Brugada syndrome

Although many people with Brugada syndrome do not have any symptoms, Brugada syndrome may cause fainting or sudden cardiac death due to serious abnormal heart rhythms, such as ventricular fibrillation or polymorphic ventricular tachycardia. == Causes ==

The individual heart muscle cells communicate with each other with electrical signals that are disrupted in those with Brugada syndrome. As a genetic condition, the syndrome is ultimately caused by changes to a person's DNA, known as genetic mutations. The first mutations described in association with Brugada syndrome were in a gene responsible for a protein or ion channel that controls the flow of sodium ions through the cell membrane of heart muscle cells – the cardiac sodium channel. Many of the genetic mutations that have subsequently been described in association with Brugada syndrome influence the sodium current in some way, or affect other ionic currents. Mutations in the SCN5A gene seem to have a prognostic value. Several other genes have been identified in association with Brugada syndrome. Some are responsible for other proteins that form part of the sodium channel, known as sodium channel β subunits (SCN1B, SCN2B, SCN3B) while others form different types of sodium channel (SCN10A). Some genes encode ion channels that carry calcium or potassium ions (CACNA1C, CACNB2, KCND3, KCNE3, KCNJ8, KCNT1), while others generate proteins that interact with ion channels. (GPD1L, PKP2, MOG1, FGF12). Another gene associated with this condition is RRAD. Although CACNA1C variants have been identified in Brugada syndrome patients, the evidence for variants (such as p.A39V and p.G490R) causing genetic aetiology is disputed . The link between Brugada Syndrome and CACNA1C variants is limited and predominantly consists of single-family cases with limited disease segregation. There is currently insufficient evidence for the impact of CACNA1C variants on Brugada Syndrome, as currently corroborated by the Genomics England Panel App. The genes associated with Brugada syndrome and their description include: Some mutations associated with Brugada syndrome can also cause other heart conditions. Those who show more than one cardiac conditions at the same time caused by a single mutation are described as having an 'overlap syndrome'. An example of an overlap syndrome is Brugada and long QT syndrome (LQT3) caused by a mutation in SCN5A that reduces the peak sodium current but simultaneously leaves a persistent current leak. Another example of an overlap syndrome would be Brugada syndrome and major aortopulmonary collateral arteries (MAPCAs) caused by a mutation in KCNT1 that leads to an abnormal gain-of-function in potassium channels of neurons and cardiomyocytes. == Mechanisms ==

The abnormal heart rhythms seen in those with Brugada syndrome are typically dangerous arrhythmias such as ventricular fibrillation or polymorphic ventricular tachycardia, but those with BrS are also more likely to experience rapid heart rates due to less dangerous arrhythmias such as AV nodal re-entrant tachycardia and abnormally slow heart rhythms such as sinus node dysfunction. There are several mechanisms by which the genetic mutations causing this condition might produce these arrhythmias. Some argue that the main reason these arrhythmias arise is due to abnormally slow electrical conduction in areas of the heart, specifically the right ventricle. The genetic variants associated with BrS support the concept as SCN5A, the gene most commonly associated with the condition, along with SCN10A, SCN1B, SCN2B and SCN3B, all directly affect the sodium current INa. The sodium current is a major contributor to the characteristic flow of electrical charge across the membrane of heart muscle cells that occurs with each heartbeat known as the action potential. INa causes the initial rapid upstroke of the action potential (phase 0), and decreasing the early peak current, as occurs in BrS-associated genetic variants, leads to slowing of the electrical conduction through the heart muscle. This slow conduction allows 'short circuits' to form, blocking the waves of electrical activity in some areas while allowing the waves to pass in others in a phenomenon known as wavebreak. Given the right circumstances, this wavebreak can allow the waves of electricity to perform a U-turn within the muscle, travelling in the reverse direction before beginning to rapidly circle around a point, referred to as re-entry, and causing an abnormal heart rhythm. Those who support this view (known as the depolarisation hypothesis) argue that conduction slowing may explain why arrhythmias in those with Brugada syndrome tend to occur in middle age, when other factors such as scarring or fibrosis that accompany old age have exacerbated the tendency to conduction slowing caused by the genetic mutation. Others suggest that the main cause of arrhythmias is a difference in the electrical properties between the inside (endocardium) and outside (epicardium) of the heart (known as the repolarisation hypothesis). The shape of the action potential differs between the epicardium and the endocardium. The action potential in cells from the epicardium shows a prominent notch after the initial spike due to a transient outward current. This notch is far less evident in cells from the endocardium, and the difference between the endocardium and epicardium are most clearly seen in the right ventricle. In those with Brugada syndrome, these differences are increased, creating a brief period within each cardiac cycle when current flows from the endocardium to the epicardium creating the characteristic ECG pattern. The differences in electrical properties between the epi- and endocardium are described as a 'transmural dispersion of repolarisation" which if large enough can lead to electrical impulses becoming blocked in some regions but not others. Once again, this wavebreak can allow the waves of electricity which usually travel in only one direction to instead begin circling around a point as a re-entrant circuit, causing an arrhythmia. A further factor promoting arrhythmias in Brugada syndrome is changes to the structure of the heart. Whilst the heart of those with Brugada syndrome may look normal, scarring or fibrosis is often seen in particular regions of the heart, specifically the right ventricular outflow tract. As Brugada syndrome can be caused by mutation in many different genes, it is possible that different mechanisms may be responsible for the arrhythmias seen in different patients. == Diagnosis ==

