Long QT, Brugada and inherited channelopathies

This page covers long QT syndrome, Andersen–Tawil syndrome, Brugada syndrome, early repolarization, CPVT and short QT syndrome, which ESC 2022 groups under primary electrical disease.^[1] It teaches how each is diagnosed, which guideline row each finding triggers, which drugs to avoid and how to screen the family.

What counts as an inherited channelopathy

AHA/ACC/HRS 2017 names the cardiac channelopathies as long QT syndrome, CPVT, Brugada syndrome, early repolarization syndrome and short QT syndrome.^[2] It adds that patients with one of these and a prior sudden cardiac arrest have a significantly increased risk of a further arrest or sudden death.^[2] ESC 2022 groups idiopathic VF, LQTS (including acquired LQTS), Andersen–Tawil syndrome type 1, Brugada syndrome, early repolarization syndromes, CPVT and SQTS under primary electrical disease.^[1] It notes that Andersen–Tawil syndrome type 1 is also classified as LQT7.^[1]

^{[1] [1] [2]}

Long QT syndrome: what it is and who gets it

ESC 2022 describes LQTS as a prolonged QT interval with ventricular arrhythmias mainly triggered by adrenergic activation.^[1] The mean age at presentation is 14 years.^[1]

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ESC 2022 says the subtypes may be grouped into three.^[1]

• Autosomal-dominant LQTS without extra-cardiac manifestation (prevalence 1 in 2500).^[1]
• Autosomal-dominant LQTS with extra-cardiac manifestation: Andersen–Tawil syndrome (LQT7), increasingly considered its own entity, and Timothy syndrome (LQT8), with prolonged QT, syndactyly, cardiac malformations, autism spectrum disorder and dysmorphism.^[1]
• Autosomal-recessive LQTS (Jervell and Lange–Nielsen syndrome), combining extreme QT prolongation with congenital deafness.^[1]

Long QT syndrome: genes and genotype-specific triggers

Rare variants in 17 genes have been associated with LQTS, but ESC 2022 notes that causality for several has been questioned.^[1] The undisputed genes are KCNQ1 (LQT1), KCNH2 (LQT2) and SCN5A (LQT3).^[1] Genetic screening identifies a mutation in 75% of LQTS cases, and these three genes account for 90% of positively genotyped cases.^[1]

The three undisputed LQTS genotypes

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Genotype also shapes treatment. ESC 2022 uses mexiletine as a genotype-specific treatment for LQT3, which reduces the length of the QT interval and the number of arrhythmic events.^[1]

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Long QT syndrome: making the diagnosis

ESC 2022 confirms the diagnostic criteria from its previous guideline: a QTc of 480 ms or more, or an LQTS risk score above 3.^[1] In the presence of arrhythmic syncope or cardiac arrest, a QTc of 460 ms or more is sufficient to consider the diagnosis.^[1]

ESC 2022: diagnosing LQTS

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Two practical points from ESC 2022 help at the bedside. With broad QRS complexes, for example with ventricular pacing or conduction defects, a formula has been proposed that adjusts QT by QRS duration.^[1] Moving the patient briskly from lying to standing while measuring the QT may be helpful for the diagnosis.^[1]

ESC 2022 does not recommend epinephrine challenge as a routine diagnostic tool, as reproducibility is modest.^[1] It adds that the epinephrine test is not recommended for LQTS due to the high false positive rate and the utility of exercise testing.^[1]

AHA/ACC/HRS 2017 gives two diagnostic rows.^[2]

• In clinically diagnosed LQTS, genetic counselling and genetic testing are recommended (COR I, LOE B-NR).^[2]
• In suspected LQTS, ambulatory ECG monitoring, recording the ECG lying and immediately on standing, and/or exercise treadmill testing can be useful for establishing a diagnosis and monitoring the response to therapy (COR IIa, LOE B-NR).^[2]

The exercise data behind that row are worth knowing. In a prospective observational study of suspected LQTS, patients with syncope or cardiac arrest and either an affected first-degree relative or a borderline or prolonged QTc had treadmill and bicycle exercise testing, with ECGs before, during and after exercise and in different positions.^[2] LQTS was confirmed by genetic testing in all affected individuals.^[2] Among those with a borderline-to-normal resting QTc, prolongation of the 4-minute recovery QTc to 445 ms or more had high sensitivity for correctly identifying LQTS.^[2] In a study of younger patients, QTc prolongation above 460 ms at 7 minutes of recovery predicted LQT1 or LQT2 versus controls.^[2]

Correcting the QT for heart rate: Bazett and Fridericia

The thresholds above are corrected QT values, so you need the correction formulae. A 2016 Journal of the American Heart Association study that compared five published formulae writes Bazett as QTcB = QT/RR^1/2 and Fridericia as QTcFri = QT/RR^1/3.^[5] That is, Bazett divides the QT by the square root of the RR interval and Fridericia by its cube root, with QT and RR measured in seconds.^[5]

The two QT correction formulae examiners ask for

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The practical consequence, in the same study: with current clinical standards, Bazett overestimated the number of patients with potentially dangerous QTc prolongation, which could lead to unnecessary safety measures such as withholding first-choice medication.^[5] The 2020 ESC sports guideline ties its athlete thresholds to Bazett.^[9] It says congenital LQTS should be suspected, on a routine ECG or 4 minutes into recovery after an exercise stress test, when the QTc by Bazett’s formula is 470 ms or more in asymptomatic male athletes or 480 ms or more in asymptomatic female athletes.^[9]

Why a normal QTc does not exclude LQTS

• AHA/ACC/HRS 2017: approximately 10% to 36% of genotype-positive patients have a QTc of 440 ms or less, most commonly in LQT1.^[2]
• AHA/ACC/HRS 2017: as many as 25% of genotype-positive patients have a QTc of 440 ms or less, so screening ECGs may be insufficient for diagnosis.^[2]
• ESC 2022: relatives with a mutation but without QT prolongation still receive a diagnosis of LQTS, because they are at risk of ventricular arrhythmia, although less frequently than phenotype-positive patients.^[1]
• AHA/ACC/HRS 2017: the yield of genetic testing in phenotype-positive LQTS is 50% to 86%, higher with marked QT prolongation or a family history of SCD; a negative test does not exclude LQTS, which relies on clinical evaluation.^[2]
• AHA/ACC/HRS 2017: in asymptomatic patients with otherwise unexplained QTc of 480 ms or more on serial ECGs, genetic testing may help confirm the diagnosis and supplement prognostic information.^[2]

