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Qt prolongation causes

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Excellent - I now have a complete, authoritative picture from Harrison's. Here is the full answer:

Causes of QT Prolongation

The QT interval reflects ventricular depolarization + repolarization. Prolongation occurs when repolarization is delayed - usually by impaired K+ outward current (IKr, IKs) or enhanced Na+/Ca2+ inward current. A corrected QT (QTc) >470 ms in men or >480 ms in women is considered prolonged.
The main risk is torsades de pointes (TdP) - a polymorphic VT that can degenerate into ventricular fibrillation.

1. Congenital Long QT Syndromes

These are ion channel mutations, accounting for ~15 subtypes. LQT1-3 together explain 80-90% of cases:
TypeGeneChannel affectedTriggerECG
LQT1KCNQ1↓ IKs (slow K+)Exercise, swimmingBroad T-wave
LQT2KCNH2↓ IKr (rapid K+)Sudden auditory stimuli, emotionNotched/low T-wave
LQT3SCN5A↑ INa (Na+ gain-of-function)SleepLong J-to-T delay
  • Romano-Ward syndrome - autosomal dominant, most common
  • Jervell and Lange-Nielsen syndrome - autosomal recessive + sensorineural deafness

2. Electrolyte Abnormalities

  • Hypokalemia - most important (reduces repolarizing K+ current; common precipitant in patients with underlying LQTS)
  • Hypomagnesemia
  • Hypocalcemia (hypercalcemia actually shortens QT)

3. Drugs (Acquired LQTS) - Largest Category

Most drugs act by blocking the hERG channel (IKr).

Antiarrhythmics

  • Class IA: Quinidine, disopyramide, procainamide
  • Class III: Sotalol, dofetilide, ibutilide, dronedarone, amiodarone, ranolazine

Antibiotics

  • Macrolides: erythromycin, clarithromycin, azithromycin
  • Fluoroquinolones: levofloxacin, moxifloxacin
  • Trimethoprim-sulfamethoxazole, clindamycin, pentamidine
  • Antimalarials: chloroquine, hydroxychloroquine

Antifungals

  • Ketoconazole, itraconazole (and azoles via CYP3A4 interactions)

Antivirals

  • Amantadine

Antipsychotics

  • Haloperidol, phenothiazines (thioridazine, trifluoperazine), ziprasidone, sertindole

Antidepressants

  • Tricyclics and tetracyclics

Antihistamines (H1 blockers)

  • Astemizole, diphenhydramine, hydroxyzine

Other drugs

  • Methadone (high-dose, especially IV)
  • Cocaine
  • Citrate (massive blood transfusions - causes hypocalcemia)
  • Loperamide (antidiarrheal, in overdose)
  • Certain anesthetic agents (e.g., sevoflurane - clinical significance uncertain)

4. Cardiac Conditions

  • Myocardial ischemia and infarction
  • Myocarditis
  • Marked bradycardia (rate-dependent QT prolongation - "pause-dependent" TdP)
  • Stress cardiomyopathy (Takotsubo)
  • Heart failure/cardiomyopathy

5. Endocrine Disorders

  • Hypothyroidism
  • Hyperparathyroidism (via hypocalcemia)
  • Pheochromocytoma
  • Hyperaldosteronism (via hypokalemia/hypomagnesemia)

6. Intracranial / Neurological Disorders

  • Subarachnoid hemorrhage (classic - massive catecholamine surge)
  • Thalamic hematoma
  • Cerebrovascular accident (stroke)
  • Encephalitis
  • Head injury

7. Nutritional / Systemic

  • Anorexia nervosa
  • Starvation, liquid protein diets
  • Celiac disease
  • Gastroplasty / ileojejunal bypass

Key Clinical Points

  • Female sex is an independent risk factor for drug-induced TdP (longer baseline QTc)
  • Combination of causes is additive - e.g., a patient on sotalol who develops hypokalemia is at high risk
  • First-degree relatives of congenital LQTS patients have increased sensitivity to drug-induced QT prolongation
  • QTc >500 ms marks significantly elevated risk of TdP
  • Acute treatment of TdP: IV magnesium sulfate 2 g + correct underlying cause + overdrive pacing if bradycardic
Sources: - Harrison's Principles of Internal Medicine 22E, p. 2013 | - Fuster and Hurst's The Heart, 15th Ed., p. 1864 | - Pfenninger and Fowler's Procedures for Primary Care, 3rd Ed.
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