What causes prolonged QT (QT interval)?

From the Guidelines

Prolonged QT interval is most commonly caused by medications, electrolyte abnormalities, and genetic conditions, with the risk of adverse events increasing significantly when the QTc exceeds 500 ms, as evident in the 2018 guideline by the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society 1.

Causes of Prolonged QT Interval

The causes of prolonged QT interval can be broadly categorized into:

• Medications: Certain antiarrhythmics (amiodarone, sotalol), antibiotics (macrolides like azithromycin, fluoroquinolones like ciprofloxacin), antipsychotics (haloperidol, quetiapine), and antidepressants (citalopram, escitalopram) are known to cause QT prolongation, as listed in the 2006 ACC/AHA/ESC guidelines for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death 1.
• Electrolyte abnormalities: Hypokalemia, hypomagnesemia, and hypocalcemia are significant contributors to QT prolongation, with hypokalemia being a major risk factor for drug-induced torsades de pointes, as highlighted in the 2010 scientific statement from the American Heart Association and the American College of Cardiology Foundation 1.
• Genetic conditions: Congenital long QT syndrome is a genetic condition that affects cardiac ion channels, and other causes include structural heart disease, hypothyroidism, hypothermia, and bradycardia.

Management and Prevention

The management of patients with prolonged QT intervals should focus on monitoring electrolytes, reviewing medications, and genetic testing when appropriate, as well as avoiding the use of QT-prolonging medications unless there is no suitable alternative, and careful monitoring of the QTc during therapy is recommended 1. Key points to remember in the management and prevention of torsades de pointes include:

• Recognition of ECG risk factors for TdP, including marked QTc prolongation to >500 ms, marked QT-U prolongation and distortion after a pause, onset of ventricular ectopy and couplets, macroscopic T-wave alternans, or episodes of polymorphic ventricular tachycardia that are initiated with a short-long-short R-R cycle sequence.
• Treatment with intravenous magnesium, removal of the offending agent, and correction of electrolyte abnormalities and other exacerbating factors, including the prevention of bradycardia and long pauses with temporary pacing if necessary, as recommended in the 2010 scientific statement from the American Heart Association and the American College of Cardiology Foundation 1.

From the FDA Drug Label

QT Prolongation 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 Cases of torsades de pointes have been spontaneously reported during postmarketing surveillance in patients receiving azithromycin Providers should consider the risk of QT prolongation which can be fatal when weighing the risks and benefits of azithromycin for at-risk groups including: patients with known prolongation of the QT interval, a history of torsades de pointes, congenital long QT syndrome, bradyarrhythmias or uncompensated heart failure patients on drugs known to prolong the QT interval patients with ongoing proarrhythmic conditions such as uncorrected hypokalemia or hypomagnesemia, clinically significant bradycardia, and in patients receiving Class IA (quinidine, procainamide) or Class III (dofetilide, amiodarone, sotalol) antiarrhythmic agents. Elderly patients may be more susceptible to drug-associated effects on the QT interval.

The cause of QT prolongation can be:

• Macrolide antibiotics, such as azithromycin 2
• Drugs known to prolong the QT interval
• Uncorrected hypokalemia or hypomagnesemia
• Clinically significant bradycardia
• Class IA (quinidine, procainamide) or Class III (dofetilide, amiodarone, sotalol) antiarrhythmic agents
• Haloperidol 3, an antipsychotic drug
• Amiodarone 4, an antiarrhythmic medication
• Other conditions, such as congenital long QT syndrome, bradyarrhythmias, or uncompensated heart failure.

From the Research

Prolonged QT Interval Causes

• Prolonged QT interval can be caused by various factors, including the use of certain medications, such as antiarrhythmic agents and other cardiovascular drugs 5, 6.
• The risk of drug-induced QT prolongation is increased by numerous predisposing factors, such as genetic predisposition, female sex, hypokalemia, and cardiac dysfunction 6.
• Certain antimicrobial agents, including macrolides, quinolones, azoles, pentamidine, protease inhibitors, antimalarial drugs, and cotrimoxazole, are also associated with QT interval prolongation 7.
• The use of antiarrhythmic drugs, such as quinidine, sotalol, and amiodarone, can lead to acquired long QT syndrome by prolonging the QT interval through the inhibition of specific ion channels responsible for heart repolarization 8.

Medications Associated with QT Prolongation

• Class Ia antiarrhythmic agents, such as quinidine and procainamide, have frequently been linked to inducing arrhythmia, including torsades de pointes 6.
• Class III antiarrhythmics, such as sotalol and amiodarone, are known to prolong the QT interval by blocking I(Kr) 6.
• Macrolide antibiotics, such as clarithromycin, can also cause QT prolongation and torsades de pointes, especially in patients with additional risk factors, such as female gender, old age, heart disease, hypokalemia, and hypomagnesemia 9.

Risk Factors for QT Prolongation

• Patient-related risk factors, such as female sex, age >65 years, and uncorrected electrolyte disturbances, can increase the risk of QT prolongation 5.
• Co-prescribed medicines that could increase the risk of QT prolongation should also be considered when prescribing drugs associated with QT prolongation 5.
• Electrolyte imbalances, such as hypokalemia and hypomagnesemia, can also contribute to QT prolongation and increase the risk of torsades de pointes 9, 7.