What is congenital long QT syndrome and how is it managed?

Congenital Long QT Syndrome: Comprehensive Overview

Definition and Epidemiology

Congenital Long QT Syndrome (LQTS) is a hereditary cardiac channelopathy characterized by prolonged ventricular repolarization (prolonged QT interval on ECG) that predisposes patients to life-threatening ventricular arrhythmias, particularly torsades de pointes, leading to syncope, cardiac arrest, and sudden cardiac death. 1

• Prevalence: Approximately 1 in 2,000 to 1 in 2,500 live births 1, 2
• Mean age at presentation: 14 years, though 4% of sudden deaths occur in the first year of life 1
• Annual mortality in untreated patients: 0.3-0.9% for sudden cardiac death; 5% for syncope 1
• Critical statistic: In 12% of LQTS patients, sudden death is the first manifestation of disease 1

Genetic Basis and Classification

Molecular Genetics

Mutations in 13 genes have been identified, with genetic testing detecting disease-causing mutations in 75% of cases. 1 Three major genes account for 90% of genetically positive cases 1, 3:

• KCNQ1 (LQT1): Approximately 50% of genotyped patients; affects potassium current IKs 1, 2
• KCNH2 (LQT2): Affects potassium current IKr 1
• SCN5A (LQT3): Affects sodium channels 1

Clinical Subtypes

Three main categories exist based on inheritance pattern and associated features: 1

1. Autosomal Dominant LQTS (Romano-Ward syndrome):

   • Prevalence: 1 in 2,500 1
   • Includes LQT1-6 and LQT9-13 1
   • Isolated QT prolongation without extracardiac features 1

2. Autosomal Dominant LQTS with Extracardiac Manifestations:

   • LQT7 (Andersen-Tawil syndrome): Prolonged QT with prominent U waves, polymorphic/bidirectional VT, facial dysmorphisms, and periodic paralysis 1
   • LQT8 (Timothy syndrome): Prolonged QT, syndactyly, cardiac malformations, autism spectrum disorder, and dysmorphisms 1

3. Autosomal Recessive LQTS (Jervell and Lange-Nielsen syndrome):

   • Extremely prolonged QT interval with congenital deafness 1
   • Homozygous or compound heterozygous KCNQ1 mutations 2
   • Particularly severe prognosis 2

Important Genetic Considerations

• 30% of cases are "de novo" mutations with unaffected parents and no family history 1, 3
• Low penetrance exists: Gene carriers may have normal QT intervals and no clinical phenotype 1, 3
• 25-30% of genetically confirmed LQTS patients have QTc <440 ms 3
• A normal QT in parents does NOT rule out familial LQTS 1

Diagnostic Criteria

Electrocardiographic Thresholds

The European Society of Cardiology 2015 guidelines establish the following diagnostic criteria: 1

• QTc ≥480 ms on repeated ECGs (in absence of secondary causes) OR a Schwartz score >3 establishes clinical diagnosis 1
• QTc ≥500 ms is considered unequivocal LQTS regardless of family history or symptoms 1, 3
• QTc ≥460 ms with unexplained syncope is sufficient for diagnosis 1, 3

Neonatal-Specific Approach

For neonates with QTc >440 ms (upper limit of normal): 1, 3

1. Exclude secondary causes: Electrolyte disturbances (hypocalcemia <7.5 mg/dL, hypokalemia, hypomagnesemia), QT-prolonging drugs (macrolide antibiotics, cisapride, trimethoprim), maternal anti-Ro/SSA antibodies, CNS abnormalities 1

2. Obtain detailed family history: Early sudden death, fainting spells, seizures/epilepsy, congenital deafness 1, 3

3. Repeat ECG after a few days to confirm the finding 1, 3

4. If second ECG shows QTc ≥500 ms: The infant is very likely affected and should be treated immediately 3

5. If first QTc was 470-499 ms and second ECG is normal: Plan third ECG after 1-2 months 1

6. If first QTc was <470 ms and second ECG is normal: Dismiss the case 1

Comprehensive Diagnostic Workup

Essential components include: 3

• Serial 12-lead ECGs with manual QT measurement (computer-derived values are only 90-95% accurate) 1
• Detailed multi-generation family history specifically asking about sudden death, syncope, seizures, deafness 3
• T-wave morphology analysis: Notched T-waves in lateral precordial leads (where second portion amplitude exceeds first) may indicate LQT2 even without overt QT prolongation 1, 3
• 24-hour Holter monitoring to assess QT variability and arrhythmias 3
• Exercise stress testing to evaluate QT response to adrenergic stimulation 1
• Genetic testing and counseling (Class I recommendation) 3, 4

Measurement Technique

Accurate QTc measurement requires: 1

• Use Bazett's formula: QTc = QT/√RR (RR in seconds) 1
• Measure in leads II and V5 for best T-wave delineation 1
• Use "Teach-the-Tangent" or "Avoid-the-Tail" method to identify T-wave end 1
• Exclude low-amplitude U waves from measurement 1
• For heart rate <50 bpm: Repeat ECG after mild aerobic activity 1
• For heart rate >90 bpm: Repeat ECG after additional rest 1
• With sinus arrhythmia: Use average QT and average RR intervals 1

