Brugada syndrome and inherited channelopathies

01OverviewDefinition, clinical context and the essential points that orientate the chapter.

Inherited channelopathies alter cardiac ion currents and may cause malignant arrhythmia despite a structurally normal heart. The phenotype, trigger and ECG guide suspicion: Brugada is a right-precordial ST pattern, long-QT produces delayed repolarisation, short-QT accelerated repolarisation, and CPVT adrenergic ventricular ectopy.

Brugada risk is not determined by an ECG label alone. Previous cardiac arrest, documented spontaneous sustained ventricular arrhythmia, arrhythmic syncope and a spontaneous type 1 pattern carry much more weight than an incidental drug-induced pattern in an asymptomatic person.

Care is family-centred. Expert phenotyping, a three-generation history, targeted genomic testing and cascade screening are coordinated by an inherited cardiac conditions clinic; variants of uncertain significance must not be treated as a positive predictive test.

Key points

A type 1 Brugada ECG is coved ST elevation over 0.2 mV followed by T-wave inversion in at least one V1–V2 lead placed in the second, third or fourth intercostal space.
A spontaneous type 1 pattern is diagnostic in the right setting; fever- or sodium-channel-blocker-induced type 1 generally needs compatible clinical features for a Brugada syndrome diagnosis.
Type 2 saddleback appearances are not diagnostic alone and should not trigger an ICD without expert phenotyping.
Brugada events often occur at rest, during sleep or with fever; CPVT instead causes bidirectional or polymorphic ventricular arrhythmia during exercise or intense emotion with a usually normal resting ECG.
Treat fever promptly, maintain hydration and avoid Brugada-provocative drugs, cocaine and binge alcohol; persistent fever warrants ECG and monitored review.
An ICD is the definitive sudden-death protection for survivors of VT/VF arrest and selected high-risk symptomatic Brugada patients; most asymptomatic people do not need one.
Ajmaline or another sodium-channel challenge belongs in an experienced electrophysiology unit with high-right-precordial ECG and immediate resuscitation capability.
A negative genetic test does not exclude Brugada syndrome; first-degree relatives need clinical screening through an inherited cardiac conditions service.

02AetiologyUnderlying causes, associations and risk factors, with why each one matters.

Brugada genetic susceptibility

Pathogenic variants affecting cardiac sodium current, most recognisably SCN5A, explain a minority of Brugada cases. Many affected people are gene-negative, so diagnosis remains phenotype-led.

Inherited repolarisation disorders

Long-QT and short-QT syndromes arise from variants that prolong or abbreviate ventricular action-potential recovery. The responsible current and clinical trigger vary by genotype.

CPVT calcium-handling disease

CPVT usually reflects inherited abnormal intracellular calcium release. Affected hearts may appear structurally normal and the resting ECG may be normal despite dangerous exercise- or emotion-triggered arrhythmia.

Phenotype modifiers and phenocopies

Fever and sodium-channel-blocking drugs can unmask Brugada susceptibility, while electrolyte disturbance, ischaemia and medicines can imitate channelopathy. Correcting acquired factors is part of diagnosis and prevention.

03PathophysiologyThe causal sequence from the underlying abnormality to symptoms and harm.

1
Shared basis: altered cardiac electrophysiology
Pathogenic variants or other inherited functional susceptibility can alter sodium, potassium or calcium handling, often with little overt structural heart disease, changing conduction, repolarisation or intracellular calcium stability.
2
Brugada branch: RV outflow electrical heterogeneity
Reduced inward current and electrical heterogeneity in the RV outflow region are leading Brugada mechanisms, although their relative contribution varies. Fever or channel blockers can magnify the imbalance.
3
QT-syndrome branches: abnormal repolarisation
In long-QT syndromes, prolonged repolarisation favours early afterdepolarisations and torsades de pointes. In short-QT syndromes, abbreviated refractoriness favours re-entry; dispersion of repolarisation can add instability in either setting.
4
CPVT branch: adrenergic calcium leak
During exercise or emotion, abnormal sarcoplasmic calcium release creates delayed afterdepolarisations, progressing from ventricular ectopy to bidirectional or polymorphic VT.
5
Shared outcome: malignant ventricular arrhythmia
Polymorphic VT or VF can abruptly reduce or abolish effective cardiac output, causing seizure-like syncope, cardiac arrest or sudden death unless the rhythm terminates or is promptly defibrillated.

