Brugada Syndrome

Dr. Gagan V

• The Brugada syndrome is an autosomal dominant genetic disorder with variable expression characterized by abnormal findings on the surface electrocardiogram (ECG) in conjunction with an increased risk of ventricular tachyarrhythmias and sudden cardiac death.

• Typical ECG changes comprise of pseudo RBBB with ST elevation in V1-V3

• Brugada pattern versus syndrome

• Brugada pattern - Patients with typical ECG features but no clinical criteria

• Brugada syndrome - patients with typical ECG features and either of sustained VT ,sudden cardiac death or other clinical criteria

History• Pedro and Josep Brugada described the

syndrome in 1992 - ST-segment elevation in the right precordial electrocardiographic leads and a high incidence of sudden death in individuals with structurally normal hearts

• Right bundle branch block, persistent ST segment elevation and sudden cardiac death: a distinct clinical and electrocardiographic syndrome. A multicenter report J Am Coll Cardiol. 1992 Nov 15;20(6):1391-6.

Epidemiology• Brugada pattern

• Majority affected are asians

• Japan 0.7 and 1.0 percent. Finnish Type 2 and Type 3 ST elevation in 0.6 percent, no type 1 noted. US population 0.4 and 0.012 percentage in separate cohorts

• ECG pattern is dynamic and may be concealed, hence true incidence may be difficult

• Median age 41±15 years

• 4% of all sudden deaths and 20% sudden death in structurally normal heart

• More common in males than females

• higher rate of syncope and sudden death

• Impact of testosterone on ion currents especially outward potassium currents may be contributory

• Brugada syndrome among Brugada pattern

• Metaanalysis of 30 reports showed 10 percent event rate at 2.5 years

• Risk stratification of individuals with the Brugada electrocardiogram: a meta-analysis.

• Gehi AK, Duong TD, Metz LD, Gomes JA, Mehta D

• Cardiovasc Electrophysiol. 2006 Jun;17(6):577-83.

Pathogenesis• Genetics

• Loss of function mutations in SCN5A(3p21-24) coding for Alpha subunit of cardiac sodium channel

• The defective myocardial sodium channels reduce sodium inflow currents, thereby reducing the duration of normal action potentials. In addition, a prominent transient outward current, called I(to), in the right ventricular epicardium further shortens the action potential

• Additional genes implicated

• Cardiac calcium channel gene

• locus on chromosome 3p22-25

• Mutations in KCNE3 and KCNE2 causing gain of function in the transient outward current (Ito)

• SCN1B, GPD1-L

• Microscopic structural abnormalities and fibrosis

• Standard cardiac testing reveal no abnormalities

• Mouse model of heterozygous SCN5A knockout revealed age-dependent fibrosis and marked slowing of conduction velocity in the right ventricle

• There is some evidence that subtle structural or microscopic abnormalities occur, including dilation of the right ventricular outflow tract and localized inflammation and fibrosis

• Ventricular arrhythmias and phase two reentry

• Ventricular arrhythmias may result from the heterogeneity of myocardial refractory periods in the right ventricle.

• This heterogeneity arises from the presence of both normal and abnormal sodium channels in the same tissue, and from the differential impact of the sodium current in the three layers of the myocardium

• Autonomic tone

• An imbalance between sympathetic and parasympathetic tone may be important in the pathogenesis of Brugada syndrome, as suggested by the nocturnal occurrence of the associated tachyarrhythmias and the alteration of typical ECG changes by pharmacologic modulation of autonomic tone

• Fever

• fever is a trigger for ECG changes and cardiac arrest

• Cocaine abuse and psychotropic drugs

• Cocaine acts like class I anti arrhythmic drug via sodium channel blockade, brugada ECG patterns can be transiently induced

• Neuroleptic drugs, tricyclic antidepressants which block sodium channels can also cause brugada pattern

Clinical Features• Brugada syndrome comprises of typical ECG features

with clinical features of ventricular arrhythmias

• Sudden cardiac arrest may be initial presentation in one third of patients

• Syncope with features suggestive of tachyarrhtythmia associated syncope

• Palpitations due to ventricular arrhythmias not common, however can occur due to atrial fibrillation

• nocturnal agonal respiration may also occur

ECG Patterns• Pseudo RBBB with ST elevation in V1-V3

• Classic Brugada Type 1

• elevated ST segment (>2mm) descending with upward convexity to inverted T wave (“coved type”)

• Type 2

• ST segment elevated (>2mm) saddle back configuration

• Type 3

• Morphology either Type 1 or Type 2 but ST elevation < 2mm

• Moving the right precordial chest leads superiorly to the second or third intercostal space or using bipolar chest leads may increase the sensitivity of detecting these abnormalities

• Widened S wave characteristic of RBBB is absent

• QT prolongation can be seen in right precordial leads

• Fluctuations in ECG pattern may occur over time

• Also exclude other factors namely

• Atypical RBBB, LVH, Early repolarization, acute pericarditis, Acute MI, pulmonary embolism, Prinzmetal angina, dissecting aortic aneurysm, autonomic nervous abnormalities, Duchenne muscular dystrophy, hypothermia, hyperkalemia, hypercalcemia, ARVD, pectus excavatum, mechanical compression of RVOT by mediastinal tumor/hemopericardium

