Brugada syndrome (BrS) is a genetic disorder in which the electrical activity of the heart is abnormal due to channelopathy. It increases the risk of abnormal heart rhythms and sudden cardiac death. Those affected may have episodes of syncope. The abnormal heart rhythms seen in those with Brugada syndrome often occur at rest, and may be triggered by a fever.
About a quarter of those with Brugada syndrome have a family member who also has the condition. Some cases may be due to a new genetic mutation or certain medications. The most commonly involved gene is SCN5A which encodes the cardiac sodium channel. Diagnosis is typically by electrocardiogram (ECG), however, the abnormalities may not be consistently present. Medications such as ajmaline may be used to reveal the ECG changes. Similar ECG patterns may be seen in certain electrolyte disturbances or when the blood supply to the heart has been reduced.
There is no cure for Brugada syndrome. Those at higher risk of sudden cardiac death may be treated using an implantable cardioverter defibrillator (ICD). In those without symptoms the risk of death is much lower, and how to treat this group is less clear. Isoproterenol may be used in the short term for those who have frequent life-threatening abnormal heart rhythms, while quinidine may be used longer term. Testing people's family members may be recommended.
The condition affects between 1 and 30 per 10,000 people. It is more common in males than females and in those of Asian descent. The onset of symptoms is usually in adulthood. It was first described by Andrea Nava and Bortolo Martini, in Padova, in 1989; it is named after Pedro and Josep Brugada, two Spanish cardiologists, who described the condition in 1992. Chen Qiuyun first described the genetic abnormality of SCN5A channels.
Signs and symptoms 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. Blackouts may be caused by brief abnormal heart rhythms that revert to a normal rhythm spontaneously. If a dangerous heart rhythm does not stop by itself and is left untreated, the person may have a fatal cardiac arrest. However, blackouts can occur in those with Brugada syndrome despite a normal heart rhythm, because of a sudden drop in blood pressure, known as vasovagal syncope.
The abnormal heart rhythms seen in Brugada syndrome often occur at rest, after a heavy meal, and even during sleep. These situations are linked to periods when the vagus nerve is activated, referred to as periods of high vagal tone. Abnormal heart rhythms may also occur during fever and after excessive alcohol use. Sodium-channel-blocking medications, commonly used to treat cardiac arrhythmia, may also worsen the tendency to abnormal heart rhythms in patients with Brugada syndrome and should be avoided.
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.
A long list of factors that can generate a Brugada ECG pattern have been described, including certain medications, electrolyte disturbances such as a decrease in the levels of potassium in the blood, and a reduction in blood supply to key areas of the heart, specifically the right ventricular outflow tract. Drugs that have been implicated include antiarrhythmic medications such as flecainide, verapamil and propranolol, antidepressants such as amitryptiline, and drugs that enhance vagal tone such as acetylcholine. The ECG pattern can also be seen following excessive use of alcohol or cocaine.
Genetics Brugada syndrome is inherited in an autosomal dominant manner, meaning that only one copy of the defective gene is needed to produce the syndrome. However, a person diagnosed with the condition may be the first in their family to have Brugada syndrome if it has arisen as a new mutation. The gene in which mutations are most commonly found in Brugada syndrome, known as SCN5A, is responsible for the cardiac sodium channel. Mutations in SCN5A associated with Brugada syndrome generally cause the flow of sodium ions to decrease. However, only 20% of cases of Brugada syndrome are associated with mutations in SCN5A, as in the majority of patients with Brugada syndrome genetic testing is unable to identify the genetic mutation responsible. Over 290 mutations in the SCN5A gene have been discovered to date, each altering sodium channel function in subtly different ways. This variation partially explains the differences in severity of the condition between different persons, ranging from a highly dangerous condition causing death at a young age to a benign condition that may not cause any problems at all. However, the genetics of Brugada syndrome are complex, and it is likely that the condition results from the interactions of many genes. Because of these complex interactions, some members of a family who carry a particular mutation may show evidence of Brugada syndrome while other carrying the same mutation may not, referred to as variable penetrance. 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:
Type OMIM Gene Notes BrS1 SCN5A NaV1.5 – α subunit of the cardiac sodium channel carrying the sodium current INa. BrS2 GPD1L Glycerol-3-phosphate dehydrogenase like peptide – reduced GPD1-L activity leads to phosphorylation of NaV1.5 and decreased INa. BrS3 CACNA1C CaV1.2 – α subunit of voltage-dependent calcium channel carrying the L-type calcium current ICa(L). BrS4 CACNB2 CaVβ2B – β-2 subunit of the voltage-gated calcium channel carrying the L-type calcium current ICa(L). BrS5 SCN1B NaVβ1 – β-1 subunit of the sodium channel carrying the sodium current INa. BrS6 KCNE3 MiRP2 – β subunit to voltage-gated potassium channels. Modulates the transient outward potassium current Ito. BrS7 SCN3B NaVβ3 – β-3 subunit of the cardiac sodium channel carrying the sodium current INa.BrS8 KCNJ8 Kir6.1, carries the inward rectifier potassium current IKir.BrS9 CACNA2D1 α2δ subunit of the voltage-gated calcium channel carrying the L-type calcium current ICa(L).BrS10 KCND3 KV4.3, α-subunit of the transient outward potassium channel Ito.BrS11 RANGRF Encodes MOG1 – influences trafficking of NaV1.5.BrS12 SLMAP Sarcolemmal membrane–associated protein, a component of T-tubules and the sarcoplasmic reticulum – influences trafficking of NaV1.5.BrS13 ABCC9 SUR2A, the adenosine triphosphate (ATP)-binding cassette transporter of the IK(ATP) channel.BrS14 SCN2B NaVβ2 – Beta-2 subunit of the cardiac sodium channel carrying the sodium current INa.BrS15 PKP2 Plakophillin-2 – interacts with INa.BrS16 FGF12 Fibroblast growth factor homologous factor-1 – mutation decreases INa. BrS17 SCN10A NaV1.8 – α subunit of the neuronal sodium channel.BrS18 HEY2 Transcription factor identified in genome-wide association study.BrS19 SEMA3A Semaphorin.BrS20 KCNAB2 KVβ2, voltage-gated potassium channel β2 subunit - mutation increases Ito. 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. Brugada syndrome has been described as overlapping with arrhythmogenic right ventricular cardiomyopathy (ARVC) caused by a mutation in the PKP2 gene, causing a Brugada ECG pattern but structural changes in the heart characteristic of ARVC. 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.