Brugada Syndrome

The gene SCN5A encodes Nav1.5, the cardiac sodium channel responsible for Phase 0 of the ventricular action potential. Loss-of-function mutations in this gene reduce the peak sodium current available during depolarization. Fewer channels open, or they open less effectively, and the upstroke weakens.

In most of the ventricle, this reduction is modest and well tolerated. The plateau phase still holds because inward calcium current (I_CaL) compensates. But the RVOT epicardium is different. It carries an unusually high density of I_to, the transient outward potassium current that creates the Phase 1 notch at the beginning of the action potential.

In a healthy RVOT epicardial cell, the Phase 1 notch is a brief dip. Sodium current and calcium current together are strong enough to pull the voltage back up into the plateau. When sodium current is reduced by the SCN5A mutation, I_to runs unopposed during Phase 1. It yanks the membrane voltage down sharply, and the plateau may never recover.

The endocardium, which has low I_to density, maintains its normal action potential shape. A voltage gradient now exists across the ventricular wall: the epicardium has repolarized early while the endocardium remains depolarized at plateau voltage.

When the epicardial action potential loses its plateau entirely, a steep transmural voltage gradient develops. The endocardium is still sitting at +20 mV (plateau), while the epicardium has already fallen back to its resting potential near -85 mV.

Current flows down voltage gradients. The still-depolarized endocardium drives current outward through the wall into the already-repolarized epicardium. If enough current reaches the epicardial cells after their sodium channels have recovered from inactivation, it re-excites them. The epicardium fires a second time.

This is Phase 2 reentry: a local, transmural reentrant beat generated by the voltage mismatch between two layers of the ventricular wall. The re-excited epicardial beat can then propagate into surrounding tissue and trigger polymorphic VT or ventricular fibrillation.

The mechanism is entirely different from classical circuit reentry. There is no scar, no slow conduction zone, no isthmus. The "circuit" is the thickness of the ventricular wall, and the substrate is a differential loss of the action potential plateau.

The transmural voltage gradient in the RVOT produces a characteristic ST-segment elevation in the right precordial leads (V1 through V3). Two morphologies are recognized.

Type 1 (coved) is the diagnostic pattern. The ST segment rises ≥2 mm from baseline with a downsloping curve that falls directly into a negative T wave. There is no upward inflection between the ST segment and the T wave. This shape reflects the complete loss of the epicardial plateau: the voltage gradient is large and sustained.

Type 2 (saddleback) shows ST elevation with a positive or biphasic T wave, creating a saddle-shaped contour. This pattern is suggestive of Brugada but cannot make the diagnosis on its own. Only the Type 1 pattern is diagnostic.

A critical feature of Brugada syndrome is that the ECG pattern can be intermittent. Many patients have a normal or Type 2 pattern at baseline. The coved Type 1 morphology can be unmasked by fever (which further impairs sodium channel function), high vagal tone, or sodium channel-blocking drugs.

When Brugada syndrome is suspected but the resting ECG shows a normal or Type 2 pattern, a provocation test can reveal the diagnosis. Ajmaline or procainamide is given intravenously while the patient is monitored on continuous 12-lead ECG.

These drugs are sodium channel blockers. They further reduce the available sodium current, amplifying the imbalance between I_Na and I_to in the RVOT epicardium. If the patient carries a loss-of-function mutation in SCN5A, the added drug effect pushes the epicardial cells past their tipping point. The Phase 1 notch deepens, the plateau collapses, and the Type 1 coved pattern appears on the ECG.

A positive test (conversion from normal or Type 2 to a clear Type 1 pattern) confirms the diagnosis. The test is stopped immediately if the diagnostic pattern appears, or if significant arrhythmias develop. Ajmaline is generally preferred over procainamide because of its higher sensitivity.

The central challenge in Brugada syndrome is identifying who is at high risk for sudden cardiac death. The overall event rate among diagnosed patients is low, but the consequences of a missed high-risk patient are catastrophic.

Prior cardiac arrest carries the highest risk. A survivor of VF or aborted sudden death has an annual recurrence rate of roughly 10%. This is a clear indication for an ICD.

A spontaneous Type 1 pattern on baseline ECG (without drug provocation) identifies a higher-risk group than those whose pattern appears only with ajmaline or procainamide. The spontaneous pattern means the transmural gradient is present at rest, without any external push.

Syncope of suspected arrhythmic cause raises concern for self-terminating VF episodes. The clinical context matters: syncope during fever in a patient with spontaneous Type 1 is far more worrisome than vasovagal syncope during a blood draw.

The role of the EP study in risk stratification is debated. Some centers perform programmed ventricular stimulation to see if VF can be induced, but the predictive value of inducibility remains controversial. A negative study does not guarantee safety.

Fever management is a separate but critical part of care. Fever impairs sodium channel function in the same way the mutation does. Febrile episodes in Brugada patients can unmask the Type 1 pattern, widen the transmural gradient, and trigger VF. Patients are counseled to treat fever aggressively with antipyretics and to seek medical attention promptly.

There is no drug that corrects the underlying sodium channel defect. Treatment focuses on preventing sudden death and reducing arrhythmia burden.

An implantable cardioverter-defibrillator (ICD) is the primary therapy for high-risk patients: survivors of cardiac arrest, and those with syncope of arrhythmic origin and a spontaneous Type 1 ECG pattern. The ICD does nothing to prevent arrhythmias; it terminates VF once it occurs. The decision to implant balances the risk of sudden death against the long-term complications of the device, particularly in young patients who will live with it for decades.

Quinidine is the main pharmacologic option. It blocks I_to, the transient outward potassium current that drives the Phase 1 notch. By reducing I_to, quinidine restores the balance between inward and outward currents during early repolarization, helping the epicardial plateau survive. It is used as adjunctive therapy in patients with recurrent ICD shocks or electrical storm.

Epicardial ablation of the RVOT is an emerging approach. The strategy targets the arrhythmogenic substrate directly. By ablating the epicardial surface of the RVOT where the action potential abnormality is most pronounced, the transmural gradient is eliminated. Early results show normalization of the Brugada ECG pattern and suppression of VF, but long-term data are still accumulating.

All patients should practice strict fever avoidance. Acetaminophen or ibuprofen at the first sign of fever. Certain drugs that block sodium channels (flecainide, propafenone, certain antipsychotics) are contraindicated because they worsen the underlying deficit.