title: Screening for acute IKr block is insufficient to detect torsades de pointes liability: role of late sodium current.
abstract: BACKGROUND
  New drugs are routinely screened for IKr blocking properties thought to predict QT prolonging and arrhythmogenic liability. However, recent data suggest that chronic (hours) drug exposure to phosphoinositide 3-kinase inhibitors used in cancer can prolong QT by inhibiting potassium currents and increasing late sodium current (INa-L) in cardiomyocytes. We tested the extent to which IKr blockers with known QT liability generate arrhythmias through this pathway.
  
  
  RESULTS
  Acute exposure to dofetilide, an IKr blocker without other recognized electropharmacologic actions, produced no change in ion currents or action potentials in adult mouse cardiomyocytes, which lack IKr. By contrast, 2 to 48 hours of exposure to the drug generated arrhythmogenic afterdepolarizations and ≥15-fold increases in INa-L. Including phosphatidylinositol 3,4,5-trisphosphate, a downstream effector for the phosphoinositide 3-kinase pathway, in the pipette inhibited these effects. INa-L was also increased, and inhibitable by phosphatidylinositol 3,4,5-trisphosphate, with hours of dofetilide exposure in human-induced pluripotent stem cell-derived cardiomyocytes and in Chinese hamster ovary cells transfected with SCN5A, encoding sodium current. Cardiomyocytes from dofetilide-treated mice similarly demonstrated increased INa-L and afterdepolarizations. Other agents with variable IKr-blocking potencies and arrhythmia liability produced a range of effects on INa-L, from marked increases (E-4031, d-sotalol, thioridazine, and erythromycin) to little or no effect (haloperidol, moxifloxacin, and verapamil).
  
  
  CONCLUSIONS
  Some but not all drugs designated as arrhythmogenic IKr blockers can generate arrhythmias by augmenting INa-L through the phosphoinositide 3-kinase pathway. These data identify a potential mechanism for individual susceptibility to proarrhythmia and highlight the need for a new paradigm to screen drugs for QT prolonging and arrhythmogenic liability.
authors.affiliation: From the Vanderbilt University School of Medicine, Nashville, TN.
authors.forename: Tao
authors.initials: T
authors.lastname: Yang
authors.affiliation: From the Vanderbilt University School of Medicine, Nashville, TN.
authors.forename: Young Wook
authors.initials: YW
authors.lastname: Chun
authors.affiliation: From the Vanderbilt University School of Medicine, Nashville, TN.
authors.forename: Dina M
authors.initials: DM
authors.lastname: Stroud
authors.affiliation: From the Vanderbilt University School of Medicine, Nashville, TN.
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Mosley
authors.affiliation: From the Vanderbilt University School of Medicine, Nashville, TN.
authors.forename: Bjorn C
authors.initials: BC
authors.lastname: Knollmann
authors.affiliation: From the Vanderbilt University School of Medicine, Nashville, TN.
authors.forename: Charles
authors.initials: C
authors.lastname: Hong
authors.affiliation: From the Vanderbilt University School of Medicine, Nashville, TN. dan.roden@vanderbilt.edu.
authors.forename: Dan M
authors.initials: DM
authors.lastname: Roden
mesh_terms: D015761:4-Aminopyridine / Q000494:pharmacology; D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000818:Animals; D016466:CHO Cells; D002478:Cells, Cultured; D006224:Cricetinae; D003412:Cricetulus; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D023421:Models, Animal; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000502:physiology; D062554:NAV1.5 Voltage-Gated Sodium Channel / Q000187:drug effects* / Q000235:genetics / Q000502:physiology*; D018408:Patch-Clamp Techniques; D010627:Phenethylamines / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D026902:Potassium Channel Blockers / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012307:Risk Factors; D015398:Signal Transduction / Q000502:physiology; D013449:Sulfonamides / Q000494:pharmacology; D016171:Torsades de Pointes / Q000453:epidemiology* / Q000503:physiopathology; D014162:Transfection
chemical_list: D062554:NAV1.5 Voltage-Gated Sodium Channel; D010627:Phenethylamines; D026902:Potassium Channel Blockers; C568321:Scn5a protein, mouse; D013449:Sulfonamides; D015761:4-Aminopyridine; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; C063533:dofetilide
keywords: KCNH2 potassium channel, human; Nav1.5 voltage-gated sodium channel; phosphatidylinositol 3-kinases; potassium channels