The modified LQTS diagnostic score (ESC 2022 Table 10)

ESC 2022 Table 10 scores ECG findings, clinical history, family history and genetic findings.^[1] A score above 3 diagnoses LQTS.^[1]

Modified long QT syndrome diagnostic score (ESC 2022 Table 10); diagnosis of LQTS with a score above 3

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Notice that a pathogenic mutation alone scores 3.5, above the threshold of 3, which fits the ESC 2022 row that a pathogenic mutation diagnoses LQTS irrespective of QT duration.^[1]

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Long QT syndrome: general measures and beta-blockers

ESC 2022 says all LQTS patients receive advice on avoiding hypokalaemia, QT-prolonging medications and genotype-specific triggers.^[1]

• ESC 2022 general recommendations to prevent SCD in LQTS: avoid QT-prolonging drugs (crediblemeds.org); avoid and correct electrolyte abnormalities; avoid genotype-specific triggers for arrhythmias (Class I, Level C).^[1]
• ESC 2022 Figure 31 footnote spells these out: correction of hypokalaemia, hypomagnesaemia and hypocalcaemia, and avoidance of strenuous swimming in LQT1 and exposure to loud noises in LQT2; the preferred beta-blockers are nadolol and propranolol.^[1]

Beta-blockers and genotype-specific drugs in LQTS

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Why non-selective agents? ESC 2022 states that nadolol and propranolol have greater efficacy in reducing arrhythmic risk.^[1] AHA/ACC/HRS 2017 reports that several observational studies found propranolol, atenolol and nadolol effective for risk reduction with appropriate dosing, while metoprolol appears less effective.^[2] It adds that RCTs comparing specific beta blockers are unavailable, although many centres favour nadolol.^[2]

• AHA/ACC/HRS 2017: beta blockers reduce adverse cardiac events in LQT1 (above 95%) and LQT2 (above 75%), and in females with LQT3 by above 60%.^[2]
• AHA/ACC/HRS 2017: data on beta blockers in males with LQT3 are limited, but in selected patients they can be protective against SCA.^[2]
• AHA/ACC/HRS 2017: one study reported that atenolol reduced the risk of VA in LQT1 while nadolol was not associated with risk reduction; in LQT2, nadolol was reported to show superior efficacy.^[2]
• AHA/ACC/HRS 2017: patients on a beta blocker should undergo ongoing monitoring of QTc over time and of the adequacy of beta blockade with exertion.^[2]
• AHA/ACC/HRS 2017: QTc changes over time, particularly during puberty and during and after pregnancy, so QTc should be assessed on an ECG annually or with medication changes, with exercise testing of medication efficacy as feasible.^[2]
• AHA/ACC/HRS 2017: asymptomatic adult (male) patients with a normal QTc may choose to decline beta-blocker therapy.^[2]
• ESC 2022: silent mutation carriers present a low, but not negligible, risk of cardiac events, and beta-blockers should be considered in this group.^[1]

Mexiletine in LQT3

• ESC 2022: considering that some mutations may not respond to mexiletine, it is advisable to perform oral testing to verify that the QTc shortens by 40 ms before prescribing chronic treatment.^[1]
• ESC 2022: given the uncertain role of beta-blockers in LQT3, there are no indications on whether mexiletine should be given alone or with beta-blockers.^[1]
• AHA/ACC/HRS 2017: mexiletine is an additional medication that can be used in LQTS with recurrent ICD shocks.^[2]

Long QT syndrome: risk stratification, ICD and sympathetic denervation

AHA/ACC/HRS 2017 says the risk of adverse cardiac events from VA is influenced by resting QTc, age, sex and LQTS genotype or mutation.^[2] AHA/ACC/HRS 2017 lists high-risk features: QTc above 500 ms, LQT2 and LQT3 genotypes, females with LQT2, age below 40, symptom onset before 10 years, and prior cardiac arrest or recurrent syncope.^[2] ESC 2022 says the arrhythmic risk should be considered before starting therapy, based on genotype and QTc duration (Class IIa, Level C).^[1] It points to the 1-2-3 LQTS Risk calculator, which integrates QT interval duration and genotype.^[1]

ESC 2022: ICD and LCSD in LQTS

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AHA/ACC/HRS 2017: escalation in LQTS

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After a cardiac arrest, ESC 2022 reports a high recurrence risk even on beta-blockers (14% within 5 years on therapy), supporting an ICD in survivors.^[1] AHA/ACC/HRS 2017 notes that ventricular pacing without an ICD was associated with a significant risk of recurrent SCA or SCD in LQTS.^[2] It notes one exception: in selected LQT1 patients whose SCA occurred without beta-blocker treatment, beta-blocker therapy is offered as an alternative to an ICD in patients who refuse one.^[2]

ESC 2022 states that, because complications do occur and half of patients have breakthrough events after the procedure, LCSD is not an alternative to an ICD for high-risk patients.^[1]

• AHA/ACC/HRS 2017: LCSD can reduce VA burden, but up to 27% of high-risk patients have at least 1 recurrence; complications occur in 8% to 20%.^[2]
• AHA/ACC/HRS 2017: LCSD may be more effective in LQT1 and LQT3, and outcomes improve when it is done in centres with surgical expertise.^[2]
• AHA/ACC/HRS 2017: reduction of the QTc to below 500 ms after LCSD has been correlated with fewer recurrent ICD shocks and less frequent symptoms.^[2]
• AHA/ACC/HRS 2017: recurrent syncope on a beta blocker carries an increased risk of SCA or appropriate ICD shocks, and escalation of therapy is warranted to prevent SCD.^[2]
• AHA/ACC/HRS 2017: syncope in LQTS may also be vasovagal, from non-adherence, or from proarrhythmia due to concurrent medications.^[2]

^{[1] [2]}

What goes into the 1-2-3-LQTS-Risk model

The model is based on the genotype (LQT1, LQT2 or LQT3) and the duration of the QTc interval.^[8][7] It was derived from 1,710 patients with LQTS followed for a median of 7.1 years, and estimates the 5-year risk of life-threatening arrhythmic events while off therapy in a multivariable Cox model with QTc and genotype as independent factors.^[7]

