Long QT syndrome

LQTS can be congenital or acquired

Congenital LQTS 

• Results from pathogenic variants in genes encoding cardiac ion channels, leading to altered channel function and impaired myocardial repolarisation. To date, 17 genes have been implicated, with KCNQ1 (LQT1), KCNH2 (LQT2), and SCN5A (LQT3) accounting for over 90% of identified genotypes.

Acquired LQTS 

• Develops secondary to factors such as QT-prolonging drugs, electrolyte disturbances (hypokalaemia, hypomagnesaemia, hypocalcaemia), or bradyarrhythmias.

QT Interval and Diagnostic Thresholds

• The QT interval represents the total duration of ventricular depolarisation and repolarisation. Because it varies with heart rate, the heart rate–corrected QT interval (QTc) is used for diagnosis.
• Prolonged QTc is generally defined as:
  • >450 ms in men
  • >460 ms in women
• The European Society of Cardiology (ESC) recommends:
  • QTc ≥480 ms as diagnostic for LQTS
  • QTc 460–479 ms as borderline, requiring additional diagnostic criteria (e.g., clinical history, family history, or genetic testing).
• A QTc exceeding 500 ms is strongly associated with heightened risk of torsades de pointes and sudden cardiac death.

Congenital LQTS

• Genetic mutations identified in 17 different genes are implicated, though three genes account for the vast majority (90–95%) of cases where a genetic basis is confirmed.
  • LQT1: Caused by loss-of-function mutations in the KCNQ1 gene, which encodes the potassium channel responsible for the slow component of the delayed rectifier current (IKs). Homozygous mutations result in Jervell and Lange-Nielsen syndrome (JLNS), characterised by severe LQTS and congenital deafness.
  • LQT2: Results from loss-of-function mutations in KCNH2, encoding the potassium channel that generates the rapid component of the delayed rectifier current (IKr).
  • LQT3: Associated with gain-of-function mutations in SCN5A, which encodes the cardiac sodium channel, leading to persistent inward sodium current during the plateau phase of the action potential.
• While 17 genes have been reported, evidence supporting the pathogenic role of some remains limited or disputed, and their contribution to disease causation is uncertain.
• Congenital LQTS is most often inherited in an autosomal dominant fashion (Romano-Ward syndrome), but rare autosomal recessive syndromes exist (e.g., JLNS).

Acquired LQTS

Drug-induced

• Numerous medications prolong the QT interval by blocking cardiac ion channels, particularly IKr. Examples include:
  • Antiarrhythmics: quinidine, procainamide, sotalol, amiodarone, disopyramide, dofetilide.
  • Psychotropics: phenothiazines, tricyclic antidepressants, methadone.
  • Oncology treatments: kinase inhibitors, growth factor inhibitors, androgen-deprivation therapies, and chimeric antigen receptor T-cell therapies.
  • A continually updated resource for QT-prolonging drugs is maintained by CredibleMeds (Arizona CERT).

Electrolyte imbalances

• Hypokalaemia, hypomagnesaemia, and hypocalcaemia prolong repolarisation and enhance susceptibility to torsades de pointes.

Bradyarrhythmias

• Sudden bradycardia or atrioventricular (AV) block can precipitate pause-dependent QT prolongation.

Neurological insults

• Central nervous system lesions, especially subarachnoid haemorrhage and ischaemic stroke, may secondarily cause QT prolongation.

Nutritional factors

• Severe malnutrition, including starvation or restrictive diets such as liquid protein regimens, may provoke QT prolongation.

Exercise-related factors

• Intense training has been reported as a reversible cause of prolonged QT interval in athletes.

Congenital Mechanisms

LQT1

• Caused by heterozygous loss-of-function mutations in the KCNQ1 gene, which encodes the α-subunit of the slow-activating potassium channel (IKs).
• Dysfunctional IKs channels result in dispersion of repolarisation across the myocardial wall, predisposing to ventricular tachyarrhythmias.
• ECG findings typically show prolonged QT intervals with broad-based T waves.

