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Nonthrombotic iliac vein lesions (NIVLs) are significant causes of chronic venous insufficiency (CVI) in the left lower limb and symptom recurrence following left lower limb varicose vein treatment. The goal of this study was to explore the haemodynamic and morphological characteristics of iliac veins in patients with NIVLs. Pressure at the caudal end of the stenotic left common iliac vein (LCIV) segment, local blood flow velocity, and time-averaged wall shear stress in the stenotic segment exhibited positive correlations with the clinical CVI classification (R = 0.92, p < 0.001; R = 0.94, p < 0.001; R = 0.87, p < 0.001), while the relative retention time showed a negative correlation (R = -0.94, p < 0.001). The pressure difference (∆P) between the two ends of the stenotic segment and the velocity difference (∆V) between the stenotic segment and the caudal end were positively correlated with the clinical classification (R = 0.92, p < 0.001; R = 0.9, p < 0.001). The cross-sectional area stenosis rate and length of the stenotic LCIV segment were positively correlated with the clinical classification (R = 0.93, p < 0.001; R = 0.63, p < 0.001). The results suggest that haemodynamic assessment of the iliac vein could effectively portray blood flow disturbances in stenotic segments of the LCIV, potentially reflecting the degree of iliac vein stenosis. Haemodynamic indicators are correlated with the severity of clinical CVI symptoms., (© 2024. The Author(s).)

Background: Varicose veins affect approximately 25% of people in industrialized countries., Methods: The study aimed at detecting apoptotic cells and histopathological changes in varicose vein walls. Patients (N.=41) with varicose veins and 30 control group patients were divided into two groups according to their age (younger and older than 50 years). Apoptosis was determined by the TUNEL assay, elastin and collagen IV expression by immunohistochemistry and ultrastructural changes by transmission electron microscopy., Results: The results show that the number of apoptotic cells in the layers of varicose veins increased, in particular in a group of patients aged over 50 years. In the varicose veins as compared to control veins the elastic fibers were found to be thinner, more fragmented and disorderly arranged. Elastin and collagen IV expression was found to decline in the intima and the media of varicose veins in both age groups. Electron microscopy demonstrated hypertrophy and degeneration of smooth muscle cells. Furthermore, cells with ultrastructural feature of apoptosis were noted. In the disorganized and expanded extracellular matrix membrane-bound vesicles, ghost bodies with different size and electron density were observed. Ghost bodies seem to bud off from smooth muscle cells and are likely to be involved in extracellular matrix remodeling as they are seen in close contact with collagen fibers., Conclusions: The study demonstrates increase of apoptotic cells in the wall of varicose veins along with vein wall structural abnormalities including alterations of smooth muscle cells and decline of elastin and collagen IV expression.

One of the early symptoms of chronic venous disease (CVD) is varicose veins (VV) of the lower limbs. There are many etiological environmental factors influencing the development of chronic venous insufficiency (CVI), although genetic factors and family history of the disease play a key role. All these factors induce changes in the hemodynamic in the venous system of the lower limbs leading to blood stasis, hypoxia, inflammation, oxidative stress, proteolytic activity of matrix metalloproteinases (MMPs), changes in microcirculation and, consequently, the remodeling of the venous wall. The aim of this review is to present current knowledge on CVD, including the pathophysiology and mechanisms related to vein wall remodeling. Particular emphasis has been placed on describing the role of inflammation and oxidative stress and the involvement of extracellular hemoglobin as pathogenetic factors of VV. Additionally, active substances used in the treatment of VV were discussed.

