How does Brugada syndrome cause Ventricular Tachycardia (VTach)?

Mechanism of Ventricular Tachycardia in Brugada Syndrome

Brugada syndrome causes ventricular tachycardia through loss of function mutations in cardiac sodium channels (primarily SCN5A) that create abnormal electrical heterogeneity in the right ventricular epicardium, leading to phase 2 reentry and triggering of polymorphic VT/VF. 1

Genetic and Molecular Basis

The fundamental defect in Brugada syndrome involves mutations in the SCN5A gene encoding the cardiac sodium channel alpha subunit, identified in approximately 20-30% of cases 1. This genetic abnormality causes a reduction in sodium current density (INa), which is the primary ionic mechanism underlying the disease 2, 3.

• The loss-of-function mutations in SCN5A lead to decreased sodium channel availability and reduced inward sodium current during phase 0 of the cardiac action potential 4, 2
• This reduction in sodium current is further exacerbated by sodium channel blocking drugs, which explains why agents like flecainide, procainamide, and ajmaline can unmask or worsen the ECG pattern 1
• While SCN5A accounts for most genotype-positive cases, 18 other genes have been implicated, though the majority of patients remain genotype-negative despite having the clinical phenotype 4

Cellular Electrophysiological Mechanism

The arrhythmogenic substrate in Brugada syndrome results from abnormal electrical activity specifically localized to the right ventricular epicardium 2. The mechanism involves a complex interplay between repolarization and depolarization abnormalities:

Loss of Action Potential Dome in RV Epicardium:

• The reduced sodium current combined with a prominent transient outward potassium current (Ito) in right ventricular epicardial cells causes loss of the action potential dome (phase 2) in these cells 2
• This loss of the dome occurs in epicardium but not in endocardium, creating a transmural voltage gradient that manifests as ST-segment elevation on the surface ECG 2
• The right ventricular epicardium is particularly vulnerable because it has a naturally more prominent Ito current compared to other regions of the heart 2

Development of Electrical Heterogeneity:

• Within the right ventricular epicardium itself, some areas lose the action potential dome while adjacent areas maintain it, creating marked electrical heterogeneity 2
• This heterogeneity in repolarization creates areas with different refractory periods and conduction velocities 4
• Alterations in excitation wavelength (λ) result from these molecular abnormalities, ultimately elevating arrhythmic risk 4

Arrhythmia Initiation: Phase 2 Reentry

The specific mechanism that triggers VT/VF involves phase 2 reentry:

• Areas of epicardium that maintain the action potential dome can propagate this dome to adjacent areas that have lost it 2
• This propagation of the dome from sites where it is maintained to sites where it is lost creates a very closely coupled extrasystole 2
• These closely coupled premature ventricular contractions arise via a phase 2 reentrant mechanism 2
• The premature beats then encounter the heterogeneous substrate with marked dispersion of refractoriness, precipitating polymorphic VT or VF 2

Clinical Triggers and Modulating Factors

Several factors can unmask or exacerbate the arrhythmogenic substrate:

Fever as a Critical Trigger:

• Fever is a well-established predisposing factor for cardiac arrest in Brugada syndrome and warrants aggressive antipyretic treatment 1
• Temperature elevation likely affects sodium channel kinetics and further reduces available sodium current 5, 6

Vagotonic States:

• Increased vagal tone can precipitate arrhythmias, which explains why events often occur at rest or during sleep 1
• The type 1 Brugada ECG pattern may appear during vagotonic states 1

Pharmacological Triggers:

• Sodium channel blockers further reduce the already diminished sodium current 3
• Psychotropic medications, anesthetic agents, cocaine, and excessive alcohol can induce ST-segment elevation and trigger arrhythmias 1

Gender and Age Considerations

The clinical expression shows marked gender differences:

• 90% of affected individuals with diagnostic ECG findings are male, despite autosomal dominant inheritance 1
• Cardiac events occur predominantly in males during the third and fourth decades of life 1
• The gender difference likely reflects hormonal modulation of ion channel expression and function 1

Arrhythmia Characteristics

The ventricular arrhythmias in Brugada syndrome have specific features:

• Sudden cardiac death is caused by rapid polymorphic VT or VF 1
• These arrhythmias frequently occur at rest or during sleep, consistent with vagal predominance 1
• Patients typically do not have frequent ventricular ectopy or nonsustained VT on ambulatory monitoring, making the arrhythmic events unpredictable 1

Common Pitfall

A critical pitfall is assuming that the absence of spontaneous type 1 ECG pattern excludes significant risk—the ECG pattern can be intermittent and may require provocative testing with sodium channel blockers for diagnosis 1, 5. However, patients with only drug-induced patterns have substantially lower risk than those with spontaneous patterns 1.