Long QT syndrome (inherited)

References: Circulation 2014, HRS/EHRA/APHRS 2013 guidelines

Clinical presentation

  • Symptoms:
    • Cardiac arrest / sudden death before age 40
    • Syncope (often misdiagnosed as seizures due to twitching)
  • EKG
    • Prolonged QTc
    • T-wave alternans (marker of high cardiac electrical instability)
  • Arrhythmia triggers, specific to type (not always)
    • LQT1 = Exercise (especially swimming) or emotional stress
    • LQT2 = Sudden noise (esp on waking) or at rest
    • LQT3 = Rest or sleep

DDx

  • Inherited
  • Acquired (secondary causes)
    1. Drugs
    2. Lyte abnormalities (K, Mg, Ca)
    3. CNS event
    4. Ischemia
    5. Hypothyroid
    6. Hypothermia

Investigations

  • Goals: 
  • 12-lead EKG
  • +/- standing test, exercise stress test, or epinephrine challenge to identify concealed QTc prolongation
  • Echo to R/O structural heart disease
  • Genetic testing +/- EKG/mutation cascade testing

Diagnostic criteria

  • LQTS risk score 3.5 or more after R/O secondary causes of QT prolongation
    • Hx
      • Syncope: With stress (2), without stress (1)
      • Congenital deafness (0.5)
    • FHx
      • Family member with LQTS (1)
      • Sudden death in family member >30 y with no identifiable cause (0.5)
    • EKG
      • QTc >480 msec (3), 460-470 msec (2), 450 msec (male; 1)
      • TdP (2)
      • T-wave alternans (1)
      • Notched T-wave in 3 leads (1)
      • Low HR for age (0.5)
  • Presence of unequivocally pathogenic mutation in a LQTS gene
  • QTc (Bazett's formula) 500 msec or greater in at least 2 12-lead EKGs (R/O secondary causes of QT prolongation)
  • QTc 480-499 msec + hx of unexplained syncope in absence of a pathogenic mutation

Prognosis

  • Strongly associated with underlying cause
  • Factors associated with greater risk of cardiac events:
    • Sex
      • Males at higher risk during childhood (QTc shortens by ~20 msec with puberty)
      • Females at higher risk from adolescence onward
    • Syncope/cardiac arrest before age 7 (esp before 1 y)
    • Hx of syncope
    • EKG
      • QT interval >500 msec (esp >600 msec)
      • T-wave alternans
    • Genotype (mean QT interval, risk of cardiac event, cardiac event by 40 y)
      • LQT1 (~465 msec, 30%, 0.3%/y)
      • LQT2 (~490 msec, 46%, 0.6%/y)
      • LQT3 (~495 msec, 42%, 0.56%/y)
      • Mutation-positive individuals with no QTc-prolongation @ rest have ~10% risk of arrhythmia before age 40 in the absence of tx

Management

All

  1. Avoid QTc-prolonging drugs
  2. Correct electrolyte abnormalities (esp K, Mg)
  3. Beta-blockers
    • Indications
      • Hx of syncope or documented VT/VF
      • Asymptomatic, QTc 470 msec or greater
      • Preferred: Nadolol or propranolol extended-release
      • Also consider in genetically-diagnosed LQTS with no symptoms & QTc <470 msec
  4. Cardiac sympathectomy
    • Indications: Beta-blockers contraindicated or not effective in preventing syncope/arrhythmia; ICD contraindicated/refused
  5. ICD
    • Indications:
      • Hx of cardiac arrest
      • Recurrent syncope on beta-blocker
    • Not for 1o prevention in asymptomatic LQTS not tried beta-blocker (unless high-risk features)

Genotype-specific:

  • LQT1 or exercise-induced symptoms: Avoid vigorous exercise
  • LQT2: Avoid abrupt loud noises (e.g. alarm clock, phone ringing)
  • LQT3: Consider adding Na-channel blocker (e.g. mexiletine) for QTc >500 msec (if shortens QTc by >40 msec during monitored drug test)

Pathophysiology

  • LQTS typically displays autosomal-dominant Mendelian inheritance with variable penetrance (~25%); also rarely recessive inheritance with sensorineural deafness
  • Caused by mutations in potassium, sodium, or other ion channels
    • LQT1 = KCNQ1 gene mutation, resulting in abnormal I(ks) (slow K channel)
    • LQT2 = KCNH2 gene mutation, resulting in abnormal I(kr) (fast K channel)
    • LQT3 = SCN5A gene mutation, resulting in abnormal I(Na)
    • LQT1, 2, & 3 make up 92% of genetically-confirmed LQTS; 15-20% of LQTS patients have no known genetic mutation
    • LQT7 (Andersen-Tawil syndrome) = KCNJ2 mutation (also results in neuro-MSK symptoms)
  • Ion channel gene mutation -> increased transmural repolarization dispersion across myocardium -> triggers fluxes in transmembrane gradient -> early after depolarization (EAD) during phase 2/3 of action potential -> TdP