• QTc: the estimated risk rose by 15% for every 10-ms increment of QTc duration, for all genotypes.^[7]
• Genotype: at any QTc duration, the risk for LQT2 and LQT3 was 130% and 157% higher than for LQT1.^[7]
• Beta-blockers: in the same cohort, only nadolol significantly reduced arrhythmic risk in all genotypes compared with no therapy (hazard ratio 0.38; 95% CI 0.15 to 0.93).^[7]
• Validation: in an independent cohort the C-index was 0.69, against 0.79 in the discovery cohort.^[8]
• Threshold: ROC curve analysis suggested a 5-year risk of 5% or more as the most balanced threshold for ICD implantation, which would give a number needed to treat of 9.^[8]

The validation authors conclude that the model, the first validated 5-year risk score model for LQTS, can be used to help identify the patients at highest risk who could benefit most from an ICD and to avoid unnecessary implants.^[8]

Drugs to avoid in LQTS

ESC 2022 recommends avoiding QT-prolonging drugs in LQTS (Class I, Level C).^[1] AHA/ACC/HRS 2017 says QT-prolonging medications are potentially harmful in LQTS (COR III: Harm, LOE B-NR), and repeats this for congenital or acquired LQTS in its medication section (COR III: Harm, LOE B-NR).^[2] Its supportive text adds that they should not be used unless there is no suitable alternative, with careful QTc monitoring and consideration of stopping with marked prolongation.^[2]

AHA/ACC/HRS 2017 Table 10: commonly used QT-prolonging medications (examples; a more complete list is at crediblemeds.org)

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• AHA/ACC/HRS 2017: torsades de pointes can be precipitated by a QT-prolonging medication, or by hypokalaemia induced by diuretics or gastrointestinal illness; keeping potassium and magnesium normal when depletion is likely is an important part of management.^[2]
• AHA/ACC/HRS 2017: rare case reports describe fever prolonging the QT interval in LQT2, and fever should be reduced with antipyretics.^[2]
• AHA/ACC/HRS 2017: stimulant or non-stimulant ADHD medications were associated with increased risk of syncope or cardiac arrest in LQTS, particularly in males, in 1 study, but did not appear to be associated with increased risk in another retrospective study.^[2]
• AHA/ACC/HRS 2017: screening infants and young children is particularly important to guide therapy and institute preventive measures, including the avoidance of possible provocative medications.^[2]

Acquired QT prolongation and torsades de pointes

ESC 2022 defines torsades de pointes as a polymorphic VT in the context of QT prolongation, with continually changing QRS complexes that appear to spiral around the baseline.^[1] It asks clinicians to suspect drug-induced arrhythmia in patients on agents known to alter the heart's electrical properties (for example, QRS and/or QT prolongation) or causing electrolyte abnormalities (for example, thiazide and loop diuretics).^[1] When drug-induced arrhythmia is presumed, the offending drug is withdrawn and QT-prolonging substances such as sotalol are avoided.^[1]

• ESC 2022: withdrawal of offending agents is recommended whenever drug-induced VAs are suspected (Class I, Level B).^[1]
• ESC 2022: intravenous magnesium is effective for TdP even without hypomagnesaemia; in refractory recurrent TdP with acquired long QT, raising the heart rate with isoproterenol (isoprenaline) or transvenous pacing can suppress it.^[1]
• AHA/ACC/HRS 2017: for QT prolongation due to a medication, hypokalaemia, hypomagnesaemia or other acquired factor with recurrent torsades, intravenous magnesium sulfate is recommended to suppress the arrhythmia (COR I, LOE C-LD).^[2]
• AHA/ACC/HRS 2017: for torsades with acquired QT prolongation, potassium repletion to 4.0 mmol/L or more and magnesium repletion to normal values (eg, 2.0 mmol/L or more) are beneficial (COR I, LOE C-LD).^[2]
• AHA/ACC/HRS 2017: recurrent torsades with acquired QT prolongation and bradycardia not suppressed by intravenous magnesium: increasing the heart rate with atrial or ventricular pacing or isoproterenol is recommended (COR I, LOE B-NR).^[2]
• AHA/ACC/HRS 2017: the magnesium doses usually used for torsades are 1 to 2 g intravenously; toxicity can occur at high serum concentrations, but the risk is very small at these doses.^[2]
• AHA/ACC/HRS 2017: maintaining serum potassium between 4.5 mEq/L and 5 mEq/L shortens QT and may reduce recurrent torsades.^[2]
• AHA/ACC/HRS 2017: general genetic screening to predict medication-induced torsades is not yet supported; in LQTS, genetic testing may be performed in the index case who had medication-induced torsades and, if he or she did not survive, ECG screening of first-degree relatives may be performed.^[2]

Andersen–Tawil syndrome type 1

ESC 2022 describes a rare disease (1:1 000 000) with frequent ventricular arrhythmia such as bidirectional VT, dysmorphologies and periodic paralysis.^[1] Loss of function in KCNJ2 reduces the inward rectifier current (IK1), which increases U-wave amplitude rather than prolonging the QT.^[1]

ESC 2022: Andersen–Tawil syndrome

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Brugada syndrome: the type 1 pattern and the diagnosis

AHA/ACC/HRS 2017 describes coved ST elevation in V1 or V2, placed in the second, third or fourth intercostal space, with negative T waves in the right precordial leads.^[2] The pattern may be spontaneous or induced by a sodium channel-blocking drug, in the absence of other causes of ST elevation.^[2] ESC 2022 describes the type 1 pattern as including J-point elevation, with coved ST elevation and T-wave inversion in at least one right precordial lead, V1 or V2, placed in the second, third or fourth intercostal space.^[1]

• ESC 2022: the type 1 pattern may occur spontaneously or be induced by sodium channel-blocking drugs or fever.^[1]
• AHA/ACC/HRS 2017: the type 1 pattern may be present spontaneously, during fever or vagotonic states, or after a sodium channel blocker challenge.^[2]
• ESC 2022: it is mandatory to exclude other conditions that may explain the type 1 pattern, the so-called phenocopies.^[1]
• AHA/ACC/HRS 2017: Brugada syndrome is associated with syncope or SCA due to VF, predominantly in young males, although it has been reported in all age groups.^[2]
• AHA/ACC/HRS 2017: high ECG electrode positions in the second and third interspaces improve detection of a type 1 ECG.^[2]