Risk Stratification

Highest Risk Features

The following identify patients at highest risk for sudden cardiac death: 1, 3

• Cardiac arrest survivors: Relative risk 12.9 for recurrent arrest 1
• QTc ≥500 ms (upper quartile among affected individuals) 1
• QTc approaching 600 ms 3
• Symptomatic patients (syncope, near-syncope) 1
• T-wave alternans 3
• 2:1 AV block secondary to QT prolongation 3
• Congenital deafness (Jervell and Lange-Nielsen syndrome) 1, 3
• Carriers of two mutations 1
• Timothy syndrome 1, 2

Genotype-Specific Risk

Risk varies significantly by genetic subtype: 1, 3

• LQT2 females with QTc >500 ms: Particularly high-risk group 1, 3
• LQT3 males: High risk irrespective of QT interval duration 1
• LQT2 patients with pore region mutations: Higher risk than other KCNH2 mutations 1
• Women with LQT2: Increased risk during 9-month postpartum period 1

Genotype-Specific Triggers

Cardiac events are triggered differently by genotype: 1

• LQT1: Events during exercise, particularly swimming 1
• LQT2: Events during rest, emotion, or acoustic stimuli 1
• LQT3: Events during sleep or rest 1

Silent Mutation Carriers

Asymptomatic gene carriers have modest but real risk: 1

• 10% risk of cardiac events between birth and age 40 years 1
• Beta-blockers should be considered even in asymptomatic carriers 1

Management Strategy

First-Line Therapy: Beta-Blockers

Beta-blockers are the cornerstone of treatment and must be initiated in all diagnosed patients, even if asymptomatic, because sudden death can be the first manifestation. 1, 4

• Efficacy: 80% reduction in recurrent events in symptomatic patients; >75% reduction in adverse cardiac events 1, 4
• Genotype-specific efficacy: 1
  • Highly effective in LQT1 1
  • Incomplete protection in LQT2 and LQT3 1
• Preferred agent for LQT2: Nadolol shows superior efficacy 4
• Treatment must continue lifelong because most patients become symptomatic during childhood or adolescence 1

Lifestyle Modifications

All patients must adhere to the following: 3, 4

• Avoid all QT-prolonging medications (check www.crediblemeds.org before prescribing any new drug) 3, 4
• Correct electrolyte abnormalities promptly (potassium, magnesium, calcium) 3
• Restrict strenuous or competitive exercise 3
• Avoid genotype-specific triggers: Swimming for LQT1, loud noises/alarms for LQT2 1

Escalation of Therapy

If beta-blockers fail to prevent cardiac events or are not tolerated: 1, 4

1. Left cardiac sympathetic denervation (LCSD) should be performed without hesitation 1
2. Implantable cardioverter-defibrillator (ICD) should be considered 1, 4
3. Additional medications may be added 1
4. Pacemaker therapy in selected cases 1

ICD Indications

ICD implantation is recommended in: 1

• Cardiac arrest survivors (Class I recommendation) 1
• Patients with recurrent syncope despite adequate beta-blocker therapy 1

ICD may be considered (prophylactically) in high-risk patients: 1

• Women with LQT2 and QTc >500 ms 1
• Patients with QTc >500 ms and signs of electrical instability 1
• High-risk genetic profiles (two mutations, Jervell and Lange-Nielsen, Timothy syndrome) 1
• Asymptomatic carriers of KCNH2 or SCN5A mutations with QTc >500 ms 1

LQT3-Specific Therapy

For LQT3 patients with QTc >500 ms: 1

• Sodium channel blockers (mexiletine or ranolazine) may be considered as add-on therapy to shorten the QT interval 1

Monitoring Requirements

Ongoing surveillance includes: 3, 4

• Regular ECG monitoring to assess QTc changes over time and adequacy of beta-blockade with exertion 3, 4
• 24-hour Holter monitoring for electrical instability 3
• Clinical assessment for symptoms (syncope, palpitations, dizziness) 4
• Monitor for bradycardia (heart rate <40 bpm) even if asymptomatic 4

Family Screening and Genetic Testing

Comprehensive family evaluation is mandatory: 3

• All first-degree relatives require ECG screening 3
• Genetic counseling and testing (Class I recommendation for probands) 3, 4
• Cascade genetic testing of family members once proband mutation is identified 3
• Family screening helps identify affected members even with normal QT intervals due to low penetrance 3

Prognosis

With appropriate diagnosis and treatment, prognosis is generally good. 2

Exceptions with poor prognosis: 2

• Timothy syndrome patients 2
• Jervell and Lange-Nielsen syndrome with KCNQ1 mutations 2
• LQT3 patients with 2:1 AV block and very early arrhythmias 2

Critical Pitfalls to Avoid

• Never dismiss borderline QT prolongation (440-479 ms) in the presence of syncope or positive family history 3
• Never assume normal parental ECGs rule out familial LQTS due to low penetrance and de novo mutations 1, 3
• Never delay treatment in diagnosed patients, even if asymptomatic, because sudden death can be the first manifestation 1
• Never rely solely on computer-generated QTc values; always manually confirm measurements 1
• Never prescribe new medications without checking QT-prolonging potential at www.crediblemeds.org 3, 4
• Never discontinue beta-blockers even if patients become asymptomatic, as most become symptomatic later in life 1