Calcium/Calmodulin-Dependent Protein Kinase II Contributes to Cardiac Arrhythmogenesis in Heart Failure

Abstract

Background— Transgenic (TG) Ca/calmodulin-dependent protein kinase II (CaMKII)δ _C mice have heart failure and isoproterenol (ISO)-inducible arrhythmias. We hypothesized that CaMKII contributes to arrhythmias and underlying cellular events and that inhibition of CaMKII reduces cardiac arrhythmogenesis in vitro and in vivo. Methods and Results— Under baseline conditions, isolated cardiac myocytes from TG mice showed an increased incidence of early afterdepolarizations compared with wild-type myocytes ( P P −8 M) induced a larger amount of delayed afterdepolarizations and spontaneous action potentials in TG compared with wild-type cells ( P i rose clearly on ISO in TG but not in wild-type cells (+20�5% versus +3�4% at 10 ⁻⁶ M ISO, P −1 �s ⁻¹ , P P P P P Conclusions— We conclude that CaMKII contributes to cardiac arrhythmogenesis in TG CaMKIIδ _C mice having heart failure and suggest the increased SR Ca leak as an important mechanism. Moreover, CaMKII inhibition reduces cardiac arrhythmias in vitro and in vivo and may therefore indicate a potential role for future antiarrhythmic therapies warranting further studies.