LQT2

• Results from mutations in the KCNH2 gene (encoding the HERG channel), which carries the rapid component of the delayed rectifier potassium current (IKr).
• Impaired IKr channels cause slowed repolarisation and transmural dispersion, increasing vulnerability to torsades de pointes.
• The ECG often demonstrates low-amplitude, notched T waves.

LQT3

• Stems from gain-of-function mutations in SCN5A, which encodes the cardiac sodium channel.
• These mutations allow a late persistent sodium current to continue into the plateau phase of the action potential, prolonging repolarisation.
• ECG features include long ST segments with late-appearing T waves.

Other genetic contributions

• Additional genes (e.g., CALM1–3, TRDN, KCNE1/2, CACNA1C) have been implicated in rare forms of LQTS, although evidence supporting their causative role remains limited or disputed.
• Rarely, mutations in SCN5A have been associated with inherited complete atrioventricular block, due to persistent sodium currents prolonging the action potential.

Acquired Mechanisms

Electrolyte disturbances

• Hypokalaemia: Induces hyperpolarisation of the myocardial membrane, delaying repolarisation.
• Hypomagnesaemia: Often co-exists with hypokalaemia and promotes early after-depolarisations, prolonging repolarisation.
• Hypocalcaemia: Extends the plateau phase of the action potential, thereby prolonging repolarisation.

Drug effects

• Virtually all QT-prolonging medications act by blocking the outward IKr current (KCNH2 channel).
• Examples include:
  • Antiarrhythmics: sotalol, amiodarone, quinidine, procainamide, dofetilide, disopyramide
  • Antibiotics: macrolides, fluoroquinolones
  • Antipsychotics: haloperidol, olanzapine, phenothiazines, tricyclic antidepressants, methadone
  • Gastrointestinal prokinetics: cisapride
  • Oncology therapies: kinase inhibitors, growth factor inhibitors, androgen-deprivation therapies, and CAR-T cell therapies

Bradyarrhythmias

• Sudden sinus bradycardia or atrioventricular nodal block may cause pause-dependent QT prolongation.

Neurological insults

• Subarachnoid haemorrhage and ischaemic stroke are well-recognised triggers of secondary QT prolongation.

Nutritional factors

• Severe malnutrition, including starvation or restrictive liquid protein diets, can contribute to QT prolongation.

Exercise-related

• Intense training in athletes has been identified as a reversible cause of QT prolongation.

Genetic modifiers

• Certain polymorphisms, such as KCNE1-D85N, decrease repolarisation reserve, predisposing to acquired LQTS in susceptible individuals.

General

• Long QT syndrome (LQTS) was historically regarded as extremely rare, as only the most severe cases were recognised and reported. Improved awareness, wider screening, and genetic testing have shown that congenital LQTS is more common than previously thought.
• The estimated prevalence of congenital LQTS is 1 in 2000 to 1 in 2500 individuals worldwide, although some sources suggest a broader range of 1 in 2000 to 1 in 10,000.
• LQTS accounts for an estimated 3000 sudden deaths annually in the United States, and family history is positive for LQTS in around 40% of cases and for sudden cardiac death in about 30%.
• Untreated LQTS carries significant risk:
  • Annual sudden cardiac death rate is <0.5% in asymptomatic patients, but rises to ~5% in those with a history of syncope.
  • The 10-year mortality in untreated, symptomatic index cases approaches 50%.

Age-related demographics

• The mean age at presentation is around 14 years, with most patients presenting in childhood, adolescence, or early adulthood.
• Although rare, onset has been documented as late as the fifth decade of life.
• In children younger than 10 years, mortality risk is higher in boys, but after this age, the risk equalises between sexes.

Sex-related demographics

• LQTS is more frequently diagnosed in women, comprising 60–70% of newly identified cases. This may partly reflect sex-specific QTc thresholds (upper normal limit of 460 ms in postpubertal women vs 450 ms in men) and possibly a genuine genetic predisposition.
• Hormonal influences affect risk:
  • Pregnancy itself is not associated with increased risk of cardiac events.
  • Postpartum period carries a markedly increased risk, particularly in women with LQT2.
  • Cardiac events also correlate with menses and are reported to rise substantially after menopause, especially in LQT2, with a 3–8-fold increase in recurrent syncope.

