Long QT Interval

BASICS

DESCRIPTION

QT interval: electrocardiogram (ECG) measurement that measures the duration of repolarization of myocardial cells. Measured from the onset of the QRS complex to the end of the T wave
Corrected QT interval (QTc): QT interval corrected for heart rate (interval shortens with increased rate). See formulas.
Prolonged QTc is generally defined as >470 ms for adult males and >480 ms for adult females (1):
- 440 to 460 ms considered borderline in men
- 440 to 470 ms considered borderline in women
- 440 to 460 ms considered borderline in children aged 1 to 15 years old (2)
Most cases of prolonged QT are acquired, but genetic mutations can also cause hereditary long QT syndromes (LQTS).
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).

EPIDEMIOLOGY

Incidence
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. (1).
Prevalence

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 (2).

ETIOLOGY AND PATHOPHYSIOLOGY

Acquired
- Electrolyte abnormalities such as hypokalemia, hypomagnesemia
- Hypothyroidism
- Underlying heart disease
- Medications (3)[A]
  - Antiarrhythmic medications (quinidine, procainamide, dofetilide, sotalol, disopyramide, and amiodarone)
  - Antipsychotic medications, especially if given IV (haloperidol*, chlorpromazine*, thioridazine*, pimozide*)
  - Many antidepressants (SSRIs, SNRIs, trazodone, TCAs)
  - Antibiotics/antivirals/antifungals (clarithromycin*, erythromycin* which are also CYP3A4 inhibitors)
  - Antiemetics (metoclopramide, ondansetron, promethazine)
  - Opioids (methadone*, buprenorphine)
  - Antihistamines (cetirizine, hydroxyzine, diphenhydramine)
  - Decongestants (pseudoephedrine, phenylephrine
  - Stimulants (albuterol, phentermine)
  - Misc: chloroquine*, pentamidine*
  - *Denote "high-risk " medication for TdP.
Congenital
- Defective membrane proteins that work as channels for sodium and potassium in myocytes
Pathophysiology
- Depolarization of the myocardium results from the rapid influx of sodium through sodium channels and causes myocyte contraction, with resulting cardiac muscle contraction and systole (seen on ECG as the QRS complex).
- During repolarization, there is an efflux of potassium from the cell through both rapid (IKr) and slow (IKs) potassium channels. The T wave on an ECG represents myocyte repolarization.
- Drug-induced QT prolongation due to blockade of IKr leading to delayed repolarization (2).
- Medications, medical conditions, electrolyte disturbances, and genetic mutations that affect functioning of these membrane channels can cause delayed repolarization.
- Delayed repolarization can lead to a propensity for reentry and initiate TdP.
- TdP type rhythm may be self-limited but symptomatic (syncope or near syncope). It can also degrade into VF.

Genetics

12 different genes have been linked to LQTS (3).
Incomplete penetrance makes both diagnosis and management of asymptomatic disease challenging.
LQTS 1 (42 " 54%) is the most common. Mutation causes a defect in the IKs transport protein. Arrhythmias can be triggered by tachycardia due to exercise (swimming seems to be especially problematic) and other high catecholamine states.
LQTS 2 (35 " 45%) is a defect in the IKr transport protein that is sensitive to catecholamine surges. Sudden loud noises or emotional arousal can provoke arrhythmias.
LQTS 3 (8%) is a defect in the sodium channel that allows an excess of sodium into the cell, increasing repolarization time. Arrhythmias tend to manifest more during rest or sleep.
Jervell and Lange-Nielsen syndrome: Autosomal recessive form of LQTS that features homozygous mutations affect the IKs channel and presents with severe form of LQTS 1. Features also include deafness.
Romano-Ward syndrome: autosomal dominant form of LQTS with variable penetrance. Hearing is normal.

RISK FACTORS

For the feared complication, TdP, risk factors include the following (3):

Female ( ’ Ό2 times increased risk)
QTc >500 ms (2 to 3 times increased risk)
QTc >60 ms over previous baseline
History of syncope or presyncope
History of TdP
Bradycardia
Liver or kidney disease (by increasing blood levels of QT prolonging medications)
Medications that cause QTc prolongation
- High doses
- Fast infusions
- Combination of medications
Electrolyte abnormalities
- Hypokalemia
- Hypomagnesemia
- Hypocalcemia
For hereditary LQTS
- Catecholamine surges from exercise (especially swimming), emotional stress, loud noises

GENERAL PREVENTION

Avoid (or use with caution) causative medications, including combinations with potentially additive effects. Replete electrolytes (goal Mg >2, K 4.5 to 5.0) (4)[C]
Treat underlying medical disease (hypothyroidism, cardiac disease).
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 regarding safe participation is emerging (1)[C].

