Definition and Epidemiology
- Genetic abnormality of ventricular repolarization.
- Characterized by prolonged QT interval on surface electrocardiogram (ECG).
- Predisposes to life-threatening polymorphic ventricular tachycardia (torsades de pointes).
- Estimated incidence: 1 per 10,000 births to 1 in 2500-5000 individuals.
- Inheritance: Predominantly autosomal dominant (90% familial). Rare autosomal recessive forms exist.
Genetics and Classification
- Highly genetically heterogeneous. >600 mutations identified across 14 susceptibility genes.
- Major genes (KCNQ1, KCNH2, SCN5A) account for ~90% of confirmed genotype-positive cases.
- Approximately 15% of variance in overall LQTS susceptibility attributable to common genetic variation (polygenic architecture).
Major LQTS Genotypes
| Genotype | Gene | Chromosome Locus | Affected Ion Channel | Common Triggers | Frequency |
|---|---|---|---|---|---|
| LQT1 | KCNQ1 | 11p15.5 | IKs potassium channel alpha subunit (Loss of function) | Swimming, physical exertion, emotional stress | 35% |
| LQT2 | KCNH2 (HERG) | 7q35-36 | IKr potassium channel alpha subunit (Loss of function) | Auditory triggers (alarm clocks), postpartum period | 30% |
| LQT3 | SCN5A | 3p21-p24 | INa cardiac sodium channel alpha subunit (Gain of function/ increased late sodium current) | Sleep, rest | 10% |
Minor and Atypical Genotypes
- CALM1, CALM2, CALM3 (Calmodulin): Disrupts calcium/calmodulin-dependent inactivation of L-type calcium channels. Infantile/early childhood presentation. Severe bradycardia, atrioventricular (AV) block, severe QT prolongation.
- TRDN (Triadin): Autosomal recessive. Exercise-induced arrhythmias. Phenotypic overlap between LQTS and catecholaminergic polymorphic ventricular tachycardia (CPVT).
- CACNA1C: Timothy syndrome. Multisystem disorder (syndactyly, autism, immune deficiency) combined with severe LQTS.
- KCNJ2: Andersen-Tawil syndrome (LQT7). Skeletal/cardiac channelopathy. Prominent U-waves. Frequent ventricular ectopy and bidirectional VT. Variable QT prolongation.
- ANK2: Ankyrin-B syndrome. Sinus node dysfunction, conduction block, polymorphic VT, QT prolongation.
Associated Clinical Syndromes
- Romano-Ward Syndrome: Autosomal dominant inheritance. Isolated cardiac phenotype without extracardiac manifestations.
- Jervell and Lange-Nielsen Syndrome: Autosomal recessive inheritance. Associated with congenital sensorineural deafness. Caused by homozygous or compound heterozygous mutations in KCNE1 or KCNQ1.
Pathophysiology
- Action Potential Disruption: Prolongation of action potential results from net decrease in repolarizing current.
- Ionic Mechanism: Reduced outward potassium current (LQT1, LQT2) or increased inward late sodium/calcium current (LQT3) during phases 2 and 3.
- Arrhythmogenesis: Prolonged ventricular repolarization generates membrane potential oscillations called early after-depolarizations (EADs).
- Triggered Activity: Reopening of L-type calcium or sodium channels drives EADs. Triggered upstrokes initiate torsades de pointes (TdP).
Clinical Manifestations
- Syncope: Classic presentation. Brought on by exercise, fright, sudden startle (LQT1/LQT2), or during sleep (LQT3).
- Neurological/Nonspecific Symptoms: Seizures, presyncope, palpitations.
- Sudden Cardiac Arrest (SCA): Initial presentation in ~10% of cases.
- Catastrophic Outcomes: Sudden infant death syndrome (SIDS), drowning, intrauterine fetal demise.
- Concealed LQTS: Normal resting QTc (<440 ms). Found in up to 25% of genotype-positive individuals. Confers increased risk for aborted cardiac arrest and sudden death compared to genotype-negative relatives.
Diagnosis
Electrocardiographic (ECG) Findings
- QTc Calculation: Bazett's formula (QT interval divided by the square root of the preceding RR interval). Inaccurate at low heart rates.
- Diagnostic Thresholds: QTc >0.47 sec highly indicative; >0.44 sec suggestive. Manifest LQTS defined as QTc >470 ms in males or >480 ms in females. Normal QTc <0.45 sec.
- Morphological Abnormalities: T-wave alternans. Notched T waves in three leads.
- Rate Abnormalities: Low heart rate for age (sinus bradycardia).
