Abstract 3541: CaMKII Inhibition Improves Contractility in Human Failing Myocardium
Heart failure (HF) is known to be associated with increased CaMKII activity. There is still controversial discussion about the role of by Ca/calmodulin-dependent protein kinase (CaMKII) in HF. CaMKII has never been functionally investigated in human myocardium. We performed experiments using 25 human end-stage failing and 13 nonfailing (NF) hearts. Expression analysis revealed that CaMKII was significantly increased by 28±6% in DCM (n=10) and by 30±5% in ICM (n=7) compared to NF (n=13). Experiments with isometrically twitching trabeculae (37° C, pH 7.4, Ca2+ 2 mM, n=13 each) revealed significantly improved force-frequency-relationships (FFR) during CaMKII inhibition with KN93 (2 μM) compared to trabeculae treated with the inactive control peptide KN92 (2 μM). While at low stimulation rates (e.g. 0.5–1 Hz) force amplitudes were not different between KN93 and KN92, we found a dramatically increase of twitch force with higher frequencies during CaMKII inhibition (by 69±18% at 2 and 101±39% at 3 Hz, n=13 each, p<0.05). Post-rest behaviour (steady state/post rest) was also significantly improved in the presence of KN93 at 120 s of rest 2.4±0.5 (KN93) vs. 1.5±0.3 (KN92, n=13 each, p<0.05) indicating an improved SR Ca2+ uptake or reduced SR Ca2+ leak. In order to confirm that improved contractility due to CaMKII inhibition results from a reduced SR Ca2+ leak, Ca2+ spark frequency was measured in isolated ventricular human failing myocytes. Indeed, preliminary data show a reduced Ca2+ spark frequency by 42% in the presence of KN93 (209±65 vs. KN92 297±68 1/(pl*s), n=6). Most importantly, RyR phosphorylation at Ser 2815, which is known to be phosphorylated by CaMKII was found to be markedly reduced in trabeculae that were CaMKII inhibited during experiments (n=6 each). This result correlates well with increased force amplitude of trabeculae that were CaMKII inhibited. The present study shows for the first time that CaMKII inhibition improves myocardial contractility most likely via a reduced SR Ca2+ leak in human HF where CaMKII is increased. Thus, CaMKII inhibition appears to be a promising option for patients with HF and merits further investigation.