The Effect Of CaMKⅡ Inhibition On Systolic And Diastolic Function In Failing Heart

Background Recent studies point to CaMKⅡ as a novel therapeutic target in structural heart diseases.However,the role of CaMKII in maintaining normal diastolic function is under investigated.Objective To test the effect of CaMKII inhibition on systolic and diastolic function in heart failure(HF).Methods CaMKⅡ inhibition was achieved by in vivo daily injection of CaMKII inhibitor KN93(10μmol/kg,IP)for 1 week.HF was induced by severe aortic thoracic banding(sTAB).Results HF was produced in one week after sTAB and heart function then remains stable from the post-sTAB week 2 to 5.Compared to the HF mice treated with KN93 inactive analogue KN92,LV myocardium treated with KN93 showed a reduction of overall CaMKⅡ activity by 50±0.2%with a reduction of CaMKII-dependent pHospHorylation of PLB-Thr17(80±1%)andRyR-2815(30±7%).CaMKII inhibition in HF mice produced a significant increase in systolic function(increased EF)but impairs diastolic function(increased E/E’).LV myocytes from KN93 treated failing mice showed a significant reduction of SR Ca2+ leak;an increase in Ca2+ content,Ca2+ transient and sarcomere shortening.Importantly,KN93 treated HF myocytes showed prolonged sarcomere relaxation,abolished FDAR,increased myofilament sensitivity to Ca2+associated with decrease of CaMKII-dependent troponin-I pHospHorylation and increased stiffness of myocytes.Conclusions CaMKII inhibition significantly impairs both active and passive diastolic function.These results challenge recent idea that CaMKII inhibition is a beneficial treatment strategy in patients with structural heart disease by pointing to a caution of diastolic dysfunction.