Aetiology

Monogenic (Mendelian): ~75–80%, KCNQ1, KCNH2 and SCN5A account for ~90% of genotyped cases^[1]

Acquired: acquired long QT (QT-prolonging drugs, hypokalaemia/hypomagnesaemia, bradycardia) is a separate, reversible entity to exclude^[1]

Complex (likely polygenic): ~20–25% gene-elusive, partly reflecting polygenic QT modulation^[8]

Genetics

Inheritance: Autosomal dominant (Romano-Ward syndrome, penetrance 25–75% for QTc >460ms); rare autosomal recessive (Jervell-Lange-Nielsen syndrome with congenital deafness, homozygous/compound heterozygous KCNQ1 or KCNE1 variants, nearly 100% penetrance).

Genetic yield: ~75% with comprehensive testing. Up to 25% are gene-elusive, but phenotypic severity mirrors genotype-positive LQTS in these patients (Asatryan et al 2024, Circ Arrhythm Electrophysiol)^[8]

ClinGen-validated genes:

Gene	Subtype	% Genotype+	Channel / Mechanism	Arrhythmic Triggers
KCNQ1	LQT1	~50%	IKs loss-of-function (K⁺)	Exercise, swimming, adrenergic-dependent
KCNH2	LQT2	35–40%	IKr loss-of-function (K⁺)	Auditory triggers, emotion, postpartum; higher risk in females
SCN5A	LQT3	~10%	INa gain-of-function (Na⁺ delayed inactivation)	Rest/sleep, bradycardia; mexiletine genotype-specific benefit
CALM1/2/3	Calmodulinopathy	<1%	Calmodulin (impaired Ca²⁺-channel inactivation)	Often de novo; extreme QTc; severe early-onset, high arrhythmic risk; neurodevelopmental features
TRDN	–	<1%	Triadin; autosomal recessive	Exercise-triggered; T-wave abnormalities at rest
CACNA1C	LQT8 (Timothy)	Rare	ICaL gain-of-function (Ca²⁺)	Multiorgan syndrome: ASD, autism, syndactyly; very rare

Gene-elusive LQTS (~11–25%): Multiple mechanisms, polygenic risk score contribution, environmental QTc modulators, exercise-induced repolarisation abnormalities, new causal genes not yet identified, or variant reclassification over time. Management mirrors genotype-positive LQTS. Referral to specialised cardiogenetic clinic recommended (Asatryan et al 2024)^[8].

Modifier genes: Common variants modulate QTc and arrhythmic risk in individual patients, polygenic risk scores can refine risk stratification beyond the primary pathogenic variant (Schwartz & Crotti, NEJM 2025).

Genotype-Specific Management (Zhu et al 2024, Schwartz & Crotti NEJM 2025)^[7]^[2]^[9]

Subtype	Gene	% LQTS	Triggers	ECG Pattern	Key Management Points
LQT1	KCNQ1	~50%	Exercise, swimming (adrenergic)	Broad-based T wave	Beta-blockers most effective; nadolol preferred; restrict competitive swimming
LQT2	KCNH2	35–40%	Auditory triggers, emotion, postpartum	Notched/bifid T wave	Higher risk in females; avoid alarm clocks; K⁺ supplementation; beta-blockers effective
LQT3	SCN5A	~10%	Rest/sleep, bradycardia	Long isoelectric ST segment	Mexiletine (off-label): shortens QTc, reduces events; beta-blockers less effective; pacemaker in selected cases
Calmodulinopathies	CALM1/2/3	<1%	Variable; often de novo	Extreme QTc prolongation	Very high risk; early ICD; consider LCSD; flecainide may have role; specialist centre

Prevalence

Estimated prevalence 1 in 2,000 to 1 in 2,500 in the general population; actual prevalence may be higher due to variable penetrance, silent mutation carriers, and under-diagnosis^[7]

More common in females for arrhythmic events (especially LQT2); variable penetrance, many carriers have QTc within normal range

LQTS accounts for ~54% of sudden unexplained deaths in individuals under 35 years^[7]

Autosomal dominant forms (Romano-Ward): first-degree relatives have 50% probability of carrying the pathogenic variant, cascade genetic screening is therefore essential^[7]

At least 17 genes have been associated with LQTS; LQT1 (KCNQ1), LQT2 (KCNH2), and LQT3 (SCN5A) account for ~80–90% of genotype-positive cases^[7]

Diagnostic Criteria

LQTS Diagnostic Criteria (Schwartz Score^[3])

Definite LQTS if ANY of the following:

