A. Introduction

1. Both acquired and congenital forms of long QT Syndromes exist
2. Increasing concerns about Long QT due to risk for serious morbidity and death
   1. QTc prolongation can lead to Torsade de Pointes (TDP) or Ventricular Fibrillation
   2. Symptoms include light headedness, syncope, and death
   3. May be responsible for up to ~50% of cases of sudden infant death syndrome (SIDS) [2]
3. Long QT is usually defined as a corrected QT (QTc) interval of >0.45 seconds [20]
   1. QTc = QT interval / (Square Root of the preceding RR interval)
   2. QTc <0.41 seconds is generally considered "normal"
   3. QTc 0.41-0.45 seconds is of uncertain significance
   4. QTc >0.50 seconds generally correlates with increased risk of TDP
4. Ion Channels and the QT Interval
   1. The QT interval represents the repolarization phase of action potential
   2. Repolarization is due primarily to voltage dependent outward rectifying K+ currents
   3. QTc prolongation is usually due to either increased Na+ channel or decreased K+ channel activities
   4. The prolonged length of the QT interval in normal persons is due to inward K+ channels
   5. These inward rectifying potassium currents are also voltage dependent
   6. Hypocalcemia can prolong QT because Ca2+ can modulate a K+ channel
   7. Genotype in congenital long QT syndromes contributes strongly to prognosis
5. QTc prolongation Induction of TDP
   1. Action potential deformities called "early after-depolarizations" develop withg prolonged QT
   2. This leads to spontaneous or "triggered" upstrokes
   3. Propagation of upstrokes through the heart leadas to ventricular ectopic beat
   4. Ectopic beat can lead to an "R on T" phenomenon in multiple foci in the heart
   5. This can trigger TDP (polymorphic ventricular tachycardia)
   6. M (mid-myocardium) cells and Purkingje fibers especially susceptible to drug-induced early after-depolarizations
6. Women have slower cardiac repolarization than men, with longer QTc [3]
   1. This difference in repolarization manifests only after puberty
   2. Different phases of the menstrual cycle affect drug-induced QTc prolongation
   3. Women are more prone to drug induced TDP

B. Drugs Associated with Prolonged QT Interval [1,4,15,20]

1. Overview of QT Prolonging Drugs [21]
   1. Many of these prolong QT/QTc only slightly at usual concentrations
   2. Inhibition of metabolism of these agents can lead to toxic levels
   3. Combinations of QTc prolonging agents can also lead to arrhythmias
   4. Women appear to be more sensitive than men to QTc prolonging drugs
   5. Prolongation of the absolute QT beyond 500 msec is considered a TDP risk
   6. Most QT prolonging drugs are inhibitors of the IKr (HERG) potassium channel
   7. Listing of agents at www.qtdrugs.org
2. Anti-Arrhythmic Agents
   1. Types IA and IB and III
   2. Amiodarone - prolongs QTc but little or no risk for TDP above placebo
   3. Disopyramide
   4. Dofetilide
   5. Ibutilide - QTc prolongation is affected by stage of menstrual cycle in women [3]
   6. Procainamide
   7. Quinidine
   8. Sotalol
   9. Bepridil
   10. Can prolong QTc by up to 50 msec at clinical doses (requires in hospital drug initiation)
3. Neuroleptics [5]
   1. Most typical neuroleptics prolong QTc interval
   2. Phenothiazines particularly problematic
   3. Thioridazine (Mellaril®) carries the greatest risk of cardiac arrhythmias [18]
   4. Haloperidol, chlorpromazine, mesoridizine, pimozide prolong QTc
   5. Ziprasidone, olanzapine, risperidone only in high risk patients
   6. Droperidol, a butyrphenone usually used for nausea, associated with prolonged QTc [16]
4. Antihistamines (H1-Blockers)
   1. Terfenadine (Seldane®) - withdrawn from market
   2. Astemizole (Hismanal®) - withdrawn from market
5. Tricyclic Antidepressants [5]
6. Methadone
   1. Doses >60mg/d used for heroin abusing patients associated with prolonged QTc
   2. TDP has been reported in a number of patients
   3. Implantable defibrillators have been used in these patients
   4. LAAM, also for opiate abuse, has associated QTc prolongation and arrhythmias
7. Cisapride (Propulsid®) - drug has been withdrawn from market [4]
8. Drugs Contributing to QT Prolongation
   1. Macrolides: erythromycin, clarithromycin, troleandomycin
   2. Quinolones: moxifloxacin (Avelox®), grepafloxacin, sparfloxacin
   3. Azole antifungals - ketoconazole, fluconazole and others
   4. Digitalis toxicity
   5. Arsenic trioxide - treatment for acute promyelocytic leukemia [6]
   6. Ritonavir
   7. In most cases, these "contributing" agents inhibit P450 metabolic enzymes
   8. Effects usually due to binding to ion channels in cardiac tissue
   9. HERG (inward rectifying K+ channels) most often implicated
9. Risk of Sudden Cardiac Death from Erythromycin
   1. Associated with QTc prolongation and sudden cardiac death with 2X increased risk [22]
   2. Concomitant use of erythromycin and CYP3A4 inhibitors 5X increased risk of death [22]
10. Electrolyte Disorders Increase Risk of TDP with QTc Prolonging Drugs
    1. Hypomagnesemia and hypocalcemia may precipitate TDP in susceptible patients
    2. Hypokalemia (drug induced or otherwise) can also precipitate TDP
11. Bradycardia with atrioventricular (AV) block can precipitate TDP

