Causes of QT Interval Prolongation
Primary Etiologic Categories
QT interval prolongation results from four major categories: medications (most common and preventable), electrolyte abnormalities, structural heart disease, and congenital channelopathies. 1
Medication-Induced QT Prolongation
The most frequent and preventable cause of QT prolongation in clinical practice is drug-induced, with nearly all implicated medications blocking the IKr potassium current encoded by the HERG gene. 2
High-Risk Drug Classes
Antiarrhythmic agents:
- Class IA agents (quinidine, procainamide, disopyramide) require monitoring for QT prolongation 1
- Class III agents (sotalol, dofetilide, ibutilide) necessitate monitoring particularly 4-5 hours post-administration 1
- Amiodarone prolongs QT but has lower torsades risk compared to other Class III agents 3
Antibiotics:
- Macrolides, particularly clarithromycin, cause QT prolongation 1
- Fluoroquinolones have been associated with QT prolongation and torsades cases 3
Psychiatric medications:
- Antipsychotics including thioridazine and pimozide prolong QT 1
- Antidepressants have been reported to cause QT prolongation 3
Chemotherapy agents:
- Arsenic trioxide causes QT prolongation with an incidence of 26-93% 1
- Vandetanib is associated with QT prolongation 1
Other medications:
- Methadone is a significant cause, with both dose and baseline QT predicting prolongation; baseline and follow-up ECGs are recommended, especially if daily dosage exceeds 100 mg 1
- Buprenorphine causes far less QT prolongation than methadone 1
- Prokinetic drugs (cisapride), antihistamines, and serotonin agonists (triptans) have been implicated 2, 3
Electrolyte Abnormalities
Hypokalemia is the most significant electrolyte risk factor for QT prolongation, particularly in women. 1 Diuretic-induced hypokalemia from heart disease treatment compounds arrhythmia risk beyond the underlying cardiac condition itself, requiring vigilant electrolyte monitoring. 1
Additional electrolyte disturbances:
- Hypomagnesemia contributes to QT prolongation 1
- Hypocalcemia potentiates drug-induced QT prolongation 1
Note: Hypercalcemia actually shortens the QT interval by accelerating ventricular repolarization, not prolonging it. 4
Structural Heart Disease and Cardiac Conditions
Myocardial ischemia (both acute and chronic, including previous myocardial infarcts) prolongs QT and predisposes to sudden cardiac death, accounting for 15% of all deaths and creating substrate for arrhythmia through re-entry mechanisms. 1
Left ventricular dysfunction:
- Left ventricular hypertrophy increases QT prolongation risk 1
- Low left ventricular ejection fraction and heart failure contribute to QT prolongation 1
Inherited cardiomyopathies (hypertrophic cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, dilated cardiomyopathy) increase sudden cardiac death risk. 1
Structural congenital heart diseases and surgical sequelae predispose to arrhythmia development. 1
Congenital Long QT Syndrome
Congenital long QT syndrome has a prevalence of 1 in 2,500-5,000 live births, with the most common mutation being KCNQ1 (LQT1) affecting IKs current. 1 De novo mutations account for 30% of cases with unaffected parents. 1
Mechanism: Mutations in genes encoding cardiac ion channels required for the cardiac action potential cause abnormal repolarization. 2 These genetically determined changes in ion-channel function create baseline QT prolongation that overlaps considerably with healthy individuals. 1
Autoimmune-related cases can occur in neonates born to mothers with anti-Ro/SSA antibodies. 1
Bradyarrhythmias
Bradycardia, including sinus bradycardia and heart block, prolongs QTc and predisposes to torsades de pointes. 1 Marked bradycardia is a recognized acquired cause of QT prolongation. 5
Patient-Specific Risk Factors
Female sex is a significant risk factor, with women having inherently longer QT intervals post-puberty. 1 Female gender increases the risk of torsades and potentiates the QT prolonging effects of drugs. 3
Older age increases susceptibility to drug-associated QT effects. 1
Pharmacokinetic interactions: Concomitant use of multiple QT-prolonging drugs, combination with metabolic inhibitors (e.g., CYP3A4 inhibitors like verapamil), and high drug concentrations increase QT prolongation risk. 1
Baseline QT interval: A long QT interval at baseline predisposes to drug-induced torsades. 2
Additional Acquired Causes
Other recognized causes include:
- Cocaine use 5
- Organophosphorus compounds 5
- Subarachnoid hemorrhage 5
- Protein-sparing fasting 5
- Autonomic neuropathy 5
- HIV disease 5
Critical Warning Signs
When QTc is prolonged, the following ECG findings signal imminent torsades de pointes risk:
- Enhanced U waves and T-wave alternans 1
- Polymorphic ventricular premature beats or couplets 1
- Nonsustained polymorphic ventricular tachycardia 1
- Sudden bradycardia or long pauses 1
- Exaggerated QT-interval prolongation with T-U distortion after a pause 2
A QTc ≥500 ms or increase ≥25% from baseline mandates immediate discontinuation of offending agents and continuous monitoring until washout occurs. 1