Brugada syndrome is a genetically determined cardiological condition characterized by various disorders of the heart, which lead to a sharp increase in the risk of sudden cardiac death. Symptoms of this condition are attacks of paroxysmal tachycardia, fainting, atrial fibrillation and life-threatening ventricular fibrillation, most often occurring during sleep. Diagnosis of Brugada syndrome is made on the basis of a characteristic symptom complex, electrocardiographic data and a study of hereditary history, some forms of pathology are determined by molecular genetic methods. There is no specific treatment for the disease, antiarrhythmic therapy is used, a variety of pacemakers are used.
Brugada syndrome is a group of genetic disorders that lead to changes in the ion permeability of cardiomyocyte membranes, resulting in rhythm and conduction pathologies that create an increased risk of sudden cardiac death. For the first time such a condition was described in 1992 by two brothers – Belgian cardiologists of Spanish origin Jose and Pedro Brugada, who drew attention to the relationship of certain electrocardiological manifestations and cardiac arrhythmias. Currently, it has been established that Brugada syndrome is a hereditary condition with a presumably autosomal dominant transmission mechanism, several genes have been identified whose mutations can cause this disease. According to some reports, almost half of all cases of sudden cardiac death in the world are caused by this pathology. The prevalence of Brugada syndrome varies in different regions of the planet – in the countries of America and Europe it is approximately 1:10,000, whereas in African and Asian countries this disease is more common – 5-8 cases per 10,000 population. Brugada syndrome affects men about 8 times more often than women, manifestations of pathology occur at different ages, but most often pronounced symptoms are observed in 30-45 years.
Causes and classification
The reason for the development of disorders in Brugada syndrome is the pathological work of the ion channels of cardiomyocytes, mainly sodium and calcium. Their defect, in turn, is caused by mutations of genes encoding ion channel proteins. By the methods of modern genetics, it was possible to reliably identify 6 main genes, the defeat of which leads to the development of Brugada syndrome, several more are suspected, but there is no necessary evidence base. On this basis, a classification of this condition is built, which includes 6 forms of the disease (BrS):
BrS-1 is the most common and well–studied variant of Brugada syndrome. It is caused by a mutation of the SCN5A gene located on chromosome 3. The expression product of this gene is the alpha subunit of the type 5 sodium channel, which is widely represented in the myocardium. In addition to Brugada syndrome, mutations of this gene cause a large number of hereditary cardiac pathologies – familial atrial fibrillation, type 1 sinus node weakness syndrome and a number of others.
BrS-2 – this type of Brugada syndrome is caused by defects in the GPD1L gene, which is localized on chromosome 3. It encodes one of the components of glycerol-3-phosphate dehydrogenase, which actively participates in the work of sodium channels of cardiomyocytes.
BrS-3 – This type of Brugada syndrome is caused by a defect in the CACNA1C gene located on chromosome 12. The product of its expression is the alpha subunit of the L-type calcium channel, also present in cardiomyocytes.
BrS-4 – as in the previous case, the cause of the development of type 4 Brugada syndrome is the lesion of potential-dependent L-type calcium channels. It is caused by a mutation of the CACNB2 gene located on chromosome 10 and encoding the beta-2 subunit of the above ion channels.
BrS-5 is a common type of Brugada syndrome caused by a mutation of the SCN4B gene localized on chromosome 11. It encodes a protein of one of the small sodium channels of cardiomyocytes.
BrS-6 is caused by a defect in the SCN1B gene located on chromosome 19. In many ways, this variant of Brugada syndrome is similar to the first type of disease, since in this case, type 5 sodium channels are also affected. The SCN1B gene encodes the beta-1 subunit of this ion channel.
In addition, mutations of the genes KCNE3, SCN10A, HEY2 and some others are suspected in the development of Brugada syndrome. However, to date, it is not possible to reliably prove their role in the occurrence of this disease, so so far the number of genetic variants of Brugada syndrome is limited to six. The inheritance of all forms of this pathology is unclear, only 25% of patients have signs of autosomal dominant transmission. Presumably, there is a dominant type of inheritance with incomplete penetrance or the influence of spontaneous mutations. The reasons why Brugada syndrome affects men more often than women are also unclear – perhaps the severity of the manifestations of the disease depends on the hormonal background of the patient.
The pathogenesis of disorders in any form of Brugada syndrome is approximately the same – due to changes in the permeability of the cardiomyocyte membrane for sodium ions, the transmembrane potential and the characteristics of excitable tissues related to it are disrupted: excitability, contractility, transmission of excitation to surrounding cells. As a result, there are blockages of the conductive pathways of the heart (Gis bundles), tachyarrhythmias, which increase with increased vagal effects (during sleep). The severity of symptoms in Brugada syndrome depends on the proportion of affected sodium channels. Some medicinal substances can enhance the manifestations of the disease, they are able to inhibit the ion channels of the heart.
