broad and rounded.
  • QRS complex duration in V1–V2 matches V6.
  • Presence of a wide S wave in lateral leads, usually absent in Brugada syndrome.

Pectus excavatum

• Congenital chest wall deformity visible on physical examination.
• ECG may show negative P wave in V1, a tall R wave, and mild ST elevation.
• Diagnosis is confirmed by CT imaging showing sternal depression.

Risk of arrhythmia and sudden death

• Brugada syndrome predisposes to polymorphic ventricular tachycardia which may degenerate into ventricular fibrillation and cardiac arrest.
• Prolonged cardiac arrest can result in neurological sequelae due to hypoxia.
• ICDs reduce mortality risk but carry complications including inappropriate shocks and device-related problems.
• In follow-up studies, sudden cardiac death or ventricular fibrillation occurred in approximately 8% of patients over two years.
• Brugada syndrome is estimated to account for about 4% of all sudden deaths and up to 20% of sudden deaths in patients with structurally normal hearts.
• Mean age at sudden death is around 41 years (±15).

Prognostic markers

• High-risk features consistently associated with adverse outcomes include:
  • Previous resuscitated cardiac arrest.
  • History of cardiogenic syncope.
  • Spontaneous type 1 Brugada ECG pattern.
• Additional markers may include early repolarisation patterns, QRS fragmentation, and multiple spontaneous type 1 ECGs on follow-up.
• Electrophysiological study inducibility has shown variable prognostic value across studies.

Genetic influence

• Patients carrying SCN5A mutations often present at a younger age and demonstrate more severe electrophysiological abnormalities.
• These include higher incidence of spontaneous type 1 ECG changes, significant conduction or repolarisation disturbances, and increased atrial arrhythmia burden.
• Consequently, SCN5A mutation carriers generally have a worse prognosis compared to mutation-negative patients.

Age and sex

• Male sex is strongly associated with both higher prevalence and greater arrhythmic risk.
• Patients aged 30–50 years represent the peak risk group for life-threatening events.
• Diagnosis at age ≥55 years is generally linked to a more favourable prognosis, with mortality rates similar to those of the general population.

Dangerous arrhythmias

• The central complication of Brugada syndrome is the development of malignant ventricular arrhythmias, particularly polymorphic ventricular tachycardia and ventricular fibrillation.
• These rhythm disturbances can cause sudden loss of consciousness (syncope), cardiac arrest, or sudden cardiac death.
• Even in patients who are asymptomatic, the first manifestation may be a life-threatening arrhythmic event.
• Some individuals may experience prodromal symptoms such as dizziness, palpitations, or a racing heartbeat before a serious arrhythmia occurs.

Atrial arrhythmias

• Atrial arrhythmias, particularly atrial fibrillation and flutter, occur in around 10% of patients.
• These may appear at any point in the disease course and sometimes represent the first detectable abnormality.
• Their presence adds complexity to management due to risks of thromboembolism and difficulties with ICD programming.

Serious arrhythmic events and sudden death

• Brugada syndrome accounts for up to 28% of sudden cardiac deaths in individuals with apparently normal hearts.
• Between 5–10% of patients who survive resuscitated cardiac arrest are later diagnosed with Brugada syndrome.
• Around 1 in 25 patients are found to have had a cardiac arrest at the time of their initial diagnosis.
• In patients without ICDs, the annual incidence of sudden cardiac death is estimated at approximately 0.19%.
• Those with cardiogenic syncope have a markedly higher annual risk of malignant arrhythmias, approaching 1.4%.
• Most events arise from ventricular fibrillation initiated by short-coupled premature ventricular complexes.

ICD-related complications

• Implantable cardioverter-defibrillators (ICDs) are a cornerstone of prevention but carry important risks, especially as many recipients are under 50 years old.
• Reported complications include lead fracture, infection, and inappropriate shocks.
• A meta-analysis estimated a 4.5% annual incidence of ICD-related complications and 3.5% annual rate of inappropriate shocks.
• These risks emphasise the need to balance benefits of ICD therapy against long-term device-related morbidity, particularly in asymptomatic or lower-risk individuals.

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