04Clinical features and red flagsSymptoms, examination findings, patterns of presentation and time-critical warnings.

Type 1 Brugada pattern

Coved J-point/ST elevation above 2 mm with descending ST segment and inverted T wave in at least one high or standard right-precordial V1–V2 lead is the diagnostic ECG morphology.

Brugada clinical eventRed flag

Unexplained syncope at rest, nocturnal agonal breathing, documented polymorphic VT/VF or cardiac arrest—especially during fever—raises immediate risk concern.

Non-diagnostic saddleback

Type 2/3 saddleback patterns, incomplete RBBB, early repolarisation, lead-placement artefact and phenocopies from ischaemia or electrolyte/metabolic disturbance require expert differentiation.

CPVT phenotype

Exercise- or emotion-triggered syncope with progressive ventricular ectopy, bidirectional VT or polymorphic VT despite a normal resting ECG suggests CPVT and demands specialist restriction/treatment.

Long- and short-QT phenotypes

QT prolongation with torsades triggers or a very short QT with peaked T waves, AF or sudden death points to other channelopathies; manually verify QTc and exclude drugs/electrolytes.

Familial signal

Sudden unexplained death, drowning, single-vehicle crash, nocturnal death or seizure-like syncope in young relatives should trigger a three-generation history and inherited-cardiac assessment.

05InvestigationsWhat to request, why it matters and how to interpret it.

Investigation order

Read from the initial assessment onwards. Tests may run in parallel in urgent care; first-line, preferred, confirmatory, definitive and gold-standard labels appear only when the chapter explicitly states them.

01
12-lead ECG with high V1–V2 positionsFirst step
Why
Identify spontaneous type 1 Brugada morphology and measure PR, QRS and QTc.
Interpretation and limitations
Record V1–V2 in fourth and then second/third intercostal spaces; a type 1 pattern is coved ST elevation over 0.2 mV with T inversion in at least one of these leads.
02
Repeat ECG during fever and after correction of phenocopies
Why
Detect a dynamic pattern and separate Brugada from ischaemia, electrolyte disturbance or drug effect.
Interpretation and limitations
Fever may unmask type 1; a fever-induced pattern needs clinical context and inherited-arrhythmia review rather than automatic risk equivalence to spontaneous type 1.
03
Sodium-channel-blocker challenge
Why
Unmask type 1 morphology when suspicion remains without a spontaneous diagnostic ECG.
Interpretation and limitations
Ajmaline/procainamide challenge is specialist-only with continuous ECG and resuscitation readiness; a positive induced pattern is interpreted with symptoms and family history.
04
Exercise test with rhythm monitoring
Why
Look for CPVT ectopy and assess phenotype-specific arrhythmic response.
Interpretation and limitations
Increasing polymorphic or bidirectional ventricular ectopy with adrenergic stress supports CPVT; conduct only in an experienced service with emergency capability.
05
Echocardiography and cardiac MRI when indicated
Why
Exclude cardiomyopathy, ARVC, myocarditis, scar and other structural mimics.
Interpretation and limitations
A structurally normal heart supports but does not prove channelopathy; abnormal imaging redirects or identifies overlap disease.
06
Inherited-condition genomic and family evaluation
Why
Use a phenotype-directed gene panel and cascade testing when a pathogenic familial variant is found.
Interpretation and limitations
SCN5A explains only a minority of Brugada cases; a negative result does not exclude disease, while a VUS does not establish it.

06Differential diagnosisRealistic alternatives and the features that help distinguish them.

Brugada phenocopy

Acute ischaemia, hyperkalaemia, metabolic disturbance or drug toxicity can create a Brugada-like right-precordial pattern. Resolution after treating the cause supports a phenocopy, but does not by itself exclude latent inherited susceptibility; expert review may still be needed.

Incomplete RBBB or early repolarisation

A saddleback or J-point elevation alone is non-diagnostic. Correct lead placement and expert assessment look for the coved type 1 morphology and compatible clinical context.

Arrhythmogenic cardiomyopathy

Both can cause right-precordial ECG change and ventricular arrhythmia, but regional ventricular dysfunction or scar on imaging supports cardiomyopathy rather than an isolated channelopathy.

Acquired QT prolongation

QT-prolonging medicines, bradycardia and low potassium, magnesium or calcium commonly cause prolonged repolarisation. Correction and serial ECG help separate acquired from inherited long-QT susceptibility.

