2. • 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
3. • 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
4. 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.
5.
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
7. • 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
8. • 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.
9. 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
10. • 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
11. • 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
12. • 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
13. • 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
14. • 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
15.
16.
17. 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
18. 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
19.
20. • 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
21.
22. • 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
23. • 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
24. • 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
25. • 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
26. • 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
27. • Presence of Type 1 ECG abnormality
spontaneously versus after drug challenge
• Inducible ventricular tachyarrhythmias after EP
testing
28. Diagnostic testing and Risk
Stratification
• Drug testing
• Signal Averaged ECG
• Electrophysiological testing
• Genetic testing
29. 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.
30. • 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
31. 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)
32. 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
33. 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%
34. 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
35. • 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
36. 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
37. • 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
38. 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
39. • Patients with AF have a higher risk of VF
• Male gender and family history of SCA also
associated with higher risk
40. 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
41.
42.
43. • 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,
44. • 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
45. 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
46. • 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.
47. • 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
48. • 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
49. • 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.
50. 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.
51. • 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
52. References
• Hurst The Heart 13th Edition
• Braunwald’s Heart Disease 9th Edition
• Brugada Syndrome: Report of the Second
Consensus Conference Circulation 2005:111:659-
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