What causes non-hereditary QT (QT interval) prolongation?

Causes of Non-Hereditary QT Prolongation

Non-hereditary QT prolongation is most commonly caused by medications, electrolyte abnormalities, and various medical conditions that affect cardiac repolarization, all of which can potentially lead to life-threatening arrhythmias such as torsades de pointes. 1

Medication-Related Causes

Medications are the most frequent cause of acquired QT prolongation. Common drug classes include:

High-Risk Medications

• Antiarrhythmic drugs:
  • Class IA: Quinidine, disopyramide, procainamide 1, 2
  • Class III: Sotalol, dofetilide, ibutilide, amiodarone 1, 3
• Antipsychotics: Chlorpromazine, haloperidol, thioridazine, pimozide 1, 4
• Antiemetics: Domperidone, droperidol 1
• Antibiotics: Macrolides (erythromycin, clarithromycin), fluoroquinolones, pentamidine 1
• Opioid dependence agents: Methadone 1
• Prokinetic agents: Cisapride 1

Mechanism of Drug-Induced QT Prolongation

Most QT-prolonging drugs act by blocking hERG-encoded potassium channels (IKr), which delays ventricular repolarization 1. Some medications may also modify sodium channels, contributing to QT prolongation 5.

Electrolyte Abnormalities

Electrolyte disturbances are common causes of QT prolongation:

• Hypokalemia: Decreases T wave amplitude and increases U wave amplitude 1
• Hypomagnesemia: Often seen in patients with diarrhea or vomiting 1
• Hypocalcemia: Produces distinctive lengthening of the ST segment 1

Medical Conditions

Several medical conditions can cause or contribute to QT prolongation:

• Cardiac conditions:

  • Ischemic heart disease 1
  • Heart failure 1
  • Myocardial infarction 1
  • Left ventricular hypertrophy 1
  • Bradyarrhythmias 1

• Other medical conditions:

  • Central nervous system abnormalities 1
  • Thyroid disease (particularly hypothyroidism) 1
  • Renal failure 1
  • Hepatic failure 1
  • Autoimmune diseases with anti-Ro/SSA antibodies (in neonates) 1

Risk Factors for QT Prolongation and Torsades de Pointes

Several factors increase the risk of QT prolongation developing into torsades de pointes:

• Female sex 1
• Advanced age 1
• Recent conversion from atrial fibrillation 1
• Bradycardia 1
• Congestive heart failure 1
• High drug concentrations (often due to drug interactions) 1
• Concomitant use of multiple QT-prolonging drugs 1
• Rapid intravenous drug administration 1

Drug Interactions Contributing to QT Prolongation

Drug interactions can exacerbate QT prolongation through:

1. Pharmacokinetic interactions: Often involving drugs metabolized by cytochrome P450 enzymes 5

   • CYP3A4 inhibitors (e.g., verapamil, diltiazem) can increase levels of QT-prolonging drugs 3

2. Pharmacodynamic interactions: When multiple drugs with QT-prolonging effects are used together 1, 5

Clinical Approach to Suspected QT Prolongation

When QT prolongation is suspected:

1. Identify and discontinue offending agents if possible 1
2. Correct electrolyte abnormalities, particularly potassium and magnesium 1
3. Monitor cardiac rhythm for early detection of arrhythmias 1
4. Consider magnesium supplementation even when serum magnesium is normal 1
5. Consider temporary pacing for recurrent torsades de pointes 1

Important Considerations

• QT prolongation is a major risk factor for torsades de pointes, a potentially fatal ventricular arrhythmia 1
• Even drugs administered for conditions unrelated to cardiac diseases can cause QT prolongation 6
• The risk of torsades de pointes increases significantly when QTc exceeds 500 ms 1
• Patients with multiple risk factors require more careful monitoring when receiving QT-prolonging medications 1

By understanding these causes and risk factors, clinicians can better identify, monitor, and manage patients at risk for QT prolongation and its potentially life-threatening consequences.