Genetic distribution

• Between 70–85% of patients with LQTS have an identifiable pathogenic mutation.
• Over 90% of genotyped cases involve LQT1, LQT2, or LQT3.
• KCNQ1 mutations (LQT1) are the most common, present in 35–45% of genetically confirmed cases, followed by KCNH2 mutations (LQT2).
• Romano-Ward syndrome (autosomal dominant) is the most common inherited form, whereas Jervell and Lange-Nielsen syndrome is a rare autosomal recessive subtype associated with congenital deafness.

Acquired LQTS

• The prevalence of acquired LQTS is more difficult to establish and is influenced by hospital setting and comorbidity.
• In one retrospective review of hospital admissions, 0.7% of patients had a QTc >500 ms.
• Among hospitalised cancer patients, 1.5% had a QTc >500 ms.
• In the intensive care setting, QT prolongation has been reported in up to 30% of patients.

Genetic and Family History

Known gene mutations

• Mutations in KCNQ1, KCNH2, SCN5A, or CALM genes are strongly associated with congenital LQTS.

Family history

• Sudden cardiac death, cardiac arrest, or unexplained syncope at a young age in relatives.
• Hearing loss in the patient or family may indicate Jervell and Lange-Nielsen syndrome.

Medication and Acquired Risk Factors

QT-prolonging drugs

• Antiarrhythmics (quinidine, procainamide, sotalol, amiodarone, disopyramide, dofetilide).
• Psychotropics (phenothiazines, tricyclic antidepressants, methadone).
• Oncology therapies (kinase inhibitors, growth factor inhibitors, androgen-deprivation therapies, CAR-T therapies).
• Other categories: macrolide/fluoroquinolone antibiotics, gastrointestinal motility agents (e.g., cisapride).

Electrolyte and rhythm disturbances

• Hypokalaemia, hypomagnesaemia, and hypocalcaemia.
• Bradyarrhythmias or pause-dependent QT prolongation.

Nutritional triggers

• Starvation and restrictive diets such as liquid protein regimens.

Syncope and Triggering Circumstances

Exercise or adrenergic stress

• LQT1: syncope during exercise, especially swimming or diving.

Startle or emotional triggers

• LQT2: events triggered by sudden noises (doorbell, alarm clock, telephone ringing) or emotional shock.

Rest or bradycardia

• LQT3: events most often occur at night or during rest.

Postpartum and hormonal influences

• Women with LQT2 are particularly vulnerable during the first 9 months postpartum, and arrhythmic risk also increases with menses and after menopause.

Symptom Patterns

Cardiac syncope

• Often due to ventricular tachyarrhythmias or bradyarrhythmias.
• May be preceded by palpitations, chest pain, or dyspnoea.
• Typically associated with pallor and cyanosis, followed by rapid recovery with flushing.

Palpitations and arrhythmias

• May result from premature ventricular complexes or torsades de pointes.

Dizziness and near-syncope

• Reflect transient cerebral hypoperfusion.

Syndromic Associations

Andersen–Tawil syndrome (LQT7)

• Periodic paralysis, facial and skeletal dysmorphism (micrognathia, low-set ears, scoliosis, syndactyly).

Timothy syndrome (LQT8)

• Dysmorphic features (flattened nasal bridge, syndactyly), with neurodevelopmental or immune abnormalities.

Jervell and Lange-Nielsen syndrome

• Severe arrhythmic risk with associated congenital sensorineural deafness.

General Clinical Findings

• Findings on physical examination are often non-specific and may not directly indicate long QT syndrome (LQTS). 
• However, careful evaluation can provide supportive clues and reveal syndromic associations, as well as exclude other potential causes of arrhythmia or syncope.

Bradycardia

• Some patients may present with excessive bradycardia for their age, which can be associated with arrhythmic risk.

Sensorineural deafness

• Congenital hearing loss suggests Jervell and Lange-Nielsen syndrome, a severe autosomal recessive form of LQTS.

Syndromic Associations

Andersen–Tawil syndrome (LQT7)

• Skeletal abnormalities: short stature, scoliosis.
• Craniofacial features: micrognathia, low-set ears, widely spaced eyes.
• Limb anomalies: clinodactyly, syndactyly.
• May also present with periodic paralysis and variable neurocognitive findings.