QTc ≥500 ms on repeated ECGs (in absence of secondary causes)
QTc ≥480 ms with unexplained syncope
Pathogenic LQTS variant identified (regardless of QTc)
Schwartz Score ≥3.5

Schwartz Score Components:

Criterion	Points
ECG Findings
QTc ≥480 ms	3
QTc 460-479 ms	2
QTc 450-459 ms (males only)	1
Torsades de pointes	2
T-wave alternans	1
Notched T-wave in ≥3 leads	1
Clinical History
Syncope with stress/emotion	2
Syncope without stress	1
Family History
Definite LQTS in family	1
Unexplained SCD <30 years in family	0.5

Interpretation: ≥3.5 = High probability; 2-3 = Intermediate; ≤1 = Low probability

Always measure QTc in multiple leads; use Bazett's formula (QTc = QT/√RR)

Gene-Elusive LQTS: Key Pitfalls (Asatryan et al, Circ Arrhythm Electrophysiol 2024)^[8]

11–25% of LQTS patients have negative genetic testing. Severity mirrors genotype-positive LQTS, manage equally.

Most common error: Including U waves in QTc measurement → overestimation of borderline QTc. Anterior T-wave inversion in ~20% of LQTS, can mislead.
Exercise testing: QTc at 4-min recovery ≥445 ms = 90% sensitivity AND specificity for LQTS. Perform off beta-blockers for best diagnostic yield.
Do not reduce management intensity because genetics is negative, cascade ECG screening of all 1st-degree relatives still applies.
16% of patients referred to LQTS centres for second opinion ultimately did NOT have LQTS. Expert cardio-genetic review is essential.

Diagnosis

ECG patterns in Long QT Syndrome: LQT1 (broad-based T-waves), LQT2 (low amplitude/notched T-waves), LQT3 (late-onset peaked T-waves), LQT8 (Timothy syndrome). Source: ECGpedia.org

ESC 2022 Guidelines - LQTS Diagnostic Criteria & Management

Diagnostic Criteria (ESC 2022):

LQTS is diagnosed (Class I) if:

QTc ≥480 ms in repeated 12-lead ECGs (with or without symptoms), OR
Pathogenic mutation present (irrespective of QT duration)

LQTS should be considered (Class IIa) if:

QTc ≥460 ms and <480 ms in repeated ECGs + arrhythmic syncope (excluding secondary causes)

Key Management Recommendations (Class I):

Intervention	Indication
General measures	• Avoid QT-prolonging drugs • Correct electrolyte abnormalities • Avoid genotype-specific triggers
Beta-blockers	Non-selective beta-blockers (nadolol/propranolol) for documented QT prolongation
Mexiletine	LQT3 patients with prolonged QT interval
ICD	Cardiac arrest survivors
LCSD	Symptomatic when: (a) ICD contraindicated/refused, OR (b) Multiple ICD shocks/syncope due to VA

Class IIa Recommendations:

Beta-blockers for pathogenic mutation carriers with normal QTc
ICD for symptomatic patients despite beta-blockers and genotype-specific therapies
Either ICD or LCSD when beta-blockers/genotype-specific therapies not tolerated/contraindicated
1-2-3 LQTS Risk Calculator to calculate individualized SCD risk

Class IIb Recommendations:

ICD may be considered in asymptomatic high-risk patients (per 1-2-3 calculator) plus genotype-specific therapies

Class III (NOT recommended):

Routine epinephrine challenge testing
Invasive electrophysiologic study

Reference: Zeppenfeld K et al. 2022 ESC Guidelines for management of patients with ventricular arrhythmias and prevention of sudden cardiac death. Eur Heart J 2022;43:3997-4126^[1]

Clinical Presentation:

Often asymptomatic - diagnosed on screening or incidental ECG
Syncope (often misdiagnosed as seizure)
Cardiac arrest / sudden death
Palpitations (may precede syncope)

Genotype-specific triggers:

LQT1: Exercise (especially swimming)
LQT2: Auditory triggers (alarm clock, phone), emotions, postpartum
LQT3: Rest, sleep

Important: Exclude secondary causes before diagnosing congenital LQTS (electrolyte abnormalities, medications)

Investigations

First-line:

Resting 12-lead ECG (QTc measurement, T-wave morphology)
Repeat ECGs (QTc can vary)
24-hour Holter monitoring (QTc during sleep, T-wave alternans)
Exercise stress test (QTc during recovery, paradoxical QT prolongation in LQT1)

Provocation tests (specialist centres):

Epinephrine challenge test (can unmask LQTS, particularly LQT1)

Genetic testing:

Recommended in all with high clinical suspicion
Enables genotype-specific management
Facilitates family cascade screening

