Brugada syndrome is an inherited disease associated with risk of ventricular fibrillation, even in the presence of a structurally normal heart. Its penetrance is incomplete, with variable expressiveness, linked to age and sex.
It is 8 to 10 times more frequent in men than women. Mutations in the Nav1.5 sodium channel encoded by the SCN5A gene are a monogenic cause in 14-26% of cases, but many other genes are implicated.
The diagnosis of this disease is based on the electrocardiographic finding of an ST segment elevation of 2 or more millimeters, in V1 and/or V2, positioned in the second, third or fourth intercostal space.
This characteristic aspect may be present under normal conditions or after a pharmacological test by intravenous administration of sodium channel blockers, such as ajmaline or flecainide.
The incidence of Brugada syndrome has long been debated. The finding of a typical appearance on the ECG varies between 0.12% and 0.8%, while it is considered responsible for 4 to 12% of all sudden deaths. This percentage rises to 20% in patients with normal hearts.
From a clinical point of view, patients can present events such as syncope, due to fast ventricular tachycardias. If these arrhythmias are sustained, cases of sudden death may occur.
Lethal arrhythmias usually occur during sleep, or in resting conditions, suggesting the absence of a trigger effect due to an adrenergic hyperactivity, but rather to a vagal dominance.
Symptoms usually occur for the first time during adulthood, with an average age for sudden death cases of 41 years. Febrile episodes have also been frequently associated with symptoms.
However, the diagnosis of this disease is difficult because the electrocardiographic alterations can only be transient and therefore ECG can be completely normal or with minimal alterations, considered clinically not significant.
In a new study, recently published in the European Heart Journal, researchers sought to identify a specific biomarker for this disease. Considering that pathological myocardial inflammation was detected in these patients, in an extremely high percentage of cases, they focused their research on the presence of myocardial autoantibodies.
The authors of this research evaluated two patient populations: a discovery cohort and a validation cohort. Brugada syndrome subjects were defined on the basis of a clinical scoring system that included ECG data, clinical history, family history and genetic tests.
Only patients with known or probable Brugada syndrome and with a typical type 1 Brugada ECG, spontaneous or drug-induced, were included in the study.
Sera from three Brugada syndrome patients in the discovery cohort demonstrated the presence of antibodies that mass spectrometry identified as specific autoantibodies.
The target proteins were a-cardiac actin, a-skeletal actin, keratin and connexin-43.
All 18 patients included in the validation cohort showed the presence of the same four autoantibodies.
With an immunofluorescence study, the researchers also confirmed that autoantibodies detected in patients’ serum were bound to target proteins in cardiac tissue, in particular a-cardiac actin, keratin-24 and connexin-43.
Finally, by analyzing the myocardium obtained from a patient who died from the disease, and from biopsies of nine alive patients, the researchers found that each protein demonstrated abnormal aggregates within the myocardial sarcoplasm. Sodium channel protein Type 5 subunit alpha demonstrated similar large aggregates of staining within cardiomyocytes.
On the one hand, this study introduces new information on the pathophysiology of Brugada syndrome. On the other, it lays the foundations for a new auxiliary diagnostic method for this disease.
The detection of specific autoantibodies, with links to myocardial proteins, makes Brugada syndrome more and more close to a myocardiopathy, with increasingly stronger similarities with arrhythmogenic right ventricle myocardiopathy.
The biomarkers identified, corresponding to the four autoantibodies for a-cardiac actin, a-skeletal actin, keratin, and connexin-43, were extremely sensitive and specific. Even more relevant is that these biomarkers features were independent from the genetic cause of the syndrome.
Lastly, the number of patients included in this study were small and the results obtained should now be validated on much larger populations.
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