Brugada Syndrome (State-of-the-Art Review)

Authors, Journal, Affiliations, Type, DOI

• Andrew D. Krahn, Elijah R. Behr, Robert Hamilton, Vincent Probst, Zachary Laksman, Hui-Chen Han
• JACC: Clinical Electrophysiology, Vol. 8, No. 3, 2022 (March 2022), pp. 386–405
• University of British Columbia (Krahn, Laksman, Han); St. George's University of London (Behr); Hospital for Sick Children & University of Toronto (Hamilton); Nantes University Hospital (Probst); Monash University (Han)
• Type: State-of-the-Art Review
• DOI: https://doi.org/10.1016/j.jacep.2021.12.001

Overview

Brugada syndrome (BrS) is an inherited channelopathy characterised by coved ST-segment elevation ≥2 mm with T-wave inversion in the right precordial leads, predisposing to syncope and cardiac arrest predominantly during sleep. Prevalence is ~1:2,000 for type 1 ECG pattern; males account for 80–90% of diagnosed cases. This state-of-the-art review summarises the current pathophysiological understanding, diagnostic framework (including the Shanghai Score), quantified risk stratification by clinical subgroup, and a practical management algorithm covering conservative, pharmacologic, and interventional strategies.

Keywords

Brugada syndrome; ventricular fibrillation; sodium channel; SCN5A; sudden cardiac death; risk stratification; ICD; quinidine; catheter ablation; programmed ventricular stimulation

Key Takeaways

Pathophysiology

• NaV1.5 (SCN5A) is the predominant cardiac sodium channel; loss-of-function variants → reduced peak INa → slowed phase 0 upstroke and shortened action potential duration in the RVOT.
• SCN5A variants show defective gating (activation/inactivation) and/or reduced trafficking to the cell membrane. NaV1.5 function is augmented by ambient temperature — explaining fever-precipitated events.
• SCN5A is the only definitively disease-causing gene per ClinGen. SCN5A variants are identified in only ~20% of BrS patients. Other implicated genes (SCN10A, NaV1.5 β-subunits, KCND3, CACNA1C) have disputed pathogenicity.
• Polygenic mechanism: GWAS data suggest that multiple SNPs, not a single gene variant, likely account for the majority of BrS cases — explaining the familial occurrence without a single identifiable pathogenic variant.
• Depolarization hypothesis: Fibrosis and reduced connexin-43 in the epicardial RVOT → conduction delay and heterogeneity → arrhythmogenic substrate. Supported by epicardial histopathology showing increased collagen, inflammatory infiltrates, reduced Cx43, and electrogram fractionation at low-voltage zones.
• Repolarization hypothesis: Increased outward Ito during phase 2 of the action potential → transmural action potential dispersion (epicardial-endocardial gradient) → phase 2 re-entry. Prominence of Ito in the atria also contributes to atrial arrhythmias in BrS.
• Neural crest hypothesis: Abnormal cardiac neural crest cell migration impairs connexin-43 expression and outflow tract development → electrical uncoupling.
• Likely a confluence of factors producing a common ECG phenotype rather than a single mechanism.

Epidemiology

• Overall prevalence of type 1 BrS ECG: ~1:2,000; type 2/3 ECG: ~1:500. Most common in Asia, followed by Europe and the US.
• Males account for ~80–90% of diagnosed cases — disparity appears after adolescence.
• Phenotypic expression is age-dependent; prevalence in children is ~1:20,000.
• BrS accounts for up to 28% of SCD in structurally normal hearts and ~5–10% of resuscitated cardiac arrest cases.
• ~1/3 of patients at diagnosis have syncope; ~2/3 are asymptomatic.