Schwartz Diagnostic Score
Clinical tool estimating LQTS likelihood based on ECG, history, and family history.
| Category | Finding | Points |
|---|---|---|
| ECG Findings | QTc $\ge$ 480 ms | 3 |
| QTc 460–479 ms | 2 | |
| QTc 450–459 ms (males) | 1 | |
| QTc 4th minute recovery from exercise test $\ge$ 480 ms | 1 | |
| Torsades de pointes | 2 | |
| T-wave alternans | 1 | |
| Notched T-wave in 3 leads | 1 | |
| Low heart rate for age (<2nd percentile) | 0.5 | |
| Clinical History | Syncope with stress | 2 |
| Syncope without stress | 1 | |
| Congenital deafness | 0.5 | |
| Family History | Family member with definite LQTS | 1 |
| Unexplained sudden cardiac death below age 30 | 0.5 |
- Scoring Interpretation: $\le$ 1 point: Low probability. 1.5 to 3 points: Intermediate probability. $\ge$ 3.5 points: High probability.
Adjunctive Diagnostic Modalities
- Exercise Testing (CPET): Evaluates chronotropic response and QTc dynamics. Amplifies genotype-phenotype correlation.
- LQT1: QTc prolongs during exercise; remains prolonged throughout recovery.
- LQT2: QTc lengthens in early exercise; normalizes at higher heart rates.
- Holter Monitor: 24-hour ambulatory ECG to evaluate occult arrhythmias, T-wave alternans, and QT dynamics.
- Genetic Testing: Identifies pathogenic variant in ~80% of clinical cases. Essential for cascade screening of asymptomatic first-degree relatives.
Acquired/Secondary LQTS
- Electrolyte Derangements: Hypokalemia, hypocalcemia, hypomagnesemia.
- Metabolic/Nutritional: Starvation, anorexia nervosa, bulimia.
- Neurological: Central nervous system injury.
- Pharmacological Triggers:
- Antiarrhythmics: Amiodarone, sotalol, procainamide, flecainide, quinidine.
- Antimicrobials/Antifungals: Erythromycin, ketoconazole.
- Psychotropics: Risperidone, amitriptyline, methadone.
Management
Lifestyle Modifications & Prevention
- Medication Avoidance: Strict avoidance of QT-prolonging drugs (reference: crediblemeds.org).
- Trigger Avoidance: Swimming/diving (LQT1). Alarm clocks/sudden noises (LQT2).
- Hydration/Electrolytes: Replenishment during illness/activity. Avoid dehydration.
- Temperature Control: Avoid/treat hyperthermia, febrile illnesses, heat exhaustion.
- Sports Participation: Restriction historically recommended. Currently, participation considered after expert consultation, 3 months asymptomatic on targeted therapy, acquisition of personal AED, and established emergency action plan. LQT3 patients show minimal exercise risk.
Pharmacological Therapy
- Beta-Blockers: Mainstay of therapy. Decreases risk of sudden cardiac arrest.
- Indications: Recommended for all LQTS patients, including asymptomatic phenotype-negative gene carriers (unless contraindicated e.g., severe asthma).
- Agent Selection: Non-selective beta-blockers preferred. Nadolol or sustained-release propranolol superior to metoprolol/atenolol.
- Efficacy: Highly protective in LQT1 and LQT2. Less effective in LQT3.
- Sodium Channel Blockers: Mexiletine or flecainide. Decreases late sodium current. Shortens QT interval and reduces cardiac events specifically in LQT3.
Device and Surgical Therapy
- Implantable Cardioverter-Defibrillator (ICD):
- Class I Indication: Secondary prevention in patients with prior cardiac arrest.
- Class IIA Indication: Recurrent syncope despite optimal beta-blocker therapy.
- Contraindication: Asymptomatic patients without prior trial of beta-blocker therapy.
- Left Cardiac Sympathetic Denervation (LCSD):
- Reduces ventricular arrhythmia burden.
- Indicated for high-risk patients (especially LQT1).
- Utilized when ICD is contraindicated/refused, or when beta-blockers are ineffective or poorly tolerated.
- Permanent Pacing: Indicated in rare cases for drug-induced or intrinsic severe bradycardia preventing adequate beta-blockade.
Fetal and Neonatal Presentation
- Fetal Arrhythmias: High likelihood of ion channelopathy in unexplained fetal demise >20 weeks.
- Manifestations: Fetal bradycardia, 2nd-degree AV block, ventricular tachycardia.
- Characteristic Pattern: Alternating episodes of fetal tachycardia and bradycardia strongly suspect for LQTS.
- Diagnosis: Fetal magnetocardiography (fMCG) accurately assesses fetal rhythm and QT intervals.
- Neonatal ECG: Severe QT prolongation (>500 ms) with T-wave alternans pathognomonic. Requires prompt initiation of beta-blockade.