Martin, T. G.; Hunt, D. R.; Ebmeier, C. C.; Dhand, A. P.; Alamana, C.; Cleveland, J. C.; Graw, S. L.; Bruner, S.; Bristow, M. R.; Mestroni, L.; Taylor, M. R.; Burdick, J. A.; Ambardekar, A. V.; Buttrick, P. M.; Leinwand, L. A.

Restoration of cardiac function in patients with advanced heart failure is rare, and the molecular processes that regulate recovery are unknown. To identify potential mechanisms, we studied paired myocardial samples before and after left ventricular assist device therapy, where significant cardiac functional recovery occurred in ~25% of patients. We found that expression of the nuclear B isoform of Ca2+/calmodulin-dependent protein kinase II{delta} (CaMKII{delta}-B) inversely correlated with recovery. Furthermore, increased phosphorylation near the CaMKII{delta}-B nuclear localization signal in non-responders prevented its auto-activation dependent nuclear translocation. Expression of a cytoplasm-restricted CaMKII{delta}-B in cardiomyocytes dramatically remodeled the phospho-proteome and impaired contractility, while a nuclear-competent version did not. Modulating CaMKII{delta} subcellular localization may thus represent a therapeutic strategy for advanced heart failure.