Cardiovascular · PANCE / PANRE

Long QT Syndrome and Brugada Syndrome

Inherited (or acquired) channelopathies causing prolonged QT (LQTS) or RBBB-like ST elevation (Brugada) — both predispose to polymorphic VT and sudden cardiac death.

Also known as: LQTS, long QT syndrome, torsades de pointes, Brugada syndrome, channelopathy

Overview

Inherited channelopathies of cardiac repolarization producing characteristic ECG patterns and predisposing to malignant ventricular arrhythmias. Long QT syndrome (LQTS) features prolonged ventricular repolarization (corrected QT interval) and risk of torsades de pointes; acquired forms are commonly drug- or electrolyte-induced. Brugada syndrome features a coved-type ST elevation in V1-V2 with risk of polymorphic VT or ventricular fibrillation, often during sleep or febrile illness.

Epidemiology

LQTS: prevalence ~1 in 2,000; LQT1, LQT2, and LQT3 account for ~75% of genotyped cases. Brugada syndrome: prevalence ~5 per 10,000 in Europeans, much higher in Southeast Asia (lai tai, pokkuri, bangungut — historically a leading cause of sudden death in young men). Brugada is more common in males ~8-10:1.

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Risk factors

LQTS: family history of sudden death or unexplained syncope; congenital deafness (Jervell-Lange-Nielsen syndrome, LQT1 with autosomal recessive deafness)
LQTS triggers: LQT1 — exertion (especially swimming); LQT2 — auditory stimuli or postpartum; LQT3 — sleep / bradycardia
Acquired LQTS: methadone, fluoroquinolones (moxifloxacin, levofloxacin), macrolides (azithromycin, clarithromycin), antipsychotics (haloperidol, ziprasidone, quetiapine), antiemetics (ondansetron, droperidol), antiarrhythmics (sotalol, dofetilide, ibutilide, amiodarone), hypokalemia, hypomagnesemia, hypocalcemia
Brugada: family history of unexplained sudden death; fever (key trigger); sodium channel blockers (flecainide, propafenone, certain antidepressants); cocaine; vagotonic states (sleep, large meals)

Pathophysiology

LQTS results from mutations affecting cardiac repolarization channels: KCNQ1 (LQT1, slow delayed rectifier potassium current IKs), KCNH2 (LQT2, rapid delayed rectifier IKr), and SCN5A (LQT3, late sodium current INa). Prolonged action potential predisposes to early afterdepolarizations and triggered activity, generating torsades de pointes. Acquired LQTS most often results from drugs blocking the IKr (hERG) channel. Brugada syndrome is associated with SCN5A loss-of-function mutations affecting the cardiac sodium channel, producing transmural voltage gradients in the right ventricular outflow tract that promote phase 2 reentry and polymorphic VT.

Clinical presentation

Symptoms

Recurrent unexplained syncope, especially in childhood or young adulthood
Documented or suspected torsades de pointes / polymorphic VT
Sudden cardiac death (may be the first manifestation)
Brugada: arrhythmic events often during sleep or fever; nocturnal agonal respiration
Seizure (often a misdiagnosis of arrhythmic syncope)
Family history of premature sudden death (<40 years)

Signs / physical exam

Exam is generally normal between events
Bradycardia in LQT3 patients (prolongs QT further)
Congenital sensorineural deafness in Jervell-Lange-Nielsen syndrome (LQTS)

Classic findings

Adolescent or young adult with exertional syncope and prolonged QTc (LQT1); young male with nocturnal sudden death and coved ST elevation in V1-V2 (Brugada Type 1).

Differential diagnosis

Acquired vs congenital LQTS — Medication review, electrolytes, family history; targeted genetic testing if congenital suspected
Catecholaminergic polymorphic VT (CPVT) — Exercise- or emotion-induced bidirectional or polymorphic VT with normal resting ECG; RYR2 or CASQ2 mutations
Short QT syndrome — QTc <340 ms with risk of AFib and sudden death; rare
Early repolarization syndrome — J-point elevation in inferior or lateral leads; small additional sudden death risk; rarely needs ICD
Right bundle branch block (true) — Brugada Type 1 ECG differs by coved ST elevation and inverted T wave in V1-V2; flecainide or ajmaline provocation if uncertain
ARVC (arrhythmogenic right ventricular cardiomyopathy) — Epsilon waves, T-wave inversion V1-V3, structural RV disease on MRI
Pulmonary embolism — Acute RV strain, S1Q3T3, but coved ST elevation V1-V2 is not the typical pattern

Diagnostic workup

Diagnostic criteria

Schwartz score for LQTS combines QTc duration, history of torsades, syncope (with/without stress), family history, and congenital deafness. Brugada syndrome is diagnosed by a spontaneous or drug-induced Type 1 pattern in ≥1 right precordial lead, plus clinical features per the 2013 HRS/EHRA/APHRS expert consensus.

