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[[Image:Brugada.png|thumb|right|Typical ECG abnormalities in Brugada syndrome: ST elevation in V1-V3, without ischemia.]]
''By: Louise R.A. Olde Nordkamp, Arthur A.M. Wilde''
[[Image:Brugada_ecg_characteristics.png|thumb|right|Typical ECG abnormalities in Brugada syndrome]]
[[Image:brugada.jpg|thumb|right|Dr. Pedro Brugada. Pedro and Josep Brugada described in 1992 a landmark publication with a case-series of 8 patients with sudden cardiac death. <cite>Brugada</cite> Currently, three brothers of the Brugada family (Pedro, Josep and Ramon Brugada) conduct research in the syndrome that has been named after them.]]
[[Image:scn5a.jpg|thumb|right|The SCN5a gen is located on the short arm (p) of chromosome 3]]


The '''Brugada syndrome is an hereditary disease that is associated with high risk of sudden cardiac death'''. It is characterized by typical ECG abnormalities: '''ST segment elevation in the precordial leads (V1 - V3)'''.
[[Image:Brugada.png|thumb|right|Typical ECG abnormalities in Brugada syndrome: ST elevation in V1-V3, without ischemia.<cite>Wilde</cite>]]
'''Brugada syndrome''' refers to a hereditary disease that is associated with a risk of sudden cardiac death. It is characterized by typical ECG abnormalities: ST segment elevation in the precordial leads (V1 - V3).<cite>Brugada</cite>


==Characteristics of the Brugada syndrome:==
The Brugada brothers were the first to describe the characteristic ECG findings and link them to sudden death. Before that, the characteristic ECG findings, were often mistaken for a right ventricle myocardial infarction and already in 1953, a publication mentions that the ECG findings were not associated with ischemia as people often expected.


*Inheritable arrhythmia syndrome with [[w:Autosomal_dominant|autosomal dominant]] inheritance. If one of the two parents is affected, each child (both males and females) has a 50% chance of inheriting the disease.
==General features==
*Males are more often symptomatic than females, probably by the influence of sex hormones on cardiac arrhythmias and/or ion channels, and a different distribution of ion channels across the heart in males versus females.
*The diagnosis is based on ECG findings.
*The arrhythmias usually occur in patients between 30 and 40 years of age. (range 1-77 yrs) and often during rest or while sleeping (high vagal tone).
*It is an inheritable cardiac arrhythmia <cite>Brugada2</cite> syndrome with an autosomal dominant inheritance.
*In only about 30% of patients, genetic defects can be detected in the ([http://ghr.nlm.nih.gov/gene=scn5a SCN5A]) gene which encodes the cardiac sodium channel (loss-of-function mutation). In much smaller quantities, mutations may be found in the GPD1L gene (which probably influences cardiac sodium channel function) or in cardiac calcium channel encoding genes (CACNxxx). In the remaining patients, the disease is probably multi-genetic or caused by yet unknown genetic defects.
*Males are often more symptomatic than females, probably by the influence of sex hormones on cardiac arrhythmias and/or ion channels.
*The right ventricle is most affected in Brugada syndrome, and particularly (but not specifically) the right ventricular outflow tract .
*The arrhythmias typically occur in patients between 30-40 years of age and often during rest or while sleeping.
*The prevalence varies between 5-50:10.000, largely depending on geographic location. In some southeast Asian countries the disease is considered endemic and believed to be the second cause of death among young men (after car accidents). In these countries Brugada syndrome is believed to underly (in part) the 'Sudden Unexpected Death Syndrome' (SUDS). This relation has, however, not been thoroughly investigated and there are almost no epidemiological studies into Brugada syndrome ECGs (apart from Japan). In different Asian countries, different names have been given to SUDS: in the Phillipines it is called ''bangungut'' (to rise and moan in sleep) and in Thailand ''lai tai'' (death during sleep).  
*The right ventricle is most affected in Brugada syndrome, and particularly (but not specifically) the right ventricular outflow tract.


The Brugada brothers were the first to describe the characteristic ECG findings and link them to sudden death. Before that, the characteristic ECG findings, were often mistaken for a [[Right_Ventricle_MI|right ventricle myocardial infarction]] and already in 1953, a publication mentions that the ECG findings were not associated with ischemia as people often expected.<cite>osher</cite>
*The prevalence varies between 5-50:10.000, largely depending on the geographic location (especially in some Southeast Asian countries the disease is more prevalent).  


