Omecamtiv mecarbil in chronic heart failure with reduced ejection fraction, GALACTIC‐HF: baseline characteristics and comparison with contemporary clinical trials

Aims: The safety and efficacy of the novel selective cardiac myosin activator, omecamtiv mecarbil, in patients with heart failure with reduced ejection fraction (HFrEF) is tested in the Global Approach to Lowering Adverse Cardiac outcomes Through Improving Contractility in Heart Failure (GALACTIC‐HF) trial. Here we describe the baseline characteristics of participants in GALACTIC‐HF and how these compare with other contemporary trials. Methods and Results: Adults with established HFrEF, New York Heart Association functional class (NYHA) ≥ II, EF ≤35%, elevated natriuretic peptides and either current hospitalization for HF or history of hospitalization/ emergency department visit for HF within a year were randomized to either placebo or omecamtiv mecarbil (pharmacokinetic‐guided dosing: 25, 37.5 or 50 mg bid). 8256 patients [male (79%), non‐white (22%), mean age 65 years] were enrolled with a mean EF 27%, ischemic etiology in 54%, NYHA II 53% and III/IV 47%, and median NT‐proBNP 1971 pg/mL. HF therapies at baseline were among the most effectively employed in contemporary HF trials. GALACTIC‐HF randomized patients representative of recent HF registries and trials with substantial numbers of patients also having characteristics understudied in previous trials including more from North America (n = 1386), enrolled as inpatients (n = 2084), systolic blood pressure < 100 mmHg (n = 1127), estimated glomerular filtration rate < 30 mL/min/1.73 m2 (n = 528), and treated with sacubitril‐valsartan at baseline (n = 1594). Conclusions: GALACTIC‐HF enrolled a well‐treated, high‐risk population from both inpatient and outpatient settings, which will provide a definitive evaluation of the efficacy and safety of this novel therapy, as well as informing its potential future implementation

Modulation of plant cytokinin levels in the Wolbachia -free leaf-mining species Phyllonorycter mespilella

International audienceAs phytohormones lie at the very core of molecular mechanisms controlling the plant physiology and development, they have long been hypothesized to be involved in insect-induced plant manipulations. Cytokinins (CKs) are phytohormones now widely recognized to be utilized by leaf-mining and gall-inducing insects in the control of the physiology of their host plant. In some leaf-mining moth species, larvae can supply the hormones themselves, bacterial symbionts contributing to the production of CKs. Our objective was to investigate whether closely related leaf-miner species sharing the same ecological niche but differing in their Wolbachia infection status develop similar strategies to manipulate their host plant. An extensive identification and quantification of CKs has been used to elucidate physiological patterns relevant for the plant-insect interactions. Our results show that modulation of plant CK levels is impaired in the Wolbachia-free leaf-mining moth Phyllonoryc-ter mespilella (H€ ubner) (Lepidoptera: Gracillariidae) contrasting with results previously observed in the closely related moth species Phyllonorycter blancardella (Fabricius) that produce and deliver CKs to the plant through an intricate interaction with Wolbachia. Our study suggests that mechanisms underlying colonization of the host plant and adaptation to fluctuating environmental conditions are different between the two leaf-miner species and that P. mespilella larvae most likely do not produce CKs. This species rather only buffers the degradation of CKs naturally occurring during the senescence of leaves leading to few active CKs being maintained at a sufficiently high level to induce and maintain a 'green island' phenotype (photosynthetically active green patches in otherwise senescing leaves). This study further provides converging experimental evidence pointing toward the influence of bacterial symbionts in the ability of leaf-mining moths to control the physiology of their host plant with consequences for their ecology and evolutionary diversification