page_title: Brugada syndrome
section_title: Mechanisms
hierarchical_section_title: Brugada syndrome / Mechanisms
caption_attribution_description: English: Cartoon showing a wave of depolarisation traversing excitable tissue undergoing wavebreak and re-entry
context_page_description: Brugada syndrome is a genetic disorder in which the electrical activity within the heart is abnormal. It increases the risk of abnormal heart rhythms and sudden cardiac death. Those affected may have episodes of passing out. The abnormal heart rhythms seen in those with Brugada syndrome often occur at rest. They 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, 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. In those without symptoms the risk of death is much lower, and how to treat this group is less clear.
context_section_description: 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 inward 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.
caption: Adjacent regions of cardiac tissue with differing refractory periods can lead to a normally smooth wavefront of depolarisation undergoing wavebreak leading to re-entrant arrhythmias
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