Chronic exposure (2-48 hours) to certain IKr blockers like dofetilide generated arrhythmogenic afterdepolarizations and ≥15-fold increases in late sodium current via the PI3K pathway.
Some IKr blockers induce arrhythmias by augmenting late sodium current via the PI3K pathway after chronic exposure, indicating that acute IKr block screening is insufficient for detecting Torsades de Pointes liability.
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.
Yang et al. (Wed,) conducted a other in Torsades de Pointes Liability. IKr blockers (e.g., dofetilide) vs. Acute exposure was evaluated on Late sodium current (INa-L) and arrhythmogenic afterdepolarizations. Chronic exposure (2-48 hours) to certain IKr blockers like dofetilide generated arrhythmogenic afterdepolarizations and ≥15-fold increases in late sodium current via the PI3K pathway.