Long QT Syndrome

Authors, Journal, Affiliations, Type, DOI

• Authors: Peter J. Schwartz, Lia Crotti
• Journal: New England Journal of Medicine, 2025;393:2023-34
• Affiliations: Istituto Auxologico Italiano IRCCS, Center for Cardiac Arrhythmias of Genetic Origin and Laboratory of Cardiovascular Genetics, Milan; University of Milano-Bicocca, Department of Medicine and Surgery, Milan
• Type: Review article (narrative review)
• DOI: https://doi.org/10.1056/NEJMra2400853

Overview

This authoritative narrative review by Schwartz and Crotti — the world's leading LQTS clinicians — updates pathophysiology, diagnosis, and management of congenital long QT syndrome. The three major genes (KCNQ1, KCNH2, SCN5A) account for approximately 90% of cases, with distinct gene-specific triggers and treatment implications. The central argument is that triple therapy (beta-blockers + mexiletine + left cardiac sympathetic denervation) with yearly reassessment can manage virtually all patients, reducing ICD implantation to ~5% — sharply contrasting with practices in some US centres implanting ICDs in up to 50%. Gene therapy via suppression-replacement approach shows promise in animal models but is not yet clinically ready.

Keywords

Long QT syndrome, QT interval, torsades de pointes, beta-blockers, mexiletine, left cardiac sympathetic denervation, ICD, gene therapy, acquired LQTS, modifier genes, KCNQ1, KCNH2, SCN5A, calmodulinopathy, repolarisation reserve

Key Takeaways

Genetic Basis

• Three major genes account for ~90% of cases: KCNQ1 (LQT1, ~50%), KCNH2 (LQT2, ~40%), SCN5A (LQT3, ~10%); all identified in 1995–1996
• KCNQ1 and KCNH2 encode IKs and IKr potassium channels; SCN5A gain-of-function causes persistent sodium influx (INaLate) during the plateau phase — all prolonging ventricular repolarisation
• During adrenergic activation, IKs becomes the predominant repolarisation current — if QTc fails to shorten appropriately with increasing heart rate, VF may ensue; this is the physiological basis of LQT1 exercise vulnerability
• Homozygous/compound heterozygous KCNQ1 or KCNE1 variants cause autosomal recessive Jervell–Lange-Nielsen syndrome (sensorineural deafness + severe LQTS)
• Additional genes: CACNA1C (Timothy syndrome — GOF, LQT8), CALM1/CALM2/CALM3 (calmodulinopathies — impair Cav1.2 Ca²⁺-dependent inactivation)
• Variants of uncertain clinical significance are common; periodic reclassification using phenotype robustness, familial cosegregation, and functional evaluation is expected
• Modifier genes: identified via South African KCNQ1-A341V founder population (wide QTc spectrum despite identical variant); modulate QTc in either direction; inform risk stratification and provide novel therapeutic targets
• Polygenic risk scores: common variant aggregates modulate LQTS susceptibility — especially in genotype-negative patients

Epidemiology

• Documented prevalence 1:2000 live births (prospective study, n=44,000 infants); actual prevalence is probably higher because genotype-positive–phenotype-negative persons were excluded from that study
• Sudden cardiac death is often the first symptom — timely diagnosis is critical; missed diagnosis remains too common
• Up to 10% of sudden infant deaths in the first year of life and some in utero deaths carry LQTS-causing variants
• Without genetic testing, sudden infant death in the first months is labelled SIDS — providing a rationale for neonatal ECG screening