Epilepsy or reflex syncope

A typical vasovagal prodrome and situational trigger support reflex syncope, whereas abrupt exertional, febrile or nocturnal events raise arrhythmic concern. Convulsive movements can occur during either cerebral hypoperfusion or epilepsy.

07ManagementImmediate care, first-line treatment, alternatives and escalation.

01patternSuspected Brugada patternFirst stepA right-precordial Brugada-like pattern or compatible syncope/family history is found.

1Check symptoms, family history, fever, medications/recreational drugs and reversible phenocopies; repeat correctly placed standard and high-right-precordial ECGs.
2If spontaneous type 1 or arrhythmic symptoms are present, obtain urgent electrophysiology/inherited-cardiac review and restrict driving according to specialist advice.
3If the ECG is non-diagnostic but suspicion persists, arrange specialist sodium-channel challenge; never give ajmaline as an unsupervised diagnostic trial.
4Risk-stratify using arrest/VT/VF, syncope mechanism and spontaneous versus induced pattern—not genetic result or family history alone—and discuss observation versus ICD.

02feverFever in known or suspected Brugada syndromeTemperature is raised or a febrile illness develops.

1Start prompt antipyresis with an appropriate adult paracetamol dose, fluids if safe and treatment of the infection; avoid overdose or duplicate paracetamol products.
2Seek urgent clinical advice and obtain an ECG; attend hospital for persistent high fever, type 1 change, syncope, palpitations or inability to maintain hydration.
3Use continuous monitoring for significant fever with a type 1 pattern or arrhythmic symptoms and involve the inherited-arrhythmia service.
4Review all prescribed/over-the-counter drugs against the specialist avoidance list and avoid cocaine, binge alcohol and dehydration.

03stormVT/VF arrest or electrical stormCardiac arrest, recurrent polymorphic VT/VF or repeated appropriate ICD shocks occurs.

1Follow RCUK ALS immediately: CPR, defibrillation and correction of reversible causes; do not delay shocks for channelopathy confirmation.
2Call electrophysiology and critical care urgently, treat fever/electrolyte disturbance, stop provoking drugs and interrogate/reprogramme the ICD when present.
3For Brugada electrical storm, an expert centre may use continuous IV isoprenaline and/or quinidine despite these being specialist off-label/named-patient strategies; ECG and haemodynamic monitoring are mandatory.
4After control, assess ICD indication/programming and consider epicardial right-ventricular-outflow-tract substrate ablation for recurrent VF or shocks at a specialist centre.

04familyFamily or SADS pathwayBrugada/channelopathy is diagnosed, or a young relative has unexplained sudden death.

1Refer first-degree relatives to an inherited cardiac conditions clinic for a three-generation pedigree and phenotype-directed ECG/exercise/imaging assessment.
2Where possible retain appropriate post-mortem tissue and use a molecular-autopsy pathway for SADS; do not order broad consumer panels in isolation.
3If a pathogenic/likely pathogenic familial variant is identified, offer counselling and targeted cascade testing; do not cascade a VUS as though causal.
4Give each phenotyped relative condition-specific trigger, medicine, exercise, pregnancy and emergency advice; a negative genotype does not erase a positive phenotype.

Key medicines and prescribing safety4 treatments · regimens, roles and cautions

Prompt fever control in Brugada syndrome while the cause is assessed and hydration/monitoring arranged.

Paracetamol

1 g orally every 4 hours as required for fever, no more than four doses (4 g) in 24 hours; do not continue beyond 3 days without medical review.

Do not combine with another paracetamol-containing product. Use a lower maximum or seek prescriber advice with low body weight, severe liver/renal impairment, malnutrition or hazardous alcohol use; persistent fever still needs urgent review.

Increases adrenergic drive and can suppress recurrent Brugada VF as emergency adjunctive therapy in an expert centre.

Isoprenaline infusion

Brugada electrical storm is a specialist off-label exception. A current UK SmPC infusion starts at 0.01 microgram/kg/min IV and allows 0.01 microgram/kg/min increments to 0.15 microgram/kg/min; the electrophysiology/critical-care team titrates to arrhythmia suppression under continuous ECG and BP monitoring.

The UK SmPC is licensed for bradycardia/AV block and lists pre-existing ventricular arrhythmia as a contraindication; Brugada storm use therefore requires explicit expert guideline-based risk–benefit justification, not routine ward prescribing. It is not the RCUK standard tachyarrhythmia drug algorithm.

A non-selective beta blocker is first-line long-term therapy for CPVT, not for Brugada syndrome.