DIAGNOSIS

HISTORY

Evaluate for syncope, near syncope, and associated precipitating events (such as emotional triggers, swimming, diving).
Evaluate for history of seizures in patient or in family (tonic " clonic movement may due to cerebral hypoperfusion during episodes of ventricular arrhythmia or due to seizure-like activity during a syncopal episode.).
Detailed medication history
Evaluate for family history of sudden death and syncope.
Congenital deafness

PHYSICAL EXAM

Usually normal physical exam
If underlying cardiac disease present, may have findings specific to cardiac condition
Evaluate for signs of hypothyroidism.
Congenital deafness may be present in some forms of LQTS.

DIAGNOSTIC TESTS & INTERPRETATION

Initial Tests (lab, imaging)

ECG
Metabolic panel
Calcium level
Magnesium level
TSH

Follow-Up Tests & Special Considerations

Echocardiogram to evaluate for cardiomyopathy
Outpatient cardiac rhythm monitoring
Consider provocative testing (epinephrine infusion, exercise stress testing) to evaluate for QTc interval changes and/or to evaluate for coronary artery disease (2)[C].
- Genetic testing for LQTS mutations

Test Interpretation

QTc calculation using ECG is best done by measuring the QT interval in lead II and measuring the RR interval immediately preceding this QT interval. The Bazett formula is commonly used, although it overcorrects for tachycardia and undercorrects for bradycardia (2).
Bazett formula: QTc = QT/ ’ (RR) (all measurements in seconds, and RR obtained by direct measurement or 60/heart rate)
Fridericia formula is similar to Bazett but uses a cube root instead of a square root of the RR interval. QTc = QT/(RR) ’ ;

TREATMENT

GENERAL MEASURES

VT, TdP, and VF should be treated emergently as per ACLS guidelines.
Cardiac pacing may be needed emergently for drug-induced TdP to prevent bradycardia.
Withdraw offending agents, correct electrolytes (2)[C].

MEDICATION

First Line

For Tdp: magnesium sulfate 2 g infused over 2 to 15 minutes, followed by continuous infusion of 2 to 4 mg/min if needed. Monitor for magnesium toxicity in those with renal insufficiency (2)[C].
For hereditary LQTS, to prevent life-threatening arrhythmias: Propranolol or nadolol are generally regarded as the best ²-blockers for management of LQTS, though rigorous studies are lacking (4)[B].
²-Blockers are effective in decreasing but not eliminating the risk of fatal arrhythmias.
For high-risk patients or those who remain symptomatic on a ²-blocker, implantable cardiac defibrillators (ICDs) with or without pacemaker is an important consideration (2)[B].

Second Line
Atenolol or metoprolol may be used, although switching from other ²-blockers may precipitate lethal or near-lethal events (4)[B].

ISSUES FOR REFERRAL

Refer to cardiologist for establishing diagnosis, especially for hereditary LQTS.
Symptomatic prolonged QT

SURGERY/OTHER PROCEDURES

ICD for those with a history of major cardiac events
Left cervical-thoracic sympathetic denervation was used for symptomatic LQTS prior to the advent of ²-blockers. It is still an option for those patients with LQTS who are refractory to ²-blocker therapy (3)[B].

INPATIENT CONSIDERATIONS

Admission Criteria/Initial Stabilization

Patients with TdP, VT, and VF should be promptly treated as per ACLS guidelines. Correct electrolytes on an emergent basis. Evaluate for acquired QT prolongation. If no cause is found, consider hereditary LQTS.
Patients with prolonged QTc and syncope/near syncope should be monitored on telemetry during evaluation.
Monitor ECG if initiating medications or combining medications that may prolong QT, suggest at baseline, within 30 days, and then annually (3)[C].
Monitor electrolytes and urgently treat hypomagnesemia and hypokalemia in those with significantly prolonged QT, and discontinue or change offending medications (5)[C].

Nursing

Avoid sudden loud noises or emotional stress for those who have LQTS.
Review adherence to ²-blocker therapy.
Notify others if telemetry monitoring reveals prolonged QT interval in hospitalized patients " they are at risk for poor outcomes (6).