Background: To determine the composition of skin pigmentation in chronic venous insufficiency (CVI) and other less common vascular conditions of lower limbs., Methods: Forty-five skin biopsies were obtained from 17 patients. Samples were taken from pigmented regions and compared with control non-lesional samples from the same patient. Perl's Prussian Blue was used to identify haemosiderin and Schmorl's for melanin., Results: Seven patients presented with CVI, one with concurrent livedo vasculopathy (LV). One patient had LV only. Two patients had acroangiodermatitis (AAD). Six patients had post-sclerotherapy pigmentation (PSP), one with concurrent post-inflammatory hyperpigmentation (PIH). One patient had PIH only. The predominant pigment in CVI samples was haemosiderin. C5-C6 patients showed increased epidermal melanin. LV, AAD, and PSP samples showed dermal haemosiderin but no increase in epidermal melanin. PIH samples showed prominent epidermal melanin whilst no haemosiderin was detected., Conclusion: The predominant pigment in CVI and other vascular conditions was haemosiderin. Melanin was present in later stages of CVI (C5-C6) and in PIH., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Objective: Cyanoacrylate glue closure was first used in humans 10 years ago to treat venous reflux of the axial veins. Studies have since shown its clinical efficacy in vein closure. However, great need exists to elucidate further the types of specific adverse reactions that cyanoacrylate glue can cause for better patient selection and to minimize these events. In the present study, we systematically reviewed the literature to identify the types of reported reactions. In addition, we explored the pathophysiology contributing to these reactions and proposed the mechanistic pathway with inclusion of actual cases., Methods: We searched the literature for reports of reactions following cyanoacrylate glue use in patients with venous diseases between 2012 and 2022. The search was performed using MeSH (medical subject headings) terms. The terms included cyanoacrylate, venous insufficiency, chronic venous disorder, varicose veins, vein varicosities, venous ulcer, venous wound, CEAP (clinical, etiologic, anatomic, pathophysiologic), vein, adverse events, phlebitis, hypersensitivity, foreign body granuloma, giant cell, endovenous glue-induced thrombosis, and allergy. The search was limited to the literature reported in English. These studies were evaluated for the type of product used and the reactions noted. A systematic review, in accordance with the PRISMA (preferred reporting items for systematic reviews and meta-analyses) method, was performed. Covidence software (Melbourne, VC, Australia) was used for full-text screening and data extraction. Two reviewers reviewed the data, and the content expert served as the tiebreaker., Results: We identified 102, of which, 37 reported on cyanoacrylate use other than in the context of chronic venous diseases and were excluded. Fifty-five reports were determined appropriate for data extraction. The adverse reactions to cyanoacrylate glue were phlebitis, hypersensitivity, foreign body granuloma, and endovenous glue-induced thrombosis., Conclusions: Although cyanoacrylate glue closure for venous reflux is generally a safe and clinically effective treatment choice for patients with symptomatic chronic venous disease and axial reflux, some adverse events could be specific to the properties of the cyanoacrylate product. We propose mechanisms for how such reactions can occur based on histologic changes, published reports, and case examples; however, further exploration is necessary to confirm these theories., (Copyright © 2023 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.)

Abstract: Chronic lower extremity venous insufficiency can cause local dystrophy, and some patients will develop calf dystrophic calcification. In this case report, the authors describe a patient with varicose veins of both lower extremities, venous insufficiency of the lower extremities, recurring ulcers on the left leg for more than 20 years, and diabetes mellitus with dystrophic calcification of the calf. The patient's left leg ulcer showed extensive chronic inflammation, pathological calcification, and necrosis of the subcutaneous tissue with a thickness of approximately 0.5 to 1 cm. The computed tomography, X-ray, and hematoxylin-eosin staining results confirmed calcification; the leg skin thickened because of inflammatory irritation. After 11 months of treatment, the calcified and necrotic calcification and necrotic tissue were removed, and the wound healed., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Magnesium is the second most common cation in the cell. In addition to its role as a cofactor in many enzymatic pathways in physiological processes, it is necessary for the regular functioning of vascular smooth muscle cells. Magnesium deficiency has been associated with exacerbation of inflammation, which plays a role in the aetiopathogenesis of many diseases., Aim: To investigate the potential relationship between serum magnesium level and the development of chronic venous insufficiency by comparison with healthy individuals., Methods: The study included 394 patients with venous insufficiency based on physical examination findings and colour Doppler ultrasonography, and 206 controls without venous insufficiency. Venous insufficiency was defined by colour Doppler as reflux lasting 0.5 seconds or more in superficial veins, and longer than one second in femoral and popliteal veins. Clinical, haematological and biochemical parameters, including serum magnesium level and indicators of inflammation, were compared between groups., Results: A total of 600 participants were included. There was no significant difference between the groups in terms of age and gender. In total, 187 (47.46%) patients with chronic venous insufficiency and 105 (50.97%) of the control group were male (p=0.414). The median age of the patients with chronic venous insufficiency was 48 (min-max: 41-49), and the median age of the control group was 49.00 (min-max: 45.00-60.25) (p=0.064). Serum magnesium level was found to be significantly lower in the group with chronic venous insufficiency compared to the control group; 1.90 mg/dL (min-max: 1.82-2) versus 2.1 mg/dL (min-max: 2-2.2) (p<0.001), respectively., Conclusion: Low serum magnesium levels may pose a potential risk for the development of chronic venous insufficiency, which is common in the community.