Propranolol for CPVT

When nadolol is unavailable or unsuitable, an inherited-arrhythmia specialist may use propranolol; the UK SmPC arrhythmia range is 10–40 mg orally three or four times daily, but CPVT dosing is individualised to exercise-test suppression and tolerance.

CPVT use and dose selection are specialist-led. Avoid abrupt withdrawal; assess asthma, bradycardia, AV block, hypotension and adherence, and verify suppression with monitored exercise testing.

Specialist add-on for CPVT with persistent exercise-induced ventricular arrhythmia; it is not routine Brugada treatment and sodium-channel blockers can unmask Brugada.

Flecainide for CPVT

CPVT use is specialist-led and off-label; titrate an individual prescription against exercise-test suppression, ECG/QRS and renal function. The cited product SmPC's licensed ventricular-arrhythmia start is 100 mg orally twice daily and maximum 400 mg/day, but those product doses must not be adopted as a CPVT protocol.

CPVT use is specialist-only; obtain ECG, QRS, renal function and structural/ischaemic assessment. Reduce in renal impairment/older adults and stop or review for QRS widening, proarrhythmia or suspected Brugada overlap.

08ComplicationsImportant consequences, why they occur and why they matter clinically.

VT, VF and sudden cardiac death

Electrical instability can generate torsades, bidirectional or polymorphic VT and VF. Cardiac arrest may be the first manifestation in an otherwise healthy person with a normal examination.

Recurrent syncope and trauma

Self-terminating ventricular arrhythmia produces abrupt cerebral hypoperfusion, causing falls, road accidents or drowning. Seizure-like activity may delay recognition of the cardiac cause.

Electrical storm and repeated ICD therapy

Clusters of ventricular arrhythmia can trigger repeated appropriate shocks, psychological distress and myocardial injury. Fever, provocative drugs and device programming require urgent specialist review.

Conduction or overlap disease

Some sodium-channel variants also cause sinus-node dysfunction, AV block or overlapping repolarisation phenotypes, complicating diagnosis, family counselling and device decisions.

09Monitoring and follow-upTreatment response, safety checks and longer-term review.

Review symptoms, syncope circumstances, fever episodes, medicines and family events in an inherited cardiac conditions clinic.
Repeat standard/high-right-precordial ECG when clinically indicated, especially during fever or after a new potentially provoking medicine.
Interrogate any ICD for appropriate/inappropriate therapy, lead integrity and arrhythmia burden; repeated shocks need urgent strategy review.
For CPVT, use supervised exercise testing to titrate beta blocker/flecainide and assess adherence and residual ectopy.
Maintain an updated three-generation pedigree and cascade-screen new at-risk first-degree relatives as the family changes.
Monitor medicine-specific ECG, BP, renal/hepatic parameters and adverse effects; specialist off-label rescue therapy requires continuous monitoring.

10Special situationsVariants, exceptions and circumstances that change the usual approach.

Lead position can reveal the phenotype

Moving V1–V2 to the second or third intercostal spaces samples the RV outflow tract and increases sensitivity for a type 1 pattern.

Fever is a diagnostic and therapeutic stress

Temperature can reduce sodium-channel function, unmasking type 1 and raising VF risk; treat it promptly and record an ECG rather than waiting for routine follow-up.

Induced is not spontaneous

A drug-induced type 1 ECG in an asymptomatic person carries different implications from spontaneous type 1 with arrhythmic syncope; expert context prevents unnecessary ICD harm.

Normal resting ECG does not exclude CPVT

CPVT is an adrenergic disease; the diagnostic ventricular ectopy may emerge only with exercise or emotion.

Genotype is not the diagnosis

Many Brugada patients have no identified variant, and an SCN5A variant can cause overlap phenotypes. Phenotype and segregation remain essential.

A shock is not a full treatment plan

An ICD terminates VF but recurrent shocks need fever/drug correction, programming, specialist pharmacotherapy and sometimes substrate ablation.

11Common pitfallsFrequent interpretation and management errors.

01
Calling a saddleback type 2 appearance diagnostic Brugada syndrome without expert review.
02
Giving an unsupervised sodium-channel-blocker challenge or using standard lead placement only.
03
Reassuring a febrile Brugada patient without antipyresis, ECG advice and escalation criteria.
04
Implanting an ICD solely for an asymptomatic induced pattern without individual risk assessment.
05
Using a negative genetic result to discharge a phenotypically affected patient or their family.