Primary Chronic Venous Insufficiency Is Distinguished by Attenuated Circulating Inflammatory Mediators and Healing Networks

Abstract

Inflammation promotes venous leg ulcers (VLUs) in post-thrombotic syndrome. However, it is not clear how inflammation affects VLU in primary venous reflux. Computational modeling has demonstrated differences in cytokine and chemokine networks in other wound healing paradigms. We hypothesize that serum inflammatory mediators are differentially expressed and disorganized in primary chronic venous insufficiency (CVI), which may be a mechanism for future VLU. Participants were recruited prospectively with Institutional Review Board approval. Blood was obtained during sclerotherapy or endovenous thermal ablation for primary CVI without ulcer (Clinical, Etiology, Anatomy, and Pathophysiology [CEAP] class C2-C4). Control patients without CVI underwent phlebotomy from great saphenous and antecubital veins. Demographics, Venous Clinical Severity Score, and body mass index (BMI) were collected. Twenty-five mediators previously shown to be important in wound healing were measured in serum with Luminex. Values were compared using Mann-Whitney U test. Pearson correlations among mediators (nodes; Fig, ●) that were above a specific threshold prompted connection between nodes (edges; Fig, —). Correlations were mapped as networks (MATLAB; MathWorks, Natick, Mass). “Complexity” was determined from number of connections for each mediator and total number of mediators. A robustness index measuring network strength was calculated by dividing number of connections at a Pearson correlation threshold of 0.95/0.7 Demographics, BMI, Venous Clinical Severity Score, and mean and standard error of the mean mediator values for patients (N = 42) and controls (leg; N = 7) are shown in the Table. Significant differences (P < .05) were demonstrated in 20 of 25 mediators; most reflected lower concentrations in patients. In controls, arm and leg values were nearly identical to one another and across patients. The Fig demonstrates networks of inflammatory mediators for each group, showing lower network complexity and robustness in CVI vs controls. The robustness index for patients, control leg, and control arm was 0.096, 0.169, and 0.241, respectively. CVI associates not only with age and BMI but also with diminished expression of many inflammatory compounds instrumental for wound healing. The relationship among these mediators is similarly weak. In contrast, mediators within competent veins show little variability and a high degree of correlation that is lacking in CVI. Dysregulated inflammatory networks in response to injury from venous hypertension may be a predisposing factor to further venous damage and VLU. Normalizing venous competency may improve baseline cytokine and chemokine interactions and the response to microstresses that can lead to wounds.TableDemographics for inflammatory mediators drawn from leg veins of patients and controlsPatients (N = 42)Controls (N = 7)PMeanSEMMeanSEMGM-CSF19.13.661.60.0<.001IFN-γ235.458.90.0<.001IL-12p7012.92.6410.0<.001IL-17A10.12.227.50.0<.001IL-710.31.530.50.0<.001MIG1227.2195.4313.40.0<.001sIL-2RA696.962.3252.10.0<.001IL-10183.151.50.0.001IL-1b7.51.520.90.0.001IL-437.79107.40.0.001IFN-α251.812.4110.50.0.002IL-1RA117.821.9306.90.0.002MIP-1β33.32.655.60.0.003IL-12p40116.628.7252.10.0.005IP-10685.365.3311.10.0.005IL-1512.92.4240.0.009TNF-α27.64.848.20.0.011IL-551.57.80.2.012IL-24.91.17.60.1.015IL-1332.812.737.20.3.045IL-68.71.520.80.0.059IL-814.23.214.80.4.157Eotaxin100.68.11130.4.265MCP-1343.729.9334.70.3.658MIP-1α5.91.82.60.21RangeRangeAge, years55.731-8834.721-47.008BMI, kg/m23219-482320-26.004VCSS6.52-141.10-2<.001Female71%43%BMI, Body mass index; GM-CSF, granulocyte-macrophage colony-stimulating factor; IFN, interferon; IL, interleukin; MCP, monocyte chemotactic protein; MIG, monokine induced by γ interferon; MIP, macrophage inflammatory protein; SEM, standard error of the mean; sIL, soluble interleukin; TNF, tumor necrosis factor; VCSS, Venous Clinical Severity Score.Values are reported as picogram/milliliter unless otherwise indicated. Open table in a new tab