Electrocardiography Brugada syndrome is diagnosed by identifying characteristic patterns on an electrocardiogram. although the Type 3 pattern is frequently merged with the Type 2 pattern in contemporary practice. • Type 1 has a coved type ST elevation with at least 2 mm (0.2 mV) J-point elevation and a gradually descending ST segment followed by a negative T-wave. The most commonly used drugs for this purpose are ajmaline, flecainide, and procainamide, with some suggestions indicating that ajmaline may be the most effective. Precaution must be taken in giving these medications as there is a small risk of causing abnormal heart rhythms. Other investigations Invasive electrophysiological studies, in which wires are passed through a vein to stimulate and record electrical signals from the heart, can sometimes be used to assess the risk of a person with Brugada syndrome experiencing dangerous abnormal heart rhythms. Risk stratification is also sometimes performed using a signal averaged ECG. File:Brugada syndrome type1 example1 (CardioNetworks ECGpedia).png|Type 1 Brugada ECG pattern (note non-standard lead position, V5 is placed one intercostal space above V1 and V6 is placed one intercostal space above V2).. File:Brugada syndrome type2 example1 (CardioNetworks ECGpedia).png|Type 2 Brugada ECG pattern == Treatment ==

The main aim when treating people with Brugada syndrome is to reduce the risk of sudden death due to serious abnormal heart rhythms such as ventricular fibrillation or polymorphic ventricular tachycardia. While some with this condition are at high risk of serious heart rhythm disturbances, others are at much lower risk, meaning that some may require more intensive treatment than others. and treating fever promptly with an antipyretic. Implantable defibrillator In people felt to be at higher risk of sudden cardiac death, an implantable cardioverter-defibrillator (ICD) may be recommended. An ICD can also function as a pacemaker, preventing abnormally slow heart rates that can also occur in people with Brugada syndrome. Implanting an ICD is a relatively low-risk procedure and is frequently performed as a day case under local anaesthetic. Because of the small risk associated with implanting an ICD, as well as the cost of the devices, ICDs are not recommended for all people with Brugada syndrome but are instead reserved for people deemed at higher risk of sudden cardiac death. It is most frequently used in people with Brugada syndrome who have an ICD and have experienced several episodes of life-threatening arrhythmias, but may also be used in people at high risk of arrhythmias but in whom an ICD is not appropriate. In this procedure, wires are passed through a vein in the leg into the heart, or through a small hole underneath the sternum. These wires are used to find the area of the heart responsible for initiating the arrhythmias. The tip of one of these wires is used to make a series of tiny burns, intentionally damaging the area of abnormal heart muscle that has been causing the problem. Current recommendations suggest that this treatment should be reserved for those with Brugada syndrome who have had repeated shocks from an ICD. == Epidemiology ==

Between 1 and 30 per 10,000 people are affected by Brugada syndrome. Brugada syndrome is more common in people of Asian descent and is the most common cause of sudden death in young males without known underlying cardiac disease in Thailand and Laos. In these countries Brugada syndrome is likely to be responsible for many cases of sudden unexpected nocturnal death syndrome (SUNDS). Local names vary – in the Philippines the condition has been known as Bangungut meaning "a scream followed by sudden death during sleep", == History ==

Brugada syndrome is named after the Spanish cardiologists Josep and Pedro Brugada who described the condition in 1992, Brugada syndrome was described as a cause for the sudden unexplained cardiac death syndrome seen in Thai men in 1997. The first genetic mutations affecting the SCN5A gene associated with the syndrome were identified by their brother Ramon Brugada in 1998, with many more mutations affecting at least 19 genes subsequently identified by others. Studies in the 2000s led to competing theories surrounding the mechanisms by which abnormal heart rhythms were generated. Research into Brugada syndrome is ongoing, identifying new genetic variants, exploring mechanisms of arrhythmias, and searching for better treatments. == Society and culture ==

• A 1992 segment of the television series Unsolved Mysteries profiled the Guamanian Santos family that had lost various members due to unidentified heart issues. Surviving members of the family were ultimately diagnosed with Brugada syndrome. • The British television soap opera EastEnders featured a storyline in which one of the characters experienced cardiac arrest due to Brugada syndrome. • In episode 8 of the 8th season of the TV sitcom Scrubs ("My Lawyer's in Love"), Perry Cox asks a final question of intern Ed which he is unable to answer. He is subsequently fired. One correct answer to his question is Brugada Syndrome, while Long QT syndrome would have also been an acceptable answer. • In "Transplant", Season 2, Episode 2, a patient of South Asian descent is diagnosed with it. • Season 3 Episode 8 of St. Elsewhere "Sweet Dreams" references Sudden Unexplained Nocturnal Death Syndrome with a storyline about a Filipino man admitted with tightness in his chest and arm pain who dies in his sleep with his hair turning white. == See also ==