Exclude secondary causes of QT prolongation:

Medications (check www.crediblemeds.org)
Electrolyte abnormalities (K+, Mg2+, Ca2+)
Hypothyroidism, bradycardia, structural heart disease

Treatments

Class I Recommendations (Expert Consensus 2013)

RECOMMENDED for all LQTS patients:

Lifestyle: Avoid QT drugs (CredibleMeds.org), correct electrolytes
Beta-blockers if: (a) Asymptomatic with QTc ≥470 ms, OR (b) Symptomatic
LCSD if: ICD refused/contraindicated OR beta-blockers ineffective
ICD for cardiac arrest survivors
Clinical expert evaluation for competitive sports

Class IIa (Can be useful):

Beta-blockers for asymptomatic with QTc ≤470 ms
ICD for recurrent syncope on beta-blockers
LCSD for breakthrough events on therapy

Lifestyle modifications (all patients):

Avoid QT-prolonging drugs (check www.crediblemeds.org)
Maintain normal electrolytes (K+ 4-5 mmol/L)
Avoid loud alarms/sudden awakening (LQT2)
Genotype-specific restrictions (avoid swimming in LQT1)

Medical therapy:

Beta-blockers (Grade I, all symptomatic; Grade IIa, asymptomatic high-risk^[1]): Highly effective in LQT1/LQT2; less so in LQT3. Reassess annually (Schwartz & Crotti, NEJM 2025^[2]).
- Nadolol (preferred, long-acting, once/twice daily, consistent levels^[4]):
  - Start 40 mg once daily → target 80–160 mg once daily (up to 3 mg/kg/day in children)
  - UK: Available via SPECIALS / named patient import, arrange in advance through hospital pharmacy
  - Renally cleared, reduce dose if eGFR <50 ml/min; avoid if eGFR <30
- Propranolol (alternative, especially in children or if nadolol unavailable):
  - Start 20–40 mg two to three times daily → target 80–160 mg twice daily (total 160–320 mg/day)
  - Paediatric: 2–4 mg/kg/day in 3–4 divided doses
  - Short-acting formulation available; longer-acting (LA/SR) preferred for compliance
- Bisoprolol (alternative if nadolol/propranolol not tolerated): 2.5–10 mg once daily, note less evidence specifically for LQTS
Mexiletine (LQT3-specific, Grade IIa, off-label^[1]): Sodium channel blocker, reduces persistent INa, shortens QTc in SCN5A-positive LQT3.
- Start 50–100 mg three times daily with food → target 150–200 mg three times daily
- Maximum 900 mg/day; check QTc after dose changes (should shorten in LQT3)
- Monitor LFTs; avoid if significant hepatic impairment
Potassium supplementation/replacement: Target K⁺ 4.5–5 mmol/L in LQT2 (IKr current hypersensitive to hypokalaemia). Oral KCl supplements or dietary advice; IV replacement if hospitalised.
Avoid in all LQTS: QT-prolonging drugs (check www.crediblemeds.org), hypokalaemia, hypomagnesaemia, high-dose diuretics, sudden bradycardia.

ICD therapy:

Secondary prevention after cardiac arrest
Primary prevention if syncope on beta-blockers or very high-risk features

Left cardiac sympathetic denervation (LCSD):

For patients with recurrent events despite beta-blockers
ICD contraindicated or declined

Related Resources

Complications

Torsades de pointes: causing syncope, seizures, aborted cardiac arrest and sudden death, with genotype-specific triggers (LQT1 exertion and swimming, LQT2 auditory and postpartum, LQT3 rest and sleep)^[1]
Postpartum arrhythmia surge: particularly in LQT2
ICD-related complications: inappropriate shocks and lead failure over decades in young patients

Risk Stratification

High-risk features (consider ICD):

Cardiac arrest survivor (secondary prevention)
Syncope despite adequate beta-blocker therapy
QTc >500ms
LQT2 or LQT3 genotype with high-risk features
Female with LQT2 in postpartum period

Beta-blocker therapy indicated:

All symptomatic patients (syncope, cardiac arrest)
Asymptomatic with QTc >470ms (females) or >450ms (males)
Some advocate beta-blockers for ALL genotype-positive individuals

Risk modifiers:

LQT1: Male sex protective; events common during exercise/swimming
LQT2: Female sex higher risk; postpartum period very high risk (continue beta-blockers)
LQT3: Male sex higher risk; events during sleep
QTc >500ms = very high risk regardless of genotype

Pregnancy Management

ESC 2018 Pregnancy Guidelines - LQTS (mWHO Class II-III)

