1. Brugada Syndrome
Dr. Salah Atta, MD
Consultant of Electrophysiology and pacing, SBCC,
Ad-Dammam
Ass. Professor of Cardiology, Assiut Universoity

2. Objectives
 Definition of Brugada Syndrome and
Historical Background
 Presentation and Diagnosis
 Differential Diagnosis
 Genetics and Prevalence.
 Pathophsiology of Brugada Syndromre
 How to know which patient to treat ? (Risk
Stratification)
 How to treat? ( Treatment Options )

3. Brugada Syndrome is…
 Itis an example of an inherited channelopathy
disorder characterized by sudden death due to
ventricular fibrillation or polymorphic VT.
A clinical-electrocardiographic diagnosis based
on syncopal or sudden death episodes in
patients with a structurally normal heart with a
characteristic electrocardiographic pattern
(right bundle branch block, ST segment
elevation in V1 to V3) .

4. Historical Background
Is it Brugada or Martini or whom
syndrome?!
 In 1953, Osher and Wolff reported a dynamic
ECG abnormality (Osher-Wolff ECG), simulating
an acute myocardial infarction, in a healthy man.
The description was similar to Brugada pattern.
A similar ECG pattern, this time associated with
an aborted sudden death and occurring in a 42-
year-old male on the 2nd of October 1984, was
seen in Padua, Italy.

5. Historical Background
 Shortly after, A new “syndrome” characterized by a
clinical event (sudden or aborted sudden death)
associated with the abnormal ECG findings, was first
presented at the National Congress of Italian
Cardiologists by Nava et al. who published the first
ECG characteristic of the syndrome in 1988.
 In 1989 Martini et al described six patients with
apparently idiopathic VF, 3 of them had upsloping ST
elevation, RBBB and inverted T waves. They
documented subtle structural abnormalities in the RV
(Martini B et al. Ventricular fibrillation without
apparent heart disease.. Am Heart J 1989) .

6.  In 1992 Pedro and Josep Brugada described 8
cases and introduced the term ‘Right bundle
branch block, ST segment elevation and sudden
death syndrome’ .
 The first patient in their series with this
syndrome was seen in 1986. The patient was a
three year old boy from Poland. With multiple
episodes of loss of consciousness and the child's
sister had died suddenly at age two after
multiple episodes of aborted sudden death,
both had the characterestic ECG.

7. The ECG of the 1st two patients reported by Brugada et
.al 1992

8. Presentation
 Brugada syndrome patient may present with
syncope due to polymorphic ventricular
tachycardia (VT) or resuscitated sudden
death in the third or fourth decade of life.
affects otherwise healthy men aged 30-50
years, but affected patients aged 0-84 years
have been reported. The mean age of
patients who die suddenly is 41 years
(Antzelevitch C on 2005)

9. Sex:
 Brugada syndrome is 8-10 times more
prevalent in men than in women, although
the probability of having the mutated gene
does not differ by sex. The expression of
the mutation therefore appears to be much
higher in men than in women (Eckardt et al
2008).
 Animal models suggest that the influence of
testosterone on ion currents (particulary outward
K+ currents) may contribute to this finding.

10. Prevalence
 BS is reported to be responsible for 4% of all
sudden deaths and 20% of sudden deaths in those
without structural heart disease and is a leading
cause of death in subjects under the age of 40
years. A family history is present in about 20 to
30% of patients.
 It is difficult to estimate the exact incidence of BS
in the general population but the prevalence is
quoted as 1 in 2000.

11. Prevalence
 The condition is particularly common in South
East Asia and amongst immigrants of South Asian
origin and in the Japanese population the
prevalence is reported to be 0.12 to 0.14%.
 BS has also been reported as Sudden Unexplained
Death Syndrome (SUDS) or Sudden Unexplained
Nocturnal Death Syndrome (SUNDS). The ECG
changes of BS are dynamic and can vary
spontaneously which also makes it difficult to
assess its exact incidence.

12. Genetics
 This condition is genetically transmitted as an
autosomal dominant syndrome with incomplete
penetrance. It is present in a familial and sporadic
pattern.
 Mutations in SCN5A (Locus 3p21-24), which
encodes for the alpha subunit of the cardiac Na+
channel, is found in 18-30% of families with BS.
 This gene defects leads to a number of
abnormalities in the Na+ channel:
– Failure of expression
– Accelerated inactivation
– Prolonged recovery from inactivation

13.  Mutations in SCN5A are also associated with:
– Isolated AV conduction defect
– Congenital long QT syndrome type 3
– Congenital sick sinus syndrome
– Familial dilated cardiomyopathy with conduction
defects and susceptibility to AF.
 Differences in clinical manifestations may be due
to differences in electrophysiologic abnormalities
induced by specific different mutations.