Timothy syndrome (LQT8)

• Dysmorphic features: small upper jaw, flattened nasal bridge, cutaneous syndactyly, and low-set ears.
• May also exhibit congenital heart disease, cognitive and behavioural abnormalities, musculoskeletal disorders, and immune dysfunction.

Excluding Other Causes of Syncope

• Examination should also focus on identifying structural or functional heart disease that may mimic LQTS presentations, such as:
  • Heart murmurs of hypertrophic cardiomyopathy
  • Valvular disease
  • Other congenital or acquired cardiac abnormalities

First-line Tests

12-lead resting ECG

• Obligatory in all suspected cases.
• Measure QT and QTc (Bazett’s formula: QT/√RR), averaging 3–5 beats and using tangent or threshold methods; record values in seconds.
• Assess T-wave morphology (monophasic vs multiphasic, notching, amplitude) and look for T-wave alternans.
• Recognise genotype-linked patterns:
  • LQT1: prolonged QT with broad-based T waves.
  • LQT2: low-amplitude, notched T waves.
  • LQT3: long ST segment with late-appearing T wave.

Serum electrolytes

• Check potassium, magnesium, calcium in all patients with QT prolongation; correct abnormalities promptly.

Rhythm assessment for bradyarrhythmia/AV block

• Identify pause-dependent QT prolongation or complete AV block (P–QRS dissociation, slow ventricular rate, QRS widening).

Tests to Consider (Context-Dependent)

Holter/ambulatory ECG monitoring

• Evaluates diurnal QT/QTc behaviour (including during nocturnal bradycardia and post-extrasystolic pauses).
• Detects non-sustained ventricular arrhythmias in asymptomatic individuals.
• “QT clock” or other Holter-derived measures may increase sensitivity for intermittent QTc prolongation.

Exercise (treadmill/bicycle) testing

• Helpful when QTc is borderline on resting ECG.
• Particularly informative for LQT1, in whom QT/QTc may fail to shorten or may lengthen with exertion; supports exercise prescription and counselling.

Adrenaline (epinephrine) provocation

• Consider in borderline cases, especially for suspected LQT1.
• Perform only with immediate access to advanced life support and external defibrillation.
• A positive response is QT/QTc prolongation with adrenergic stimulation.

Echocardiography (± cardiac MRI)

• Not diagnostic for LQTS, but useful to exclude structural disease (e.g., hypertrophic cardiomyopathy, valvular pathology) or to evaluate associated congenital heart disease in syndromic forms (e.g., LQT8/Timothy).

Genetic testing

• Purpose: confirm subtype, aid risk stratification, and enable cascade family screening.
• Yield: ~70% sensitivity in clinically definite LQTS; multiple pathogenic variants predict higher breakthrough event risk on follow-up.
• When to test: strong clinical suspicion; QTc ≥500 ms on serial ECGs without a reversible cause; or when clinical scoring is high.
• In asymptomatic individuals with borderline QTc (<480 ms) and no family history, routine testing is not indicated.

Adjunctive/Advanced Tools

Standing test (orthostatic QT response)

• In congenital LQTS, QTc may paradoxically increase immediately after standing (sympathetic surge), improving diagnostic yield vs baseline QTc; effect may be ameliorated by β-blockers.

Short-term QT variability (STV[QT])

• Increased beat-to-beat QT variability may serve as a non-invasive additive marker in symptomatic congenital LQTS while awaiting genetic results.

Automated T-wave analysis

• Quantitative T-wave metrics (e.g., right/left slopes, T-peak–T-end, T-wave “centre of gravity”) can help distinguish acquired from congenital QT prolongation and predict breakthrough arrhythmic risk in LQT1/LQT2.

Polygenic risk score (PRS) for drug-induced LQTS

• Weighted combinations of common QT-modifying variants (GWAS-derived) identify patients at higher risk of drug-induced QTc prolongation and torsades de pointes; validated in large cohorts, with ongoing work in diverse ancestries.

