What are the causes of QT interval prolongation?

From the Guidelines

QT prolongation is most commonly caused by medications, electrolyte abnormalities, and certain medical conditions, with the most recent and highest quality evidence suggesting that medications such as antiarrhythmics, antibiotics, antipsychotics, antidepressants, and antiemetics are major contributors to QT prolongation 1. The causes of QT interval prolongation can be multifactorial, including:

• Medications:
  • Antiarrhythmics (amiodarone, sotalol, procainamide)
  • Certain antibiotics (macrolides like azithromycin, fluoroquinolones like ciprofloxacin)
  • Antipsychotics (haloperidol, quetiapine)
  • Antidepressants (citalopram, escitalopram)
  • Antiemetics (ondansetron)
• Electrolyte disturbances:
  • Hypokalemia (low potassium)
  • Hypomagnesemia (low magnesium)
  • Hypocalcemia (low calcium)
• Medical conditions:
  • Congenital long QT syndrome
  • Structural heart disease
  • Hypothyroidism
  • Bradycardia According to the 2017 AHA/ACC/HRS guideline for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death, QT-prolonging medications should not be used in patients with long QT syndrome unless there is no suitable alternative, and careful monitoring of the QTc during therapy is recommended 1. The underlying mechanism involves delayed repolarization of cardiac cells, specifically affecting potassium channels that regulate the heart's electrical recovery phase. It is essential to correct electrolyte abnormalities, review and potentially modify medications, and monitor cardiac rhythm in high-risk patients to prevent torsades de pointes, a potentially fatal ventricular arrhythmia associated with QT prolongation.

From the FDA Drug Label

In post marketing experience, there were cases reported of QT prolongation in patients who overdosed on quetiapine [see OVERDOSAGE (10. 1)] , in patients with concomitant illness, and in patients taking medicines known to cause electrolyte imbalance or increase QT interval [see DRUG INTERACTIONS (7.1)] Prolonged cardiac repolarization and QT interval, imparting a risk of developing cardiac arrhythmia and torsades de pointes, have been seen in treatment with macrolides, including azithromycin Erythromycin has been associated with prolongation of the QT interval and infrequent cases of arrhythmia

The causes of QT interval prolongation include:

• Overdose of certain medications, such as quetiapine 2
• Concomitant illness 2
• Medicines known to cause electrolyte imbalance or increase QT interval, such as certain antibiotics 2
• Macrolide antibiotics, such as azithromycin 3 and erythromycin 4
• Electrolyte imbalance, such as hypokalemia or hypomagnesemia 2, 3, 4
• Congenital long QT syndrome 3
• Bradycardia or uncompensated heart failure 3
• Class IA or Class III antiarrhythmic agents 2, 3, 4

From the Research

Causes of QT Interval Prolongation

The QT interval can be prolonged due to various factors, including:

• Drug-induced QT interval prolongation, which can be caused by a wide array of drugs, including antipsychotic drugs, antiarrhythmic medications, and other medications 5, 6, 7, 8
• Genetic variation, which can affect the pharmacokinetics and pharmacodynamics of drugs, increasing the risk of QT interval prolongation 6, 8
• Congenital long QT syndrome, which is a rare monogenic disorder caused by mutations in ion channel subunits or regulatory protein coding genes 8
• Acquired QT prolongation, which can be caused by various factors, including hypokalemia, hypomagnesemia, bradycardia, increased age, female sex, congestive heart failure, and polymorphisms of genes coding ion channels or enzymes involved in drug metabolism 7, 8
• External triggers, such as hypothermia therapy and exposure to antiarrhythmic medications, which can cause QT interval prolongation immediately following cardiac arrest 9

Risk Factors for QT Interval Prolongation

Several risk factors have been identified for QT interval prolongation, including:

• Use of QT prolonging drugs, which is the most frequent cause of acquired QT prolongation 5, 6, 7, 8
• Genetic variants that potentiate the QT prolonging effect of drugs 6, 8
• Pharmacokinetic interactions, which can involve drugs that are metabolized by cytochrome P450 enzymes 6, 8
• Pharmacodynamic gene-drug interactions, which can be due to genetic variants that affect the pharmacodynamics of drugs 6, 8
• Ethnicity, with Caucasians being more sensitive to drug-induced QT interval prolongation than other ethnicities 6
• Female sex, which is a risk factor for QT interval prolongation 7, 8
• Increased age, which is a risk factor for QT interval prolongation 7, 8
• Congestive heart failure, which is a risk factor for QT interval prolongation 7, 8
• Polymorphisms of genes coding ion channels or enzymes involved in drug metabolism, which can affect the pharmacokinetics and pharmacodynamics of drugs 7, 8