Causes of QTc Prolongation
QTc prolongation results from medications (especially antiarrhythmics and macrolide antibiotics), electrolyte abnormalities (hypokalemia, hypomagnesemia, hypocalcemia), structural heart disease, congenital channelopathies, and bradyarrhythmias—with drug-induced causes being the most common and preventable etiology in clinical practice. 1
Medication-Induced QTc Prolongation
High-Risk Antiarrhythmic Drugs
The most frequent offenders requiring hospitalization for monitoring during initiation include: 1
- Class IA agents: Quinidine, procainamide, disopyramide
- Class III agents: Sotalol, dofetilide, ibutilide (monitor 4-5 hours post-administration)
- Ajmaline
Moderate-Risk Medications
Drugs with less frequent but significant QT-prolonging potential include: 1
- Amiodarone (causes marked QT prolongation but paradoxically has low torsades de pointes risk)
- Macrolide antibiotics: Azithromycin 2, erythromycin 3, clarithromycin 1
- Antipsychotics: Haloperidol 4, chlorpromazine, thioridazine, pimozide 1
- Antiemetics: Domperidone, droperidol 1
- Chemotherapy agents: Arsenic trioxide (26-93% incidence, highest among cancer therapies) 1, vandetanib 1
- Opioid dependence agents: Methadone 1, 5
- Gastrointestinal agents: Cisapride 1, proton pump inhibitors 6, prokinetic agents 6
Critical caveat: Always check www.crediblemeds.org or www.torsades.org for updated drug lists, as new medications are continuously identified. 1
Electrolyte Abnormalities
Primary Electrolyte Disturbances
- Hypokalemia (most significant risk factor, particularly in women) 1, 7
- Hypomagnesemia (moderate to severe) 1
- Hypocalcemia (particularly in men) 7
Important note: While electrolyte abnormalities are widely cited, recent evidence suggests the association may not be as strong as traditionally believed when measured at hospital admission. 8 However, severe electrolyte disorders—especially when combined with other risk factors—warrant continuous monitoring until correction. 1
Paradoxical Effect
- Hypercalcemia actually shortens the QT interval by compressing the ST segment and accelerating ventricular repolarization, which can also be arrhythmogenic. 9
Cardiac Conditions and Structural Heart Disease
Structural Abnormalities
- Left ventricular hypertrophy 1
- Low left ventricular ejection fraction/heart failure 1, 5
- Myocardial ischemia 1
- Valvular heart disease (particularly mitral valve prolapse) 1
Bradyarrhythmias (High-Risk Triggers)
- Complete heart block with ventricular rate <40 bpm 1
- Sinus pauses and sick sinus syndrome 1
- Post-conversion pauses (after atrial fibrillation/flutter conversion to sinus rhythm) 1
- Compensatory pauses after premature ventricular contractions 1
- Post-ablation complete heart block (AV junction ablation) 1
Mechanism: Bradycardia-dependent QT prolongation creates the substrate for torsades de pointes, particularly following short-long-short cycle sequences. 1
Congenital Long QT Syndrome
Genetic Channelopathies
- Prevalence: 1 in 2,500-5,000 live births 5
- Most common mutation: KCNQ1 (LQT1) affecting IKs current 5
- De novo mutations: Account for 30% of cases with unaffected parents 5
- Autoimmune-related: Neonates born to mothers with anti-Ro/SSA antibodies 5
Clinical pearl: Drug exposure can unmask subclinical congenital LQTS, and certain DNA polymorphisms (frequency up to 15% in some populations) increase susceptibility to drug-induced prolongation. 1
Metabolic and Systemic Conditions
Endocrine and Metabolic
- Hypothyroidism 1, 4, 7
- Starvation/malnutrition with associated electrolyte disorders 1
- Renal failure 1
- Hepatic failure 1
Neurological
- Central nervous system abnormalities (subarachnoid hemorrhage, stroke) produce QT prolongation and T-wave inversion 1, 5
Patient-Specific Risk Factors
Demographic Factors
- Female sex (women have inherently longer QT intervals post-puberty; normal upper limit 460-480 ms vs. 440-470 ms in men) 1, 7
- Older age (elderly more susceptible to drug-associated QT effects) 1, 2, 3
Drug Interactions
- Concomitant use of multiple QT-prolonging drugs 1
- Combination with metabolic inhibitors (e.g., CYP3A4 inhibitors with macrolides) 1, 3
- High drug concentrations (exception: quinidine causes torsades even at therapeutic levels) 1
- Rapid intravenous administration 1
Clinical Context
- Recent conversion from atrial fibrillation 1
- Digitalis therapy 1
- Therapeutic hypothermia post-cardiac arrest 1
ECG Indicators of Imminent Torsades de Pointes
When QTc is prolonged, the following ECG findings signal immediate arrhythmia risk: 1
- Enhanced U waves
- T-wave alternans
- Polymorphic ventricular premature beats or couplets
- Nonsustained polymorphic ventricular tachycardia
- Sudden bradycardia or long pauses
Management threshold: QTc ≥500 ms or increase ≥25% from baseline mandates immediate discontinuation of offending agents and continuous monitoring until washout occurs. 1