Long QT Syndrome

Definitions

• Long QT syndrome (LQTS): a ventricular electrical disorder characterized by delayed myocardial repolarization and demonstrated as prolonged QT interval on electrocardiogram (ECG)
• QT interval: reflects the average duration of a ventricular action potential
• Normal QT interval:
  • On average: 400–440 milliseconds
  • After puberty, women tend to have a longer QT interval than men.
• Prolonged QT interval:
  • Males:
    • Normal: ≤ 430 milliseconds
    • Borderline prolonged QT interval: 431–450 milliseconds
    • Prolonged QT interval: > 450 milliseconds
  • Females:
    • Normal: ≤ 450 milliseconds
    • Borderline prolonged QT interval: 451–470 milliseconds
    • Prolonged QT interval: > 470 milliseconds
• Torsades de pointes:
  • A life-threatening arrhythmia associated with LQTS
  • Form of polymorphic ventricular tachycardia
  • Caused by early after-depolarizations
  • Irregular QRS complexes twisting around the isoelectric line (torsade de pointes = “twisting of points”)
  • Rate of 160–250/min
  • Often terminates spontaneously, but can lead to sudden cardiac death

Etiology

Congenital long QT syndrome

Pathophysiology:

• Defects in genes coding for ion channels (i.e., cardiac channelopathies)
  • Change in flow of positive ions affects repolarizing current in cardiomyocytes → prolongs the action potential (QT prolongation) → leads to early after-depolarization →  increased risk of torsades de pointes 
  • These genetic mutations account for 80% of LQTS cases: 
    • Loss-of-function mutations in KCNQ1-encoded and KCNH2-encoded  potassium channels: prolong action potential duration by reducing K efflux
    • Gain-of-function mutations in the SCN5A-encoded sodium channels: prolong action potential duration by the contribution of increased late sodium currents (which raises Na [sodium] influx)
• Sympathetic innervation of the heart:
  • A trigger for torsades de pointes is a surge in sympathetic tone (such as an extreme emotional event).
  • Stimulation of left stellate ganglion prolongs the QT interval 
  • Not found in acquired LQTS

Types of congenital LQTS:

1. Type 1 is the most common congenital form.
   • Up to 45% of LQTS cases
   • Defect in KCNQ1 gene
2. Type 2
   • Up to 40% of LQTS cases
   • Defect in KCNH2 gene
3. Type 3
   • Up to 10% of LQTS cases
   • Defect in SCN5A gene

Variety of associated conditions:

• Romano-Ward syndrome: 99% of cases; congenital LQTS without extracardiac manifestations (autosomal dominant)
• Jervell and Lange-Nielsen syndrome: congenital LQTS + sensorineural hearing loss (autosomal recessive)
• Anderson-Tawil syndrome: congenital LQTS + periodic paralysis
• Timothy syndrome: congenital LQTS + cutaneous syndactyly + autism

Acquired long QT syndrome

• Iatrogenic/pharmacologic: 
  • Most common cause
  • LQTS caused by blocking potassium outflow during the rapid repolarization phase:
    • Antiarrhythmic drugs
    • Antibiotics (macrolides, fluoroquinolones, antifungals, HIV antiretroviral drugs, antimalarial drugs)
    • Antihistamines (older nonsedating antihistamines, e.g., terfenadine)
    • Opioids (methadone, fentanyl)
    • Psychotropic agents (antidepressants, antipsychotics)
    • Gastric motility drugs (cisapride), antiemetics (ondansetron)
    • Antineoplastics
    • Beta-2 agonists
    • Diuretics (due to resultant electrolyte abnormalities)
• Metabolic disorders:
  • Electrolyte disturbances: hypokalemia, hypocalcemia, hypomagnesemia
  • Hypothyroidism
  • Anorexia nervosa, starvation (due to resultant electrolyte abnormalities)
• Bradyarrhythmias:
  • Sinus node dysfunction
  • Atrioventricular (AV) block (2nd or 3rd degree)
• Other: 
  • Myocardial infarction (MI)
  • Intracranial disease 
  • HIV infection 
  • Hypothermia
  • Toxic exposure (e.g., organophosphates)

Clinical Manifestations

Congenital long QT syndrome

• Often diagnosed in the first 3 decades of life
• Most commonly asymptomatic
  Diagnosis may be made:
  • When a patient seeks medical attention after a cardiac event in a family member
  • As an incidental finding in an ECG done for another indication
• Those with symptoms present with:
  • Syncope
  • Syncope followed by seizure (may be misdiagnosed as primary seizure disorder)
  • Sudden cardiac arrest (SCA)
  • In rare cases, the sentinel event is sudden cardiac death (SCD).
• LQTS type 1: 
  • Cardiac events preceded by exercise (62% of events) or stress
  • Swimming is a highly specific trigger!
• LQTS type 2:
  • Arrhythmia after an extreme emotional event, exercise, or auditory stimuli (sudden noise or alarm/telephone ringing)
  • Postpartum cardiac event: almost exclusively in LQTS 2
  • Cardiac events can also occur at rest or during sleep.
• LQTS type 3
  • The majority of cardiac events occur during rest or sleep.