Diagnostic Criteria and Practical Notes

Schwartz score (clinical diagnostic score)

• Combines ECG findings (QTc thresholds, torsades, T-wave alternans/morphology, heart rate for age), clinical history (syncope with/without stress, congenital deafness), and family history (definite LQTS or early sudden death).
• Score >3 (≥4) indicates a high probability of LQTS and supports genetic testing.

QTc calculation and pitfalls

• Prefer consistent methodology; be aware Bazett’s formula over-corrects at high rates and under-corrects at low rates—interpret in clinical context.
• When QTc is borderline or normal but suspicion remains, use dynamic testing (exercise/ambulatory/adrenergic) and family ECG review.

Inherited Arrhythmic Syndromes

Brugada syndrome

• Signs/Symptoms: Syncope or sudden death, often during rest or sleep.
• Investigations: Resting ECG shows coved-type ST elevation in leads V1–V3 with right bundle branch block pattern; QT interval usually normal.

Short QT syndrome

• Signs/Symptoms: Syncope, palpitations, or sudden cardiac death.
• Investigations: Resting ECG shows abnormally short QT interval (<330 ms) and tall, peaked T waves.

Catecholaminergic polymorphic ventricular tachycardia (CPVT)

• Signs/Symptoms: Arrhythmias triggered by exertion or emotional stress; history overlaps with LQTS.
• Investigations: Resting ECG normal; exercise test reveals bidirectional or polymorphic ventricular tachycardia. Genetic testing identifies RyR2 (dominant) or CASQ2 (recessive) mutations.

Structural Heart Diseases

Acquired structural heart disease

• Signs/Symptoms: Prior history of coronary artery disease, myocardial infarction (MI), or valvular disease.
• Investigations:
  • Echocardiography: regional wall motion abnormalities (post-MI), valvular stenosis/regurgitation, or ventricular dysfunction.
  • ECG: Q waves in prior infarction.

Hypertrophic cardiomyopathy

• Signs/Symptoms: Syncope, palpitations, exertional dyspnoea, sudden cardiac death in young athletes.
• Investigations: Echocardiography demonstrates asymmetric septal hypertrophy and dynamic LV outflow obstruction; ECG shows LV hypertrophy and repolarisation changes.

Coronary artery anomalies

• Signs/Symptoms: Syncope or sudden cardiac death, particularly during exercise.
• Investigations: Echocardiography, CT angiography, or MRI defines anomalous coronary origin/course.

Syncope Syndromes

Neurocardiogenic (vasovagal) syncope

• Signs/Symptoms: Triggers include micturition, coughing, prolonged standing, heat, or emotional stress. Prodrome of sweating, warmth, and nausea; recovery with nausea/vomiting.
• Investigations: Orthostatic BP measurement or tilt-table testing shows hypotension; ECG is normal with preserved QT interval.

Neurological syncope

• Signs/Symptoms: Panic-related (hyperventilation, paraesthesiae), migraine-related (headache, visual disturbance, photophobia, phonophobia).
• Investigations: Normal QT interval on ECG; further neurological assessment may be warranted.

Epilepsy

• Signs/Symptoms: Triggered by sleep deprivation, alcohol, flashing lights, or certain drugs. Aura may precede seizure. Events include tonic–clonic movements, tongue biting, incontinence; prolonged postictal confusion follows.
• Investigations: EEG reveals epileptiform activity; ECG shows normal QT.

Other Considerations

Drug-induced QT prolongation

• Signs/Symptoms: Similar to congenital LQTS with syncope or arrhythmia.
• Investigations: Careful drug history; ECG shows QT prolongation.

Sudden cardiac death

• Signs/Symptoms: May be final manifestation of various arrhythmic or structural causes, including LQTS.
• Investigations: Post-mortem genetic and pathological evaluation may be required.

General

• Management of long QT syndrome (LQTS) depends on whether the condition is congenital or acquired, the patient’s clinical history, and their risk profile. 
• Treatment focuses on lifestyle modifications, pharmacotherapy, and device therapy where indicated, with additional genotype-specific considerations.

