Key concept — Phase 1 notch: After the rapid sodium-driven upstroke (phase 0), there is a brief repolarization dip called the phase 1 notch, driven by the transient outward potassium current (I_to). The depth of this notch varies across the ventricular wall:

• Epicardium: I_to is prominent → deep phase 1 notch
• Endocardium: I_to is minimal → shallow/absent phase 1 notch

This epicardial-endocardial difference is greatest in the right ventricular outflow tract (RVOT) — the area of the heart directly underlying leads V1–V3.

The RVOT has the highest density of I_to channels in the entire heart. Under normal conditions, the balance between the inward sodium current (I_Na in phase 0) and the outward I_to in phase 1 keeps the epicardial AP stable. But if I_Na is reduced (as in BrS), the I_to current becomes relatively unopposed, and the phase 1 notch deepens dramatically — potentially causing loss of the action potential dome in the epicardium.

When the epicardium loses its plateau (dome) while the endocardium retains it, you get a transmural voltage gradient. This gradient:

1. Produces the characteristic ST elevation on surface ECG (the voltage difference between depolarized endocardium and already-repolarized epicardium creates a current of injury pattern)
2. Creates a substrate for phase 2 re-entry — the dome can "re-enter" from sites that still have it to sites that have lost it, triggering ventricular tachyarrhythmias (VT/VF)

Associated with an ion channel gene mutation — the cardiac sodium channel gene SCN5A — resulting in loss of function, leading to ↓ inward sodium current. ^[3][4]

Autosomal dominant with variable penetrance. ^[3]

Important: Only ~20–30% of patients with clinical BrS have an identifiable genetic mutation. This means a negative genetic test does NOT exclude BrS. Conversely, having an SCN5A mutation alone without clinical features does not make the diagnosis.

While BrS is fundamentally a genetic condition, there are numerous factors that can unmask or exacerbate the phenotype:

There are three ECG types in Brugada syndrome: ^[4]

For types 2/3 ECG pattern, make the diagnosis by converting patient to type 1 ECG pattern: ^[4]

• Flecainide provocative test ± high V1/V2 placement (2nd intercostal space) ^[4]
• Other sodium channel blockers used: ajmaline (gold standard in Europe), procainamide

Timing of events: Events characteristically occur:

• At rest or during sleep (70% nocturnal) — this is the opposite of LQTS types 1 and 2, where exercise and adrenergic stimulation are triggers
• During fever (a recognized and important trigger)
• After heavy meals (vagal surge)
• After alcohol consumption

Physical examination in BrS is characteristically normal — the heart is grossly structurally normal. There are no murmurs, no signs of heart failure, no cardiomegaly.

ECG findings in BrS include: ^[2][4][5]

1. ST elevation in V1–V3 (right precordial leads):

   • Type 1 (coved): ≥ 2mm J-point elevation, concave or straight ST segment descending into a negative T wave
   • The "coved" shape looks like the inside of a cave — the ST segment smoothly transitions into an inverted T wave without returning to baseline

2. Apparent RBBB pattern: The r' in V1 may resemble incomplete or complete RBBB, but it is actually caused by delayed RVOT depolarization rather than true right bundle conduction delay

3. J-point elevation / prominent J (Osborn) wave: The J point is elevated because of the transmural voltage gradient at the end of the QRS

4. Dynamic nature: Brugada is dynamic → patients will show periodic normalization of the ECG ^[3]. The ECG can fluctuate between normal, Type 2/3, and Type 1 patterns even within the same day

5. Unmasked by:

   • Sodium channel blockers (flecainide, ajmaline, procainamide)
   • Fever
   • Vagal maneuvers
   • High V1/V2 placement (2nd intercostal space) ^[4] — placing the precordial leads one intercostal space higher can sometimes unmask the pattern

Family history of SCD < 45 years is a key clinical feature ^[4]. Because BrS is autosomal dominant, affected families often have multiple members with the ECG pattern or a history of unexplained sudden death, particularly:

• Young males
• Death during sleep
• Unexplained drowning (arrhythmia in water)
• "Epilepsy" that was actually arrhythmic syncope

Phenocopies = they cause a Brugada pattern on ECG, with the underlying cause being: ^[3]

Only exception would be Brugada syndrome → with current criteria permitting diagnosis with even one lead ^[7] — unlike MI which requires ST changes in ≥ 2 contiguous leads. This is an important distinguishing point when reading ECGs.

