What causes a prolonged QT interval?

Causes of Prolonged QT Interval

QT interval prolongation results from medications (most common and preventable), electrolyte abnormalities, structural heart disease, congenital channelopathies, and bradyarrhythmias. 1

Medication-Induced QT Prolongation (Most Common Cause)

Drug-induced QT prolongation represents the most frequent and preventable etiology in clinical practice. 1

Antiarrhythmic Drugs

• Class IA agents (quinidine, procainamide, disopyramide) require monitoring for QT prolongation 1, 2
• Class III agents (sotalol, dofetilide, ibutilide) necessitate monitoring particularly 4-5 hours post-administration 1, 3
• Amiodarone prolongs QT but carries lower torsades risk compared to other Class III agents 4

Antibiotics

• Macrolides (clarithromycin, erythromycin, azithromycin) block cardiac potassium channels and prolong QT 1, 5
  • Intravenous erythromycin carries the highest risk of torsades de pointes 5
  • Azithromycin has lower risk than other macrolides but remains a recognized cause 5
• Fluoroquinolones (moxifloxacin, levofloxacin) significantly prolong QT 5
• Trimethoprim causes QT prolongation through IKr blockade 5
• Vancomycin and piperacillin/tazobactam do NOT prolong QT and represent safe alternatives in at-risk patients 5

Psychotropic Medications

• Antipsychotics (thioridazine, pimozide) cause QT prolongation 1
• Antidepressants prolong QT interval 6
• Methadone is a significant cause, with both dose and baseline QT predicting prolongation; baseline and follow-up ECGs are recommended, with additional evaluation if daily dosage exceeds 100 mg 7
• Buprenorphine causes far less QT prolongation than methadone 7

Chemotherapy Agents

• Arsenic trioxide and vandetanib cause QT prolongation with incidence of 26-93% for arsenic trioxide 1

Electrolyte Abnormalities

• Hypokalemia is a significant risk factor for QT prolongation, particularly in women 1
• Hypomagnesemia contributes to QT prolongation 1
• Hypocalcemia potentiates drug-induced QT prolongation 7
• Note: Hypercalcemia actually shortens the QT interval by accelerating ventricular repolarization 8

Structural Heart Disease and Cardiac Conditions

• Left ventricular hypertrophy increases risk of QT prolongation 1
• Low left ventricular ejection fraction and heart failure contribute to QT prolongation 1
• Myocardial ischemia (both acute and chronic, including previous myocardial infarcts) prolongs QT and predisposes to sudden cardiac death 7, 1
• Ischemic heart disease is attributable to 15% of all deaths and creates substrate for arrhythmia through re-entry mechanisms 7
• Inherited cardiomyopathies (hypertrophic cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, dilated cardiomyopathy) increase sudden cardiac death risk 7
• Structural congenital heart diseases and surgical sequelae predispose to arrhythmia development 7

Congenital Long QT Syndrome

• Prevalence of 1 in 2,500-5,000 live births 1
• Most common mutation is KCNQ1 (LQT1) affecting IKs current 1
• De novo mutations account for 30% of cases with unaffected parents 1
• Autoimmune-related cases occur in neonates born to mothers with anti-Ro/SSA antibodies 1
• Genetically determined changes in ion-channel function create baseline QT prolongation that overlaps considerably with healthy individuals 7

Patient-Specific Risk Factors

• Female sex is a significant risk factor; women have inherently longer QT intervals post-puberty 1, 4
• Older age increases risk of drug-associated QT effects 1
• Concomitant use of multiple QT-prolonging drugs compounds risk 1
• Combination with metabolic inhibitors (e.g., CYP3A4 inhibitors like verapamil) increases QT prolongation risk 7, 1
• High drug concentrations increase QT prolongation risk 1

Bradyarrhythmias

• Bradycardia and long pauses prolong QT interval and can signal imminent torsades de pointes risk 1
• Sick sinus syndrome with symptomatic arrhythmias increases torsades risk, especially after cardioversion in atrial fibrillation patients 3

Critical Clinical Thresholds

• QTc ≥500 ms or increase ≥25% from baseline mandates immediate discontinuation of offending agents and continuous monitoring until washout occurs 1
• ECG warning signs of imminent torsades de pointes include enhanced U waves, T-wave alternans, polymorphic ventricular premature beats or couplets, nonsustained polymorphic ventricular tachycardia, and sudden bradycardia 1

Common Clinical Pitfall

Diuretic-induced hypokalemia from treatment of heart disease adds to arrhythmia risk beyond the underlying cardiac condition itself, creating a compounded risk scenario that requires vigilant electrolyte monitoring. 7