Clinical Presentation and Diagnosis

• Key ECG features: QTc prolongation + bizarre T-wave morphology (biphasic, notched, alternans); pattern recognition is extremely important
• Upper limits of normal QTc (Bazett formula): 440 ms (men), 460 ms (women)
• QTc >500 ms discriminates moderate-to-high arrhythmic risk
• T-wave alternans: beat-to-beat amplitude variation; prefibrillatory sign and marker of major cardiac electrical instability
• Tangent method for QTc measurement underestimates actual ventricular repolarisation; Q-to-T-wave-return-to-baseline is the correct measurement approach; longest QTc lead is the most important value
• Gene-specific triggers: LQT1 = exercise/swimming; LQT2 = sudden auditory stimuli, sleep disruption, postpartum period; LQT3 = rest/sleep
• Schwartz Score: clinical diagnostic probability tool (≥3.5 = high probability; 1.5–3 = intermediate; ≤1 = low)
• Exercise stress test: marked QTc prolongation at 4th minute of recovery is highly specific for LQTS — the only provocation test that is truly useful; complete TP-wave fusion at peak exercise is a novel diagnostic marker
• Epinephrine challenge: NOT recommended (confirmed by ESC guidelines) — dangerous arrhythmogenic potential; can misleadingly suggest LQTS in normal individuals
• Stand-up test: limited value per current evidence
• Genotype-negative phenotype-positive patients should be treated identically to genotype-positive patients (arrhythmic risk is similar; n=832)
• Exercise-induced QT prolongation mimicking LQTS: asymptomatic, no family history, genotype-negative teenagers undergoing intensive training; reversible with 3–4 months of detraining — sports physicians must be aware to avoid mislabelling

Therapy — Four Cornerstones

Beta-Blockers

• Mainstay since mid-1970s; efficacy confirmed independent of genotype
• Only two confirmed effective beta-blockers: propranolol (2.0–3.5 mg/kg/day) and nadolol (1.0–1.5 mg/kg/day)
• Metoprolol should NOT be used — higher recurrence of events (Chockalingam 2012)
• Most beta-blocker "failures" are due to non-adherence or co-administration of QT-prolonging drugs
• Should be prescribed also for genotype-positive–phenotype-negative patients (few gene-specific exceptions: asymptomatic LQT1 males still symptom-free at age 25)
• In genotype-negative patients with borderline QTc prolongation: once beta-blocker therapy is started, withdrawing it is difficult — largely for medicolegal reasons

Left Cardiac Sympathetic Denervation (LCSD)

• Thoracoscopic removal of lower half of left stellate ganglion + T1–T4 thoracic ganglia (prevents Horner's syndrome)
• Mechanism: major reduction in norepinephrine release at ventricular level without postdenervation supersensitivity and without heart-rate reduction
• In electrical storms: 90% reduction in annual ICD shock incidence; clinically significant QTc shortening in most patients
• QTc shortening post-LCSD is associated with greater long-term protection
• When syncope recurs despite full-dose beta-blockers → LCSD should be implemented without hesitation
• ICD should not be placed without first discussing LCSD vs ICD pros and cons with the patient; there is no longer justification for routine ICD without offering LCSD information

Mexiletine

• LQT3: proposed 1995 as first gene-specific therapy; most (not all) LQT3 variants respond
• LQT2: ~70% of patients show QTc shortening with mexiletine — substantially broadening its clinical use beyond LQT3
• Acute oral drug test: administer 6–8 mg/kg oral mexiletine; check whether QTc shortens >40 ms within 2 hours; only start long-term therapy in responders — avoids unnecessary chronic therapy in non-responders

ICD

• Major international variation: some US centres implant in ~50%; two largest international LQTS centres (Mayo Clinic, Auxologico) implant in ~5%
• Transvenous ICD preferred over subcutaneous — allows pacing (essential when beta-blocker dose must be increased in patients with low heart rate or during electrical storms)
• 946-patient study: most ICD recipients had not suffered a cardiac arrest; many had not failed beta-blocker therapy; 45% of LQT3 ICD recipients were asymptomatic; 25% had an adverse event in 5 years
• 2861-patient study: only a minority of guideline ICD candidates actually needed an ICD
• Applying risk scores at the initial visit before therapy initiation (as ESC 2022 recommends) → likely excessive ICD use; risk should be reassessed after therapeutic optimisation
• Triple therapy (BB + mexiletine + LCSD) with yearly reassessment allows virtually all patients to survive with minimal ICD use

ICD Indications (Schwartz/Crotti Framework)

• Survivors of cardiac arrest while adhering to adequate drug therapy
• Syncope despite full-dose beta-blockers when LCSD + mexiletine are unavailable
• Syncope despite full-dose beta-blockers AND LCSD

Gene Therapy

• Gene silencing (small RNAs): variant-specific — hundreds of LQTS variants limit applicability
• Suppression-replacement (SupRep) therapy: mutation-agnostic; validated in LQT1 and LQT2 cellular models, rabbit models, and calmodulinopathy models; suppresses both alleles and delivers shRNA-immune replacement cDNA
• Challenges: dose precision required (undertreatment → persistent LQTS; overtreatment → SQTS); inhomogeneous transduction → heterogeneous repolarisation → proarrhythmic risk; safety concerns from gene therapy adverse events in other disease programmes
• Current effective therapies limit gene therapy candidates to extreme-risk patients (infants with early cardiac events, calmodulin variants, p.R1623Q in SCN5A) who continue to have appropriate ICD shocks despite full therapy