Understanding the diagnostic criteria for BrS requires knowing that they have evolved considerably since the original 1992 description. The most clinically relevant frameworks are:

1. Original 2002 / 2005 Consensus Criteria — required Type 1 ECG pattern + clinical features
2. 2013 HRS/EHRA/APHRS Expert Consensus — simplified: Type 1 ECG pattern alone (spontaneous or provoked) is sufficient, but clinical context aids risk stratification
3. 2022 ESC / 2020 APHRS/HRS Consensus — current standard; retains Type 1 as the sole diagnostic ECG, with provocation test for suggestive but non-diagnostic cases

The diagnosis of Brugada Syndrome requires:

Type 1 ECG pattern (spontaneous or induced) in ≥ 1 lead among V1–V3 ^{[2][3][4][7][9][10]}

That's it for the ECG criterion. Let's unpack this:

Type 1 ECG Pattern — Detailed Description:

• J-wave / ST elevation with ≥ 0.2 mV (2mm) at peak ^[2]
• Coved morphology: the elevated ST segment descends smoothly and directly into a negative T wave with little or no isoelectric separation ^[2]
• This must be present in ≥ 1 of leads V1–V3 (standard or high placement)

Clinical Adjuncts That Support the Diagnosis (not required but strengthen it):

• Syncope ^[4]
• Documented VF / VT ^[4]
• Nocturnal agonal respiration ^[4]
• Family history of SCD < 45 years ^[4]
• Family member with confirmed Type 1 BrS ECG pattern

Three types, dynamic, differentiated by their ST configuration. Patients can change and switch between different types. E.g. fever can cause Type 1. ^[9]

Type 3 can be normal, found in normal people. ^[9]

Several features make BrS diagnosis unusual compared to other cardiac conditions:

1. Do not require findings in 2 consecutive leads for diagnosis — if you find these characteristic findings in 1 lead, can already diagnose ^[3]
2. Dynamic nature: The ECG can fluctuate between types and even normalize completely → patients will show periodic normalization of the ECG ^[3], so a single normal ECG does NOT exclude BrS
3. Provocation may be needed: If clinical suspicion is high but the resting ECG is Type 2, Type 3, or even normal, pharmacological provocation can unmask the hidden Type 1 pattern

The test works on exactly the same pathophysiological principle as the disease itself. BrS is caused by ↓ I_Na. By giving a sodium channel blocker, you further reduce I_Na pharmacologically, which tips the already borderline RVOT epicardial action potential over the edge → loss of AP dome → transmural gradient → Type 1 ECG pattern becomes manifest.

Pharmacological stress testing using Na-channel blocker (Flecainide, Ajmaline) — i.e. it's the same principle as LQTS using epinephrine and exercise testing as a stress test ^[3]

Sensitivity: Ajmaline >> Procainamide >> Flecainide ^[9][10]

From the GC lecture slides and Cardiology lecture slides — these are high-yield exam points:

Conversion of type 2/3 to type 1 is considered 'diagnostic' ^[9][10]

PVC or VT may be precipitated ^[9][10] — This is why the test must be done in a monitored setting with resuscitation equipment immediately available. You are deliberately worsening the very substrate that causes lethal arrhythmias!

Predictive value among those without type 2/3 ECG or a clear likelihood of BrS is unknown ^[9][10] — Don't just test everyone. The test is meaningful only when clinical suspicion exists.

Class I indication for patients with 'suggestive clinical characteristics' ^[9][10]

Brugada is very sensitive to sodium blockers → provocation test, give patient this, successfully convert Type 2/3 back to Type 1, considered positive ^[9]

Have to be careful, can precipitate ^[9] — referring to precipitating dangerous ventricular arrhythmias during the test.

