Index
It is a genetic condition that causes abnormal electrical activity in the heart and increases the risk of sudden cardiac death.
Those affected may have episodes of fainting.
The abnormal heart rhythm often occurs when a person is resting and can be triggered by fever.
Often, the condition is inherited from a person’s parents; approximately a quarter of the people have a family history. Some cases may be due to a new mutation or certain medications.
The most commonly involved gene is SCN5A, which creates the cardiac sodium channel. The diagnosis is typically by electrocardiogram (ECG). However, the abnormalities may not be present consistently.
Medications such as ajmaline can be used to reveal changes in the electrocardiogram. Similar electrocardiogram patterns can 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 can be treated with an implantable cardioverter-defibrillator (ICD).
In those without symptoms, the risk of death is much lower, and the way of treating this group is less clear.
Isoproterenol can be used in the short term for those who have abnormal heart rhythms that are life-threatening frequently, while quinidine can be used in the long term. Tests can be recommended to family members of people.
The condition affects between 1 and 30 per 10,000 people. It is more common in men than women of Asian descent.
The onset of symptoms is usually in adulthood. It is named after the Spanish cardiologists Pedro and Josep Brugada, who described the disease in 1992. His brother Ramón Brugada was the first to describe a possible genetic cause in 1998.
Signs and symptoms
Although many people with Brugada syndrome have no symptoms, Brugada syndrome can cause fainting or sudden cardiac death due to severe abnormal heart rhythms, such as ventricular fibrillation or polymorphic ventricular tachycardia.
Blackouts can be caused by abnormal and brief heart rhythms spontaneously returning to normal. If a dangerous heart rhythm does not stop on its own and is not treated, the person may have a fatal cardiac arrest.
However, blackouts may occur in those with Brugada syndrome despite a normal heart rhythm due to 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, or even during sleep.
These situations are related to the periods when the vagus nerve is activated, known as periods of high vagal tone.
Abnormal heart rhythms can also occur during fever or after an excess of alcohol.
Certain medications can also worsen the tendency to abnormal heart rhythms in patients with Brugada syndrome and should be avoided by these patients.
Causes
Individual cells of the heart communicate with each other with electrical signals, which are altered in people with Brugada syndrome.
As a genetic condition, the syndrome is ultimately caused by changes in a person’s DNA, known as genetic mutations.
The first mutations associated 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 cardiac 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 or affect other ion currents.
A long list of factors can generate a Brugada electrocardiogram pattern has been described.
It includes certain medications and electrolyte disturbances, such as decreased potassium levels and reduced blood supply to critical areas of the heart, specifically the right ventricle outflow tract.
Medications that have been implicated include antiarrhythmic medications such as flecainide, verapamil, and propranolol, antidepressants such as amitriptyline, and medications that improve vagal tone such as acetylcholine.
The electrocardiogram pattern can also be observed after excessive use of alcohol or cocaine.
Genetics
Brugada syndrome is inherited in an autosomal dominant manner, which means 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 emerged as a new mutation.
The gene in which mutations are found most frequently in Brugada syndrome, known as SCN5A, is responsible for the cardiac sodium channel.
Mutations in the SCN5A gene associated with Brugada syndrome generally decrease the flow of sodium ions, known as the loss of function mutations.
However, only 20% of cases of Brugada syndrome are associated with mutations in SCN5A since, in most patients with Brugada syndrome, genetic tests can not identify the responsible genetic mutation.
More than 290 mutations in the SCN5A gene have been discovered, each of which alters the function of the sodium channel in subtly different ways.
This variation partially explains the severity of the condition between different people, ranging from a hazardous condition that causes death at a young age to a benign condition that may not cause any problems.
However, the genetics of Brugada syndrome is complex, and the condition is likely the result of the interactions of many genes.
Due to these complex interactions, some members of a family that carry a particular mutation may show evidence of Brugada syndrome. In contrast, others with the same mutation may not refer to variable penetrance.
Several other genes have been identified in association with Brugada syndrome.
Some are responsible for other proteins part of the sodium channel, known as β subunits (SCN1B, SCN2B, SCN3B). In contrast, others form different types of sodium channels (SCN10A).
Some genes encode ion channels that carry calcium or potassium ions (CACNA1C, CACNB2, KCND3, KCNE3, KCNJ8), while others generate proteins that interact with ion channels. (GPD1L, PKP2, MOG1, FGF12).
Some mutations associated with Brugada syndrome can also cause other heart conditions.