Objectives: The treatment of a refluxing perforator is indicated in the setting of severe chronic venous insufficiency, but there are limited data on the presence of multilevel disease in these patients. This study sought to evaluate whether the presence of a pathologic perforator is predictive of the presence of central venous pathology., Methods: This study was a retrospective review of the institutional Vascular Quality Initiative database. Consecutive patient limbs were identified that underwent intervention of refluxing perforators. The patients who underwent imaging, including magnetic resonance imaging or computed tomography (group A), were compared with those who did not undergo imaging (group B). The treated limbs in group A were also compared with the contralateral limbs as an internal control. Anatomical findings on imaging were analyzed by two independent investigators. The primary outcome was the presence and degree of central venous stenosis as measured by an orthogonal diameter reduction of >50% by axial imaging. Secondary outcomes included demographic and clinical differences between the two groups, frequency of central venous intervention, and duration of ulcer healing. Standard statistical analysis was performed., Results: Ninety-three patient limbs underwent treatment of a pathologic perforator, with 30 in group A and 63 in group B. The following demographic and clinical variables were higher in group A compared with group B: male sex, body mass index, deep venous thrombosis history, recent or active anticoagulation use, perforator diameter, Clinical Etiology Anatomy Pathophysiology class 4, 5, or 6, and Venous Clinical Severity Score. Radiographic analysis of group A revealed concordance of a treated pathologic perforator with an ipsilateral central venous stenosis in 53.3% of patients, and a higher frequency of common iliac vein stenosis (50% vs 21.4%, P = .024) and external iliac vein stenosis (20% vs 0%, P = .012) compared with the contralateral limbs. When separated by the left or right limb, the left limbs exhibited a greater degree of common iliac vein stenosis as compared with the contralateral limbs (50.7% ± 20.9% vs 16.3% ± 16.5%, P < .001) as well as a greater frequency of >50% common iliac vein stenosis (46.7% vs 13.3%, P = .046). The right limbs exhibited a greater frequency of >50% external iliac vein stenosis as compared with the contralateral limbs (33.3% vs 0%, P = .022)., Conclusions: This study suggests that patients with severe chronic venous insufficiency who undergo treatment for a pathologic perforator may have additional ipsilateral central venous pathology, supporting the presence of multilevel disease. Additional axial imaging might unmask central venous pathology and provide another option for treatment., (Copyright © 2021 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.)

Objective: Current minimally invasive techniques for ablation in superficial venous reflux are limited to thermal based systems requiring tumescent anesthesia, non-thermal chemical sclerosants and permanent glue implantation. The aim of this feasibility study was to determine the safety and efficacy of a novel mechanical-only ablation (MOA) device called EnVena, in a recognised large animal model with chronic follow up., Methods: Venous ablation of six lateral saphenous veins in three sheep was performed using the EnVena device. Luminal patency and vein wall fibrosis were evaluated by histologic analysis at 51 and 89 days., Results: All treated veins demonstrated fibrotic occlusion in contiguous segments at 51 and 89 days on histological analysis. From 45 consecutive segments spanning the treatment length across the six treated veins, 26 (57%) were fully occluded, 7 (16%) were impinged or partially occluded and 12 (27%) were open. There were no device related complications during the follow up period., Conclusions: A purely mechanical approach to superficial venous ablation demonstrated safety and efficacy in a recognized large animal model based on histological findings.

Background: Chronic venous disease is a debilitating condition involving great saphenous vein (GSV) incompetence., Objective: To investigate the efficacy and effectiveness of cyanoacrylate embolization (CAE) versus radiofrequency ablation (RFA) in patients with incompetent GSVs., Materials and Methods: PubMed, Embase, and the Cochrane library were searched. The primary outcomes were the Venous Clinical Severity Score (VCSS), Aberdeen Varicose Vein Questionnaire (AVVQ), closure rate, and visual analog scale (VAS) for pain., Results: This meta-analysis included 378 and 590 patients who underwent CAE and RFA, respectively. Cyanoacrylate embolization was comparable with RFA in VCSS (weighted mean difference [WMD] = -0.03, 95% confidence interval [CI]: -0.18 to 0.12, p = .686), AVVQ (WMD = -0.08, 95% CI: -0.38 to 0.21, p = .570), closure rate (odds ratio [OR] = 0.61, 95% CI: 0.18-2.01, p = .414), and VAS (standardized mean difference [SMD] = 0.24, 95% CI: -0.59 to 1.06, p = .523). There were no significant differences between CAE and RFA regarding the occurrence of phlebitis (OR = 1.22, 95% CI: 0.70-2.13, p = .479) and pigmentation (OR = 0.48, 95% CI: 0.18-1.31, p = .153), but CAE had a lower risk of ecchymosis (OR = 0.45, 95% CI: 0.25-0.81, p = .007) and paresthesia (OR = 0.16, 95% CI: 0.03-0.99, p = .049)., Conclusion: Cyanoacrylate embolization and RFA demonstrated no significant differences in VCSS, AVVQ, closure rate, and pain score for patients with incompetent GSVs. Patients in the CAE group had a lower risk of ecchymosis and paresthesia compared with the RFA group., (Copyright © 2021 by the American Society for Dermatologic Surgery, Inc. Published by Wolters Kluwer Health, Inc. All rights reserved.)

