Abstract 951: A Rapid Delayed-Rectifier Current Activator Ameliorates Repolarization and Suppresses Arrhythmias in Rabbit Models of Acquired Long QT Syndrome: A Novel Therapeutic Approach Targeting Underlying Ionic Mechanisms
Background: Impaired cardiomyocyte repolarization leads to prolonged action potentials reflected as long QT (LQT) intervals associated with increased susceptibility to Torsades de Pointes (TdP). Current pharmacological treatment of LQT syndrome is often inadequate. This study evaluated the antiarrhythmic effect of a novel compound (NS1643) that activates the rapid delayed-rectifier K+ current, IKr, in two rabbit models of spontaneous TdP related to abnormal IKr function.
Methods and Results: We used two clinically-relevant rabbit models of spontaneous TdP to which we infused NS1643 or vehicle (VCL):
3-week AV block with ventricular bradypacing;
dofetilide (DOF) induced IKr inhibition in methoxamine-sensitized rabbits.
Bradypaced rabbits developed frequent ventricular ectopy and TdP. Infusion of NS1643 (45 mg/kg/hr) completely suppressed arrhythmic activity and shortened the QT interval, whereas VCL had no effect (Fig A and B⇓). NS1643 (35 mg/kg/hr) reduced the number of ectopic beats and episodes of ventricular tachycardia caused by infusion of DOF (1.8 mg/kg/hr, Fig C⇓), and reversed QT prolongation caused by a DOF load (0.6 mg/kg, Fig D⇓). In patch clamp experiments on cardiomyocytes isolated from normal and bradycardic rabbits, NS1643 increased IKr by 75 and 50% respectively (*p<0.01 for each). Similarly, NS1643 restored IKr suppressed by 5 nM DOF (0.28±.03 pA/pF pre-DOF vs 0.20±.01 pA/pF* DOF vs 0.27±.02 pA/pF DOF+NS1643).
Conclusions. Pharmacological activation of IKr reverses acquired LQT syndrome and TdP caused by cardiac remodeling and IKr blocking drugs. IKr activation is an interesting novel potential treatment approach for patients with LQT syndrome.