Diagnosis

• Type 1 ECG (diagnostic): Coved ST-segment elevation ≥2 mm with negative T-wave in V1–V2 at standard or high lead positions (ICS 2–4). Types 2/3 are saddleback — not diagnostic alone.
• High precordial lead positions (V1/V2 at ICS 2–4) increase diagnostic yield ~1.5× versus standard positions.
• Shanghai Score (Antzelevitch et al. 2016):
  • ≥3.5 points = probable/definite BrS
  • 2–3 points = possible BrS
  • <2 points = non-diagnostic
  • ECG: spontaneous type 1 (3.5 pts); fever-induced type 1 (3 pts); type 2/3 → type 1 with SCB (2 pts)
  • Clinical: cardiac arrest/VF (3 pts); nocturnal agonal respirations (2 pts); arrhythmic syncope (2 pts); unexplained syncope (1 pt); AF <30 yrs (0.5 pt)
  • Family: definitive BrS in 1st/2nd-degree relative (2 pts); suspicious BrS-related SCD (1 pt); unexplained SCD <45 yrs (0.5 pt)
  • Genetic: probable pathogenic BrS gene mutation (0.5 pt)
• Sodium channel blocker (SCB) provocation: Indicated in type 2/3 ECG or clinical/family history suspicion. Ajmaline (most potent; mainly Europe) > flecainide/pilsicainide > procainamide (least potent; North America). Class 1a agents act during activated state; class 1c during inactivated state — different electrophysiological profiles. False-positive rate with high-dose ajmaline: ~8% of positive challenges in high-risk families (Tadros); ~27% of AVNRT patients and 4.5% of healthy controls (Hasdemir).
• Echocardiogram should be performed in all patients to exclude structural heart disease.
• Cardiac MRI may be considered in complex cases to delineate RVOT structure and function.
• Genetic testing: Recommended when type 1 ECG is present (spontaneous or provoked) to enable family screening. Penetrance in families with identified variants is ~50%. Clinical screening (not genetic testing alone) remains the basis for family screening. Only SCN5A testing is routinely recommended — other gene testing only in consultation with a genetics expert when ≥2 family members are phenotypically affected and SCN5A is negative.
• Family screening: All first-degree relatives of BrS or unexplained SCD cases; standard + high-lead ECG ± SCB provocation. In adults, one-time screening is adequate if SCB-negative. In paediatric members: ECG at age 3, then every 3 years until age 15 (age-related phenotypic expression); avoid routine SCB provocation before age 15 due to higher adverse event risk.

Risk Stratification

• Established high-risk markers:
  • Spontaneous type 1 ECG: 2–6× relative risk for SAE across multiple studies
  • Cardiogenic syncope: 2.5–5× relative risk for SAE (not non-cardiogenic syncope)
• Quantified annual SAE rates (resuscitated CA + SCD):
  • Cardiogenic syncope + spontaneous type 1 ECG: 2.3–3.7%/year
  • Cardiogenic syncope + drug-induced type 1: 0.98–1.96%/year
  • Asymptomatic + spontaneous type 1 ECG: 0.8–1.2%/year
  • Asymptomatic + drug-induced type 1: 0.21–0.3%/year
• Age and sex: Not independent risk markers in multivariate analysis. Patients ≥55 years at diagnosis have SAE rates comparable to the general population.
• Family history of SCD: Not consistently predictive in large cohort studies; early familial SCD (first-degree relative <35 years) may confer risk (Sieira et al.).
• "Brugada burden" concept (Viskin et al.):
  • Spatial burden: Type 1 ECG changes in peripheral leads (in addition to right precordial) independently associated with SAEs — confirmed in large multicentre study (Honarbakhsh et al., n=1,110).
  • Temporal burden: Higher proportion of spontaneous type 1 ECGs during follow-up + greater ST-segment burden on 24-hour Holter both predict more cardiac events.
• Other ECG markers: f-QRS, QRS duration, S-wave duration, rJ interval, early repolarization pattern, Tpeak-end duration, QTc, and signal-average ECG have all been proposed — most remain unvalidated in large studies adjusting for established risk factors. Atrial fibrillation is an independent predictor of SAE (Calò et al.).
• Programmed ventricular stimulation (PVS): Controversial. Two major registries — FINGER (n=1,029) and PRELUDE (n=308) — failed to show predictive utility. Pooled analysis (Sroubek et al., n=1,312) found OR 2.7 for SAE with inducibility, but positive predictive value remained low. Authors recommend PVS only as a "tie-breaker" in selected intermediate-risk patients (e.g., young patient with spontaneous type 1 ECG + syncope of uncertain origin where easily induced VF would drive ICD recommendation). Not recommended for routine use.
• SCN5A variants and risk: Two studies (Japan, Thailand) found SCN5A variants independently predictive of SAE; not confirmed in European FINGER registry.

Management

Conservative

• All BrS patients: avoid Brugada-aggravating drugs (brugadadrugs.org), avoid excessive alcohol, avoid illicit substances (cocaine, cannabis).
• Prompt antipyretic treatment for any febrile illness — fever unmasks BrS phenotype and precipitates SAEs, especially in children.
• Correct acute metabolic disturbances (hypokalemia, hyperkalemia, metabolic acidosis).

Pharmacologic

• Quinidine: Class Ia agent that also inhibits Ito (phase 1 potassium current) and ICaL (phase 2) → prolonged effective refractory period → antiarrhythmic. Reduces VF inducibility at PVS in ~90% of patients (Belhassen series, n=60). Useful for: recurrent ICD shocks, ICD-declined patients, atrial fibrillation co-management.
  • QUIDAM trial (hydroquinidine vs. placebo): did not demonstrate benefit (underpowered, n not specified); however, no SAEs occurred in the hydroquinidine arm.
  • Side effects: diarrhea, thrombocytopenia, anemia, lupus reactions, neurologic effects, proarrhythmia — therapy cessation in ~1/3 of patients.
  • Low-dose quinidine (≤600 mg/d): Improves tolerability while providing reasonable antiarrhythmic benefit. Evening administration offers theoretical overnight protection. Regular blood count monitoring required.
• Isoproterenol (IV): For acute electrical storm/VF — increases ICaL to counteract arrhythmia. Recommended for short-coupled PVC-triggered VF.
• Phosphodiesterase III inhibitors (cilostazol, milrinone): Alternative to isoproterenol — also potentiate ICaL.