PRECONCEPTION COUNSELLING:

Risk stratification:
- LQT1, asymptomatic, QTc <500ms, on beta-blocker: mWHO II (low-moderate risk)
- LQT2: mWHO III (high risk) - highest cardiac event risk in pregnancy and especially POSTPARTUM
- LQT3, symptomatic LQTS, QTc >500ms, ICD: mWHO III (high risk)
Pregnancy-specific risks:
- LQT2: 2.7-fold increased arrhythmic event risk during pregnancy; 4.6-fold in first 9 months postpartum (HIGHEST RISK GENOTYPE)
- LQT1: Low risk during pregnancy (progesterone shortens QT); postpartum risk minimal
- LQT3: Intermediate risk; bradycardia during sleep may worsen arrhythmia substrate
Baseline assessment:
- 12-lead ECG with manual QTc calculation (Bazett formula acceptable)
- Exercise test (unmask QT behaviour, assess beta-blocker efficacy)
- Holter monitoring if palpitations/presyncope history
- Review ICD if present (programming, battery, lead integrity)
Medications:
- Beta-blockers: ESSENTIAL - do NOT stop (nadolol preferred for LQT1/LQT2; metoprolol acceptable)
- Mexiletine (LQT3): Limited pregnancy data but considered safe if essential
- Avoid ALL QT-prolonging drugs - check www.crediblemeds.org
Genetic counselling: 50% transmission risk (autosomal dominant); prenatal testing available

PREGNANCY MANAGEMENT:

Monitoring frequency:
- LQT2: Monthly cardiology review (high risk)
- LQT1/LQT3: Each trimester if stable and asymptomatic
- ECG each visit (monitor QTc evolution)
- Holter if palpitations, presyncope, or any symptoms
QTc evolution in pregnancy:
- Generally SHORTENS slightly in 2nd/3rd trimester (progesterone effect)
- BUT some LQT2 women have PARADOXICAL QTc prolongation
- Monitor closely if QTc increasing or >500ms
Beta-blocker management:
- DO NOT STOP - essential for arrhythmia prevention
- Nadolol 40-160mg/day (preferred, long half-life) OR metoprolol 100-200mg/day
- Monitor heart rate - target resting HR 60-70 bpm
- May need dose increase in pregnancy (increased drug metabolism)
Electrolyte management:
- Check potassium and magnesium each trimester
- Maintain K+ 4-5 mmol/L (supplement if <4.0)
- Supplement Mg2+ if levels low or if hyperemesis/frequent vomiting
Avoid triggers:
- QT-prolonging medications (antibiotics, antiemetics, antihistamines) - check ALL drugs
- LQT2 specific: Avoid sudden loud noises/alarms

LABOUR & DELIVERY:

Delivery planning:
- Deliver at tertiary centre (high-risk, especially LQT2)
- MDT planning at 32-34 weeks
- External defibrillator immediately available
Mode of delivery:
- Vaginal delivery preferred if stable
- Elective caesarean section if: ICD present, recurrent syncope, QTc >550ms, obstetric indications
- Assisted second stage to reduce sympathetic surge
Anaesthesia:
- Epidural SAFE and preferred (reduces catecholamine surge from pain)
- Avoid QT-prolonging drugs: Ondansetron (antiemetic) contraindicated - use alternatives (metoclopramide, cyclizine)
- GA if needed: Propofol safe; avoid volatile anaesthetics (some prolong QT)
Intrapartum monitoring:
- Continuous ECG monitoring throughout labour
- Have IV magnesium sulphate available (torsades treatment)
- ICD: Reprogram if concerned about T-wave oversensing; keep magnet available
Continue beta-blockers THROUGHOUT labour - do not skip doses

POSTPARTUM - HIGHEST RISK PERIOD (ESPECIALLY LQT2):

Critical first 9 months postpartum (LQT2):
- 4.6-fold increased arrhythmic event risk compared to non-pregnant state
- Hormonal withdrawal (falling progesterone) → QT prolongation
- Sleep deprivation, emotional stress, fatigue
Immediate postpartum management:
- Monitor 24-48 hours postpartum (CCU/telemetry if LQT2)
- DO NOT STOP BETA-BLOCKERS - this is CRITICAL
- ECG on day 1 postpartum and at discharge (monitor QTc)
Outpatient monitoring (LQT2):
- Cardiology review at 2 weeks, 6 weeks, 3 months, 6 months, 9 months postpartum
- ECG at each visit
- Holter if any palpitations/symptoms
- Patient education: Report immediately - palpitations, lightheadedness, syncope
Beta-blocker compliance:
- Counsel extensively about arrhythmia risk if stopped
- Continue same dose as pregnancy (or increase if QTc rising)
- Nadolol/metoprolol compatible with breastfeeding
Sleep deprivation management:
- Particularly important for LQT3 (events during sleep)
- Encourage partner assistance with night feeds
Breastfeeding: Safe and encouraged; beta-blockers compatible
Contraception: All methods safe; progesterone-only methods may be protective (shorten QT)