The provocation test is positive (diagnostic) if:

• The ECG converts to a Type 1 coved pattern (≥ 0.2 mV J-point elevation with coved descent into negative T wave) in ≥ 1 of V1–V3

The test should be stopped immediately if:

• Type 1 pattern appears (test is positive — no need to give more drug)
• PVCs or VT develop
• QRS widens by > 30% from baseline (safety cutoff)

Repeat ECG at 2nd or 3rd intercostal space → high precordial lead ECG, move up from 4th, closer to the outflow tract, may see Brugada ^[3]

Why? Standard V1 and V2 are placed at the 4th intercostal space. The RVOT sits anatomically higher — closer to the 2nd–3rd intercostal space. By placing V1/V2 one or two intercostal spaces higher, you bring the electrodes directly over the RVOT epicardium, improving sensitivity for detecting the characteristic pattern.

Flecainide provocative test ± high V1/V2 placement (2nd ICS) ^[4]

This is the cornerstone of BrS diagnosis. It is also the single most important first step in evaluating any patient with syncope, palpitations, or suspected arrhythmia.

What to look for:

Standard vs High Lead Placement:

• Always obtain ECG with both standard V1/V2 (4th ICS) AND high V1/V2 (2nd or 3rd ICS) ^[3][4]
• This improves sensitivity because the electrodes are moved closer to the RVOT

Already detailed above. Key findings and interpretation:

Purpose: Exclude underlying structural heart disease → suggest alternative diagnosis ^[2]

In BrS, the echo should be entirely normal. Any structural abnormality should prompt reconsideration of the diagnosis.

Purpose: More sensitive than echo for detecting subtle structural abnormalities, particularly:

• ARVC: fibrofatty infiltration of RV, RV aneurysms, late gadolinium enhancement (LGE)
• Myocarditis: patchy LGE in non-coronary distribution
• Subtle RVOT abnormalities: some BrS patients show mild fibrosis in the RVOT anterior wall on high-resolution MRI — this is an area of evolving research and may represent overlap between "pure channelopathy" and subtle structural substrate

Purpose: Identify pathogenic mutation (primarily SCN5A) for:

• Confirming diagnosis in borderline cases
• Cascade family screening — if proband has a known mutation, first-degree relatives can be tested

Important limitations:

• Only ~20–30% of clinically diagnosed BrS patients have a detectable SCN5A mutation

• 20 genes have been associated with BrS, but most are rare and have uncertain pathogenicity

• A negative genetic test has limited exclusion value (unlike LQTS where genetic testing is ~75% sensitive)

Electrophysiological study: role unclear (?prognostic role), probably unnecessary ^[2]

Uncertain diagnostic value of dynamic QRS change in Brugada / QTc change in long QT syndromes ^[8]

Purpose: Primarily to exclude alternative diagnoses rather than to diagnose BrS

Once a proband is diagnosed:

• First-degree relatives should undergo:
  • 12-lead ECG (standard + high leads)
  • Clinical assessment for symptoms (syncope, palpitations, nocturnal events)
  • Genetic testing if the proband's mutation is known
• If the Brugada of the patient is latent or intermittent: ^[3]
  • Repeat ECG periodically
  • Repeat ECG at 2nd or 3rd ICS → high precordial lead ECG
  • Administration of ajmaline, procainamide or flecainide

This applies to every patient with BrS — symptomatic or asymptomatic, ICD or no ICD.

Catheter ablation: treatment of choice for refractory ventricular arrhythmias in many cardiomyopathies / channelopathies ^[3]

Radiofrequency catheter ablation for ventricular arrhythmia in patients with Brugada syndrome can effectively reduce the burden of ventricular arrhythmias. Indicated in patients with or without an ICD who experience recurrent ICD shocks ^[11]

How it works (from first principles):

• The arrhythmogenic substrate in BrS is the RVOT epicardium — the area where the AP dome is lost and phase 2 re-entry originates
• Epicardial catheter ablation targets this area by delivering radiofrequency energy to the RVOT epicardial surface, creating thermal lesions that destroy the abnormal epicardial tissue
• By eliminating the epicardial cells with the abnormal repolarization, you remove the transmural gradient and the substrate for re-entry
• Post-ablation, the Type 1 ECG pattern often normalizes and VT/VF can no longer be induced

Genetic counseling ^[3] is an integral part of BrS management:

Follow up → since the annual incidence of arrhythmic events is around 0.5 to 1.2% per year ^[3]

Lithium cardiovascular effects: unmasked or modulated Brugada pattern ^[12]

Lithium can unmask or modulate BrS ECG patterns — possibly through effects on cardiac Na+ channels or intracellular ion homeostasis. Patients with BrS should ideally avoid lithium; if essential for psychiatric management, very close ECG monitoring is required.