Acquired LQTS

Identification and removal of causative factors

• Review drug history for QT-prolonging agents (antiarrhythmics such as quinidine, procainamide, sotalol, amiodarone, disopyramide, dofetilide; psychotropics such as phenothiazines, tricyclic antidepressants, methadone; oncology therapies including kinase inhibitors, growth factor inhibitors, androgen-deprivation therapies, CAR-T cell therapies).

Correction of metabolic abnormalities

• Measure and correct serum electrolytes: hypokalaemia, hypomagnesaemia, hypocalcaemia.
• Aim for “high-normal” potassium (≥4.0–4.5 mmol/L).

Bradyarrhythmias or AV block

• Consider pacing (temporary or permanent) if QT prolongation is pause-dependent or if symptomatic bradycardia persists.

Monitoring

• Serial ECGs until QT interval normalises.
• If QT-prolonging therapy cannot be withdrawn, institute beta-blocker therapy and strict monitoring.

Congenital LQTS without Previous Cardiac Event

Risk stratification

• Low risk (<49% probability of first event before 40 years): QTc <500 ms in LQT1 or LQT2; QTc <500 ms in men with LQT3; women with LQT3 irrespective of QTc.
• High risk (≥50% probability): QTc ≥500 ms in LQT1, LQT2, or men with LQT3.
• The 1-2-3 LQTS risk calculator can refine prediction of life-threatening events.

Lifestyle modification

• Avoid strenuous or competitive exercise unless assessed by an expert.
• LQT1: avoid swimming without clearance and supervision.
• LQT2: avoid sudden auditory triggers (e.g., alarm clocks, telephones in bedrooms).
• Replace electrolytes lost through vomiting, diarrhoea, or excessive sweating.
• Avoid QT-prolonging medications and stimulants.

Beta-blockers

• Mainstay of treatment, preferably non-selective agents (nadolol, propranolol).
• Prevent arrhythmias by blunting adrenergic surges but do not shorten QT.
• Particularly effective in LQT1 and LQT2; less so in LQT3.
• Exercise testing can help assess treatment efficacy.
• Should also be considered for mutation-positive patients with normal QTc.

Congenital LQTS with Previous Cardiac Event

Lifestyle modification and beta-blockers

• Indicated in all patients, regardless of risk category.

Implantable cardioverter-defibrillator (ICD)

• Recommended for:
  • Survivors of cardiac arrest.
  • Patients with recurrent arrhythmic syncope despite optimal beta-blockade.
  • High-risk patients (QTc ≥500 ms, LQT2 subtype, multiple mutations, Jervell and Lange-Nielsen syndrome).
• Consider single- vs dual-chamber devices depending on individual factors.

Mexiletine

• Used in LQT3 (sodium channel gain-of-function) when syncope or ICD shocks occur despite beta-blockers.
• Must confirm QTc shortening ≥40 ms on trial before long-term use.
• Role in other subtypes is under investigation.

Left cardiac sympathetic denervation (LCSD)

• Indicated for recurrent syncope despite therapy, frequent ICD shocks, or where ICD implantation is unsuitable (e.g., young children).
• Minimally invasive thoracoscopic LCSD is now available.
• Breakthrough events may still occur in ~50% of cases.

Pacemaker therapy

• Considered in combination with beta-blockers for:
  • Patients with persistent symptoms despite LCSD.
  • Those ineligible for ICDs.
• Prevents bradycardia and pause-dependent torsades, but does not replace the protective effect of ICD defibrillation.

Silent Carriers Without Prior Diagnosis

• Individuals who harbour a genetic mutation but remain unidentified may live without symptoms and have a largely normal lifespan.
• These carriers can still transmit the mutation to their children, who may then present with clinically significant disease.
• Prognosis in this group is linked to QTc interval, genotype, and family background, even if the index individual is unaffected.

Known Carriers Without Symptoms

• Patients detected through family screening or incidental ECGs generally do well when placed under regular surveillance.
• Beta-blockers may be prescribed if they have risk markers such as marked QTc prolongation.
• Lifestyle adjustments (avoidance of QT-prolonging medications and electrolyte imbalance) are recommended to prevent progression to symptomatic disease.

