Causes of Prolonged QT Interval
Prolonged QT interval results from medications (most common and preventable), electrolyte abnormalities, structural heart disease, congenital channelopathies, and bradyarrhythmias, with drug-induced causes being the predominant etiology in clinical practice. 1
Medication-Induced QT Prolongation
Drug-induced QT prolongation represents the most common and preventable cause, requiring systematic evaluation of all medications 1:
Antiarrhythmic Drugs
- Class IA agents (quinidine, procainamide, disopyramide) require monitoring for QTc prolongation 1
- Class III agents (sotalol, dofetilide, ibutilide, amiodarone) necessitate monitoring particularly 4-5 hours post-administration 1, 2
Psychiatric Medications
- Antipsychotics including thioridazine, pimozide, haloperidol, ziprasidone, and chlorpromazine cause QT prolongation 1, 3, 2
- Quetiapine causes moderate QT prolongation (approximately 6 ms on average), though less than thioridazine 4, 5
- The FDA label for quetiapine specifically warns to avoid combination with other QT-prolonging drugs and in patients with cardiac arrhythmias, hypokalemia, hypomagnesemia, or congenital QT prolongation 5
- Antidepressants including venlafaxine and citalopram contribute to QT prolongation, particularly in polypharmacy scenarios 6, 7
Antibiotics
- Macrolides (clarithromycin) and fluoroquinolones (gatifloxacin, moxifloxacin) cause QT prolongation 1, 2
Other High-Risk Medications
- Methadone causes significant dose-dependent QT prolongation; baseline and follow-up ECGs are recommended, with additional evaluation if daily dosage exceeds 100 mg 1, 3, 5
- Chemotherapy agents including arsenic trioxide (26-93% incidence) and vandetanib 1
- Antiemetics such as ondansetron and domperidone 6, 2
Critical Drug Interaction Considerations
- CYP3A4 inhibitors (verapamil) combined with QT-prolonging drugs increase risk through metabolic inhibition 1
- Polypharmacy with multiple QT-prolonging medications creates additive effects that are frequently underrecognized 4, 6, 7
Electrolyte Abnormalities
Electrolyte disturbances represent critical correctable risk factors requiring aggressive correction 1:
- Hypokalemia is a significant risk factor, particularly in women, and commonly results from diuretic therapy 1, 3
- Hypomagnesemia contributes to QT prolongation and requires monitoring 1
- Hypocalcemia potentiates drug-induced QT prolongation 1
- Diuretic-induced hypokalemia creates compounded risk when combined with underlying cardiac conditions, requiring vigilant electrolyte monitoring 1
Cardiac Structural Disease
Structural heart abnormalities increase baseline QT prolongation risk 1:
- Left ventricular hypertrophy and heart hypertrophy 1, 5
- Low left ventricular ejection fraction and heart failure (particularly reduced ejection fraction) 1, 3
- Myocardial ischemia (both acute and chronic, including previous myocardial infarcts) prolongs QT and predisposes to sudden cardiac death 1
- Inherited cardiomyopathies (hypertrophic cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, dilated cardiomyopathy) 1
- Congenital heart diseases and surgical sequelae 1
Congenital Long QT Syndrome
Hereditary channelopathies create baseline QT prolongation 3:
- Prevalence of 1 in 2,500-5,000 live births 1, 3
- KCNQ1 (LQT1) affecting IKs current is the most common mutation 1, 3
- De novo mutations account for 30% of cases with unaffected parents 1, 3
- Autoimmune-related cases occur in neonates born to mothers with anti-Ro/SSA antibodies 1, 3
- Genetically determined ion-channel dysfunction creates baseline prolongation that overlaps considerably with healthy individuals 1
Bradyarrhythmias
Slow heart rates prolong QTc and predispose to torsades de pointes 1:
- Sinus bradycardia and heart block 1
- AV nodal blocking agents (adenosine, calcium channel blockers, digoxin, beta-blockers) should be avoided in pre-excited atrial fibrillation as they may paradoxically increase ventricular response 1
Patient-Specific Risk Factors
Individual characteristics modify QT prolongation risk 1:
- Female sex: Women have inherently longer QT intervals post-puberty 1
- Older age increases susceptibility to drug-associated QT effects 1
- Central nervous system abnormalities can produce QT prolongation and T wave inversion 3
Critical Thresholds and Warning Signs
QTc ≥500 ms or increase ≥25% from baseline mandates immediate discontinuation of offending agents and continuous monitoring until washout occurs 1:
- Enhanced U waves 1
- T-wave alternans 1
- Polymorphic ventricular premature beats or couplets 1
- Nonsustained polymorphic ventricular tachycardia 1
- Sudden bradycardia or long pauses 1
Common Clinical Pitfalls
- Failing to recognize additive effects of multiple QT-prolonging medications 4
- Assuming all psychiatric medications carry equal QT prolongation risk (valproate does NOT prolong QT) 4
- Neglecting to monitor electrolytes in patients on diuretics receiving QT-prolonging drugs 1
- Overlooking drug-drug interactions involving CYP3A4 inhibitors 1