title: Slow delayed rectifier potassium current blockade contributes importantly to drug-induced long QT syndrome.
abstract: BACKGROUND
  Drug-induced long QT syndrome is generally ascribed to inhibition of the cardiac rapid delayed rectifier potassium current (IKr). Effects on the slow delayed rectifier potassium current (IKs) are less recognized. Triggered by a patient who carried the K422T mutation in KCNQ1 (encoding the α-subunit of the IKs channel), who presented with excessive QT prolongation and high serum levels of norfluoxetine, we investigated the effects of fluoxetine and its metabolite norfluoxetine on IKs.
  
  
  RESULTS
  ECG data from mutation carriers and noncarriers revealed that the K422T mutation per se had mild clinical effects. Patch clamp studies, performed on HEK293 cells, showed that heterozygously expressed K422T KCNQ1/KCNE1 channels had a positive shift in voltage dependence of activation and an increase in deactivation rate. Fluoxetine and its metabolite norfluoxetine both inhibited KCNQ1/KCNE1 current, with norfluoxetine being the most potent. Moreover, norfluoxetine increased activation and deactivation rates. Computer simulations of the effects of norfluoxetine on IKs and IKr demonstrated significant action potential prolongation, to which IKs block contributed importantly. Although the effects of the mutation per se were small, additional IKs blockade by norfluoxetine resulted in more prominent QTc prolongation in mutation carriers than in noncarriers, demonstrating synergistic effects of innate and drug-induced IKs blockade on QTc prolongation.
  
  
  CONCLUSIONS
  IKs blockade contributes importantly to drug-induced long QT syndrome, especially when repolarization reserve is reduced. Drug safety tests might have to include screening for IKs blockade.
authors.affiliation: Heart Center, and Departments of Anatomy, Embryology, and Physiology, Cardiology, Hospital Pharmacy, Academic Medical Center, University of Amsterdam, the Netherlands; and Department of Hospital Pharmacy, Reinier de Graaf Group Hospitals, Delft, the Netherlands.
authors.forename: Christiaan C
authors.initials: CC
authors.lastname: Veerman
authors.forename: Arie O
authors.initials: AO
authors.lastname: Verkerk
authors.forename: Marieke T
authors.initials: MT
authors.lastname: Blom
authors.forename: Christine A
authors.initials: CA
authors.lastname: Klemens
authors.forename: Pim N J
authors.initials: PN
authors.lastname: Langendijk
authors.forename: Antoni C G
authors.initials: AC
authors.lastname: van Ginneken
authors.forename: Ronald
authors.initials: R
authors.lastname: Wilders
authors.forename: Hanno L
authors.initials: HL
authors.lastname: Tan
mesh_terms: D000200:Action Potentials; D002478:Cells, Cultured; D003198:Computer Simulation; D004452:Echocardiography; D004562:Electrocardiography; D005080:Exercise Test; D005260:Female; D005473:Fluoxetine / Q000009:adverse effects*; D006801:Humans; D051657:KCNQ1 Potassium Channel / Q000235:genetics*; D008133:Long QT Syndrome / Q000139:chemically induced* / Q000235:genetics*; D008875:Middle Aged; D016296:Mutagenesis; D009154:Mutation; D018408:Patch-Clamp Techniques; D010375:Pedigree; D024642:Potassium Channels, Voltage-Gated / Q000235:genetics*; D012307:Risk Factors; D017367:Selective Serotonin Reuptake Inhibitors / Q000009:adverse effects*
chemical_list: D005473:Fluoxetine; D051657:KCNQ1 Potassium Channel; D024642:Potassium Channels, Voltage-Gated; D017367:Selective Serotonin Reuptake Inhibitors; C489622:KCNE1 protein, human
keywords: drug-induced long QT syndrome; fluoxetine; long QT syndrome; potassium channels; torsade de pointes