Rationale:: Heart failure (HF) is known to be associated with increased Ca²⁺/calmodulin-dependent protein kinase (CaMK)II expression and activity. There is still controversial discussion about the functional role of CaMKII in HF. Moreover, CaMKII inhibition has never been investigated in human myocardium.Objective:: We sought to investigate detailed CaMKIIδ expression in end-stage failing human hearts (dilated and ischemic cardiomyopathy) and the functional effects of CaMKII inhibition on contractility.Methods and Results:: Expression analysis revealed that CaMKIIδ, both cytosolic δ_Cand nuclear δ_Bsplice variants, were significantly increased in both right and left ventricles from patients with dilated or ischemic cardiomyopathy versus nonfailing. Experiments with isometrically twitching trabeculae revealed significantly improved force frequency relationships in the presence of CaMKII inhibitors (KN-93 and AIP). Increased postrest twitches after CaMKII inhibition indicated an improved sarcoplasmic reticulum (SR) Ca²⁺loading. This was confirmed in isolated myocytes by a reduced SR Ca²⁺spark frequency and hence SR Ca²⁺leak, resulting in increased SR Ca²⁺load when inhibiting CaMKII. Ryanodine receptor type 2 phosphorylation at Ser2815, which is known to be phosphorylated by CaMKII thereby contributing to SR Ca²⁺leak, was found to be markedly reduced in KN-93–treated trabeculae. Interestingly, CaMKII inhibition did not influence contractility in nonfailing sheep trabeculae.Conclusions:: The present study shows for the first time that CaMKII inhibition acutely improves contractility in human HF where CaMKIIδ expression is increased. The mechanism proposed consists of a reduced SR Ca²⁺leak and consequently increased SR Ca²⁺load. Thus, CaMKII inhibition appears to be a possible therapeutic option for patients with HF and merits further investigation.

The HeartMate 3 left ventricular assist system (LVAS) is intended to provide long-term support to patients with advanced heart failure. The centrifugal flow pump is designed for enhanced hemocompatibility by incorporating a magnetically levitated rotor with wide blood-flow paths and an artificial pulse. The aim of this single-arm, prospective, multicenter study was to evaluate the performance and safety of this LVAS. The primary endpoint was 6-month survival compared with INTERMACS (Interagency Registry for Mechanically Assisted Circulatory Support)-derived performance goal. Patients were adults with ejection fraction ≤ 25%, cardiac index ≤ 2.2 l/min/m(2) without inotropes or were inotrope-dependent on optimal medical management, or listed for transplant. Fifty patients were enrolled at 10 centers. The indications for LVAS support were bridge to transplantation (54%) or destination therapy (46%). At 6 months, 88% of patients continued on support, 4% received transplants, and 8% died. Thirty-day mortality was 2% and 6-month survival 92%, which exceeded the 88% performance goal. Support with the fully magnetically levitated LVAS significantly reduced mortality risk by 66% compared with the Seattle Heart Failure Model-predicted survival of 78% (p = 0.0093). Key adverse events included reoperation for bleeding (14%), driveline infection (10%), gastrointestinal bleeding (8%), and debilitating stroke (modified Rankin Score > 3) (8%). There were no pump exchanges, pump malfunctions, pump thrombosis, or hemolysis events. New York Heart Association classification, 6-min walk test, and quality-of-life scores showed progressive and sustained improvement. The results show that the fully magnetically levitated centrifugal-flow chronic LVAS is safe, with high 30-day and 6-month survival rates, a favorable adverse event profile, and improved quality of life and functional status. (HeartMate 3™ CE Mark Clinical Investigation Plan [HM3 CE Mark]; NCT02170363).