Antiarrhythmic effect of IKr activation in a cellular model of LQT3

BackgroundLong QT syndrome type 3 (LQT3) is an inherited cardiac disorder caused by gain-of-function mutations in the cardiac voltage-gated sodium channel, Nav1.5. LQT3 is associated with the polymorphic ventricular tachycardia torsades de pointes (TdP), which can lead to syncope and sudden cardiac death. The sea anemone toxin ATX-II has been shown to inhibit the inactivation of Nav1.5, thereby closely mimicking the underlying cause of LQT3 in patients.ObjectiveThe hypothesis for this study was that activation of the IKr current could counteract the proarrhythmic effects of ATX-II.MethodsTwo different activators of IKr, NS3623 and mallotoxin (MTX), were used in patch clamp studies of ventricular cardiac myocytes acutely isolated from guinea pig to test the effects of selective IKr activation alone and in the presence of ATX-II. Action potentials were elicited at 1 Hz by current injection and the cells were kept at 32°C to 35°C.ResultsNS3623 significantly shortened action potential duration at 90% repolarization (APD90) compared with controls in a dose-dependent manner. Furthermore, it reduced triangulation, which is potentially antiarrhythmic. Application of ATX-II (10 nM) was proarrhythmic, causing a profound increase of APD90 as well as early afterdepolarizations and increased beat-to-beat variability. Two independent IKr activators attenuated the proarrhythmic effects of ATX-II. NS3623 did not affect the late sodium current (INaL) in the presence of ATX-II. Thus, the antiarrhythmic effect of NS3623 is likely to be caused by selective IKr activation.ConclusionThe present data show the antiarrhythmic potential of selective IKr activation in a cellular model of the LQT3 syndrome.