==Genes linked to the Brugada Syndrome==
 
{| class="wikitable" border="0" cellpadding="0" cellspacing="0" width="800px"
==Clinical diagnosis==
The clinical diagnosis of Brugada syndrome is confirmed in an individual with the following:
 
{| class="wikitable"
|-
! colspan="2" align=left | '''Findings'''
|-
|-
!colspan="6"|Table 2: Here is a list of the Genes linked to the Brugada syndrome.
| ECG || Type 1 ECG with coved type ST-elevation
|- align=center
|-
|'''Type'''
! colspan="2" align=left | '''And at least one of the following'''
|'''OMIM'''
|'''Gene'''
|'''Protein'''
|'''Functional role in cardiomyocytes'''
|'''Effect of mutation'''
|-
!colspan="6"|Autosomal dominant inheritance
|-
|BrS1
|#601144
|SCN5A
|Na<sub>v</sub>1.5
|&alpha; subunit of I<sub>Na</sub> channel
|Loss of function of I<sub>Na</sub>
|-
|BrS2
|#611777
|GPD1-L
|G3PD1L
|Not fully established
|Loss of function of I<sub>Na</sub>
|-
|BrS3
|#611875
|CACNA1C
|Ca<sub>v</sub>1.2
|&alpha;<sub>1C</sub> subunit of I<sub>Ca,L channel</sub>
|Loss of function of I<sub>Ca,L</sub>
|-
|BrS4
|#611876
|CACNB2b
|Ca<sub>v</sub>&beta;2b
|&beta;2b subunit of I<sub>Ca,L</sub> channel
|
|-
|BrS5
|#612838
|SCN1B
|Na<sub>v</sub>&beta;1
|&beta; subunit of I<sub>Na</sub> channel
|Loss of function of I<sub>Na</sub>
|-
|-
|BrS6
| rowspan="8" | '''Clinical history'''
|#613119
|KCNE3
|KCNE3 (MiRP2)
|&beta; subunit of voltage-dependent K<sup>+</sup> channels
|Gain of function of I<sub>to</sub>
|-
|-
|BrS7
| - Documented ventricular fibrillation
|#613120
|SCN3B
|Na<sub>v</sub>&beta; 3
|&beta; subunit of I<sub>Na</sub> channel
|Loss of function of I<sub>to</sub>
|-
|-
|NC
| - Self-terminating polymorphic ventricular tachycardia
|#613123
|HCN4
|HCN4
|&alpha; subunit of I<sub>f</sub>
|Gain of function of I<sub>f</sub>
|-
|-
|NC
| - Syncope
|
|CACNA2D1
|Ca<sub>v</sub>&alpha;<sub>2</sub> &delta;-1
|</sub>&alpha;<sub>2</sub> &delta; subunit of I<sub>Ca,L</sub> channel
|Loss of function of I<sub>Ca,L</sub>
|-
|-
|NC
| - A family history of sudden cardiac death <45yrs
|
|MOG1
|MOG1
|Regulates tra?cking of Na<sub>v</sub>1.5 to the membrance
|Loss of function of I<sub>Na</sub>
|-
|-
|NC
| - Coved-type ECGs in family members
|
|KCND3
|K<sub>v</sub>4.3
|&alpha; subunit of I<sub>to</sub> channel
|Gain of function of I<sub>to</sub>
|-
|-
|NC
| - Inducibility of VT/VF during programmed electrical stimulation
|
|KCNE1L (KCNE5)
|KCNE1L
|&beta; subunit of voltage-dependent K<sub>+</sub> channels
|Gain of function of I<sub>to</sub>
|-
|-
|NC
| - Noctural agonal respiration
|
|KCNJ8
|K<sub>ir</sub>6.1
|&alpha; subunit of I<sub>K,ATP</sub>
|Gain of function of I<sub>K,ATP</sub>
|-
|NC
|
|SCN1B''b''
|Na<sub>v</sub>&beta;1B
|&beta; subunit of I<sub>Na</sub>
|Loss of function of I<sub>Na</sub> and gain of function of I<sub>to</sub>
|-
|colspan="6" bgcolor="#99CCFF"|OMIM: Online Mendelian Inheritance in Man compendium of human genes and genetic phenotypes; BrS1–BrS7: Brugada syndrome types 1–7; NC: no consensus; I<sub>Ca,L</sub>: L-type calcium current; I<sub>f</sub>: hyperpolarization-activated current; I<sub>K,ATP</sub>: ATP-sensitive potassium current; I<sub>Na</sub>: fast sodium current; I<sub>to</sub>: transient outward potassium current.
|}
|}


==Diagnosis and treatment==
==Physical examination==
Patients can present with symptoms of arrhythmias:
*Out-of-hospital-cardiac-arrest
*Syncope, pre-syncope (weakness, lightheadedness, dizziness)
*Chest pain
*Shortness of breath
*Paleness
*Sweating