14. AF in Brugada
 Pts with BS are at increased risk of atrial
arrhythmias, which is consistent with the
diffuse nature of the Na+ channel
abnormality.
 In one report where 59 pts with BS were
compared to 31 matched controls,
spontaneous AF occurred in 20% of the BS
pts and none of the controls in three years
of follow up. In this study there was a
significant correlation between the presence
of AF and inducibility of sustained
ventricular arrhythmia at EP
(Brdachar P et al 2004).

15. Diagnostic Criteria
 BS is not well defined. The ECG changes
alone of BS type 1 constitute Brugada
pattern but not BS.
 The first consensus report of 2002 proposed
the diagnostic ECG criteria mentioned
before. In a subsequent consensus report
published in 2005, the definitions were
revised

16. Type I- Diagnostic
 Type I: V1-V3 (in more than
one lead) ST segment
elevation >2mm, “coved”
shape, inverted T-wave.
 Coupled with one of:
– Documented VFib
– Polymorphic VT
– FH of sudden cardiac death
<45 yo
– Type I EKG in family
members
– VT inducable in EP lab
– Syncope
– Nocturnal agonal respiration

17. Types II and III- Suggestive
 II: V1-V3 ST segment elevation
>2mm, “saddleback” shape, pos or
biphasic T.
 III: <1 mm elevation, either coved
or saddleback.
 Appearance of type 2 or 3 ST
elevation (saddle back) in >1 R
precordial lead under baseline
conditions, with conversion to type
1 during Na+ channel blocker
challenge and one of the Features
described previously.
 The criteria is 77% sensitivity
among gene mutation carriers.

18. Drug Challenge Test
– Challenge with sodium channel blockers: In some
patients, the intravenous administration of drugs
that block sodium channels may unmask or modify
the ECG pattern, aiding in diagnosis and/or risk
stratification in some individuals.
– Only In symptomatic patients with the type 2 or 3
patterns, the drug challenge is recommended to
clarify the diagnosis.
– Infuse flecainide 2 mg/kg (maximum 150 mg) over
10 minutes, procainamide 10 mg/kg over 10
minutes, ajmaline 1 mg/kg over 5 minutes, or
pilsicainide 1 mg/kg over 10 minutes with contiuous
ECG and haemodynamic monitoring and readiness
for CPR. (Antzelevitch et al 2005).

19. Provocative Factors
 Many clinical situations have been reported
to unmask or exacerbate the ECG pattern
of Brugada syndrome. Examples are a
febrile state, hyperkalemia, hypokalemia,
hypercalcemia, alcohol or cocaine
intoxication, and the use of certain
medications, including sodium channel
blockers, vagotonic agents, alpha-adrenergic
agonists, beta-adrenergic blockers,
heterocyclic antidepressants, and a
combination of glucose and insulin
(Antzelevitch 2005)

20. Pathophysiology
 The exact mechanisms underlying the ECG
alterations and arrhythmogenesis in
Brugada syndrome are disputed.
(Meregalli PG et al in 2005)
 Brugada syndrome is an example of a
channelopathy, Specifically, in 10-30% of
cases, mutations in the SCN5A gene, which
encodes the cardiac voltage-gated sodium
channel, have been found.

21. Pathophysiology
 During phase 1 of the normal action
potential, the inward Na+ current and
transient outward K+ current, ITo, cause a
normal spike and dome morphology.
 In the presence of weak Na+ current, the
unopposed outward K+ current ITo and
ICa, cause accentuation of the action
potential notch in the RV epicardium,
creating voltage gradient with the
endocardium resulting in accentuated J
wave and ST segment elevation associated
with the Brugada pattern.

23. Pathophysiology
Arrhythmias develop because of
inhomogeneous repolarization in
different areas of the RV epicardium
leading to the so-called phase 2 re-entry
and to the development of closely
coupled extrasystoles leading to VT/VF.
Triggering extrasystoles have left bundle
branch

25. Defective sodium
channels: shorter AP
(phase 0), deeper
notch (phase I), and
shorter phase 2.
Creates juxtaposition
of depolarized and
repolarized cells,
setting up possibility
of PHASE 2
RENTRY, closely
grouped PVCs, and
VT or V Fib.
On EKG, ST segment
not at baseline
because no longer
have uniform
repolarization of the
entire ventricle.
Nattel and Carlsson Nature Reviews Drug Discovery 5, 1034–1049 (December 2006) | doi:10.1038/nrd2112

27. Differential Diagnosis
Atypical right bundle branch block
Left ventricular hypertrophy
Early repolarization
Acute pericarditis
Acute myocardial ischemia or infarction
Prinzmetal angina
Pulmonary embolism
Dissecting aortic aneurysm
Mediastinal tumor or hemopericardium
compressing the right ventricular outflow tract
(RVOT)

28. Differential Diagnosis
Arrhythmogenic right ventricular dysplasia and/or
cardiomyopathy
Various abnormalities of the central and autonomic
nervous systems
Overdose of a heterocyclic antidepressant
Cocaine intoxication
Duchenne muscular dystrophy
Friedreich ataxia
Thiamine deficiency
Hypercalcemia
Hyperkalemia
Hypothermia
Pectus excavatum
Effects of athletic training

29. Risk Stratification
 To identify patients at high risk of SCD
who may benefit from ICD.
 Many studies done for this purpose.
 Prior History of SCA: 69% recur within 5
years. SCD reported in about 8.2% of pts
with BS during 24 months follow up.
 A history of syncope, a spontaneously
abnormal ECG, and inducibility during
programmed electrical stimulation (by one
study) significantly increased this risk
(Brugada J et al in Circulation 2003 ).

