Neutrophil-lymphocyte ratio as a link between complex pedal ulcers and poor clinical results after infrainguinal surgical revascularization.

BACKGROUND: Our aim was to evaluate the influence of preoperative neutrophil-lymphocyte ratio (NLR) on patency and clinical results after infrainguinal surgical revascularization for chronic limb ischemia. METHODS: Retrospective analysis of 150 infrainguinal autologous bypasses performed to infragenicular popliteal artery or tibial vessels in 140 (93%) patients with chronic limb-threatening ischemia (CLTI) and in 10 (7%) with disabling claudication. NLR was calculated using blood samples obtained 24 hours preoperatively. The cohort was stratified into 2 groups according to interquartile ranges of NLR: "ELEVATED-NLR" (Quartile 4 N.=37) and "LOW-NLR" (Quartile 1-2-3 N.=113). Reperfused ulcers were described using the WIfI classification. Patency, freedom from MALE and amputation-free survival at 24 months were calculated using the Kaplan-Meier method. Univariate comparisons between NLR groups were performed using the Log-Rank test. Statistical differences on univariate analysis were adjusted in a multivariate model (Cox regression). RESULTS: NLR values were similar between CLTI and claudication. Ischemic ulcers were more frequent, (83.4% vs. 59.3% P<0.01), more severe (W2-3: 37.8% vs. 22.1% P=0.01) and pedal infection was deeper (fI 2-3: 40.5% vs. 18.6% P=0.003) in "ELEVATED-NLR" group. Severe ischemia (I3) was similar between groups. High NLR values were independent predictors of patency loss (HR: 1.77 CI95% [1.01-3.10] P=0.04), MALE (HR: 2.04 CI95% [1.03-4.04] P=0.04) and worse amputation-free survival (HR:2.10 CI95% [1.06-4.14] P=0.03) rates at 24 months. CONCLUSIONS: High preoperative NLR values are associated with severe and deep infected ulcers and predicts primary patency loss, higher major adverse limb events and worse amputation-free survival rates on long-term follow-up after infrainguinal surgical revascularization.

Aspirin-Dependent Platelet Inflammatory Inhibition in Healthy Subjects Decreases NLRP-1 Inflammasome.

BACKGROUND: Inflammation and endothelial dysfunction are implicated in the onset of atherosclerosis. Inflammasome activation takes part in the pathogenesis of the atherosclerotic disease. This study investigated the influence of platelet inflammatory inhibition on the transcription of intracitosolic nucleotide-binding oligomerization domain-like receptor protein 1 (NLRP-1) inflammasome in endothelial cells. METHODS: This experimental study enrolled 10 healthy volunteers with no cardiovascular risk factors and normal results on vascular examination. They received low doses of aspirin (100 mg/day) for seven days. A venous blood sample was collected in all subjects before aspirin intake and after the experimental week. Human aortic endothelial cell (HAEC) cultures were exposed to baseline plasma and plasma from subjects after aspirin intake. NLRP-1 gene expression was analyzed in these cultures. RESULTS: HAEC cultures that were exposed to plasma from subjects at baseline showed higher expression of NLRP-1 than HAECs exposed to plasma of healthy volunteers after one week on salicilate intake (relative quantification, 1.077 ± 0.05 vs. 1.002 ± 0.06; odds ratio, 1.8; 95 confidence interval, 1.1-2.9; P < 0.01). CONCLUSIONS: Data observed in the our study indicate that in HAECs, the intracytosolic NLRP-1 expression is attenuated by the auto/paracrine platelet inhibition by aspirin, without direct platelet-endothelial cell interaction.

Rationale and Design of Randomized Clinical Trial for the Assessment of Macitentan Efficiency as Coadjuvant Treatment to Open and Endovascular Revascularization in Critical Limb Ischemia.

INTRODUCTION: Critical limb ischemia (CLI) is defined by ischemic rest pain, tissue loss, or both, secondary to arterial insufficiency, and its prevalence is increasing mainly as a result of the worldwide high prevalence of diabetes. Currently, there are no available conclusive data on the efficacy of any coadjuvant therapy after revascularization procedure benefiting amputation and patency rates. Macitentan is an orally active dual endothelin (ET) receptor antagonist that may contribute to reduce the amputation rate and improve revascularization patency in CLI. METHODS/DESIGN: REVASC is a proposed pilot, open-label, controlled, randomized, single-center clinical double-blind trial to be conducted in Spain on a study population of European patients with CLI, which will compare the clinical outcomes and cost-effectiveness of macitentan coadjuvant treatment after limb revascularization with the standard antiplatelet treatment strategy for severe limb ischemia. Patients are randomized 1:1 to receive macitentan or placebo for 12 weeks. The primary clinical end point will be amputation-free survival rate at 12 months, defined as the time to major (above the ankle) amputation for the index (trial) limb or death from any cause, whichever comes first. Secondary outcomes include overall survival, quality of life, in-hospital mortality and morbidity, repeat interventions, healing of tissue loss, and hemodynamic changes following revascularization. Sample size is estimated as 120 patients. The economic analysis will consist of two components: a "within-study" analysis, which will be based on study end points; and a "model-based" analysis, which will extrapolate and compare costs and effects likely to accrue beyond the study follow-up period. DISCUSSION: The REVASC trial is designed to be pragmatic and represents current practice of the real-world population management after limb revascularization for CLI due to atherosclerosis. Current evidence does not support any coadjuvant treatment. A new pathway of treatment may be opened with the use of ET receptor antagonists in these patients.