Acquired long QT syndrome

• Symptoms are only present with an episode of arrhythmia.
• Symptoms vary with the rate and duration of torsades de pointes as well as with comorbidities:
  • Palpitations
  • Light-headedness or presyncope
  • Syncope 
  • Sudden cardiac arrest

Diagnosis

The diagnosis of long QT syndrome can be made via an ECG of the patient and/or 1st-degree relatives.

ECG findings

• Prolonged QTc (corrected QT interval)
  • The QT interval needs to be “corrected” to account for varying heart rates and is often automatically reported as the QTc.
  • Correction formula: QTc = QT interval ÷ √RR interval (in sec)
  • QTc interval > 450 ms in males
  • QTc interval > 470 ms in females
• LQTS can degenerate into fatal arrhythmias, especially torsades de pointes:
  • Short-lived but can have multiple successive episodes
  • Can progress to ventricular fibrillation
  • ECG findings include:
    • Prolonged QTc in last sinus beat preceding onset of arrhythmia
    • Tachycardia of 160–250/min
    • Wide QRS complexes (> 120 ms) with QRS axis rotating over a sequence of 5–20 beats
    • Irregular RR interval
• Ambulatory ECG monitoring: may provide corroborative information for suspected cases of congenital LQTS

Exercise testing

• To assess exercise-associated arrhythmias
• Check QT responses (exercise and recovery) and changes in T wave
• Variable response with type of congenital LQTS
• QTc > 470 ms at 2–5 minute recovery is suggestive of LQTS 1 (where cardiac events commonly occur during exercise)

Genetic analysis

• For intermediate and highly suspicious cases of congenital LQTS based on clinical presentation, family history, and ECG
• For asymptomatic patients with serial ECGs showing QTc > 460 ms

Additional tests

• Medication review
• Laboratory tests (metabolic panel, thyroid-stimulating hormone [TSH])
• Other cardiac workup based on probable cause (myocardial perfusion, echocardiogram)

Management

Congenital LQTS

• Reduce the risk of fatal arrhythmias:
  • Avoid QT-prolonging drugs
  • Electrolyte repletion
  • Avoid triggers of arrhythmia (swimming/exercise, emotional distress, noise; LQTS specialist consult for sports participation recommended)
• First-line medications: beta-blockers (propranolol or nadolol)
• Left cardiac sympathetic denervation:
  • Rarely performed
  • May work in some patients who do not respond to or cannot tolerate beta-blockers
  • Not curative; high-risk patients will still need an implantable cardioverter-defibrillator (ICD)
• Recurrent symptoms despite medical therapy warrant placement of an ICD.

Acquired LQTS

• Correct treatable medical causes quickly (e.g., electrolyte abnormalities and metabolic disturbances)!
• Remove the offending drug.

In the setting of torsades de pointes

• Hemodynamically stable patients:
  •  IV magnesium sulfate, cardiac monitoring
  • Overdrive pacing: for those not responsive to IV magnesium
• Hemodynamically unstable patients:
  • Defibrillation
  • IV magnesium sulfate

Clinical Relevance

Predisposing factors

The following medical conditions may commonly predispose QT prolongation:

• Hypothyroidism: the deficiency of T3 and T4. Hashimoto’s disease (autoimmune thyroiditis) is the leading cause of hypothyroidism in non-iodine deficient regions. Hypothyroidism is diagnosed by the estimation of TSH and free T4. It is treated by the administration of synthetic T4.
• Hypokalemia: plasma potassium < 3.5 mEq/L. Risk factors for hypokalemia include aging, poor dietary intake, diuretic use, and gastrointestinal losses. 
• Hypocalcemia: low serum ionized calcium levels. Calcium levels are regulated by the parathyroid hormone (PTH), which is secreted by the parathyroid gland. The presentation of patients with hypocalcemia can range from asymptomatic to life-threatening dysrhythmias.

Differential diagnosis

The following conditions may be included in a differential diagnosis for prolonged QT interval:

• Vasovagal syncope: a drop in blood pressure resulting in poor blood and oxygen flow to the brain that results in temporary loss of consciousness. 
• Myocardial infarction: obstruction of coronary arteries resulting in decreased blood supply to the myocardium. The typical presentation of MI is chest pain, shortness of breath, and diaphoresis. Patients may have syncope or sudden death.

Complications

Untreated QT prolongation may evolve into the following complications:

• Torsades de pointes: a specific form of polymorphic ventricular tachycardia in patients with a long QT interval. It is characterized by rapid and irregular QRS complexes, which appear to be twisting around the baseline.
• Ventricular tachycardia: a group of arrhythmias with heart rate > 100/min that originates from within the ventricle. There are 3 main types of ventricular tachyarrhythmias: ventricular fibrillation, monomorphic ventricular tachycardia, and polymorphic ventricular tachycardia. 
• Cardiac arrest: the sudden complete cessation of cardiac activity with hemodynamic collapse. Cardiac rhythms known to produce a pulseless cardiac arrest are shockable rhythms (ventricular fibrillation, pulseless ventricular tachycardia) and non-shockable rhythms (pulseless electrical activity, asystole). Rapid identification and intervention are critical to saving a patient’s life.