Long QT syndrome

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.