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Long QT Syndromes  

Introduction

1. Both acquired and congenital forms of long QT Syndromes exist
2. Usually defined as a corrected QT (QTc) interval of >0.45 seconds
   • QTc <0.41 seconds is generally considered "normal"
   • QTc 0.41-0.45 seconds is of uncertain significance
3. Increasing concerns due to risk for serious morbidity and death
   • Symptoms usually due to Torsade de Pointes (TDP) or Ventricular Fibrillation
   • Light headedness, syncope, and death may occur
4. Ion Channels and the QT Interval
   The QT interval represents the repolarization phase of action potential
   Repolarization is due primarily to voltage dependent outward rectifying K+ currents
   The prolonged length of the QT interval in normal persons is due to inward K+ channels
   These inward rectifying potassium currents are also voltage dependent
   Hypocalcemia can prolong QT because Ca2+ can modulate a K+ channel

Drugs Associated with Prolongation of QT Interval

1. Antihistamines - Terfenadine (Seldane®) ,  Astemizole (Hismanal®)
2. Tricyclic Antidepressants
3. Phenothiazines and other Typical Neuroleptics
4. Cisapride (Propulsid®)
5. Drugs Contributing to QT Prolongation -
   • Erythromycin, Clarithromycin
   • Azole antifungals - ketoconazole, fluconazole and others
   • Digitalis toxicity
   • In most cases, these agents inhibit P450 metabolic enzymes
6. Hypomagnesemia and hypocalcemia may precipitate TDP in susceptible patients
7. Bradycardia with atrioventricular (AV) block can precipitate TDP

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Congenital Prolonged QT Syndromes

Long QT Syndrome 1

• Jervell and Lange-Nielsen Syndrome
• Autosomal recessive with deafness
• Arises due to mutatations in both chr 11p15 genes KVLQT1
• Homozygous mutations of KVLQT1 leads to QTc prolongation
• KVLQT1 codes for a part of the cardiac slow delayed rectifier potassium current channel

Long QT Syndrome 2

• LQT2 is due to mutation in K+ channel subunit called HERG
• HERG is human ether-a-go-go, also a leg shaking mutation in fruit flies
• HERG codes for a protein with six transmemebrane subunits

Long QT Syndrome 3

• Mutations in cardiac sodium (Na+) channel
• All mutations causing this disease are found in cytopaslmic loop called III-IV linker
• This loop forms the h (delayed) gate of the Na channel
• Failure to close the h gate properly will prolong depolarization and slow repolarization

Romano-Ward Syndrome [4]

• Autosomal dominance without deafness
• Linked to short arm of chromosome 11 (chr 11p15), chr 7q, and chr 3p21
• These genes encode cardiac potassium (chr 11p and 7q) and sodium ion channels [5]
• Extent of QTc prolongation does not not predict morbidity or mortality

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