This is the most feared and most important complication — and the entire reason BrS matters clinically.

SCD due to VF is the first and only clinical event in some patients ^[15]

Pathophysiology (from first principles):

• ↓ I_Na → unopposed I_to in RVOT epicardium → loss of AP dome → transmural voltage gradient → phase 2 re-entry → polymorphic VT → degenerates into VF → cessation of cardiac output → death within minutes if not defibrillated

Key statistics:

• Arrhythmia recurrence rate is 40% over a 2–3-year follow-up ^[15] — this is the recurrence rate in patients who have already had an event and are not treated with ICD. This extraordinarily high recurrence rate is why ICD is so strongly indicated in survivors of cardiac arrest
• Annual incidence of arrhythmic events is around 0.5 to 1.2% per year ^[3] — this applies to the broader population of BrS patients including asymptomatic ones
• SCD due to VF may be the first and only clinical event in some patients ^[2][15] — meaning there is no "warning" syncope before the fatal event in a proportion of cases. This is what makes risk stratification so challenging and so critically important

Why does SCD typically occur at night?

• In the majority of cases, malignant tachyarrhythmias occur at rest and at night (vagal influence) ^[15]
• During sleep, parasympathetic (vagal) tone is at its peak. Vagal stimulation:
  • ↓ heart rate → longer diastolic intervals → more time in the vulnerable repolarization window
  • ↓ I_Ca,L (acetylcholine-mediated) → less inward current during plateau → further facilitates AP dome loss
  • ↑ I_K,ACh (acetylcholine-activated potassium current) → more outward current → compounds dome loss
• This is the pathophysiological basis for the classic SE Asian "death during sleep" phenomenon (Lai Tai, Bangungut, Pokkuri)

Even when not immediately fatal, recurrent VT/VF episodes cause significant morbidity:

Other abnormalities, eg. AF, 1st degree heart block, LAD, fragmented QRS ^[2]

• Prevalence: ~10–25% of BrS patients develop AF — significantly higher than age-matched controls
• Why? The SCN5A mutation affects sodium channels throughout the heart, not just the ventricles. Atrial myocytes also depend on I_Na for conduction. Reduced atrial Na+ current → slowed intra-atrial conduction → creates substrate for re-entrant wavelets → AF
• Clinical significance:
  • AF may cause inappropriate ICD shocks — the ICD may misinterpret the rapid ventricular response during AF as VT and deliver a shock. This is one of the most common causes of inappropriate shocks in BrS patients with ICDs
  • AF itself may produce haemodynamic compromise and thromboembolic risk
  • AF in a young male with no obvious cause should raise suspicion for underlying channelopathy

The SCN5A gene encodes the principal cardiac sodium channel (Nav1.5) that is expressed throughout the entire conduction system. Loss-of-function mutations can therefore affect not just the RVOT, but also:

LQT/Brugada overlap syndrome ^[15]

Possible overlap with arrhythmogenic right ventricular dysplasia (ARVD) ^[15]

Since BrS patients are typically young adults (mean age ~30–40s) who will carry the ICD for decades, device-related complications accumulate significantly over their lifetime.

Subcutaneous ICD (S-ICD) has been developed in part to address the lead-related complications of transvenous ICDs. By placing the lead subcutaneously (no intravascular component), it eliminates the risk of endocarditis, venous thrombosis, and intracardiac lead extraction. However, S-ICD cannot provide anti-tachycardia pacing or bradycardia pacing — so it is not suitable for BrS patients with concomitant sinus node dysfunction or conduction disease.