ONGOING CARE

FOLLOW-UP RECOMMENDATIONS

On routine visits, ask about syncope, presyncope, and palpitations in those who have QTc prolongation.

Patient monitoring: Consider ECG and/or outpatient cardiac rhythm monitoring with any medication additions or dosage changes that may cause further prolongation of the QTc.
For those who may have symptomatic QTc prolongation of any cause, prompt evaluation is warranted.
Check labs for electrolyte imbalances, correct as needed.

PATIENT EDUCATION

Educate patients with QTc prolongation about medications side effects and possibility of medication interactions.
Patients with congenital forms of LQTS should be aware of, and avoid situations that may trigger torsade (depending on their specific gene mutation)
Large emotional and psychological impact of diagnosis. Additional reading by Fortescue shares personal impact of LQTS.
Information and support from groups listed (see "Additional Reading " ) may be helpful.

PROGNOSIS

Untreated, quite poor. Perhaps 20% of untreated patients presenting with syncope die within 1 year, 50% within 10 years (3).

REFERENCES

11 Abrams DJ, Macrae CA. Long QT syndrome. Circulation. 2014;129(14):1524 " 1529.22 Kallergis EM, Goudis CA, Simantirakis EN, et al. Mechanisms, risk factors, and management of acquired long QT syndrome: a comprehensive review. ScientificWorldJournal. 2012;2012:212178.33 Clarke CJ, McDaniel GM. The risk of long QT syndrome in the pediatric population. Curr Opin Pediatr. 2009;21(5):573 " 578.44 Wilde AA, Ackerman MJ. Beta-blockers in the treatment of congenital long QT syndrome: is one beta-blocker superior to another? J Am Coll Cardiol. 2014;64(13):1359 " 1361.55 QT prolongation, torsades de pointes, and medication safety. Pharmacist 's Letter/Prescriber 's Letter. 2010;26(4):260421.66 Laksman Z, Momciu B, Seong YW, et al. A detailed description and assessment of outcomes of patients with hospital recorded QTc prolongation. Am J Cardiol. 2015;115(7):907 " 911.

ADDITIONAL READING

Chockalingam P, Crotti L, Girardengo G, et al. Not all beta-blockers are equal in the management of long QT syndrome types 1 and 2: higher recurrence of events under metoprolol. J Am Coll Cardiol. 2012;60(20):2092 " 2099.
Fortescue EB. A piece of my mind. Keeping the pace. JAMA. 2014;311(23):2383 " 2384.
Levine E, Rosero SZ, Budzikowski AS, et al. Congenital long QT syndrome: considerations for primary care physicians. Cleve Clin J Med. 2008;75(8):591 " 600.
Morita H, Wu J, Zipes DP. The QT syndromes: long and short. Lancet. 2008;372(9640):750 " 763.
van Noord C, Eijgelsheim M, Stricker BH. Drug- and non-drug-associated QT interval prolongation. Br J Clin Pharmacol. 2010;70(1):16 " 23.
Webster G, Berul CI. Congenital long-QT syndromes: a clinical and genetic update from infancy through adulthood. Trends Cardiovasc Med. 2008;18(6):216 " 224.
Yap YG, Camm AJ. Drug induced QT prolongation and torsades de pointes. Heart. 2003;89(11):1363 " 1372.
http://www.crediblemeds.org (Medication lists and additional resources related to long QT and torsade de pointes)
Cardiac Arrhythmias Research and Education Foundation (http://www.longqt.org)
Sudden Arrhythmia Death Syndromes Foundation (http://www.sads.org)

CODES

ICD10

I45.81 Long QT syndrome

ICD9

426.82 Long QT syndrome

SNOMED

9651007 Long QT syndrome (disorder)
442946007 Aquired long QT syndrome
442917000 Congenital long QT syndrome

CLINICAL PEARLS

Evaluate for acquired causes before making a diagnosis of hereditary LQTS.
For accurate diagnosis, calculate QTc manually.
The ideal management of TdP is prevention; avoid multiple "stacking " risk factors and seek alternates to high-risk medications, correct electrolytes, and monitor treatment with serial ECGs if no alternatives exist.
Magnesium sulfate is the treatment of choice during ACLS for TdP.
²-Blockers are initial treatment of choice for hereditary LQTS.

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