Pathophysiology of Brugada Syndrome
Brugada syndrome is primarily caused by a genetic dysfunction of cardiac sodium channels, most commonly due to mutations in the SCN5A gene, leading to reduced sodium current and creating an electrical substrate for ventricular arrhythmias in a structurally normal heart. 1
Genetic Basis
The pathophysiological mechanisms of Brugada syndrome involve:
- Primary genetic mutation: In approximately 25-30% of cases, mutations in the SCN5A gene encoding the cardiac sodium channel alpha subunit (Nav1.5) have been identified 1
- Inheritance pattern: Autosomal dominant transmission with variable penetrance 1
- Gender influence: Clinical expression is strongly modified by gender, with 90% of affected individuals with diagnostic ECG being male 1
- Other genetic factors: While SCN5A is the most common, mutations in at least 18 other genes have been implicated in Brugada syndrome 2
Ion Channel Dysfunction
The fundamental abnormality involves:
- Loss of function: Mutations cause reduced sodium current (INa) through various mechanisms 3, 4, 5
- Specific mechanisms of sodium channel dysfunction include:
Electrophysiological Consequences
The ion channel abnormalities lead to:
- Transmural voltage gradient: Particularly affecting the right ventricular outflow tract 1
- Conduction abnormalities: Localized to the right ventricular outflow tract due to involvement of peripheral fascicles of the right bundle branch 1
- Repolarization abnormalities: Three different types have been described, with Type 1 ("coved" type) being diagnostic 1
- Arrhythmogenic substrate: Creates vulnerability to ventricular fibrillation and sudden cardiac death 1
ECG Manifestations
The characteristic ECG findings reflect the underlying pathophysiology:
- J-point elevation: Early, high take-off (≥2 mm) in leads V1-V3 1
- ST-segment elevation patterns:
- Type 1 (diagnostic): "Coved" ST-segment elevation followed by negative T wave
- Type 2: "Saddle-back" morphology with high takeoff ST-segment elevation
- Type 3: Either coved or saddleback morphology with J-point elevation 1
- Associated conduction abnormalities: Right bundle branch block pattern and S1, S2, S3 pattern mimicking left anterior hemiblock 1
Arrhythmia Mechanisms
The pathophysiological abnormalities predispose to:
- Rapid polymorphic ventricular tachycardia or ventricular fibrillation 1
- Timing of events: Arrhythmias typically occur at rest or during sleep, not during exercise 1
- Autonomic influence: Increased vagal tone and/or withdrawal of sympathetic activity can trigger arrhythmias 1
- Dynamic ECG changes: The ECG pattern can be intermittent with transient normalization 1
Precipitating Factors
Several factors can enhance ST-segment elevation and trigger arrhythmias:
- Fever: A well-documented trigger for cardiac arrest in Brugada syndrome 1
- Electrolyte disturbances: Can exacerbate the ECG abnormalities 1
- Increased vagal tone: Associated with arrhythmic events 1
- Pharmacological agents: Sodium channel blockers can unmask or worsen the ECG pattern 1
Clinical Implications
Understanding the pathophysiology has important clinical implications:
- Risk stratification: Spontaneous Type 1 ECG pattern carries higher risk than drug-induced pattern 1
- Drug responses: Mutations can bidirectionally affect blocking actions of antiarrhythmic drugs 6
- Diagnostic approach: Sodium channel blockers (flecainide, ajmaline) can unmask the ECG pattern in concealed forms 1
- Therapeutic targets: Isoproterenol can be useful for treating electrical storm by counteracting the vagal predominance 1
The complex pathophysiology of Brugada syndrome explains its characteristic ECG patterns, arrhythmic manifestations, and response to various physiological and pharmacological influences, all occurring in the absence of structural heart disease.