Device Therapy

• Secondary prevention ICD: Indicated for all patients with resuscitated cardiac arrest (Class I).
• Primary prevention ICD: Recommended for BrS + cardiogenic syncope (spontaneous or provoked type 1).
• Asymptomatic patients with spontaneous type 1 ECG: close follow-up; avoid primary prevention ICD unless additional high-risk features present (expert decision-making).
• Asymptomatic patients with vasovagal syncope or syncope of uncertain origin + spontaneous type 1 ECG: consider implanted loop recorder.
• Annual SAE rate vs. ICD complication rates: 3.3%/year inappropriate shocks + 4.5%/year other complications (lead malfunction, infection, psychological — meta-analysis, n=1,539). SCD incidence without ICD ~0.19%/year vs. ~0.10%/year with ICD (Probst et al., n=1,613).
• Subcutaneous vs transvenous ICD:
  • S-ICD preferred in young patients without pacing requirement (mitigates intravascular infection risk).
  • Transvenous dual-chamber system preferred when sinus node dysfunction or atrial tachyarrhythmia discrimination is needed.
  • ~15% of BrS patients fail initial S-ICD sensing screening; SCB provocation or exercise testing may identify additional patients with inappropriate morphology.
• Children: epicardial approach with subcostal device may be required.

Catheter Ablation

• Combined epicardial + endocardial approach:
  • Epicardial substrate modification in anterior RVOT
  • Endocardial elimination of triggering PVCs
  • SCB provocation during procedure unmasks additional substrate.
  • Proposed endpoint: resolution of J-point elevation despite pharmacologic provocation.
• Pappone et al. series (n=135): acute ECG normalization in 100%; persistence of normalization at median 10 months in 133/135 (98.5%).
• Currently indicated for: recurrent ICD shocks not managed with medical therapy; ICD-declined or ICD-contraindicated patients.
• Insufficient data to support ablation in asymptomatic patients.

Future Directions

• Polygenic risk scoring (PRS) from GWAS loci may improve diagnosis and risk stratification.
• Autoantibodies to cardiac-specific proteins (α-cardiac actin, α-skeletal actin, keratin, connexin-43) under investigation as novel diagnostic biomarkers.
• Need for multi-variable risk prediction models integrating noninvasive ECG parameters with PVS findings.
• Ablation strategies may be recommended earlier if prospective data confirm durability.

Limitations of the Document

• State-of-the-art review — no new primary data; conclusions based on cited cohort studies, registries, and meta-analyses.
• Risk stratification data draws on registries with varied patient populations, follow-up durations, and definitions of endpoints (SAE = resuscitated CA + SCD in most, but syncope included in some studies).
• Most risk stratification studies involve predominantly male, middle-aged populations — generalisability to women, children, and elderly is limited.
• QUIDAM trial for hydroquinidine was underpowered — efficacy remains formally unproven.
• Ablation evidence is predominantly from single large series (Pappone) with median 10-month follow-up — long-term durability unknown.
• PVS utility remains unresolved — studies have not consistently adjusted for all noninvasive ECG risk predictors simultaneously.

Key Concepts Mentioned

• concepts/Shanghai-Score-System — diagnostic scoring framework detailed in Table 2
• concepts/Sudden-Cardiac-Death — BrS accounts for up to 28% of SCD in structurally normal hearts
• concepts/Electrical-Storm — management of VF storm in BrS (isoproterenol, cilostazol)
• concepts/Cardiac-Action-Potential — pathophysiological basis of BrS; sodium channel phases

Key Entities Mentioned

• entities/Brugada-Syndrome — primary subject of this review
• entities/SCN5A — only definitively disease-causing gene; polygenic mechanism discussed
• entities/Early-Repolarization-Syndrome — J-wave syndrome partner; shared quinidine/isoproterenol management

Wiki Pages Updated

• wiki/sources/brs-jaccep-2022.md (created)
• wiki/entities/Brugada-Syndrome.md (updated: quantified SAE rates, Brugada burden, QUIDAM trial, ICD vs. complication data, family screening protocol, SCB provocation details)
• wiki/concepts/Shanghai-Score-System.md (updated: SCB provocation comparison, scoring asymmetry, limitations)
• wiki/sourceindex.md (updated)
• wiki/wikiindex.md (updated)