The age at which the first signs of Brugada syndrome appear is very different in different patients – cases of this pathology have been reported both in children 3-4 years old and in senile people. One of the first manifestations of pathology are changes in the electrocardiogram in the complete absence of other clinical symptoms, therefore, this disease is often detected by chance. In most cases, the pronounced clinic of Brugada syndrome occurs at the age of 30-45 years, this is preceded by an asymptomatic period of 10-12 years, during which the only sign of pathology is changes in the ECG.
Usually patients with Brugada syndrome complain of causeless dizziness, fainting, frequent attacks of tachycardia, especially at night or during daytime rest. Sometimes there is an abnormal reaction to taking certain medications – first-generation antihistamines, beta-blockers, vagotonic drugs. Their use in Brugada syndrome may be accompanied by increased side effects, as well as palpitations, fainting, a drop in blood pressure and other negative manifestations. No other symptoms are detected in this disease, which explains the rare treatment of patients to a cardiologist or other specialists – in some cases, the manifestations of Brugada syndrome are quite rare and poorly expressed. However, this does not reduce the risk of sudden cardiac death due to this pathology.
To determine the Brugada syndrome, electrocardiographic techniques are used, the study of the patient’s hereditary history, molecular genetic analysis. It is possible to suspect the presence of this disease in the presence of syncopal phenomena (dizziness, fainting) of unclear origin, complaints of sudden attacks of tachyarrhythmias. Changes in the electrocardiogram in Brugada syndrome can be determined against the background of a complete absence of clinical symptoms of the disease. At the same time, cardiologists distinguish three main types of ECG changes that differ slightly from each other. A typical picture of an electrocardiogram in Brugada syndrome is reduced to the elevation (elevation) of the ST segment above the isoelectric line and a negative T wave on the right thoracic leads (V1-V3). Signs of blockage of the right leg of the Gis bundle can also be determined, with Holter monitoring, attacks of paroxysmal tachycardia or atrial fibrillation are detected.
As a rule, the hereditary history of patients with Brugada syndrome is burdened – among relatives or ancestors there are cases of deaths from heart failure, death in a dream or sudden cardiac death. This fact, as well as the presence of the above symptoms and changes on the ECG, gives grounds for molecular genetic diagnostics. Currently, geneticists in the vast majority of clinics and laboratories determine the Brugada syndrome caused only by mutations of the SCN5A and SCN4B genes (types 1 and 5 of pathology), methods of genetic diagnosis have not yet been developed for other forms. This condition should be differentiated with the body’s reaction to taking certain medications, chronic myocarditis and other cardiological pathologies.
Treatment and prevention
Specific methods of treatment of Brugada syndrome do not exist at the moment, therefore, they are limited only to combating the manifestations of this disease, as well as preventing life-threatening attacks of tachyarrhythmia and fibrillation. Amiodarone is most widely used in this condition, disopyramide and quinidine are used somewhat less frequently. However, drug therapy for Brugada syndrome is ineffective in some cases, the only reliable means of preventing arrhythmia and sudden cardiac death in this case is implantation of a cardioverter-defibrillator. Only this device is able to evaluate the work of the patient’s myocardium and, in case of pathological and life-threatening changes in the heart rhythm, bring it back to normal by means of an electric discharge.
Many traditional antiarrhythmic drugs for Brugada syndrome are contraindicated, as they inhibit the activity of sodium channels of cardiomyocytes and enhance the manifestations of pathology. The means prohibited for this disease include aimalin, propafenone, procainamide. Therefore, patients with Brugada syndrome should be sure to inform specialists about the existing diagnosis in order to avoid prescribing the wrong antiarrhythmic agent. In the presence of such a disease in relatives or cases of sudden cardiac death in the family, an ECG examination should be performed regularly for the earliest possible diagnosis of this condition.
The prognosis of Brugada syndrome is uncertain, since the severity of the symptoms of the disease is very variable and depends on a number of factors. In the presence of only electrocardiographic manifestations of pathology without pronounced clinical symptoms, the prognosis is relatively favorable. If Brugada syndrome is accompanied by loss of consciousness and arrhythmia attacks – without installing a cardioverter defibrillator, the risk of sudden cardiac death increases many times. When using this device, the prognosis improves somewhat, since the device can correct pathological changes in the heart rate around the clock.