What are the congenital and acquired causes of a prolonged QT interval?

Causes of Prolonged QT Interval

Prolonged QT interval results from two major categories: congenital channelopathies caused by mutations in cardiac ion channel genes (primarily KCNQ1, KCNH2, and SCN5A) and acquired causes including medications, electrolyte abnormalities, and structural heart disease, with drug-induced prolongation being the most common and preventable etiology in clinical practice. 1, 2

Congenital Causes

Genetic Long QT Syndrome (LQTS)

• Congenital LQTS is a genetic channelopathy affecting approximately 1 in 2,000 to 1 in 5,000 individuals, caused by mutations in genes encoding cardiac potassium or sodium channels. 1, 3

• The three major LQTS genes account for approximately 75% of all cases: 1

  • KCNQ1 (LQT1) - encodes IKs potassium channel α-subunit, causing loss of function
  • KCNH2 (LQT2) - encodes IKr potassium channel α-subunit, causing loss of function
  • SCN5A (LQT3) - encodes Nav1.5 sodium channel α-subunit, causing gain of function with persistent late sodium current

• Approximately 30% of congenital LQTS cases arise from de novo mutations, meaning unaffected parents and no family history, which is critical to recognize since absence of family history does not exclude the diagnosis. 1, 2

• Low penetrance exists in LQTS, meaning gene carriers may not show clinical phenotype and may have normal QT intervals, so a normal QT in parents does not rule out familial LQTS. 1

• The remaining 20% of congenital LQTS cases remain genotype-negative despite comprehensive genetic testing. 1

Neonatal-Specific Congenital Causes

• Neonates born to mothers with autoimmune diseases who are positive for anti-Ro/SSA antibodies may show transient QT prolongation, sometimes with QTc values exceeding 500 ms, which typically disappears by the sixth month of life concomitantly with antibody clearance. 1, 2

Acquired Causes

Medication-Induced QT Prolongation

Drug-induced QT prolongation is the most frequent and preventable cause in clinical practice, with nearly all implicated drugs blocking the IKr potassium current. 2, 4

• Antiarrhythmic drugs: 2

  • Class IA agents: quinidine, procainamide, disopyramide
  • Class III agents: sotalol, dofetilide, ibutilide (require monitoring 4-5 hours post-administration)

• Antibiotics: 1, 2

  • Macrolides: erythromycin, clarithromycin, spiramycin
  • Trimethoprim

• Psychiatric medications: 2

  • Antipsychotics: thioridazine, pimozide

• Gastrointestinal agents: 1

  • Prokinetics: cisapride (blocks IKr current)

• Chemotherapy agents: 2

  • Arsenic trioxide (26-93% incidence of QT prolongation)
  • Vandetanib

• Opioid analgesics: 2

  • Methadone causes significant dose-dependent QT prolongation
  • Buprenorphine causes far less QT prolongation than methadone

• Other non-cardiac agents: 2

  • Antihistamines
  • Serotonin agonists (triptans)

Electrolyte Abnormalities

Electrolyte disturbances are common correctable causes that must be aggressively addressed: 1, 2

• Hypocalcemia (< 7.5 mg/dL) - produces distinctive lengthening of the ST segment and potentiates drug-induced QT prolongation 1, 2

• Hypokalemia - decreases T wave amplitude, increases U wave amplitude, and is particularly dangerous in women; often encountered in infants with vomiting or diarrhea and in patients on diuretics 1, 2

• Hypomagnesemia - decreases T wave amplitude and increases U wave amplitude, commonly seen with gastrointestinal losses 1, 2

Cardiac and Structural Causes

• Myocardial ischemia - both acute and chronic ischemia (including previous myocardial infarcts) prolong QT and predispose to sudden cardiac death, accounting for 15% of all deaths 2

• Left ventricular hypertrophy - increases QT prolongation risk 2

• Heart failure and low left ventricular ejection fraction - contribute to QT prolongation 2

• Inherited cardiomyopathies - hypertrophic cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, and dilated cardiomyopathy increase sudden cardiac death risk 2

• Structural congenital heart disease and surgical sequelae - predispose to arrhythmia development 2

Bradyarrhythmias

• Bradycardia (including sinus bradycardia and heart block) prolongs QTc and predisposes to torsades de pointes. 2

Central Nervous System Abnormalities

• CNS abnormalities can produce QT prolongation and T wave inversion. 1

Patient-Specific Risk Factors

Certain patient characteristics amplify the risk of QT prolongation and torsades de pointes:

• Female sex - women have inherently longer QT intervals post-puberty and are at higher risk for drug-associated QT effects 2, 4

• Older age - increases susceptibility to drug-associated QT effects 2

• Concomitant use of multiple QT-prolonging drugs - creates additive risk 2

• Combination with metabolic inhibitors - particularly CYP3A4 inhibitors like verapamil increase drug concentrations and QT prolongation risk 2

• High drug concentrations - increase QT prolongation risk 2

• Baseline prolonged QT interval - predisposes to drug-induced torsades de pointes 2

Critical Warning Signs

ECG indicators that signal imminent torsades de pointes risk when QTc is prolonged include: 2

• Enhanced U waves
• T-wave alternans
• Polymorphic ventricular premature beats or couplets
• Nonsustained polymorphic ventricular tachycardia
• Sudden bradycardia or long pauses
• Exaggerated QT prolongation with T-U wave distortion after a pause

A QTc ≥500 ms or increase ≥25% from baseline mandates immediate discontinuation of offending agents and continuous monitoring until washout occurs. 2

Common Pitfalls to Avoid

• Do not assume absence of family history excludes congenital LQTS - 30% of cases are de novo mutations 1, 2

• Do not rely on parental ECGs to rule out familial LQTS - low penetrance means gene carriers may have normal QT intervals 1

• Do not overlook diuretic-induced hypokalemia - this creates compounded risk beyond the underlying cardiac condition and requires vigilant electrolyte monitoring 2

• Always check www.crediblemeds.org before prescribing medications - to identify QT-prolonging drugs 5, 2

• Do not ignore genotype-positive individuals with normal resting QTc - 25-36% still have adverse events 5