What is Brugada syndrome and its pathophysiology?

Brugada Syndrome and Its Pathophysiology

Brugada syndrome is a genetic cardiac channelopathy characterized by ST-segment elevation in the right precordial leads (V1-V3) on ECG, structurally normal heart, and increased risk of sudden cardiac death due to ventricular arrhythmias caused primarily by mutations in the cardiac sodium channel gene (SCN5A). 1

Definition and Clinical Characteristics

Brugada syndrome is a primary electrical disease of the heart with the following key features:

• Characterized by distinctive ECG pattern: J-point segment elevation in leads V1 to V3 with right bundle-branch block appearance 1
• ECG pattern can be intermittent or only revealed during pharmacological challenge with sodium channel blockers 1
• Structurally normal heart with primary channelopathy 1
• High risk of sudden cardiac death (SCD) from rapid polymorphic ventricular tachycardia or ventricular fibrillation 1
• Cardiac events typically occur at rest or during sleep 1
• Predominantly affects males (>90% of diagnosed cases) 1
• Cardiac events (syncope or cardiac arrest) occur most commonly in the third and fourth decades of life 1

Pathophysiology

The pathophysiological mechanisms of Brugada syndrome involve:

1. Genetic Basis:

   • Autosomal dominant inheritance pattern 1
   • Primary genetic defect involves the cardiac sodium channel gene (SCN5A) in approximately 20-30% of cases 1, 2
   • More than 18 other genes have been implicated in BrS pathogenesis, affecting sodium, potassium, and calcium channels 3, 2
   • Most cases do not have a single identifiable causative gene variant, suggesting a multifactorial etiology 4, 2

2. Electrophysiological Mechanisms:

   • Three main hypotheses explain the arrhythmogenic substrate 3:
     • Repolarization disorder: Reduced sodium current in the right ventricular epicardium creates transmural voltage gradient
     • Depolarization disorder: Conduction delay in the right ventricular outflow tract
     • Current-load mismatch: Imbalance between available current and current required for activation

3. Anatomical Substrate:

   • Growing evidence suggests the presence of an epicardial arrhythmogenic substrate within the right ventricular outflow tract 4
   • Alterations in excitation wavelength (λ) ultimately elevate arrhythmic risk 3

4. Triggering Factors:

   • Fever can acutely predispose to cardiac arrest in Brugada syndrome 1
   • Certain medications (particularly sodium channel blockers) can unmask or exacerbate the ECG pattern 1
   • Most arrhythmic events occur during rest or sleep 1

Diagnostic Considerations

• Diagnosis is based on characteristic ECG pattern (spontaneous or drug-induced) 1
• Important to distinguish from Brugada phenocopy (BrP), which presents similar ECG patterns but is caused by reversible conditions 5
• Pharmacological challenge with sodium channel blockers (flecainide, procainamide, or ajmaline) can unmask the ECG pattern in concealed forms 1

Risk Stratification

Risk factors for sudden cardiac death include:

• History of syncope or previous cardiac arrest 1
• Spontaneous (rather than drug-induced) Brugada ECG pattern 1
• Male gender 1
• Age in third to fourth decade 1

Management Implications

• Implantable cardioverter-defibrillator (ICD) is the only proven effective therapy for preventing SCD 1
• Isoproterenol can be useful for treating electrical storm 1
• Quinidine may be reasonable for treating electrical storm 1
• Epicardial ablation is emerging as a treatment option for recurrent arrhythmias 4

Important Caveats

• Family history does not reliably predict cardiac events among family members 1
• Asymptomatic individuals with characteristic ECG but no family history are not necessarily at low risk 1
• The role of electrophysiological testing in risk stratification remains controversial 1
• Fever management is crucial as it can trigger arrhythmic events 1, 4
• Certain medications should be avoided in Brugada syndrome patients 4

Recent advances in understanding Brugada syndrome include the development of human-induced pluripotent stem cell-derived cardiomyocyte models, which may provide novel insights into disease mechanisms and potential therapeutic approaches 6.