ESC 2022: diagnosing Brugada syndrome

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Why the caution about induced patterns? ESC 2022 notes that drug or fever provocation is less specific than previously thought, with a 2–4% prevalence in healthy subjects and a higher prevalence in AVNRT or accessory pathway patients in one study.^[1] Its panel therefore requires other clinical features with an induced type 1 pattern, such as documented polymorphic VT/VF, arrhythmic syncope or relevant family history.^[1] By contrast, a spontaneous type 1 pattern diagnoses BrS regardless of symptoms, due to its rarity in the general population and its association with risk.^[1]

The Shanghai score (J-wave syndromes expert consensus)

Examiners still ask for the Shanghai score. The J-wave syndromes expert consensus conference report proposed a diagnostic score system for BrS, the Proposed Shanghai BrS Score.^[6] Its weighting of variables is based on expert opinion informed by cohort studies that typically do not include all the variables presented.^[6] The guideline diagnostic rows above are ESC 2022’s; the score is the consensus panel’s proposal.^[6][1]

Proposed Shanghai Score System for diagnosis of Brugada syndrome (J-wave syndromes expert consensus, Table 2)

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• Within the ECG, clinical history and family history categories, points are awarded only once, for the highest-scoring item.^[6]
• The score requires at least one ECG finding: one item from the ECG category must apply.^[6]
• 3.5 points or more: probable/definite BrS; 2–3 points: possible BrS; below 2 points: nondiagnostic.^[6]

The sodium channel blocker challenge

ESC 2022 lists sodium channel blocker testing for BrS among the common provocative tests.^[1] AHA/ACC/HRS 2017 says procainamide, flecainide or ajmaline may be useful to provoke type 1 ST elevation when Brugada syndrome is suspected as the cause of symptoms but the baseline ECG shows no type 1 pattern.^[2]

ESC 2022 Table 6: intravenous provocative diagnostic tests for Brugada syndrome

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• AHA/ACC/HRS 2017: in suspected Brugada syndrome without a spontaneous type 1 pattern, a sodium channel blocker challenge can be useful for diagnosis (COR IIa, LOE B-NR).^[2]
• AHA/ACC/HRS 2017: the challenge should be stopped with ventricular arrhythmia, marked QRS widening or a type 1 Brugada pattern.^[2]
• AHA/ACC/HRS 2017: asymptomatic patients with a family history of Brugada syndrome may be offered a challenge, but a positive test does not require chronic therapy because risk is low in this setting; in asymptomatic patients with a type 1 Brugada ECG, the challenge offers no additional diagnostic value.^[2]

Brugada syndrome: genetics and triggers to avoid

• ESC 2022: the yield of genetic testing is approximately 20%, and SCN5A is the only gene with evidence of association for clinical testing; SCN5A testing is recommended for probands (Class I, Level C).^[1]
• AHA/ACC/HRS 2017: the yield in phenotype-positive patients is approximately 20% to 30%, a negative test does not exclude the diagnosis, and genotype is not correlated with the risk of adverse events.^[2]
• AHA/ACC/HRS 2017: in suspected or established Brugada syndrome, genetic counselling and testing may be useful to facilitate cascade screening of relatives (COR IIb, LOE C-EO).^[2]
• ESC 2022: mapping and histopathology data suggest that an abnormal fibrotic arrhythmogenic substrate in the epicardial RVOT is responsible for the right precordial ST elevation and VF.^[1]

ESC 2022 gives one general recommendation for all patients with BrS (Class I, Level C).^[1]

• Avoid drugs that may induce ST-segment elevation in the right precordial leads (brugadadrugs.org).^[1]
• Avoid cocaine, cannabis and excessive alcohol intake.^[1]
• Treat fever with antipyretic drugs.^[1]

AHA/ACC/HRS 2017 lists some psychotropic medications, anaesthetic agents, cocaine, excessive alcohol and fever as potential triggers of VF and SCA.^[2] It says these agents should be avoided, and fever warrants early and aggressive measures to reduce temperature.^[2]

Brugada syndrome: risk stratification and the ICD

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Start with the syncope history. ESC 2022 says a detailed history, including absence of prodrome or specific triggers, is essential to separate arrhythmic from non-arrhythmic syncope.^[1] AHA/ACC/HRS 2017 places patients with spontaneous coved ST elevation and syncope or prior SCA at the highest risk for potentially lethal ventricular arrhythmia.^[2]

ESC 2022: risk and therapy in Brugada syndrome

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AHA/ACC/HRS 2017: Brugada syndrome

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The asymptomatic spontaneous type 1 patient

This is where the guidelines are least certain. ESC 2022 says risk stratification of asymptomatic patients remains challenging and electrophysiological studies remain controversial.^[1] A multicentre pooled analysis linked inducible sustained VA with higher future risk, but inducibility was potentially actionable only in asymptomatic patients with a spontaneous type 1 ECG.^[1]

• ESC 2022: a spontaneous type 1 pattern and other ECG markers such as early repolarization and QRS fragmentation have been associated with higher risk.^[1]
• AHA/ACC/HRS 2017: the specificity of programmed stimulation decreases when triple extrastimuli are included.^[2]
• AHA/ACC/HRS 2017: in symptomatic Brugada syndrome, programmed stimulation for risk stratification adds nothing, as an ICD is warranted.^[2]
• AHA/ACC/HRS 2017: a family history of Brugada syndrome or SCA is not a significant predictor of adverse events.^[2]

Quinidine, cilostazol and ablation

• ESC 2022: quinidine adverse effects can occur in up to 37% of patients, and quinidine is inaccessible in many countries; cilostazol, a phosphodiesterase-3 inhibitor, can be an alternative.^[1]
• ESC 2022: ablation of the abnormal epicardial areas can markedly suppress recurrent VF and normalise the ECG in above 75% of patients.^[1]
• AHA/ACC/HRS 2017: in a series treated with quinidine there were no deaths over a mean follow-up above 9 years, although adverse effects occurred in 38%; the authors felt quinidine could be an alternative to the ICD in selected patients.^[2]

