Increased CAMKII Activity Impairs Contractile Function in Human HCM Myocardium

Background and Rationale: we have previously shown that the myocardium of patients with Hypertrophic Cardiomyopathy (HCM) shows increased CaMKII activity with respect to non-HCM non-failing surgical patients (controls). We found higher phosphorylation levels of several tested CaMKII targets, such as L-Type Ca2+ channels, Na+ channels and phospholamban (Coppini et al., Circulation 2013). Such changes are likely to determine significant deleterious effects on the electrical and mechanical function of HCM myocardium.Methods: we assessed the effects of a selective inhibitor of CaMKII, the cell-permeant Autocamtide-related Inhibitory Peptide II (AIP-II), on force and intracellular Ca2+ in intact trabeculae and cardiomyocytes isolated from surgical septal samples of HCM patients who underwent myectomy.Results: HCM trabeculae display an increased diastolic tension and a slower kinetics of isometric force generation when compared to control trabeculae. AIP-II determines a reduction of diastolic tension, with larger effects at fast pacing rates (−13±3 % at 2Hz). Additionally, AIP-II accelerated the kinetics of force generation in HCM muscles (time to peak contraction at 1Hz: 255±17 ms at baseline vs. 232±10 ms with AIP-II, p<0.05). Accordingly, in HCM cardiomyocytes AIP-II lowered intracellular diastolic Ca2+ levels (from 278 ± 40 nM to 159 ± 28 nM, p<0.01) and reduced the frequency-dependent increase of diastolic [Ca2+]. The kinetics of Ca2+ transients, however, were not significantly affected by AIP-II. This suggests that reduced CaMKII phosphorylation of myofilament proteins may underlie the accelerated contractile kinetics observed in HCM trabeculae following AIP-II exposure.Discussion: The results indicate that increased activation of CaMKII plays a significant role in determining the abnormalities of myocardial contraction in HCM. Pharmacological inhibition of CaMKII may represent a viable option to reduce diastolic dysfunction in HCM patients.