Patients Presenting With Fainting Episodes

• Those who experience syncopal attacks are at greater risk for recurrent events.
• Meticulous correction of potassium, magnesium, and calcium disturbances is vital, as is strict avoidance of QT-prolonging agents.
• Beta-blockers provide the greatest protection, while ICDs are considered for those with ongoing events despite therapy.

Patients With a History of Cardiac Arrest

• Survivors of a prior arrest represent the highest-risk subgroup.
• These patients require aggressive intervention, typically combining beta-blockers with an ICD for secondary prevention.
• Once treated appropriately and avoidable triggers are eliminated, survival is markedly improved.

Broader Prognostic Patterns

• When treated, the majority of patients with LQTS experience favourable outcomes.
• Episodes of torsades de pointes are often self-limiting, with only 4–5% progressing to fatal arrhythmias.
• Untreated LQTS contributes to an estimated 4000 sudden deaths annually in the United States, with cumulative mortality around 6% by age 40.
• Alarmingly, up to one-third of deaths occur at the first syncopal episode, highlighting the need for early recognition and family screening.

Prognosis by Genotype

LQT1

• Greatest risk during exercise, especially swimming.
• Generally responds well to beta-blockers, with significantly reduced event rates under treatment.

LQT2

• Cardiac events often triggered by startling auditory stimuli or emotional arousal.
• Pharmacological therapy is usually effective, though postpartum women remain at elevated risk.

LQT3

• Events commonly arise at rest or during sleep.
• Less responsive to beta-blockade compared with LQT1 and LQT2.
• May require mexiletine or ICD implantation in addition to standard therapy.

Other subtypes

• LQT4 can feature atrial arrhythmias such as paroxysmal atrial fibrillation.
• Rare syndromic forms (e.g., Jervell and Lange-Nielsen, Timothy, Andersen–Tawil) carry additional risks due to associated comorbidities.
• Survivors of cardiac arrest may suffer neurological sequelae due to hypoxic injury.

General

• Patients with long QT syndrome (LQTS) are vulnerable to life-threatening rhythm disturbances, with complications ranging from recurrent syncope to sudden cardiac death.
• These adverse outcomes arise from delayed ventricular repolarisation and abnormal dispersion of electrical recovery, which provide the substrate for malignant arrhythmias.

Torsades de Pointes

• Description: A polymorphic ventricular tachycardia that arises due to dysfunctional potassium channels, delayed repolarisation, and transmural heterogeneity of recovery.
• Clinical course: Often self-terminating but may recur, leading to recurrent syncope or progression to ventricular fibrillation.
• Management:
  • Intravenous magnesium is first-line therapy.
  • Electrical cardioversion if haemodynamically unstable.
  • Temporary ventricular pacing or isoproterenol may be used in pause-dependent cases.
  • Correct hypokalaemia, hypomagnesaemia, and hypocalcaemia.
  • Stop drugs known to prolong the QT interval (e.g., quinidine, procainamide, sotalol, amiodarone, disopyramide, dofetilide, phenothiazines, tricyclic antidepressants).

Sustained Ventricular Tachycardia

• Description: Longer episodes of ventricular tachyarrhythmias that do not self-terminate.
• Significance: Increase the likelihood of haemodynamic collapse and require urgent treatment.
• Management: Advanced life support protocols, including immediate cardioversion, alongside correction of reversible metabolic or drug-induced factors.

Cardiac Arrest

• Description: Ventricular tachycardia or torsades de pointes can degenerate into ventricular fibrillation, resulting in loss of cardiac output.
• Management:
  • CPR and defibrillation following advanced life support guidelines.
  • Eliminate contributing factors such as electrolyte imbalance and QT-prolonging medications.
• Prognosis: Survivors are at high risk for recurrence and generally require long-term protective measures such as ICD implantation and strict trigger avoidance.

Sudden Cardiac Death

• Description: The most severe outcome, usually due to persistent torsades de pointes progressing to ventricular fibrillation and irreversible cardiac arrest.
• Epidemiology: LQTS is a recognised cause of sudden death in otherwise healthy young individuals.
• Triggers: Physical exertion, sudden emotional stress, startle stimuli, or medications that exacerbate QT prolongation.