Early repolarization pattern and syndrome

ESC 2022 calls the early repolarization pattern most often a benign finding, with a reported prevalence of 5.8% in adults, more common in young males and athletes.^[1] AHA/ACC/HRS 2017 adds that the pattern was lost during 10-year follow-up in above 60% of young males.^[2]

ESC 2022 lists proposed high-risk ECG features: prominent J waves of 2 mm or more, dynamic J-point changes above 0.1 mV, and J waves with a horizontal or descending ST segment.^[1] AHA/ACC/HRS 2017 asks clinicians first to rule out reversible causes such as ischaemia.^[2]

ESC 2022: early repolarization pattern and syndrome

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• AHA/ACC/HRS 2017: in asymptomatic patients with an early repolarization pattern, observation without treatment is recommended (COR I, LOE B-NR).^[2]
• AHA/ACC/HRS 2017: with an early repolarization pattern and cardiac arrest or sustained VA, an ICD is recommended if meaningful survival greater than 1 year is expected (COR I, LOE B-NR).^[2]
• AHA/ACC/HRS 2017: genetic testing is not recommended in patients with an early repolarization pattern (COR III: No Benefit, LOE B-NR); its supportive text notes that genetic testing has not reliably identified mutations predisposing to early repolarization.^[2]
• ESC 2022: at least 40% of ERS patients with VF have further episodes, 27% multiple; AHA/ACC/HRS 2017 notes that antiarrhythmic drugs other than quinidine/hydroquinidine have limited efficacy against recurrent VA.^[1][2]
• ESC 2022: as the prognosis of asymptomatic subjects with ERP is good, ICD therapy is usually not indicated.^[1]

Catecholaminergic polymorphic VT

ESC 2022 describes CPVT as a heritable disorder with catecholamine-induced bidirectional and polymorphic VT, without structural heart disease or ischaemia, and an estimated prevalence of 1 in 10 000.^[1] Manifestations usually start in the first decade, prompted by physical activity or emotional stress.^[1]

• ESC 2022 genetics: a dominant form from cardiac ryanodine receptor (RYR2) mutations and a recessive form from cardiac calsequestrin (CASQ2) mutations.^[1]
• AHA/ACC/HRS 2017: ryanodine receptor mutations have been reported in 47% of probands, de novo in above 70%; calmodulin mutations in very young patients with idiopathic VF are associated with high lethality.^[2]
• ESC 2022: most patients have a normal ECG and echocardiogram, though some show mild ECG abnormalities such as sinus bradycardia and prominent U waves.^[1]
• ESC 2022: the exercise stress test is the most important diagnostic test, because it elicits the distinguishing bidirectional or polymorphic VT.^[1]
• ESC 2022 Table 6 epinephrine test: after 10 min rest, start at 0.025 µg/kg/min for 10 min, then 0.05, 0.1 and 0.2 µg/kg/min in 5 min steps; 3 or more beats of polymorphic or bidirectional VT is positive; QTc prolongation of 480 ms or more is a contraindication; stop for systolic BP of 200 mmHg or more, non-sustained or polymorphic VT, more than 10 PVCs/min, T-wave alternans or intolerance.^[1]

ESC 2022: CPVT

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AHA/ACC/HRS 2017: CPVT

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• ESC 2022: exercise restriction and beta-blockers without intrinsic sympathomimetic activity are first-line; non-selective nadolol and propranolol are preferred.^[1]
• ESC 2022: data suggest that flecainide significantly reduces VA burden, and it should be considered with beta-blockers when control is incomplete; in selected patients intolerant of beta-blockers, flecainide alone is an option.^[1]
• AHA/ACC/HRS 2017: flecainide plus a beta blocker can suppress ventricular ectopy by as much as 76% during exercise testing or follow-up; a maximally tolerated beta blocker dose is important, and some experts prefer nadolol.^[2]
• ESC 2022: diagnosis in childhood, no beta-blocker, and complex arrhythmias on exercise testing at full beta-blocker dose independently predict arrhythmic events.^[1]
• ESC 2022: LCSD reduces recurrence of major cardiac events in previously symptomatic patients, but one-third still have arrhythmia recurrences.^[1]
• AHA/ACC/HRS 2017: therapy is not guided by genotype status, but genetic testing may facilitate screening of first-degree relatives.^[2]

Short QT syndrome

ESC 2022 calls SQTS a rare genetic disorder with a short QT interval, premature AF and VF in a structurally normal heart.^[1] It has high lethality in all age groups, including the first months of life.^[1] The probability of a first cardiac arrest by age 40 years is above 40%.^[1]

ESC 2022: short QT syndrome

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AHA/ACC/HRS 2017: short QT syndrome

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• ESC 2022: SQTS is associated with gain-of-function mutations in KCNH2 and KCNQ1 and loss of function in SLC4A; AHA/ACC/HRS 2017 reports potassium channel mutations in approximately 10% to 20%, including KCNH2 (SQT1), KCNQ1 (SQT2) and KCNJ2 (SQT3).^[1][2]
• AHA/ACC/HRS 2017: a short QTc of 340 ms or less has an estimated prevalence of 5 in 10 000 below 21 years of age and is more common in males; an incidental QTc of 320 ms or less in an asymptomatic patient warrants monitoring and follow-up without prophylactic medication.^[2]
• AHA/ACC/HRS 2017: QTc values of 300 ms or less carry increased SCD risk, especially during sleep or rest, in young persons (median QTc 285 ms).^[2]
• ESC 2022: primary prevention remains contentious and is based on prior symptoms and QTc interval; quinidine is the best supported antiarrhythmic but needs monitoring for excessive QT prolongation.^[1]
• ESC 2022: avoid drugs that shorten the QT interval, such as nicorandil.^[1]
• AHA/ACC/HRS 2017: about 18% of the small number of reported patients with an ICD received appropriate therapies during short-term follow-up.^[2]

Genetic testing and family screening

ESC 2022 ties testing of relatives to a Class IV or V variant found in the affected individual.^[1] AHA/ACC/HRS 2017 calls clinical screening of first-degree relatives crucial to identifying affected family members.^[2]

