Abstract 18209: The Effect of CaMKIIdelta Knockout on Cardiac E-C Coupling in Heart Failure

Background: CaMKII plays an important role in regulating cardiac excitation-contraction (E-C) coupling. Excessive CaMKII activation is linked to the development of cardiomyopathy and dysfunction of E-C coupling. Thus, CaMKII has been proposed to be a therapeutic target. Objective: we studied the effects of chronic CaMKII inhibition on cardiac Ca2+ handling and cell twitch in heart failure (HF) ventricular myocytes. Method and Results: Pressure-overload HF was produced in the wild type (WT) and CaMKIIdelta knockout (KO) mice by severe thoracic aortic banding (sTAB). HF mice were selected by the criteria of left ventricular (LV) ejection fraction (EF) Conclusions: This is the first model of HF with genetic CaMKII inhibition. Chronic inhibition of CaMKII reduces SR Ca2+ leak and increases SR Ca2+ contents and contractility in HF LV but aggravates cellular relaxation, especially at fast pacing rate. These results support the strategy of CaMKII inhibition in HF but also implicate physiologic level of CaMKII activity in maintaining normal ventricular relaxation.