The effect of omecamtiv mecarbil in hospitalized patients as compared with outpatients with HFrEF: an analysis of GALACTIC-HF

BACKGROUND: In the Global Approach to Lowering Adverse Cardiac Outcomes Through Improving Contractility in Heart Failure (GALACTIC-HF) trial, omecamtiv mecarbil, compared with placebo, reduced the risk of worsening heart failure (HF) events or cardiovascular death in patients with HF and reduced ejection fraction (HFrEF). The primary aim of this prespecified analysis was to evaluate the safety and efficacy of omecamtiv mecarbil by randomization setting i.e., whether participants were enrolled as outpatients or inpatients. METHODS AND RESULTS: Patients were randomized either during a HF hospitalization or as an outpatient, within one year of a worsening HF event (hospitalization or emergency department [ED] visit). The primary outcome was a composite of worsening HF event (HF hospitalization or an urgent ED or clinic visit) or cardiovascular death. Of the 8232 patients analyzed, 2084 (25%) were hospitalized at randomization. Hospitalized patients had higher NT-proBNP concentrations, lower systolic blood pressure, reported more symptoms and were less frequently treated with a renin-angiotensin system blocker or a beta-blocker than outpatients. The rate (per 100 person-years [PY]) of the primary outcome was higher in hospitalized patients (placebo group=38.3/100 PY) than in outpatients (23.1/100 PY); adjusted hazard ratio (HR) 1.21 (95%CI 1.12, 1.31). The effect of omecamtiv mecarbil versus placebo on the primary outcome was similar in hospitalized patients (HR 0.89, 95%CI 0.78, 1.01) and outpatients (HR 0.94, 95%CI 0.86, 1.02) (interaction P=0.51). CONCLUSION: Hospitalized HFrEF patients had a higher rate of the primary outcome than outpatients. Omecamtiv mecarbil reduced the risk of the primary outcome both when initiated in hospitalized patients and in outpatients

Asymmetrically localized proteins stabilize basal bodies against ciliary beating forces

Basal bodies are radially symmetric, microtubule-rich structures that nucleate and anchor motile cilia. Ciliary beating produces asymmetric mechanical forces that are resisted by basal bodies. To resist these forces, distinct regions within the basal body ultrastructure and the microtubules themselves must be stable. However, the molecular components that stabilize basal bodies remain poorly defined. Here, we determine that Fop1 functionally interacts with the established basal body stability components Bld10 and Poc1. We find that Fop1 and microtubule glutamylation incorporate into basal bodies at distinct stages of assembly, culminating in their asymmetric enrichment at specific triplet microtubule regions that are predicted to experience the greatest mechanical force from ciliary beating. Both Fop1 and microtubule glutamylation are required to stabilize basal bodies against ciliary beating forces. Our studies reveal that microtubule glutamylation and Bld10, Poc1, and Fop1 stabilize basal bodies against the forces produced by ciliary beating via distinct yet interdependent mechanisms