Genetic testing rows that drive cascade screening

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• AHA/ACC/HRS 2017: up to 15% of mutations previously linked to CPVT do not appear to cause disease, so caution is advised to avoid unnecessary treatment or sports restriction in phenotype-negative mutation carriers.^[2]
• AHA/ACC/HRS 2017: some patients may prefer not to undergo genetic testing, and genetic counselling should focus on this issue.^[2]
• AHA/ACC/HRS 2017: an ICD in an asymptomatic low-risk channelopathy patient with a family history of SCD as the sole indication is unsupported by published data.^[2]
• CSANZ 2011 (the most recent CSANZ genetic testing guideline found for this topic): genetic testing should be performed in a specialised cardiac genetic clinic or clinical genetics service where appropriate family management and genetic counselling can be offered.^[4]

After a sudden death: the decedent and the family

ESC 2022 reports that potential genetic cardiac disease can be identified in 25–49% of SCD cases below 50 years of age.^[1] In families of SADS decedents, the diagnostic yield ranged from 18 to 53%, with LQTS, BrS, CPVT and cardiomyopathy among the causes.^[1] Recent data show at least a 13% genetic yield in SADS cases.^[1]

• ESC 2022: a comprehensive autopsy is recommended, ideally in all unexpected SD and always below 50 years of age (Class I, Level B).^[1]
• ESC 2022: in SCD, retain samples suitable for DNA extraction and consult a cardiac pathologist when an inherited cause is suspected or the cause is unexplained (Class I, Level B).^[1]
• ESC 2022: after SADS, post-mortem genetic testing targeted to primary electrical disease is recommended when the decedent is young (below 50) and/or the circumstances and/or family history support a primary electrical disease (Class I, Level B); hypothesis-free exome or genome sequencing is not recommended (Class III, Level B).^[1]
• ESC 2022: refer first-degree relatives for cardiac assessment in a specialised clinic when autopsy diagnoses possible heritable cardiac disease, or in non-autopsied SD where inherited cardiac disease is suspected (both Class I, Level B).^[1]

ESC 2022: evaluating relatives of SADS decedents

^[1]

Sodium channel blocker testing in relatives cuts both ways. ESC 2022 cites one study with a 28% yield of BrS diagnoses in SADS relatives from drug challenge and high-lead ECGs, with concerns about false positives.^[1]

In an SCA survivor without a clear underlying cause, ESC 2022 recommends sodium channel blocker testing and exercise testing (Class I, Level B).^[1] It also recommends blood samples at presentation for potential toxicology and genetic testing (Class I, Level B).^[1]

^[1]

Exercise and sport

ESC 2022 recommends that athletes diagnosed with a cardiovascular disease associated with SCD are managed according to current guidelines for sports eligibility (Class I, Level C).^[1] For the channelopathies this page uses two documents: the 2020 ESC guideline on sports cardiology, published before ESC 2022, and the 2025 AHA/ACC scientific statement on competitive sports participation.^[9][10] AHA/ACC 2025 presents its advice as clinical considerations tables; the rows below come from its Table 13 on cardiac channelopathies.^[10]

• AHA/ACC 2025: competitive athletes with a cardiac channelopathy (including LQTS, CPVT and BrS) should be assessed by a paediatric or adult cardiologist with expertise in cardiac channelopathies, with shared decision-making.^[10]
• AHA/ACC 2025: an ICD should not be implanted for the sole purpose of competitive sports participation, because of a risk of about 5% per year of inappropriate shocks and about 4% per year of ICD-related complications.^[10]

Long QT syndrome and sport

ESC 2020 sports cardiology: exercise in long QT syndrome

^[9]

• ESC 2020: symptomatic athletes should not engage in competitive sports, and individuals with LQT1 should not engage in sports that involve diving into cold water, which is associated with an increased risk of arrhythmias.^[9]
• ESC 2020: ICD implantation does not constitute clearance for intensive or competitive sports.^[9]
• ESC 2020 described American guidelines as more lenient about competitive sport (except for LQT1), provided that precautions included an AED as part of the athlete’s personal sports safety gear.^[9]

AHA/ACC 2025 Table 13 lists three considerations for LQTS.^[10]

• It is reasonable for competitive athletes with a positive genetic test for LQTS but a resting QTc below 460 ms (concealed variant positive LQTS) to take part in competitive sports.^[10]
• In competitive athletes with LQTS, whether asymptomatic (QTc 460 ms or more before puberty, 470 ms or more in males, 480 ms or more in females) or previously symptomatic, who are under expert assessment and supervision, competitive sport is reasonable with shared decision-making after risk assessment, education and implementation of guideline-directed therapies.^[10]
• In competitive athletes with LQTS, including LQT1, competitive swimming and diving can be considered with appropriate precautions: swimming supervised by someone trained in CPR, pools in preference to open water, and access to an AED.^[10]

The AHA/ACC 2025 text adds that management includes non-selective long-acting beta-blockers (for example nadolol or propranolol) and emergency action planning with access to an AED, and may include mexiletine, especially in LQT3.^[10] Know the contrast for LQT1: ESC 2022 names strenuous swimming as a genotype-specific trigger to avoid and ESC 2020 advises against sports that involve diving into cold water, whereas AHA/ACC 2025 says competitive swimming and diving can be considered with appropriate precautions.^[1][9][10]

Brugada syndrome and sport

ESC 2020 sports cardiology: exercise in Brugada syndrome

^[9]

• ESC 2020’s sport table also carries an ICD row for BrS with arrhythmic syncope and/or aborted SCD (Class I, Level C). ESC 2022, the newer guideline, recommends an ICD after aborted cardiac arrest and/or documented spontaneous sustained VT (Class I, Level C) but grades a type 1 pattern with arrhythmic syncope as should be considered (Class IIa, Level C).^[9][1]
• ESC 2020: asymptomatic patients with the spontaneous type I BrS ECG pattern may compete in all sports except endurance sports associated with a rise in core temperature above 39°C (e.g. marathon running and triathlons); similar rules apply to asymptomatic genotype-positive/phenotype-negative individuals and to the concealed form of BrS.^[9]
• ESC 2020: in the majority of cases events occur during sleep or rest, during febrile states or, occasionally, from heat stroke; during febrile illness, fever should be treated aggressively.^[9]
• AHA/ACC 2025 Table 13: it is reasonable for competitive athletes with BrS to take part in competitive sports after expert assessment and management.^[10]
• AHA/ACC 2025: there are no data to support competitive sports restrictions in Brugada syndrome; these athletes should avoid known arrhythmic triggers, including heat exhaustion and exercise during febrile illnesses, and hydration during exercise should be prioritised.^[10]