1. Ackerman MJ, Priori SG, Willems S, et al. HRS/EHRA Expert Consensus Statement on the state of genetic testing for the channelopathies and cardiomyopathies. Europace. 2011;13(8):1077-1109.
2. Anderson HN, Bos JM, Haugaa KH, Morlan BW, Tarrell RF, Caraballo PJ, Ackerman MJ. Prevalence and outcome of high-risk QT prolongation recorded in the emergency department from an institution-wide QT alert system. J Emerg Med. 2018;54(1):8-15.
3. Beach SR, Celano CM, Sugrue AM, Adams C, Ackerman MJ, Noseworthy PA, Huffman JC. QT prolongation, torsades de pointes, and psychotropic medications: a 5-year update. Psychosomatics. 2018;59(2):105-122.
4. Chong DW, Ankolekar SJ, McDonald J. Torsades de Pointes in long QT syndrome. BMJ Case Rep. 2009; doi:10.1136/bcr.01.2009.1426.
5. Ebrahim MA, Williams MR, Shepard S, Perry JC. Genotype positive long QT syndrome in patients with coexisting congenital heart disease. Am J Cardiol. 2017;120(2):256-261.
6. European Society of Cardiology. 2022 ESC Guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death. Eur Heart J. 2022;43:3997-4126.
7. Giudicessi JR, Roden DM, Wilde AAM, Ackerman MJ. Classification and reporting of potentially proarrhythmic common genetic variation in long QT syndrome genetic testing. Circulation. 2018;137(6):619-630.
8. Hinterseer M, Beckmann BM, Thomsen MB, et al. Increased short-term variability of QT interval in patients with congenital long QT syndrome. Eur Heart J. 2009;30(3):289-297.
9. Moss AJ, Zareba W, Hall WJ, et al. Effectiveness and limitations of beta-blocker therapy in congenital long-QT syndrome. N Engl J Med. 2000;343(12):906-912.
10. Postema PG, Wilde AAM. The measurement of the QT interval. Curr Cardiol Rev. 2014;10(3):287-294.
11. Priori SG, Blomström-Lundqvist C, Mazzanti A, et al. 2015 ESC Guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death. Eur Heart J. 2015;36(41):2793-2867.
12. Schwartz PJ, Crotti L, George AL. Modifier genes for sudden cardiac death. Eur Heart J. 2018;39(44):3925-3931.
13. Schwartz PJ, Crotti L, Insolia R. Long-QT syndrome: from genetics to management. Circ Arrhythm Electrophysiol. 2012;5(4):868-877.
14. Schwartz PJ, Moss AJ, Vincent GM, Crampton RS. Diagnostic criteria for the long QT syndrome: an update. Circulation. 1993;88(2):782-784.
15. Sugrue A, Noseworthy PA, Kremen V, et al. Noninvasive T-wave metrics to differentiate congenital from acquired QT prolongation and to predict events in LQT1/LQT2. Heart Rhythm. 2017;14(7):1058-1067.
16. Uvelin A, Pejaković J, Mijatović V. Acquired prolongation of QT interval as a risk factor for torsade de pointes ventricular tachycardia: a narrative review for the anaesthesiologist and intensivist. J Anesth. 2017;31(3):413-423.
17. Viskin S, Postema PG, Bhuiyan ZA, et al. The response of the QT interval to standing: a bedside test for diagnosing long QT syndrome. J Am Coll Cardiol. 2010;55(18):1955-1961.
18. Viskin S, Rosso R. Exercise and the long QT syndrome: beyond the diagnosis. Heart Rhythm. 2010;7(6):758-760.
19. Wilde AAM, Amin AS. Clinical spectrum of SCN5A mutations: long QT syndrome, Brugada syndrome, and cardiomyopathy. J Cardiovasc Electrophysiol. 2018;29(5):749-759.
20. Zhou X, Bueno-Orovio A, Schilling RJ, Kirkby C, Denning C, Rajamohan D, Burrage K, Tinker A, Rodriguez B, Harmer SC. Investigating the complex arrhythmic phenotype caused by the gain-of-function mutation KCNQ1-G229D. Front Physiol. 2019;10:259.