Increased Late Sodium Current Contributes To Excess Prolongation Of Canine Ventricular Repolarization Induced By Dofetilide

Introduction: Drugs are screened for delayed rectifier potassium current (IKr) blockade to predict QT prolongation and proarrhythmic potential, but recent in vitro cell studies have shown chronic exposure (hours) to some IKr blockers (e.g. dofetilide, D) prolongs repolarization by increasing late sodium current (INa-L) via PI3 kinase inhibition. Hypothesis: Chronic D administration to intact dogs prolongs repolarization by blocking IKr and increasing INa-L. Methods: We continuously infused D into 6 dogs (6-9 μg/kg bolus+6-9 μg/kg/h IV infusion) for 7h, maintaining D plasma levels within the therapeutic range(2.4±0.2 to 5.2±0.6ng/ml). Acute and chronic D effects on action potential duration (APD) were studied in canine left ventricular (LV) subendocardial slabs using microelectrode techniques. Results: D infusion increased QTc and repolarization time (RT) continuously from baseline to 7h (Table). The INa-L blocker lidocaine (2mg/kg bolus) reduced all variables at 6.5h>0.5h (Table) (e.g. QTc: 19±2% vs 8±1%, P<.05). Chronic, but not acute, D increased apico-basal dispersion of RT, and lidocaine significantly attenuated this effect (Table). In LV subendocardium in vitro, D superfusion (0.2 μM) increased APD at 90% repolarization (APD90) from 232±8ms at baseline to 303±7 at 0.5h (P<.05) and 372±6 at 6.5h (P<.05 vs .5h)(n=6). Lidocaine (20 μM) decreased APD90 by 8±1% at 0.5h and 23±1% at 6.5h (P<.05). In comparison, moxifloxacin (100 μM), an IKr blocker with no effect on INa-L increased APD90 from 216±3ms to 282±5 at 1h (P<.05), and 289±5 at 6.5h (P>.05 vs 1h). Lidocaine reduced APD90 equally by 8% at both 1h and 6.5h (P>.05 for 1h vs 6.5h). Conclusions: Chronic D prolongs ventricular repolarization by blocking Ikr and increasing INa-L. Acquired LQT during chronic D dosing may be attributable to the INa-L increase, highlighting the need to include time and INa-L in evaluating the PI3K inhibition-derived proarrhythmic potential of new drugs.