What is the mechanism of Brugada syndrome?

Mechanism of Brugada Syndrome

Brugada syndrome is primarily a cardiac sodium channelopathy characterized by abnormal electrical activity in the right ventricular epicardium, most commonly caused by mutations in the SCN5A gene that encodes the cardiac sodium channel. 1

Pathophysiological Mechanisms

Genetic Basis

• The disease is transmitted with an autosomal dominant pattern of inheritance with incomplete penetrance 1
• Approximately 15-20% of Brugada syndrome cases are associated with loss-of-function mutations in the SCN5A gene 2
• Other less common genetic mutations have been identified in:
  • GPD1L (glycerol-3-phosphate dehydrogenase-1 like protein)
  • CACNA1C (alpha-subunit of the Ca(v)1.2 ion channel)
  • CACNB2 (beta2-subunit of the Ca(v)1.2 ion channel)
  • SCN1B and SCN3B (beta-subunits of the Na(v)1.5 sodium ion channel)
  • KCNE3 (inhibitory beta-subunit of potassium channels) 2

Electrophysiological Abnormalities

• The primary mechanism involves an imbalance of currents in the early phases of the right ventricular action potential 3
• Two main electrophysiological theories explain the syndrome:
  1. Repolarization theory: Loss of the action potential dome in right ventricular epicardium but not endocardium creates a voltage gradient that manifests as ST-segment elevation 4
  2. Depolarization theory: Delayed conduction in the right ventricular outflow tract creates conduction abnormalities 5

Arrhythmogenic Mechanism

• The electrical heterogeneity within right ventricular epicardium leads to the development of phase 2 reentry 4
• This reentry mechanism generates closely coupled premature ventricular contractions that can trigger ventricular tachycardia or fibrillation 4
• The right ventricular outflow tract appears to be the predominant site for arrhythmia initiation 3

Clinical Manifestations

ECG Characteristics

• Distinctive coved-type ST-segment elevation in the right precordial leads (V1-V3) 1
• Right bundle branch block pattern in some patients 1
• The ECG pattern can be present spontaneously or intermittently 1
• ST-segment elevation can be unmasked by sodium channel blockers (flecainide, procainamide, ajmaline) 1

Clinical Presentation

• Cardiac events (syncope or cardiac arrest) occur predominantly in males in the third and fourth decades of life 1
• Fever is a significant predisposing factor for cardiac arrest in Brugada syndrome 1
• Ventricular arrhythmias typically occur at rest or during sleep 1

Modifying Factors

Several factors can unmask or aggravate the Brugada ECG pattern:

• Sodium channel blockers
• Febrile states
• Vagotonic agents
• Tricyclic and tetracyclic antidepressants 3

Therapeutic Implications Based on Mechanism

Understanding the mechanism has led to specific therapeutic approaches:

• ICD implantation remains the only proven effective therapy for preventing sudden death 4
• Pharmacologic therapy aims to produce an inward shift in the balance of currents during early phases of the right ventricular action potential:
  • Isoproterenol can be useful for treating electrical storms by boosting calcium channel current 1, 3
  • Quinidine inhibits the transient outward current, diminishing the action potential notch 3
• Radiofrequency ablation of the right ventricular outflow tract epicardium may reduce arrhythmia vulnerability by eliminating cells with prominent action potential notch 3

The mechanistic understanding of Brugada syndrome continues to evolve, with recent evidence suggesting it may be more complex than initially thought, potentially involving multiple genetic and environmental factors that influence the electrical properties of the right ventricle 5.