private correspondence

2 Background—New drugs are routinely screened for acute IKr blocking properties thought to predict QT prolonging and arrhythmogenic liability. However, recent data suggest that chronic (hours) drug exposure to PI3 kinase (PI3K) 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, 2-48 hours ’ exposure to the drug generated arrhythmogenic afterdepolarizations and up to 15-fold increases in INa-L. Including PIP3, a downstream effector for the PI3K pathway, in the pipette inhibited these effects. INa-L was also increased, and inhibitable by PIP3, with hours of dofetilide exposure in human iPSC-derived cardiomyocytes and in CHO cells transfected with SCN5A, encoding INa. Cardiomyocytes fro