Cytoplasmic CaMKIIδ-B prevents myocardial recovery in heart failure.

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 Ca/calmodulin-dependent protein kinase IIδ (CaMKIIδ-B) inversely correlated with recovery. Furthermore, increased phosphorylation near the CaMKIIδ-B nuclear localization signal in non-responders prevented its auto-activation dependent nuclear translocation. Expression of a cytoplasm-restricted CaMKIIδ-B in cardiomyocytes dramatically remodeled the phospho-proteome and impaired contractility, while a nuclear-competent version did not. Modulating CaMKIIδ subcellular localization may thus represent a therapeutic strategy for advanced heart failure.