C. Risk Factors for TDP Related to Drugs [7,20]

1. Female sex
2. Hypokalemia
3. Hypomagnesemia
4. Diuretic use (independent of serum electrolyte levels)
5. Bradycardia
6. Congestive heart failure or cardiac hypertrophy
7. Baseline ECG that shows prolonged QTc or T wave lability
8. Marked QTc prolongation following exposure to drug
9. Increasing age may increase risk for prolonged QTc with drugs [5]
10. Single mutatant allele at any of long QT syndrome genes may contribute as well [8]
11. Most data suggest QTc or QT > 0.5 seconds is concerning [4,20]

D. Congenital Prolonged QT Syndromes [1,7,8,15]

1. Introduction
   1. Inherited syndromes with prolongation of QTc interval to >480ms (normal <440ms)
   2. Present with syncope, ventricular arrhythmias, sudden cardiac death
   3. Over 235 mutations associated with congenital LQT have been identified [23]
   4. Ion channel (mainly potassium channels, one sodium channel) mutations responsible
   5. These ion channel mutations lead to prolongation of ventricular action potential
   6. SCD risk increased in males versus females and with syncopal episodes [24]
   7. ß-adrenergic blockers are mainstay of therapy; reduce cardiac death risk [24]
   8. Genetic locus involved and QT duration are greatest risks for cardiac events (not sex) [19]
   9. Genetic algorithm for screening has been developed and appears efficient [23]
   10. 58% of probands carried nonprivate mutations in 64 codons (most efficient initial screen) [23]
   11. Automatic implantable defibrillators may be beneficial
   12. Genotype specific therapies are being developed
2. Long QT Syndrome 1 (LQT1) [9]
   1. Jervell and Lange-Nielsen Syndrome
   2. Autosomal recessive with deafness
   3. Dysfunction of slow delayed rectifier potassium (K+) channel, KS
   4. Due to homozygous mutatations in chr 11p15 gene KVLQT1
   5. Homozygous mutations of KVLQT1 leads to decreased K+ outward currents, I(Ks)
   6. Homozygous mutations of KVLQT1 or KCNE1 cause deafness
   7. Cardiac events occurred in >60% of patients with LQT1 syndrome [10]
   8. Treat with ß-blockers and K+ channel opener (such as nicorandil)
   9. ~42% of LQT syndromes
   10. Risk of cardiac event before age 40 with LQT1 is 30% [19]
3. Long QT Syndrome 2 (LQT2)
   1. LQT2 is due to mutation in rapid delayed rectifier K+ (IKr) channel subunit called HERG
   2. HERG is human ether-a-go-go gene (a leg shaking mutation in fruit flies)
   3. HERG codes for a potassium channel with six transmemebrane subunits
   4. Mutations in HERG lead to reduction in K+ outward currents, I(Kr)
   5. Cardiac events occurred in ~45% of patients with LQT2 syndrome [10]
   6. Drug induced QT prolongation usually due to inhibition of IKr
   7. Most new drugs are screened for binding to HERG channels prior to clinical development
   8. Treat with spironolactone, K+ supplements, ß-blockers
   9. ~45% of LQT syndromes, most drug associated prolongation of QTc
   10. Risk of cardiac event before age 40 with LQT2 is 46% [19]
4. Long QT Syndrome 3 (LQT3)
   1. Mutations in cardiac sodium (Na+) channel - SCN5a
   2. Disease causing mutations lead to increased inward Na+ current
   3. All mutations causing this disease are found in cytopaslmic loop called III-IV linker
   4. This loop forms the h (delayed) gate of the Na channel
   5. Failure to close the h gate properly will prolong depolarization and slow repolarization
   6. This mutation predisoposes to drugs that target the h gate (such as mexilitine)
   7. Cardiac events occurred in 18% of patients with LQT3 syndrome [10]
   8. One child resuscitated from sudden infant death (SIDS) shown to have SCN5a mutations [11]
   9. Brugada syndrome is also usually due to SCN5a mutations [14]
   10. Mexilitine, ß-blockade and cardiac pasing are used
   11. ~8% of LQT syndromes
   12. Risk of cardiac event before age 40 with LQT3 is 42% [19]
5. Long QT Syndrome 4
   1. Described in single family
   2. Genetic mutation(s) in are not known
6. Long QT Syndrome 5
   1. Mutations in KCNE1 (minK) gene
   2. KCNE1 is a component of the slow delayed rectifier K+ channel, I(KS)
   3. Result is decreased outward K+ currents
   4. Autosomal recessive
7. Long QT Syndrome 6
   1. Mutations in KCNE2 gene
   2. KCNEs is a component of the rapid delayed rectifier K+ channel, I(Kr)
   3. Result is decreased outward K+ currents
8. Romano-Ward Syndrome [12]
   1. Autosomal dominance without deafness
   2. Linked to short arm of chromosome 11 (chr 11p15), chr 7q, and chr 3p21
   3. These genes encode cardiac potassium (chr 11p and 7q) and sodium ion channels [13]
   4. Extent of QTc prolongation does not not predict morbidity or mortality
   5. Thus, Romano-Ward Syndrome is composed of LQT1, LQT2, and LQT3 genotypes

Resources

QT Corrected

References

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