Biomarkers of Neutrophil Activation in Patients with Symptomatic Chronic Peripheral Artery Disease Predict Worse Cardiovascular Outcome

Abstract

Neutrophils play a role in cardiovascular (CV) disease. However, relatively scant evidence exists in the setting of peripheral artery disease (PAD). The aims of this study were to measure biomarkers of neutrophil activation in patients with symptomatic chronic PAD compared with healthy controls, to assess their association with PAD severity, and to evaluate their prognostic value in patients with PAD. The following circulating markers of neutrophil degranulation were tested: polymorphonuclear neutrophil (PMN) elastase, neutrophil gelatinase-associated lipocalin (NGAL), and myeloperoxidase (MPO). Neutrophil extracellular traps (NETs) were quantified by measuring circulating MPO–DNA complexes. Patients with PAD underwent a comprehensive series of vascular tests. The occurrence of 6-month major adverse CV (MACE) and limb events (MALE) was assessed. Overall, 110 participants were included, 66 of which had PAD. After adjustment for conventional CV risk factors, PMN-elastase (adjusted odds ratio [OR]: 1.008; 95% confidence interval [CI]: 1.002–1.015; p = 0.006), NGAL (adjusted OR: 1.045; 95%CI: 1.024–1.066; p < 0.001), and MPO (adjusted OR: 1.013; 95%CI: 1.001–1.024; p = 0.028) were significantly associated with PAD presence. PMN-elastase (adjusted hazard ratio [HR]: 1.010; 95%CI: 1.000–1.020; p = 0.040) and MPO (adjusted HR: 1.027; 95%CI: 1.004–1.051; p = 0.019) were predictive of 6-month MACE and/or MALE. MPO displayed fair prognostic performance on receiver operating characteristic (ROC) curve analyses, with an area under the curve (AUC) of 0.74 (95%CI: 0.56–0.91) and a sensitivity and specificity of 0.80 and 0.65, respectively, for a cut-off of 108.37 ng/mL. MPO–DNA showed a weak inverse correlation with transcutaneous oximetry (TcPO2) on proximal foot (adjusted ρ −0.287; p = 0.032). In conclusion, in patients with symptomatic chronic PAD, enhanced neutrophil activity may be associated with an increased risk of acute CV events, rather than correlate with disease severity. Further research is needed to clarify the role of neutrophils in PAD natural history.

Identification of Disease-relevant, Sex-based Proteomic Differences in iPSC-derived Vascular Smooth Muscle

“…While the exact pathways upregulated are different, the upregulation of pathways related to inflammatory signals in primary cell types versus iPSC-derived cells mirrors our previous results on work in endothelial cells 83 and suggests that systemic immune-derived signals may be important for provoking a fully mature vascular cell phenotype. In terms of cardiovascular disease relevance, cytokines are key regulators of inflammatory response, especially in abdominal aortic aneurysm pathogenesis 84 , and neutrophils have been found in atherosclerotic human lesions 85 and may play a role in peripheral artery disease 86 . Thus, considering expression level of proteins in these pathways will be important for utilizing these iVSMCs for cardiovascular disease modeling.…”