Neutrophils perform an important antimicrobial function through processes such as neutrophil extracellular trap formation (NETosis). In addition to infections, NETosis has also been observed in sterile inflammatory processes such as atherosclerosis, in which factors within the plaque such as oxidized lipids, complement, inflammatory cytokines, and immune complexes can induce NETosis. NETosis contributes importantly to atherosclerotic plaque formation through multiple mechanisms. These include endothelial cell activation leading to increased leukocyte transmigration into the subintimal space. NETs also promote activation of immune cells such as monocytes, macrophages, and T cells within the developing plaque, and contribute to the developing necrotic core through inducing apoptosis of monocytes/macrophages. Within advanced atherosclerotic plaques, evidence suggests that NETosis promotes thinning and rupture of the protective fibrous cap through induction of smooth muscle cell apoptosis and degradation of the extracellular matrix. Atherosclerotic plaque rupture leads to clot formation and clinical sequelae of atherosclerosis, with extracellular histones and myeloperoxidase released in NETosis contributing to this pro-thrombotic milieu. Taken together, NETosis appears to play an important role in multiple key aspects of atherogenesis and advanced plaque instability, thus representing a viable therapeutic target for ongoing clinical trials.
Background and Aims In SELECT, subcutaneous semaglutide (target dose 2.4 mg) weekly in adults with pre-existing cardiovascular disease and body mass index >= 27 kg/m(2) without diabetes significantly reduced major adverse cardiovascular events (MACE) by 20% vs placebo. This analysis explored potential mediators of this cardiovascular benefit. Methods Changes from randomization to 24 months in body weight, waist circumference, plasma high-sensitivity C-reactive protein (hsCRP), glycated haemoglobin (HbA(1c)), lipids, blood pressure, estimated glomerular filtration rate, and urinary albumin-to-creatinine ratio were examined individually, and in combination, as potential mediators of MACE risk reduction, using the Vansteelandt repeated regression method (a counterfactual approach). Results Semaglutide significantly (P < .05) improved all potential mediators investigated. Point estimates for % mediation were largest for waist circumference (64.0% [95% confidence interval (CI) 27.5, 179.6]), hsCRP (42.1% [17.9, 110.5]), HbA(1c) (29.0% [-20.7, 120.5]), and body weight (19.5% [-33.0, 110.7]), examined separately, but all had wide CIs. Supplementary analyses suggested unreliability of estimates for body weight and waist circumference, potentially due to differing relationship of body weight and waist change to MACE between treatment arms. Multivariable analysis estimated joint mediation for all potential mediators combined to be 31.4% (95% CI -30.1, 143.6). When variables other than body weight and waist circumference were considered, % mediation was 46.0% (95% CI -6.0, 161.0). Conclusions Mediation analyses could not fully ascribe the effects of semaglutide on MACE to known risk factors in SELECT with any certainty. Further investigation of potential additional biomarkers and mediators of semaglutide's cardiovascular protective effect are of interest. [GRAPHICS] .
