Abstract 1077: Calmodulin Kinase Inhibition Prevents the Arrhythmogenesis in RyR2 R4496C+/- knock-in Mice
Background: Calcium leak from mutant ryanodine receptor induced triggered activity (TA) is the likely mechanism for arrhythmias in catecholaminergic polymorphic ventricular tachycardia (CPVT). Previously we demonstrated that inhibition of Ca2+/calmodulin-dependent protein kinase II (CaMKII) can completely abolished and prevent TA in our RyR2R4496C+/- knock-in mice (HE) in vitro. Whether it also prevents the arrhythmogenesis in vivo and the underlying mechanism are unknown.
Methods and results: we found that KN93 (30 μmol/kg IP), a CaMKII inhibitor, completely abolished the ventricular tachyarrhythmia induced by epinephrine (Epi) 2 mg/kg and caffeine (Caf) 120 mg/kg in HE mice, but not in saline-treated HE mice (0/12 vs 6/12, P<0.05). Isolated ventricular myocytes from wild-type (WT) and HE mice were studied with whole cell patch clamp. KN93 (1 μmol/L) significantly reduced the ICaL by 33% in presence of Epi (200 nmol/L) and Caf (300 μmol/L) (n=5, P0.05). Then we evaluated the SR Ca2+ contents by caffeine-induced Na+/Ca2+ exchange current (see Fig⇓), Epi and Caf significantly reduced the SR Ca2+ contents in HE cells (P<0.01), but not in WT cells; interestingly KN93 reversed the Epi+Caf-induced SR calcium depletion in HE cells (P<0.05).
Conclusions: The inhibition of CaMKII signalling pathway may represent a promising therapeutic strategy in CPVT. The comprehensive roles of inhibiting calcium influx and healing SR calcium leak are the likely underlying mechanism for antiarrhythmic effects of CaMKII inhibition in CPVT.