31. Risk Straification
 Gehi et al performed a meta analysis of 30
prospective studies on 1,545 patients and
concluded that a history of syncope or
sudden death (SCD), the presence of
spontaneous Type 1 Brugada ECG and male
gender predict a more malignant natural
history. Family history of SCD, the
presence of SCN5A mutation and EPS were
not predictive.
J.Cardiovasc Electrophysiol 2006

32. EPS for risk stratification
 The role of EPS remains controversial in
the Brugada syndrome.
 Electrophysiological testing had a low
positive predictive value (23%), but over a
3-year follow-up, it had a very high
negative predictive value (93%) .

33. EP Testing
 Onestudy by Brugada et al showed that
inducibility may be a good predictor of
outcome.
However, in circulation 2002, Priori
reported a poor predictive value of
invasive EP testing.

34. EP Testing
 The subsequent study by Gehi published in
journal of Carcdiovascular
lectrophysiology, 2006 concluded that EPS
was not of use in guiding the management
of patients with Brugada syndrome . This
was further confirmed in larger recent
studies. (kamakura et al 2009, Probst V et al
Circulation, 2010).

37. Treatment Options
Medical tratment:
 Amiodarone is useless, B blockers and Na+
channel blockers may be deleterious.
 Quinidine, however, may be beneficial. Possibly
by blockade of I(to), the transient outward current,
that increases heterogeneity and may promote
ventricular premature beats and trigger VT or VF.
For this purpose large doses are needed (1200-
1500mg/d (Antzelevitch 1999).
 Isoproterenol, which boosts the L-type calcium
current, can also counteract the ionic current
imbalance and can be used in managing electerical
storms of BS (Antzelevitch 2001).

38. Drug therapy
 So At this stage, apart from quinidine, no
other oral drug therapy is available for
treatment of BS.
 This situation may alter in future;
phosphodiesterase inhibitors and tedesamil
and dimethyl lithospermate B (dmLSB) a
Chinese herbal medicine are drugs that are
being investigated.

39. Prophylactic Measures
 Aggressive treatment of all febrile episodes
is recommended with antipyretics like
aspirin and paracetamol and cold sponges.
 Avoid Hypokalemia
 Avoid large carbohydrate meals and
 Avoid Alcohol and very hot baths.

40. Drugs to be avoided
Drugs that can cause Brugada-like changes on
the ECG are best avoided and include:
 Class 1 antiarrhythmic drugs like flecainide,
 beta and alpha adrenergic blockers,
 Ca++ channel blockers like verapamil.
 Nitrates, K+ channel openers like
nicorandil,
 Tricyclic and Tetracyclic antidepressants,
phenothiazines and SSRI like fluoxetine,
 Alcohol and cocaine intoxication.

41. ICD Therapy
 ICD therapy can prevent SCD in the BS,
however, the risk of SCD varies
significantly from patient to patient.
 Indications for ICD implantation were
published in the report of the Second
Consensus Conference on Brugada
syndrome (Antzelevitch et al 2005)

42. Report of the Second Consensus Conference on Brugada syndrome Antzelevitch et al
2005

43. ICD Recommendations
 In2006 ACC/AHA/ESC issued the following
guidelines regarding BS:
– There is evidence/general agreement to support ICD
implantation in all pt’s with a previous cardiac arrest.
– The weight of evidence/opinion supports the use of an
ICD in pt’s with a spontaneous type 1 ECG and a
history of syncope.
– The weight of evidence/opinion supports ICD
implantation in BS pt’s with a history of VT but not
cardiac arrest.

44. Conclusion
 Brugada Syndrome is an example of
Chanellopathy related disease with special ECG
pattern and risk of sudden cardiac death.
 Genetic origin can only be proved in about 50% of
the cases and mostly related to loss of function
mutation of the Na chnanels.
 The common victim is a middle aged male who is
otherwise healthy and is more prevalent in SE
Asia.

45. Conclusion
 History of Cardiac arrest in addition to type one
ECG pattern are the most important predictive
factors of ominous outcome.
 EP study has a limited and debatable role in risk
stratification of patients.
 Medical treatment may have a role in the acute
situation but ICD is the only definitive treatment
of diagnosed patients at risk of SCD.

46. Thank you