*Patients who are symptomatic (unexplained syncopes, ventricular tachycardias or aborted sudden cardiac death) may have a symptom recurrence risk of 2 to 10% per year. In these patients an [[:w:nl:Internal_Cardiac_Defibrillator|ICD]] implant is advisable. Further, life-style advice is given (see below).
Other clinical presentations of Brugada syndrome may include sudden infant death syndrome (SIDS) and sudden unexpected nocturnal death syndrome (SUDS), which is seen in southeast Asia in which young persons die from cardiac arrest with no identifiable cause (also known as ''bangungut'' in the Philippines, ''lai tai'' in Thailand, ''pokkuri'' in Japan and ''dab tsog'' in Laos.
*Some groups advise an electrophysiological investigation (inducibility of ventricular fibrillation) for risk assessment in Brugada patients,<cite>brug2</cite><cite>brug3</cite> but others could not reproduce the predictive value of these tests,<cite>priori</cite><cite>eckhardt</cite> so the value of inducibility is controversial.
*In large studies familial sudden death did not appear to be a risk factor for sudden death in siblings.
*In asymptomatic patients in whom the Brugada ECG characteristics are present (either spontaneously or provoked by fever or sodium channel blockers like ajmaline, procainimde or flecainide) life style advice is given. This advice includes:
**A number of medications should not be taken (including sodium channel blockers and certain anti-depressants and anti-arrhythmics, see [http://www.brugadadrugs.org www.BrugadaDrugs.org])
**Rigorous treatment of fever with paracetamol/Tylenol, as fever may elicit a Brugada ECG and arrhythmias in some patients.
* Spontaneous Type I ECGs do appear to be more prevalent in patients who experienced symptoms.


For a full list of the diagnostic criteria, see <cite>Wilde</cite>
However, most patients with Brugada syndrome are asymptomatic and are under medical attention because of family screening for sudden cardiac death/Brugada syndrome or because a Brugada ECG was found coincidentally.


==Electrocardiographic criteria==
==ECG tests==
[[Image:Brugada_lead_placement.png|thumb|right|Changed lead positions of leads V3 and V5 to increase the sensitiviy to 'catch' a Brugada pattern on the ECG]]
[[File:PlaatjesBrS_graphs.svg|thumb|right|400px|<cite>Brugada2</cite>]]
Three ECG repolarization patterns in the right precordial leads are recognized in the diagnosis of Brugada syndrome.
The ECG in Brugada syndrome is characterized by ST-segment elevations directly followed by a negative T-wave in the right precordial leads (V1-V3) and in leads positioned one or two intercostal space higher. It is referred to as a coved type Brugada ECG, or type 1 ECG, and cannot be explained by electrolyte disturbances, ischemia or structural heart disease. This specific ECG hallmark typically fluctuates over time, and can also be presented as a type 2 or type 3 ECG or even a normal ECG. The type 2 ST-segment elevation has a saddleback appearance with a high takeoff ST-segment elevation of ≥ 2mm, a trough displaying ≥1mm, and then either a positive or a biphasic T wave. Type 3 has either a saddleback or coved appearance with a ST-segment elevation of <1mm (figure 1). Type 2 and 3 are not diagnostic of the BrS. In some patients a type 1 ECG may only be unmasked or modulated by sodium channel blockers (such as ajmaline or flecainide) a febrile state, vagotonic agents, α-adrenergic agonists, β-adrenergic blockers, tricyclic or tetracyclic antidepressants, a combination of glucose and insulin, hyperkalemia, hypokalemia, hypercalcemia, and alcohol or cocaine toxicity.
[[Image:Brugada_syndrome_type1_example2.png|thumb|300px|An example of a Brugada type I ECG]]


'''Type I''' is the only ECG criterion that is diagnostic of Brugada syndrome. The type I ECG is characterized by a J elevation >=2 mm (0.2 mV) a coved type ST segment followed by a negative T wave (see figure). Brugada syndrome is definitively diagnosed when a type 1 ST-segment is observed in >1 right precordial lead (V1 to V3) in the presence or absence of a sodium channel–blocking agent, and in conjunction with one of the following:
==Genetic diagnosis==
*documented ventricular fibrillation (VF)
In only ~30% genetic variants can be detected in the SCN5A<cite>SCN5A</cite> gene, which results in a loss of function of the cardiac sodium channel function. This impairs the fast upstroke in phase 0 of the action potential and leads to conduction slowing in the heart. In the remaining patients sometimes cardiac calcium channel genes (CACNxxx) or potassium channel genes (KCNxx) are involved, but in most of the Brugada syndrome patients no genetic defects are found.<cite>FINGER</cite>
*polymorphic ventricular tachycardia (VT)
*a family history of sudden cardiac death at <45 years old
*coved-type ECGs in family members
*inducibility of VT with programmed electrical stimulation
*syncope
*nocturnal agonal respiration.
The sensitivity of the ECG for Brugada syndrome can be increased with placement of ECG leads in the intercostal space above V1 and V2 (V1ic3 and V2ic3)


Electrocardiograms of Brugada patients can change over time from type I to type II and/or normal ECGs and back.
A type III ECG is rather common and is considered a normal variant, but also the Type II is a normal variant (albeit suggestive of Brugada syndrome).