ABSOLUTE CONTRAINDICATIONS TO PREGNANCY:

Recurrent cardiac arrest despite beta-blockers and ICD
Electrical storm (generally not pregnancy-specific but would preclude pregnancy)

GENOTYPE-SPECIFIC SUMMARY:

LQT1: Low risk in pregnancy (progesterone protective); minimal postpartum risk
LQT2: HIGHEST RISK - close monitoring pregnancy + 9 months postpartum essential
LQT3: Intermediate risk; sleep deprivation postpartum may increase events

Follow-up

Pragmatic surveillance approach informed by ESC 2022 Ventricular Arrhythmia guidelines (which do not mandate fixed monitoring intervals)^[1].

Advanced / complicated = prior cardiac arrest or syncope, markedly prolonged QTc, breakthrough events on therapy, or appropriate ICD therapy.

Genotype-positive / phenotype-negative (G+/P−) = a confirmed pathogenic-variant carrier with no overt disease expression yet.

	Genotype+ / Phenotype−	Uncomplicated / Stable	Advanced / Complicated
Frequency	Annual (concealed LQTS)	Annual	Every 6 months
Clinical review	Symptoms; QT-drug & adherence counselling	Symptoms, syncope, adherence, QT-drug review	As above + device check
ECG	Annual (QTc may be normal)	Annual 12-lead (QTc trend)	Each visit
Holter / ambulatory	As indicated	Periodic / symptom-directed	As indicated
Exercise / stress test	Consider (may unmask LQT1)	As indicated (paradoxical QT response, esp. LQT1)	As indicated
Echocardiography	Baseline	Baseline (exclude structural disease)	If symptoms change
Family screening	–	Cascade ECG ± genetic testing	–

Disclaimer: This table is general guidance based on published guidelines and does not replace clinical judgement. The responsible clinician is accountable for determining the appropriate, individualised follow-up plan for each patient.

Key Points

Screen first-degree relatives with ECG and consider genetic testing if variant identified
Check www.crediblemeds.org before prescribing ANY medication^[1]
Do NOT stop beta-blockers abruptly (rebound tachycardia can be fatal)^[1]
Maintain K+ 4-5 mmol/L; replace promptly if low^[1]
LQT2 pregnancy/postpartum VERY HIGH RISK - mandatory close monitoring for 9 months postpartum
Genotype guides triggers: LQT1 avoid competitive swimming; LQT2 avoid sudden loud noises
Normal QTc does NOT exclude LQTS if genotype-positive
ICD does NOT replace beta-blocker therapy

References & Review Date

Last reviewed: June 2026

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;43(40):3997–4126. doi:10.1093/eurheartj/ehac262
Schwartz PJ, Crotti L. Long QT syndrome. N Engl J Med. 2025;393:2023–2034. PubMed
Schwartz PJ, et al. Diagnostic criteria for the long QT syndrome: an update. Circulation. 1993;88(2):782–784. doi:10.1161/01.CIR.88.2.782
van der Werf C, et al. Nadolol versus propranolol in patients with long QT syndrome. Heart Rhythm. 2013;10(11):1692–1698. doi:10.1016/j.hrthm.2013.07.034
Regitz-Zagrosek V, et al. 2018 ESC Guidelines for the management of cardiovascular diseases during pregnancy. Eur Heart J. 2018;39(34):3165–3241. doi:10.1093/eurheartj/ehy340
Joint Formulary Committee. British National Formulary (BNF). bnf.nice.org.uk
Zhu W, Bian X, Lv J. From genes to clinical management: a comprehensive review of long QT syndrome pathogenesis and treatment. Heart Rhythm O2. 2024;5(8):573–586. doi:10.1016/j.hroo.2024.07.006
Asatryan B, Murray B, Gasperetti A, et al. Unraveling complexities in genetically elusive long QT syndrome. Circ Arrhythm Electrophysiol. 2024;17(2):e012356. doi:10.1161/CIRCEP.123.012356
Priori SG, Schwartz PJ, Napolitano C, et al. Risk stratification in the long-QT syndrome. N Engl J Med. 2003;348(19):1866–1874. doi:10.1056/NEJMoa022147

Long QT Syndrome (LQTS)