• Brugada like ECG can occur after DC cardioversion briefly or for few hours

• Provoking factors

• ECG abnormalities can be unmasked by

• Sodium channel blocker e.g.: Flecainide, procainamide, ajmaline

• Pacing, vagal manœuvres increased alpha adrenergic tone

• Beta blockers, TCAs, lithium, alcohol and cocaine toxicity

• Fever, hypokalemia, hyperkalemia and hypercalcemia

• Sudden cardiac arrest and syncope

• Most important clinical manifestations

• Due to ventricular tachyarrhythmias

• Occur between ages 22 and 56, more common at night than day, more during sleep than awake

• SCA not usually related to exercise

• Frequent premature VPCs are seen prior to onset of arrhythmia

• Atrial fibrillation

• Patients with Brugada syndrome are more prone to atrial tachyarrhythmias especially atrial fibrillation

• Patients with AF indicate greater disease severity and higher chance for ventricular fibrillation

• Due to diffuse nature of myocardial sodium channel abnormality

• Nocturnal agonal respiration

• Gasping breaths during sleep, may represent aborted arrhythmia

• ominous symptom

• Equivalent of syncope/ventricular arrhythmia

• Asymptomatic patients

• Risk of cardiac arrest much less

• subgroups at risk

• Presence of Type 1 ECG abnormality spontaneously versus after drug challenge

• Inducible ventricular tachyarrhythmias after EP testing

Diagnostic testing and Risk Stratification

• Drug testing

• Signal Averaged ECG

• Electrophysiological testing

• Genetic testing

Drug testing• Type 1 Brugada ECG can be unmasked by sodium channel

blockers

• Not recommended in patients who have documented ventricular fibrillation, polymorphic ventricular tachycardia, unexplained syncope strongly suggestive of a tachyarrhythmia, or nocturnal agonal respiration

• For patients whose resting ECG shows either the type 2 or 3 Brugada pattern and who have a family history of sudden cardiac death at less than 45 years of age and/or a family history of type 1 Brugada pattern ECG changes

• For patients whose resting ECG shows either the type 2 or 3 Brugada pattern who are asymptomatic and have no family history of sudden cardiac death, drug challenge not recommended.

• Drugs for drug challenge

• Flecainide – 2 mg/kg over 10 minutes intravenously or 400 mg PO

• Procainamide – 10 mg/kg over 10 minutes intravenously

• Ajmaline – 1 mg/kg over five minutes intravenously

• Pilsicainide – 1 mg/kg over 10 minutes intravenously

• Termination of drug challenge

• Development of a diagnostic type 1 Brugada ECG pattern

• ≥2 mm increase in ST segment elevation in patients with a type 2 Brugada ECG pattern

• Development of ventricular premature beats or other arrhythmias

• Widening of the QRS ≥30 percent above baseline

• Requires continuous ECG monitoring, sustained ventricular arrhythmias can occur

Signal Averaged ECG• The signal-averaged electrocardiogram (SAECG) is

a computerized technique for detecting subtle abnormalities in the surface electrocardiogram (ECG) that are not visible to the naked eye.

• In a prospective study of 43 patients with Brugada syndrome, the presence of late potentials on signal-averaged electrocardiogram was significantly predictive of arrhythmic events. Patients with late potentials had a significantly higher arrhythmic event rate over 34 month follow-up compared with those without late potentials (72.4 versus 14.3 percent)

Electrophysiological Testing

• Not necessary in patients with known or suspected Brugada

• Unlikely to impact treatment in patients with known Brugada and high risk features

• EP testing results have been inconsistent

• Inducible ventricular arrhythmia during EP testing predictor of future arrhythmic events

• Not proven in all studies

Genetic testing• Sequencing of SCN5A

• Family screening and risk stratification

• Limited utility as presence does not confirm Brugada and absence does not exclude Brugada

• Only 15 - 30 percent of patients have mutation in SCN5A

• Not all patients with mutation have Brugada, average penetrance noted is 16%

Diagnosis and criteria

• Diagnosis is made from clinically significant events and typical ECG events

• Type 1

• Appearance of type 1 ST segment elevation (coved type) in more than one right precordial lead (V1 - V3) in the presence or absence of a sodium channel blocker, plus at least one of the following:

• Documented ventricular fibrillation

• Polymorphic ventricular tachycardia (VT)

• Family history of sudden cardiac death at less than 45 years of age

• Family history of type 1 Brugada pattern ECG changes

• Inducible VT during electrophysiology study

• Unexplained syncope suggestive of a tachyarrhythmia

• Nocturnal agonal respiration

• Type 2

• Appearance of type 2 ST segment elevation (saddle-back type) in more than one right precordial lead under baseline conditions, with conversion to type 1 following challenge with a sodium channel blocker, plus at least one of the following:

• Documented ventricular fibrillation

• Polymorphic ventricular tachycardia (VT)