Background: Varicose veins are commonly caused by valvular reflux in the saphenous vein. Most insurance companies will approve venous ablation (VA) for the treatment of junctional reflux only and will deny coverage for symptomatic patients with significant nonjunctional reflux of the saphenous vein at the deep system. The present study compared the outcomes of VA for patients with junctional reflux and patients with nonjunctional reflux., Methods: A retrospective, single-center review of consecutive patients who had undergone VA using radiofrequency in an outpatient office was performed from 2012 to 2016. The patients' electronic medical records were reviewed for the characteristics, imaging findings, and outcomes. A telephone survey inquiring about the intensity of symptoms using a numeric rating scale of 0 to 10 before and after treatment was also conducted, with higher number correlating with increasing symptom severity. Patients were grouped according to the location of reflux, either at the saphenofemoral-saphenopopliteal junction or below the junction (nonjunctional). The patient characteristics and outcomes were compared between the two groups. Clinical success was defined by symptom improvement or resolution. Technical success was defined by vein closure on duplex ultrasonography., Results: A total of 265 patients (224 with junctional reflux [84.5%] and 41 with nonjunctional reflux [15.5%]) had undergone VA of 343 veins. The mean patient age was 58.8 ± 15 years. No differences in age, sex, or race were present between the two groups. Patients with junctional reflux were significantly more likely to have undergone bilateral treatment (33.3% vs 12.2%; P = .006). No difference was found in CEAP (clinical, etiologic, anatomic, pathophysiologic) class, laterality, or type of vein treated. On ultrasonography, the veins with junctional reflux had significantly larger diameters (5.8 ± 2.1 mm vs 4.8 ± 1.8 mm; P = .004). However, the veins with nonjunctional reflux had a longer reflux time (5.5 ± 0.6 seconds vs 4 ± 1.7 seconds; P < .0001). The clinical success rates, technical success rates, and incidence of complications were not different between patients with junctional reflux and those with nonjunctional reflux. The telephone survey was completed by 217 patients after a mean follow-up of 24.9 ± 11.3 months. The survey results demonstrated no differences in improvement in pain or swelling or recurrence of pain or swelling after 2 years., Conclusions: Junctional reflux in the saphenous vein is more likely to be bilateral compared with nonjunctional reflux. The location of reflux did not affect patient presentation or outcomes after VA., (Copyright © 2020 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.)