CPVT and sport: the documents differ

ESC 2022 recommends avoiding competitive sports, strenuous exercise and stressful environments in all patients with CPVT (Class I, Level C).^[1] AHA/ACC 2025 Table 13 instead grades CPVT by phenotype.^[10]

• Asymptomatic, genotype-positive, with no exercise-induced ventricular ectopy on exercise stress testing: competitive sport is reasonable, with discussion about prophylactic CPVT-directed medical therapy.^[10]
• Asymptomatic CPVT with exercise-induced ventricular ectopy on a positive stress test: competitive sport can be considered with shared decision-making after optimisation of therapies and normalisation of the stress test.^[10]
• Previously symptomatic CPVT: combination therapy with a beta-blocker and flecainide, and possibly LCSD, is required before competitive sport is resumed.^[10]

Athletes in general

ESC 2022: athletes

^[1]

• ESC 2022: pre-participation evaluation with history, examination and ECG appears effective in identifying cardiovascular disease in young athletes (35 years or under), through symptoms such as exertional syncope or ECG abnormalities consistent with inheritable cardiomyopathies or channelopathies.^[1]
• AHA/ACC/HRS 2017: postmortem data show 25% to 40% of SCD in athletes are autopsy-negative, suggesting a role for genetic molecular disorders.^[2]
• AHA/ACC/HRS 2017: in general, arrhythmia management in athletes follows that in non-athletes, and many athletes on therapy for inherited disorders are able to participate, depending on the nature and severity of disease and with appropriate precautions and counselling about potential residual risks.^[2]

Differential diagnosis

Mimics and look-alikes

^{[1] [2]}

Complications and pitfalls

• ICDs in channelopathies (AHA/ACC/HRS 2017): appropriate therapy for VF/fast VT in 8% to 33%, but inappropriate shocks and device complications in 8% to 35%; concurrent beta blockers in LQTS and CPVT, optimal programming and appropriate lead selection are needed to minimise inappropriate shocks.^[2]
• Metoprolol appears less effective in LQTS, whereas observational studies support propranolol, atenolol and nadolol with appropriate dosing (AHA/ACC/HRS 2017).^[2]
• Sodium channel blocker challenge in a patient who already has a type I Brugada pattern is not recommended (ESC 2022, Class III, Level C).^[1]
• Epinephrine challenge is not recommended for routine LQTS diagnosis (ESC 2022, Class III, Level C).^[1]
• An invasive electrophysiologic study is not recommended in LQTS (ESC 2022, Class III, Level C), and PES is not recommended for stratification of SCD risk in CPVT (ESC 2022, Class III, Level C).^[1]
• Catheter ablation in asymptomatic BrS is not recommended (ESC 2022, Class III, Level C).^[1]
• LCSD in CPVT (AHA/ACC/HRS 2017): may reduce recurrent ICD shocks by 32% to 75%, but recurrent syncope, SCA or SCD is reported in 9% to 32%, with minor complications in 20% to 70%.^[2]

Prognosis

• LQTS (ESC 2022): estimated annual SCD rate below 0.5% when asymptomatic and untreated, around 5% with a history of syncope; 14% recurrence within 5 years on beta-blockers after cardiac arrest.^[1]
• LQTS (AHA/ACC/HRS 2017): risk is influenced by resting QTc, age, sex and genotype; in asymptomatic males it is highest in childhood, and young women with LQT2 and QTc above 500 ms are at increased risk, especially in the 9 months postpartum.^[2]
• LQTS with a normal QTc (AHA/ACC/HRS 2017): lower risk than with a prolonged QTc, but still higher than in genotype-negative age- and sex-matched people.^[2]
• Brugada (ESC 2022): recurrent VF risk of 48% at 10 years after cardiac arrest; arrhythmic events at an incidence of 0.5% per year in asymptomatic patients.^[1]
• CPVT (AHA/ACC/HRS 2017): SCA or SCD reported in 3% to 13% of patients.^[2]
• SQTS (ESC 2022): probability of a first cardiac arrest above 40% by age 40 years.^[1]
• ERS (AHA/ACC/HRS 2017): recurrent VF in at least 40% after cardiac arrest or VF.^[2]

Special populations

Pregnancy and the post-partum period

ESC 2025 says women with primary arrhythmia syndromes generally tolerate pregnancy well.^[3] It asks for genetic counselling, clinical re-evaluation, treatment optimisation and ICD evaluation before pregnancy, with indicated treatment continued through pregnancy and post-partum.^[3] In LQTS, retrospective studies show no higher risk during pregnancy itself, but increased risk post-partum (up to 12 months), especially in LQT2.^[3]

ESC 2025: primary arrhythmia syndromes in pregnancy

^[3]

• ESC 2022 (dated; Recommendation Table 47) recommends continuing beta-blockers during pregnancy and post-partum in women with LQTS or CPVT (Class I, Level C); ESC 2025 now gives the pregnancy and lactation rows above, and the 2022 row still covers the post-partum period where the 2025 rows are silent.^[1][3]
• AHA/ACC/HRS 2017: in mothers with LQTS, a beta blocker should be continued during pregnancy and throughout the postpartum period, including in women who are breastfeeding (COR I, LOE B-NR).^[2]
• AHA/ACC/HRS 2017: a large retrospective LQTS registry analysis found an odds ratio of 40.8 for syncope, SCA or SCD in the 9 months postpartum, and beta blockers during pregnancy were independently associated with decreased risk.^[2]
• AHA/ACC/HRS 2017: maternal beta blockers are associated with lower newborn birth weight and hypoglycaemia, but not with miscarriage; fetal bradycardia, which is associated with fetal LQTS, should not on its own prompt stopping the beta blocker.^[2]
• ESC 2025: nadolol has higher breast-milk excretion than propranolol (relative infant dose 4%–7%); avoid changing beta-blocker after delivery, and evaluate any switch from nadolol to propranolol before pregnancy.^[3]
• ESC 2025: the foetal risk of mexiletine is unknown, so treatment decisions in pregnancy should be shared with the woman.^[3]
• ESC 2025: deliver with rhythm monitoring, electrolyte control and post-operative ECG monitoring until anaesthetic drugs are eliminated; women with LQTS and CPVT continue beta-blockers through labour and delivery.^[3]
• ESC 2025: the only retrospective study in pregnant women with BrS showed no increased risk of cardiac events in pregnancy or post-partum; no pregnancy data exist for SQTS, and when choosing an antiarrhythmic drug during pregnancy, quinidine is the best option in the absence of more robust data.^[3]

