Long QT Interval
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- QT interval: the measurement interval from the beginning of the QRS complex to the end of the T wave on the surface electrocardiogram (ECG). This represents the period from the onset of depolarization to completion of repolarization of the ventricular myocardium.
- Corrected QT interval (QTc): The QT interval has an inverse relationship with heart rate. The QTc is the QT interval corrected for heart rate. See formulas.
- Prolonged QTc is generally defined as >450 ms for adult males and >470 ms for adult females (1):
- Most cases of prolonged QT are acquired, but several genetic mutations cause inherited long QT syndrome (LQTS) (3).
- Prolonged QTc from any cause can precipitate polymorphic ventricular tachycardia (VT) called torsade de pointes (TdP), leading to dizziness, syncope, and sudden cardiac death from ventricular fibrillation (VF).
Incidence of medication-induced QTc prolongation and TdP varies with medication and a host of other factors. Exact incidences are difficult to estimate but may be 1:2,000 to 1:2,500 (2).
- Hereditary LQTS is estimated to occur in 1/2,500 to 1/7,000 births.
- Five thousand people across the United States may die yearly due to LQTS-related cardiac arrhythmia.
Etiology and Pathophysiology
- Demographics: increasing age, female sex
- Electrolyte abnormalities: hypokalemia, hypocalcemia, and hypomagnesemia
- Noncardiac disease: hypothyroidism renal impairment, and hepatic impairment
- Cardiac disease: heart failure, LVH, and myocardial ischemia (2)
- Scenarios: rapid increase in the QT interval >60 ms, conversion from atrial fibrillation/bradycardia (5)
- Medications (3)
- Antiarrhythmic medications (quinidine, procainamide, dronedarone, dofetilide, sotalol, disopyramide, and amiodarone)
- Antipsychotic medications: especially if given IV (haloperidol*, chlorpromazine*, thioridazine*, pimozide*)
- Antidepressants: most commonly used drugs responsible (SSRIs, SNRIs, trazodone, TCAs)
- Antibiotics/antivirals/antifungals/antiprotozoals/antimalarials: macrolides (clarithromycin*, erythromycin* also CYP3A4 inhibitors), fluoroquinolones, quinine, and chloroquine
- Antiemetics: metoclopramide, ondansetron, promethazine
- Opioids: methadone*, buprenorphine
- Antihistamines: cetirizine, hydroxyzine, diphenhydramine
- Decongestants: pseudoephedrine, phenylephrine
- Stimulants: albuterol, phentermine
- Misc: chloroquine*, pentamidine*, various antimuscarinics, and anticonvulsants
- *Denote “high-risk” medication for TdP (2,5)
- Loss of function mutations in several potassium ion membrane channels or gain of function mutations in the sodium or calcium ion membrane channels in cardiac myocytes (6)
- Depolarization (phase 0) of the myocardium results from the rapid influx of sodium through sodium channels (INa) causing myocyte contraction during systole; seen on ECG as the QRS complex
- Repolarization occurs through the efflux of potassium from the cell (phases 2 and 3) by rapid (IKr) and slow (IKs) components of the delayed rectifier; represented by the T wave on an ECG
- Drug-induced QT prolongation most often due to blockade of the IKr channel leading to delay in phase 3 rapid repolarization (2)
- In both cases, deviation from normal ion channel function leads to transmural dispersion of repolarization currents across the myocardium triggering early after depolarizations which may devolve into TdP (3,6).
- Prolonged QT interval alone does not denote imminent risk for TdP; TdP is often self-limited, but TdP can cause syncope or degrade to VF (2).
- 13+ distinct genotypes are linked to LQTS (1,6).
- Penetrance is highly variable making both diagnosis and management challenging (3).
- LQT1 (40–55%) is the most common cause of LQTS. Loss of function in the KCNQ1 gene coding for the IKs transport protein; arrhythmias triggered by sympathetic activation (stress/exercise—especially swimming), leading to shorter ventricular repolarization
- LQT2 (30–45%) results from a mutation in the KCNH2 gene causing a defect in the IKr transport protein; at risk for cardiac events due to abrupt catecholamine surges like auditory stimuli/emotional arousal (postpartum)
- LQT3 (5–10%) is caused by a mutation in the SCN5A gene leading to a gain of function in the alpha subunit of the INa transport protein. Excessive sodium accumulates in the cell, increasing repolarization time; prominent during sleep due to amplified inward flow of sodium at low heart rates (1,3,6)
- LQT4 to LQT13—<1% of the total frequency
- Jervell and Lange-Nielsen syndrome (JLNS): autosomal recessive inheritance through homozygous or compound heterozygous mutations of the KCNQ1 or KCNE1 genes. Reduced function in the IKs transport protein; associated with sensorineural hearing loss
- Romano-Ward syndrome (RWS): most common. Results from any of the 13 identified gene mutations; autosomal dominant with variable penetrance and normal hearing
- Others: Andersen-Tawil syndrome (LQT7), Timothy syndrome (LQT8). Both are very rare (3,6).
- Female (~2 times increased risk)
- QTc >500 ms (2 to 3 times increased risk)
- QTc >60 ms over previous baseline
- For every 10 ms increase in the QTc, there is a 5–7% increased risk for developing TdP.
- History of syncope or presyncope
- History of TdP
- Liver or kidney disease (by increasing blood levels of QT-prolonging medications)
- Medications that cause QTc prolongation
- High doses
- Fast infusions
- Combination of medications
- Medications that inhibit CYP3A4
- Electrolyte abnormalities
- For hereditary LQTS
- Catecholamine surges from exercise, emotional stress, loud noises, postpartum
- Avoid (or use with caution) causative medications, including combinations with potentially additive effects (1,2,5)[C].
- Replete electrolytes (goal Mg >2, K 4.5 to 5.0) (2)[C].
- Treat underlying diseases.
- Avoid strenuous sports in LQTS.
- Avoid sudden loud noises in LQTS (alarm clocks, doorbells, telephones).
- 36th Bethesda Conference recommends restriction of athletes from participation to class 1A activities (e.g., bowling, golf, riflery), although evidence of safe participation is emerging (3)[C].