Those that show more than one heart condition simultaneously caused by a single mutation are described with an ” overlap syndrome. “
An example of an overlap syndrome is Brugada and long QT syndrome (LQT3), caused by a mutation in the SCN5A gene that reduced the maximum sodium current but at the same time left a persistent current leak.
Brugada has been described as an overlap with arrhythmogenic myocardiopathy of the right ventricle, caused by a mutation in the PKP2 gene, which causes a Brugada electrocardiogram pattern but structural changes in the heart, characteristic of arrhythmogenic myocardiopathy of the right ventricle.
Mechanisms
The abnormal heart rhythms seen in patients with Brugada syndrome are dangerous arrhythmias such as ventricular fibrillation or polymorphic ventricular tachycardia.
People with Brugada syndrome are also more likely to experience less severe cardiac forms such as AV retrograde tachycardia and abnormally slow heart rhythms such as sinus node dysfunction.
Several mechanisms by which genetic mutations that cause this condition can produce these arrhythmias.
Some argue that these arrhythmias arise mainly from abnormally slow electrical conduction in areas of the heart, specifically the right ventricle.
This slow conduction allows ‘short circuits’ to form, blocking waves of electrical activity in some areas and allowing waves to pass in others. This is known as wave break promotion and re-entry.
Those who support this view (known as the depolarization hypothesis) argue that decreased driving may explain why arrhythmias in those with Brugada syndrome tend to occur in middle age.
When other factors such as scarring or fibrosis tend to occur as we get older, the tendency to decelerate driving is caused by the genetic mutation.
Others suggest that the leading cause of arrhythmias is a difference in electrical properties between the interior (endocardium) and the exterior (epicardium) of the heart (known as the repolarization hypothesis).
The pattern of electrical activity that an individual cardiac cell shows when it contracts (known as an action potential) differs between the epicardium and the endocardium.
The action potential in epicardial cells shows a prominent notch after the initial peak due to a transient internal current.
This notch is much less evident in the endocardium cells, and the difference between the endocardium and the epicardium is more clearly seen in the right ventricle.
In those with Brugada syndrome, these differences increase, creating a brief period within each cardiac cycle when the current flows from the endocardium to the epicardium and creates the characteristic pattern of the electrocardiogram.
This is described as a ” transmural dispersion of repolarization. ” These differences, if they are large enough, can also allow the development of arrhythmias by blocking the electrical impulse in some regions but not in others.
Another factor that promotes arrhythmias in Brugada syndrome is changes in the heart’s structure.
While the hearts of people with Brugada syndrome may appear normal, scarring or fibrosis is often seen in particular heart regions, specifically the outflow tract of the right ventricle.
As a mutation in many different genres can cause Brugada syndrome, different mechanisms may be responsible for the arrhythmias observed in patients.
Diagnosis
Electrocardiograph
Brugada syndrome is diagnosed by identifying characteristic patterns on an electrocardiogram. The pattern seen in the electrocardiogram includes ST elevation in leads V1-V3 with the appearance of a right bundle branch block.
There may be evidence of decreased electrical conduction within the heart, as shown by a prolonged PR interval.
These patterns may always be present but may appear only in response to certain medications, when the person has a fever, during exercise, or due to other triggers.
The electrocardiogram pattern may become more apparent when performing an electrocardiogram in which some of the electrodes are placed in different positions than usual.
Three forms of the Brugada electrocardiogram pattern have been described.
- Type 1 has a concave ST-type elevation with at least 2 mm (0.2 mV) elevation at point J and a gradually descending ST segment followed by a negative T wave.
- Type 2 has a saddle pattern with a J-point elevation of at least 2 mm and an ST elevation of 1 mm with a positive or biphasic T wave. The type 2 pattern can occasionally be seen in healthy subjects.
- Type 3 has a coved (type 1) or rear saddle (type 2) pattern, with a J-point elevation of less than 2 mm and an ST elevation of less than 1 mm. The type 3 pattern is not uncommon in healthy subjects.
According to current recommendations, only a type 1 electrocardiogram pattern, which occurs spontaneously or in response to medication, can be used to confirm the diagnosis of Brugada syndrome since type 2 and 3 patterns are not observed infrequently in people without the disease.
Proving tests
Some drugs, particularly the antiarrhythmics that block the cardiac current of sodium INa, can reveal a Brugada type 1 pattern in susceptible persons.
These medications can help diagnose those suspected of having Brugada syndrome (for example, survivors of unexplained cardiac arrest or family members of a person with Brugada syndrome).