Acquired Long QT Syndrome

• Causes: IKr-blocking drugs (>200 drugs with TdP potential), hypokalemia, bradycardia, heart block
• Individual repolarisation reserve (genetically modulated) determines susceptibility; common, rare, and ultrarare genetic variants all contribute
• Three predictors of latent congenital LQTS in acquired LQTS: age <40 years, QTc >440 ms at baseline, arrhythmic episodes → if present, offer molecular genetic testing
• Rare variants consistently associated with acquired LQTS: KCNE1-p.D85N and SCN5A-p.S1103Y
• 61 common genetic variants collectively explain up to 30% of variability in acquired LQTS (common variant PRS — not yet recommended outside research)
• Correction of the offending factor prevents recurrences
• Excessive physical training can induce marked QT prolongation mimicking LQTS — reversible with detraining

Limitations of the Document

• Narrative review (not systematic/meta-analysis) — subject to expert selection bias in cited evidence
• Authors (Schwartz, Crotti) advocate for conservative ICD use from a single high-volume European centre; their low ICD implant rates (5%) may reflect exceptional expertise not reproducible in non-specialist centres
• Emerging pharmacological therapies (lumacaftor-ivacaftor for LQT2 trafficking defects, SGK1 inhibitors) discussed from preliminary/preclinical data only — not yet standard of care
• Gene therapy section is encouraging but major safety and dosing challenges remain; clinical timeline is unknown
• Sports liberalisation (LIVE-LQTS, Circulation 2024) referenced but not detailed; guidance evolving

Key Concepts Mentioned

• concepts/Torsades-de-Pointes — primary arrhythmic mechanism in LQTS; degenerates to VF and SCD
• concepts/Schwartz-Score — clinical diagnostic probability tool; exercise QTc a key provocation criterion
• concepts/Left-Cardiac-Sympathetic-Denervation — cornerstone of triple therapy; 90% ICD shock reduction in electrical storms
• concepts/Cardiac-Repolarization — IKs/IKr/INaLate mechanistic basis; repolarisation reserve concept
• concepts/Gene-Silencing-Therapy — SupRep mutation-agnostic approach validated in LQT1/LQT2/calmodulinopathy
• concepts/Calmodulinopathy — CALM1/2/3 LQTS; SupRep validated; extreme QTc >600 ms
• concepts/Modifier-Genes — NOS1AP, KCNQ1 intronic modifiers; phenotypic modulation
• concepts/Precision-Medicine-LQTS — genotype-specific therapy; triple therapy with yearly reassessment
• concepts/Drug-Induced-Arrhythmia — acquired LQTS mechanisms; IKr reserve depletion; three risk predictors

Key Entities Mentioned

• entities/Long-QT-Syndrome — comprehensive genotype-specific clinical framework updated
• entities/KCNQ1 — LQT1 (~50%); IKs loss-of-function; recessive JLN with KCNE1
• entities/KCNH2 — LQT2 (~40%); IKr loss-of-function; mexiletine effective in ~70%
• entities/SCN5A — LQT3 (~10%); INaLate gain-of-function; first gene-specific therapy (mexiletine, 1995)
• entities/Andersen-Tawil-Syndrome — separate channelopathy entity

Wiki Pages Updated

• wiki/sources/lqts-nejm-2025.md — created (this file)
• wiki/entities/Long-QT-Syndrome.md — updated: gene frequencies, acquired LQTS section, mexiletine LQT2 data, ICD overuse evidence, SupRep calmodulinopathy, exercise-induced LQTS, new contradictions
• wiki/concepts/Left-Cardiac-Sympathetic-Denervation.md — updated: 90% ICD shock reduction data in electrical storms
• wiki/concepts/Torsades-de-Pointes.md — updated: acquired LQTS rare variants (KCNE1-D85N, SCN5A-S1103Y)
• wiki/sourceindex.md — new entry added
• wiki/wikiindex.md — entity entry updated
• log.md — appended