Abstract 14816: Screening for Acute Ikr Block is Insufficient to Detect Torsades Liability: Role of Late Sodium Current
Background: New drug entities are routinely screened for IKr blocking properties that are thought to predict QT prolonging and arrhythmogenic liability. However, recent data suggest that chronic (hours) but not acute exposure to PI3 kinase (PI3K) inhibitors used in cancer can prolong QT by inhibiting K+ currents and increasing late Na+ 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: As expected, acute exposure to dofetilide, an IKr blocker without other recognized electropharmacologic actions, did not alter ion currents or action potentials (APs) in adult mouse cardiomyocytes, which lack IKr. By contrast, chronic exposure (5 hours) to the drug prolonged APs, generated afterdepolarizations in 15/19 cells, and markedly increased INa-L: 0.55±0.06 (control) vs 2.77±0.24 pA/pF after 5 hr (±SE, n=10, p<0.001); K+ current was unaltered. Including PIP3, a downstream effector for the PI3K pathway, in the pipette reversed these effects. INa-L was also increased, and inhibited by pipette PIP3, with 5 hr dofetilide exposure in human iPSC-derived cardiomyocytes and in CHO cells transfected with SCN5A. The effects of dofetilide were time- and concentration-dependent: increased INa-L was observed with ≥10 nM and ≥2 hr exposure. Chronic exposure to E4031 and d-sotalol, thought to be arrhythmogenic by blocking IKr, also increased INa-L in CHO cells but there was little or no effect with haloperidol or moxifloxacin, IKr blockers that are less arrhythmogenic. Moxifloxacin (5 hr; 100 μM) did not alter APs or induce afterdepolarizations in mouse cardiomyocytes.
Conclusions: Chronic (hours) exposure to some but not all drugs designated as arrhythmogenic IKr blockers can generate arrhythmias by augmenting INa-L through the PI3K pathway. Screening new drugs for acute IKr block is insufficient to identify long QT-related arrhythmogenic drug actions.
- © 2013 by American Heart Association, Inc.