Dan Roden
Faculty Member
Last active: 2/8/2016

Screening for acute IKr block is insufficient to detect torsades de pointes liability: role of late sodium current.

Yang T, Chun YW, Stroud DM, Mosley JD, Knollmann BC, Hong C, Roden DM
Circulation. 2014 130 (3): 224-34

PMID: 24895457 · PMCID: PMC4101031 · DOI:10.1161/CIRCULATIONAHA.113.007765

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.

METHODS AND 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.

© 2014 American Heart Association, Inc.

MeSH Terms (26)

4-Aminopyridine Action Potentials Animals Cells, Cultured CHO Cells Cricetinae Cricetulus Drug Evaluation, Preclinical Female HEK293 Cells Humans Mice Mice, Inbred C57BL Models, Animal Myocytes, Cardiac NAV1.5 Voltage-Gated Sodium Channel Patch-Clamp Techniques Phenethylamines Phosphatidylinositol 3-Kinases Potassium Channel Blockers Proto-Oncogene Proteins c-akt Risk Factors Signal Transduction Sulfonamides Torsades de Pointes Transfection

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