However, in those who have not observed a pattern of the diagnostic electrocardiogram. The drugs blocking the sodium current can be administered in a controlled environment in these cases.
The drugs most commonly used for this purpose are ajmaline, flecainide, and procainamide, with some suggestions that ajmaline may be more effective.
When administering these medications, great care must be taken as there is a small risk of causing abnormal heart rhythms.
Genetic test
Genetic tests can help identify patients with Brugada syndrome, most commonly in relatives of a person with Brugada syndrome. However, sometimes they are performed on a person who has died suddenly and unexpectedly.
However, the interpretation of the results of the genetic tests is a challenge.
In family members who carry a particular genetic variant associated with Brugada syndrome, some family members may show evidence of Brugada syndrome on their electrocardiograms. In contrast, others do not have a phenomenon known as variable penetrance.
This means that carrying a genetic mutation associated with Brugada syndrome does not necessarily imply that a person is affected by the condition.
To complicate matters further, genetic variants are sometimes identified in people with Brugada syndrome who are not the cause of the disease but rather a standard variant that occurs as a spectator.
Other investigations
Invasive electrophysiological studies, in which wires pass 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 sometimes also performed using an electrocardiogram averaged over the signal.
Ambulatory monitoring of the electrocardiogram, including the implantation of a loop recorder, is sometimes used to assess whether dizziness or fainting in a person with Brugada syndrome is due to abnormal heart rhythms or other causes such as vasovagal syncope.
Treatment
The main goal in treating people with Brugada syndrome is to reduce the risk of sudden death due to severe abnormal heart rhythms, such as ventricular fibrillation or polymorphic ventricular tachycardia.
While some with this condition have a high risk of severe heart rhythm disturbances, others have a much lower risk, which means that some may require more intensive treatment.
In addition to treating the person with Brugada syndrome, it is often essential to investigate your immediate family members to see if they also have the condition.
Lifestyle
The first line of treatment, suitable for all people with Brugada syndrome, regardless of the risk of arrhythmias, is lifestyle advice.
People should be warned to recognize and avoid things that may increase the risk of serious arrhythmias.
These include avoiding excessive alcohol consumption, certain medications, and treating fever quickly with acetaminophen.
Although the abnormal heart rhythms observed in Brugada syndrome tend to be more frequent at rest or even during sleep, some people with Brugada syndrome experience arrhythmias during strenuous exercise.
Therefore, some doctors may advise people with Brugada syndrome that, while gentle exercise is beneficial, strenuous exercise should be avoided.
Implantable defibrillator
An implantable cardioverter-defibrillator (ICD) may be recommended for people with an increased risk of sudden cardiac death.
These tiny devices implanted under the skin continuously control the heart rate. If the device detects a life-threatening arrhythmia, it can cause a small electrical shock, stunning the heart at an average rate.
An implantable cardioverter-defibrillator can also function as a pacemaker, which avoids the abnormally slow heart rates that can occur in people with Brugada syndrome.
The implantation of an implantable cardioverter-defibrillator is a relatively low-risk procedure and is often performed as a day case under local anesthesia.
However, complications such as infection, hemorrhage, or unnecessary discharges can occur, which can sometimes be severe.
Because of the risk of implanting an implantable cardioverter-defibrillator and the cost of the devices, implantable cardioverter defibrillators are not recommended for everyone. However, they are reserved for people at higher risk of sudden cardiac death.
Medication
Quinidine is an antiarrhythmic drug that may reduce the possibility of severe abnormal heart rhythms in some people with Brugada syndrome.
It is most often used in people with Brugada syndrome who have an implantable cardioverter-defibrillator and have experienced several episodes of life-threatening arrhythmias.
It can also be used in people with a high risk of arrhythmias but in those who do not use an implantable cardioverter-defibrillator is not appropriate.
Isoprenaline, a drug similar to adrenaline, can be used in an emergency for people with Brugada syndrome who have frequent, life-threatening recurrent arrhythmias, known as “thunderstorms.”
Therefore, this medication should be administered as a continuous infusion into a vein and is unsuitable for long-term use.
Catheter ablation
Another treatment option for people with Brugada syndrome is radiofrequency catheter ablation. In this procedure, the wires pass through a vein in the leg to the heart or through a small hole below the sternum.
These wires are used to find the heart area responsible for initiating arrhythmias. The tip of one of these wires is used to make a series of minor burns, which intentionally damage the area of the abnormal heart muscle that has been causing the problem.