A recent study suggests that''' fractionation of the QRS complex''' is a marker of a worse prognosis in Brugada syndrome.<cite>Morita</cite>
==Risk Stratification==
[[File:PlaatjesBrS_pyramid.svg|thumb|right|400px|Risk stratification scheme according to clinical variables in Brugada syndrome
<cite>priori</cite>]]
Brugada syndrome patients with symptoms (a history of VT/VF or cardiac syncope) and spontaneous coved-type ECG are at risk for future arrhythmic events. However, risk stratification<cite>strat</cite> in asymptomatic Brugada syndrome patients is still ill-defined. Family history of sudden cardiac death, male gender and inducibility of VT/VF during programmed electrical stimulation<cite>PRELUDE</cite> is not consistently shown to be a risk factor. Therefore, risk stratification is best done by an expert cardio-genetics cardiologist.<cite>priori</cite>


{| class="wikitable" font-size="90%"
==Treatment==
|- style="text-align:center;background-color:#6EB4EB;"
===Lifestyle modification===
|+'''ST segment abnormalities in the different types of Brugada syndrome'''<cite>Wilde2</cite>
*All Brugada syndrome patients should avoid drugs that could manifest a type 1 ECG and VF. These drugs are listed on [http://www.brugadadrugs.org www.BrugadaDrugs.org].
|-
*Fever may also provoke type 1 ECG and VF. Patients with fever are advised to go to the hospital to make an ECG. When ECG changes are present, monitoring is warranted and antipyretics are needed.
!
!Type I
!Type II
!Type III
|-
!J wave amplitude
|>= 2mm
|>= 2mm
|>= 2mm
|-
!T wave
|Negative
|Positive or biphasis
|Positive
|-
!ST-T configuration
|Coved type
|Saddleback
|Saddleback
|-
!ST segment (terminal portion)
|Gradually descending
|Elevated >= 1mm
|Elevated < 1mm
|-
|}


 
===Medication/Other therapies:===  
<gallery caption="Examples of Brugada syndrome type I">
*[[ICD]] implantation is first line therapy in Brugada patients with a previous cardiac arrest, [[ventricular tachycardia]] or cardiac [[syncope]]. ICD implantation in asymptomatic patients is not advised and needs careful judgement regarding the low annual rate of arrhythmic events and high incidence rate of complications (7.5 per 100 patient-years).  
Image:Brugada_syndrome_type1_example1.png
*In Brugada patients with recurrent VF events or ICD shocks, isoproterenol or quinidine are known to be effective for VF suppression in both children and adults.  
Image:Brugada_syndrome_type1_example2.png
*Ablation of a fractionated electrogram in the epicardial right ventricular outflow tract is a promising option for VF suppression in Brugada patients in a small study, but still has to be proven in larger cohorts of Brugada patients.
Image:Brugada_syndrome_type1_example3.png
Image:Brugada_syndrome_type1_example4.png
Image:Brugada_syndrome_type1_example5.png
Image:Brugada_syndrome_type1_example6.jpg|Brugada ECG during ajmaline testing
</gallery>
<gallery caption="Examples of Brugada syndrome type II">
Image:Brugada_syndrome_type2_example1.png
Image:Brugada_syndrome_type2_example2.jpg
</gallery>
 
==External links==
*Cardiogenetics website of the AMC [http://www.cardiogenetica.nl cardiogentica.nl]
*[http://www.brugada.org Brugada.org ]
*[http://www.genereviews.org/servlet/access?id=8888891&key=ghdBRjkdNXE6y&gry=INSERTGRY&fcn=y&fw=E0gK&filename=/profiles/brugada/index.html Genereview Brugada]
*[http://www.brugadadrugs.org Brugada drugs contains lists of medications that should be avoided in patients with Brugada syndrome and medication that can be used to diagnose the syndrome]


==References==
==References==
<biblio>
<biblio>
#Brugada pmid=1309182
#Wilde pmid=15898165
#Wilde pmid=15898165
#Brugada pmid=1309182
#osher pmid=13104407
#brug2 pmid=11772879
#brug3 pmid=12776858
#priori pmid=11901046
#priori pmid=11901046
#Wilde2 pmid=12417552
#strat pmid=16836701
#Morita pmid=18838563
#SCN5A pmid=20031634
#eckhardt pmid=15642768
#FINGER pmid=20100972
#PRELUDE pmid=22192666
#Brugada2 pmid=22715240
</biblio>
</biblio>
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