Lower limbs venous insufficiency refers to a wide variety of venous disorders grouped by the term of chronic venous disease (CVD). Hemodynamic and hormonal changes related to pregnancy period, may promote the development of CVD affecting approximately 1 in 3 women. It has been shown that the presence of this condition is associated with damage and placental suffering. Thus, taking IGF-1/PAPP-A/STC-2, inflammatory cytokines production, PI3K/Akt and Wnt/ β-catenin pathways as a part of the alterations that occurs in the placenta due to CVD, the aim of this study will be to examine the main components of these pathways. Genic and protein expression of PAPP-A, STC-2, IGF-1, IRS-4 Wnt-1, β-catenin, c-myc, Cyclin D1, IL-4/IL-6 and PI3K/Akt/mTOR pathway will be analysed through RT-qPCR and immunohistochemical techniques in women with CVD (n=62) and pregnant women without this condition (HC) (n=52). PAPP-A, IGF-1, IL-4, IL-6, IRS-4, PI3K, Akt, mTOR, Wnt-1, β-catenin, c-myc and Cyclin D1 expression were found to be increased in women with CVD, whereas STC-2 were decreased in this group, compared to non-affected women. Our study has demonstrated that IGF-1/PAPP-A/STC-2 axis, PI3K/Akt and Wnt/β-catenin pathways, along with c-myc, Cyclin D1 and inflammatory cytokines are altered in placenta women with CVD. These results extent the knowledge that CVD is associated to a placenta damage with abnormal tissue environment and cellular regulation., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Chronic venous insufficiency (CVI) is a common disorder associated with a variety of symptoms in later disease stages; despite the high prevalence of this pathology, suitable pharmaceutical therapies have not been explored to date. In this context, it was recently reported that a chronic increase in venous wall stress or biomechanical stretch is sufficient to cause development of varicose veins. Recent evidence demonstrate that flavonoids are natural substances that convey the circulatory system functionality, playing a key role in blood flow. Particularly, troxerutin, diosmin and horse chestnut extract, appear protective for the management of vascular diseases. The aim of the present study was to evaluate the effect of a flavonoid compound, containing troxerutin, diosmin and horse chestnut extract on in vitro model on HUVECs cells, due to its production of vasculoregulatory and vasculotropic molecules, on an ex-vivo model on mesenteric vessel contraction, to regularize mesenteric microcirculation and on in vivo model of CVI-induced by saphene vein ligation. Furthermore, the flavonoid compound capacity of extensibility and compatibility with peripheral veins was investigated through a tissue block culture study. The degree of absorption, the contractile venous activity, the histological analysis, the immunoistochemical and immunofluorescence evaluation for VEGF and CD34 were performed, together with inflammatory mediators dosage. For the first time, this research revealed the therapeutic potential of a compound, enriched with flavonoids, to be a supportive treatment, suitable to reduce varicose vein pathophysiology and to regularize venous tone., (Copyright © 2020. Published by Elsevier Inc.)

Chronic venous insufficiency (CVI) is one of the most common vascular pathologies worldwide. One of the risk factors for the development of CVI is aging, which is why it is related to senile changes. The main trigger of the changes that occur in the venous walls in CVI is blood flow reflux, which produces increased hydrostatic pressure, leading to valve incompetence. The cellular response is one of the fundamental processes in vascular diseases, causing the activation of cell signalling pathways such as c-Jun N-terminal kinase (JNK). Metabolic changes and calcifications occur in vascular pathology as a result of pathophysiological processes. The aim of this study was to determine the expression of JNK in venous disease and its relationship with the role played by the molecules involved in the osteogenic processes in venous tissue calcification. This was a cross-sectional study that analyzed the greater saphenous vein wall in 110 patients with (R) and without venous reflux (NR), classified according to age. Histopathological techniques were used and protein expression was analysed using immunohistochemistry techniques for JNK and markers of osteogenesis (RUNX2, osteocalcin (OCN), osteopontin (OPN)). Significantly increased JNK, RUNX2, OCN, OPN and pigment epithelium-derived factor (PEDF) protein expression and the presence of osseous metaplasia and amorphous calcification were observed in younger patients (<50 years) with venous reflux. This study shows for the first time the existence of an osteogenesis process related to the expression of JNK in the venous wall., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Objective: The objective of this study was to analyze whether compression stocking therapy in the human varicose vein wall may change the levels of biomarkers associated with vein insufficiency., Methods: Dilated collateral varicose vein samples were obtained from patients showing chronic venous disease (class 2 of the Clinical, Etiology, Anatomy, and Pathophysiology classification). Before elective surgery, 12 patients underwent compression stocking therapy (for 1 month) and 9 patients did not (control group). Expression levels of biomarkers associated with endothelial functionality (nitric oxide synthase 3), inflammation (interleukin-6, interleukin-10), oxidative stress (Gp91 phox subunit of NADPH oxidase), and coagulation (factor Xa) were determined. P-selectin, an inflammatory and thrombosis-related biomarker, was also measured., Results: Compression stockings increased the content of nitric oxide synthase 3 (control, 16.48 [16.04-17.40] AU; compression, 83.71 [67.70-91.85] AU; P < .001) in the varicose vein wall that was accompanied by reduction of both interleukin-6 levels (control, 38.72 [33.48-48.52] pg/μg protein; compression, 14.49 [11.05-17.41] pg/μg protein; P = .001) and the expression of Gp91 phox subunit of NADPH oxidase (control, 63.24 [53.79-77.03] AU; compression, 36.85 [35.66-52.27] AU; P < .010). P-selectin (control, 77.37 [61.86-85.00] AU; compression, 54.31 [49.60-67.50] AU; P = .017) and factor Xa (control, 90.78 [75.02-100.00] AU; compression, 14.50 [13.77-36.20] AU; P < .001) were also reduced in the varicose vein wall of compression stocking-treated patients. However, P-selectin lost its statistical significance after adjustment by dyslipidemia., Conclusions: In the varicose vein wall, compression stocking therapy improved the content levels of biomarkers associated with endothelial functionality, inflammation, oxidative stress, and coagulation., (Copyright © 2020 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.)