• Family history of sudden cardiac death at less than 45 years of age

• Family history of type 1 Brugada pattern ECG changes

• Inducible VT during electrophysiology study

• Unexplained syncope suggestive of a tachyarrhythmia

• Nocturnal agonal respiration

Differential Diagnosis• Differential diagnosis of Brugada pattern

• Atypical right bundle branch block

• Arrhythmogenic right ventricular cardiomyopathy

• Early repolarization

• Acute pericarditis

• Acute myocardial ischemia or infarction

• Hypothermia

• Differential diagnosis of VT or sudden death in structurally normal heart

• Congenital long QT syndrome (LQTS)

• Acquired LQTS with polymorphic ventricular tachycardia (VT)

• Catecholaminergic polymorphic VT

• Idiopathic VT

• Idiopathic ventricular fibrillation

• Short QT syndrome

• Commotio cordis

Prognostic Factors• Patients presenting with aborted sudden death

are at highest risk of recurrence (69% at 54±54 months of followup)

• Syncope and type 1 ECG have recurrence rate of 19% at 26±36 months of followup

• Among asymptomatic patients, patients with spontaneous type I pattern had highest risk

• Those with ECG changes provoked only by drugs had least risk

• Patients with AF have a higher risk of VF

• Male gender and family history of SCA also associated with higher risk

Treatment

• Drug therapy of little use hence ICD implantation almost first line therapy for all patients

• Patients with regular arrhythmias may need antiarrhythmics to decrease frequency of ICD shocks

• Patients with Brugada pattern do not require any therapy

• In one early non-randomized study of 63 patients with the Brugada syndrome in which patients received either an ICD (35 patients), pharmacologic therapy (15 patients), or no specific therapy (13 patients) and were followed for nearly three years, 32 percent developed ventricular arrhythmias. There were no deaths in the ICD group compared with mortality rates of 26 and 31 percent among those treated pharmacologically or not treated,

• The role of the ICD in patients with Brugada syndrome and a lower risk profile is less clear

• Potential therapeutic role for cardiac pacing - arrhtyhmias, SCA at sleep/rest and associated with slow heart rates

• Focal RF ablation of the Ventricular premature beats that trigger VF/VT is potentially valuable

Drug Therapy• In contrast to the known benefits of ICD for the

termination of ventricular arrhythmias and prevention of sudden cardiac death (SCD), there are no proven pharmacologic treatments for preventing SCD in the Brugada syndrome

• Data suggesting benefit from quinidine

• Beneficial effect of quinidine is postulated to be mediated by blockade of I(to), the transient outward current, that increases heterogeneity and may promote ventricular premature beats that act as the trigger for VT/VF

• Other class I antiarrhythmic drugs may be deleterious, particularly sodium channel blockers

• sodium channel blockade can induce ventricular premature beats or ventricular tachycardia in patients with Brugada syndrome

• Amiodarone is the most effective agent for the prevention of ventricular tachyarrhythmias, although there are more potential side effects with its use than with most other antiarrhythmic agents.

• The administration of cilostazol, a phosphodiesterase inhibitor that impairs platelet aggregation and is approved for the treatment of intermittent claudication, may have a beneficial effect in patients with the Brugada syndrome by mediating an increase in calcium current and reduction in I(to) due to an increase in heart rate.

• Tedisamil an experimental antiarrhythmic agent which blocks ITO is a therapeutic candidate. May be more potent than quinidine because it lacks the relatively strong inward current blocking actions of quinidine

• Goal is to develop a cardioselective and specific blocker ITO

• Screening of first degree relatives

• All first degree relatives to undergo clinical history and 12 lead ECG

• First degree relatives with history of syncope and Type 1 ECG - diagnostic of Brugada syndrome, and treated accordingly

• First degree relatives no history of syncope but with Type 1 ECG - Brugada syndrome without symptoms, treated accordingly

• First degree relatives with history of syncope and normal appearing ECG - indeterminate

• Followup with serial ECGS 3 to 4 times over 1 to 2 years

• Can be considered for provocative pharmacological challenge

• Symptomatic younger patients should receive annual ECGS as ECG changes can appear later in life

• First degree relatives with no syncope and normal ECGs are considered negative screening, no followup needed.

Sudden Unexpected Nocturnal Death Syndrome

(SUNDS)• Described in young, apparently healthy males from

Southeast Asia

• lai tai (death during sleep) in Thailand, bangungut (to rise and moan in sleep followed by death) in the Philippines, and pokkuri (unexpected sudden cardiac death at night) in Japan

• A low serum potassium level may contribute to sudden cardiac arrest (SCA) in these patients.

• High carbohydrate meal may precipitate SCA, perhaps by increasing the secretion of insulin which drives extracellular potassium into cells.

• Majority of patients with SUNDS have the ECG manifestations of Brugada syndrome

• Have mutations in SCN5A

• SUNDS and Brugada syndrome are phenotypically, genetically, and functionally the same disorder

• Management should be as same as that of Brugada

References

• Hurst The Heart 13th Edition

• Braunwald’s Heart Disease 9th Edition

• Brugada Syndrome: Report of the Second Consensus Conference Circulation 2005:111:659-670