Children and newborns

• AHA/ACC/HRS 2017: due to the increased risk of adverse cardiac events in young patients with LQTS and CPVT, screening infants and young children is particularly important to guide therapy and institute preventive measures.^[2]
• AHA/ACC/HRS 2017: as 50% of offspring may be affected, with the highest risk of adverse events in infancy and childhood, screening the newborn for LQTS at birth and during infancy is important.^[2]
• ESC 2022: in SADS families without a diagnosis, children of decedents are followed until adulthood (Class I, Level C).^[1]
• ESC 2022: SQTS has high lethality in all age groups, including the first months of life.^[1]
• AHA/ACC/HRS 2017: exercise testing of beta-blocker adequacy can be particularly beneficial in school-aged patients.^[2]

Evidence, guidelines and regional differences

Where the documents differ (selected rows)

^{[1] [2] [3] [9] [10]}

Among the guidelines checked for this topic, AHA/ACC/HRS 2017 is the newest ACC/AHA ventricular arrhythmia guideline, and no newer held ACC/AHA guideline carries channelopathy rows.^[2] No NHFA/CSANZ channelopathy guideline newer than ESC 2022 or AHA/ACC/HRS 2017 was found; the CSANZ material located dates from 2007 and 2011.^[4]

Where the evidence is thin

• ESC 2022: risk stratification of asymptomatic BrS remains challenging, and electrophysiological studies remain controversial.^[1]
• ESC 2022: primary prevention in SQTS remains contentious.^[1]
• ESC 2022: there are no indications on whether mexiletine in LQT3 should be given alone or with beta-blockers.^[1]
• AHA/ACC/HRS 2017: RCTs comparing specific beta blockers in LQTS are unavailable; in CPVT, direct comparison data among beta blockers are unavailable.^[2]
• ESC 2022: data for risk stratification of suspected ERS without prior cardiac arrest are unavailable.^[1]

Exam pearls

• A pathogenic mutation alone scores 3.5 on the modified LQTS score, above the diagnostic threshold of 3 (ESC 2022 Table 10).^[1]
• LQT1 exercise and strenuous swimming; LQT2 emotional stress and loud noises; LQT3 sleep (ESC 2022).^[1]
• Andersen–Tawil: KCNJ2 loss of function raises U-wave amplitude rather than prolonging QT (ESC 2022).^[1]
• A sodium channel blocker test is not recommended in a patient with a prior type I Brugada pattern (ESC 2022, Class III, Level C).^[1]
• Brugada general advice includes cannabis as well as cocaine and excessive alcohol (ESC 2022).^[1]
• CPVT ICD: long delays and high rates before defibrillation (ESC 2022).^[1]
• Early repolarization genetic testing: not recommended for the pattern (AHA/ACC/HRS 2017, III: No Benefit) and may be considered in ERS (ESC 2022, IIb).^[2][1]
• ESC 2025 Recommendation Table 6 footnote c (except for atenolol) applies to its beta-blocker rows for LQTS and CPVT in pregnancy and for phenotype-negative variant carriers.^[3]
• Bazett divides QT by RR^1/2 (the square root) and Fridericia by RR^1/3 (the cube root), with QT and RR in seconds; Bazett overcorrects at high heart rates (Vandenberk 2016).^[5]
• Shanghai score: a spontaneous type 1 pattern scores 3.5, and 3.5 points or more means probable/definite BrS; at least one ECG finding is required.^[6]
• 1-2-3-LQTS-Risk is based on genotype and QTc; ROC analysis suggested a 5-year risk of 5% or more as the most balanced threshold for an ICD, with a number needed to treat of 9.^[8]
• ESC 2020 sport: competitive sport, with or without an ICD, is not recommended in LQTS with prior cardiac arrest or arrhythmic syncope (Class III, Level C).^[9]

References10ShowHide

1. [1]Zeppenfeld K, et al. 2022 ESC Guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death. Eur Heart J, 2022.PMID 36017572
2. [2]Al-Khatib SM, et al. 2017 AHA/ACC/HRS Guideline for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society. Circulation, 2018.PMID 29084731
3. [3]De Backer J, et al. 2025 ESC Guidelines for the management of cardiovascular disease and pregnancy. Eur Heart J, 2025.PMID 40878294
4. [4]Ingles J, et al. Guidelines for genetic testing of inherited cardiac disorders. Heart Lung Circ, 2011.PMID 22000298
5. [5]Vandenberk B, et al. Which QT Correction Formulae to Use for QT Monitoring? J Am Heart Assoc, 2016.PMID 27317349
6. [6]Antzelevitch C, et al. J-Wave syndromes expert consensus conference report: Emerging concepts and gaps in knowledge. Europace, 2017.PMID 28431071
7. [7]Mazzanti A, et al. Interplay Between Genetic Substrate, QTc Duration, and Arrhythmia Risk in Patients With Long QT Syndrome. J Am Coll Cardiol, 2018.PMID 29650123
8. [8]Mazzanti A, et al. Independent validation and clinical implications of the risk prediction model for long QT syndrome (1-2-3-LQTS-Risk). Europace, 2022.PMID 34505884
9. [9]Pelliccia A, et al. 2020 ESC Guidelines on sports cardiology and exercise in patients with cardiovascular disease. Eur Heart J, 2021.PMID 32860412
10. [10]Kim JH, et al. Clinical Considerations for Competitive Sports Participation for Athletes With Cardiovascular Abnormalities: A Scientific Statement From the American Heart Association and American College of Cardiology. J Am Coll Cardiol, 2025.PMID 39976316