Labs

BMP including potassium, magnesium, calcium
TSH
Toxicology screen if drug-induced arrhythmia suspected

Imaging

12-lead ECG with manual QT measurement and Bazett or Fridericia correction (Bazett: QTc = QT / √RR). Normal QTc <450 ms in men and <460 ms in women; LQTS strongly suspected if QTc ≥480 ms or borderline (450-480) with clinical risk factors
Brugada ECG patterns: Type 1 (coved-type ≥2 mm ST elevation followed by negative T wave in V1-V2) is diagnostic; Type 2 (saddleback) is suggestive but not diagnostic, may require provocation
Exercise stress testing and ambulatory monitoring
Echocardiography to exclude structural disease
Sodium channel blocker challenge (procainamide, ajmaline, flecainide) under monitored conditions to unmask Brugada Type 1 ECG when suspicion is high but resting ECG is non-diagnostic
Genetic testing (especially when ECG diagnostic): KCNQ1, KCNH2, SCN5A panels for LQTS; SCN5A for Brugada (positive in only ~20-30% of Brugada — clinical and ECG diagnosis remains primary)

Diagnostic algorithm

Feature	Long QT Syndrome	Brugada Syndrome
Channel/gene	KCNQ1 (LQT1), KCNH2 (LQT2), SCN5A (LQT3)	SCN5A (loss-of-function) in 20-30%
ECG	Prolonged QTc (≥460-480 ms typical threshold)	Coved ≥2 mm ST elevation, V1-V2 (Type 1)
Trigger	LQT1 exercise/swim; LQT2 noise/postpartum; LQT3 sleep	Fever, sleep, vagotonic states, sodium channel blockers
Arrhythmia	Torsades de pointes (polymorphic VT)	Polymorphic VT / VF
Demographics	Children, young adults, both sexes	Adult males >> females, Southeast Asian heritage
Acute therapy	IV magnesium, correct electrolytes	Defibrillation, isoproterenol, quinidine
Long-term therapy	Beta-blocker (nadolol, propranolol) ± ICD ± LCSD	ICD for high-risk; quinidine adjunct

Side-by-side comparison of LQTS and Brugada syndrome.

Treatment

First-line

LQTS — lifestyle: avoid QT-prolonging drugs (consult www.crediblemeds.org), maintain normal potassium/magnesium, avoid triggers based on genotype (e.g., competitive swimming in LQT1, sudden loud noises in LQT2)
LQTS — beta-blocker (nadolol or propranolol preferred over selective agents) for all symptomatic patients and most asymptomatic patients with QTc ≥470 ms — first-line therapy; titrate to attenuate exercise heart rate response
LQTS — ICD: aborted cardiac arrest, recurrent syncope on adequate beta-blockade, or very high-risk genotype/QTc combinations
LQTS — left cardiac sympathetic denervation (LCSD) for high-risk patients with breakthrough events on beta-blocker
Acute torsades de pointes: IV magnesium 2 g over 5-15 min (regardless of magnesium level), correct hypokalemia, withdraw offending agents, overdrive pacing or isoproterenol (if no contraindication and not LQTS-related) for pause-dependent torsades, defibrillate sustained VT/VF

Second-line / adjunct

Brugada — avoid triggers: aggressive fever control (acetaminophen), avoid sodium channel blocker antiarrhythmics, certain psychotropics (some tricyclics, lithium), cocaine, excessive alcohol
Brugada — ICD is the only therapy proven to prevent sudden cardiac death; indicated for cardiac arrest survivors, documented sustained VT, or spontaneous Type 1 ECG with syncope or family history of SCD
Brugada — quinidine for ICD storm or for patients with high-risk features who are not ICD candidates
Brugada — substrate ablation of the RV outflow tract epicardium for recurrent VT or refractory ICD shocks in expert centers
Family screening with ECG ± genetic testing for first-degree relatives in both LQTS and Brugada

Complications

Polymorphic VT, torsades de pointes, ventricular fibrillation
Sudden cardiac death
ICD shocks (appropriate and inappropriate), psychological impact, complications of device therapy
Drug interactions in patients on chronic medications who must avoid QT-prolonging therapies (e.g., azithromycin, ondansetron)

PANCE pearls

Always measure QTc manually — automated QT measurements are unreliable. Use the lead with the clearest T-wave end (often II or V5) and apply Bazett (or Fridericia at extreme heart rates).
LQTS genotype-trigger associations: LQT1 = exertion / swimming; LQT2 = auditory stimuli / postpartum; LQT3 = rest / sleep.
Acute torsades: IV magnesium FIRST, regardless of serum magnesium level; then correct potassium, remove offending drugs, and consider overdrive pacing for pause-dependent forms.
Brugada Type 1 ECG (coved-type) is diagnostic; fever frequently unmasks the pattern — counsel patients to be aggressive with antipyretics.
Family screening (ECG ± genetic testing) is essential in both LQTS and Brugada — first-degree relatives should be offered evaluation.

Images

Torsades de pointes — the feared arrhythmia complication of long QT syndrome

References

HRS/EHRA/APHRS 2013 — HRS/EHRA/APHRS Expert Consensus Statement on the Diagnosis and Management of Patients with Inherited Primary Arrhythmia Syndromes (Priori et al., Heart Rhythm 2013)
ACC/AHA/HRS 2017 — 2017 ACC/AHA/HRS Guideline for Management of Patients With Ventricular Arrhythmias and Prevention of Sudden Cardiac Death (Al-Khatib et al., JACC 2018)
ESC 2022 — 2022 ESC Guidelines for the Management of Patients with Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death (Zeppenfeld et al., Eur Heart J 2022)
CredibleMeds — QTdrugs lists, AzCERT (www.crediblemeds.org)

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