Introduction: To study the efficiency of internal compression therapy (ICT), a new and promising method of treatment for deep venous insufficiency, how that efficiency is achieved, and its potential side-effects, in a porcine model., Material and Methods: The femoral vein diameters of 4 pigs were first measured. ICT was then applied such as to reduce the diameter of these veins by 50%. The femoral vein diameters of 2 pigs were re-measured after 1 month. The femoral vein and its surrounding tissue were excised for immunohistopathological and genetic examination. The same procedures were applied to the remaining 2 pigs 3 months subsequently. Collagen I and IV immunohistochemical staining and Masson's trichrome and Alcian blue histochemical staining were applied during immunohistopathological examination. Collagen I, III, and IV and connective tissue growth factor (CTGF) mRNA expressions were examined for genetic examination., Results: The femoral vein diameters decreased by approximately 50% after ICT application. This decrease persisted after the first and third months. Histopathological examination revealed loose connective tissue around the venous tissue after the operation, particularly in the third month, together with perivascular fibrosis and increased collagen in connective tissue. No difference was observed between regions with and without ICT application in terms of mucinous degeneration, an indicator of tissue injury, during Alcian blue staining. Genetic examination revealed an increase in collagen I and IV and CTGF mRNA expression in perivascular tissue resulting from ICT application., Conclusion: ICT is effective both in terms of creating a durable tissue around the vein and of increasing collagen tissue and stimulating fibrosis, and has no deleterious side-effects on tissue.

Fibronectin (FN) circulating in the blood and produced by cells provides the basis of the extracellular matrix (ECM) formed in healing acute wounds. The time-dependent deposition of FN by macrophages, its synthesis by fibroblasts and myofibroblasts, and later degradation in the remodeled granulation tissue are a prerequisite for successful healing of wounds. However, the pattern of FN expression and deposition in skin lesions is disturbed. The degradation of the ECM components including FN in varicose veins prevails over ECM synthesis and deposition. FN is inconspicuous in the fibrotic lesions in lipodermatosclerosis, while tenascin-C containing FN-like peptide sequences are prominent. FN is produced in large amounts by fibroblasts at the edge of venous ulcers but FN deposition at the wound bed is impaired. Both the proteolytic environment in the wounds and the changed function of the ulcer fibroblasts may be responsible for the poor healing of venous ulcers. The aim of this review is to describe the current knowledge of FN pathophysiology in chronic venous diseases. In view of the fact that FN plays a crucial role in organizing the ECM, further research focused on FN metabolism in venous diseases may bring results applicable to the treatment of the diseases.

Background: Chronic venous disease (CVD) is secondary to venous hypertension, leading to vascular inflammation and tissue changes. The impact of CVD on skin structure and barrier function is not well characterized., Objective: We aimed to assess the characteristics of skin alterations in mild-to-moderate CVD by non-invasive techniques based on a prospective exploratory study., Material & Methods: Female subjects (30-75 years) with CVD (Stage C2 to C4, CEAP classification) were eligible. Stage C0-C1 CVD subjects were used as controls. Women with leg surgery or a medical history that could impact the results were excluded. The skin changes on lesional (LS) and non-lesional (NLS) areas were assessed by biometric analysis including skin echography, viscoelasticity evaluation, confocal microscopy and trans epidermal water loss (TEWL) measurements., Results: Thirty-four subjects were enrolled. Based on computation of 26 biometric parameters using Principal Component Analysis, a significant difference between LS and NLS zones, regardless of the CEAP class, was evidenced. C2-C4 subjects presented with dermal thickening suggesting oedema associated with decreased cell density, while no difference in skin viscoelasticity was observed compared to the C0-C1 control group. Epidermal structural modifications were associated with increased TEWL correlating with CVD severity., Conclusion: Skin alterations in CVD patients are detectable by non-invasive methods. These findings may help to better assess new therapeutic strategies.

Background: Chronic venous disease (CVD) is a prevalent lower limb venous pathology that especially affects women, who also show an increased risk of this disease during pregnancy. Studies have shown significant structural changes in the placentas of women with CVD and several markers of tissue damage have been also described. Patients and Methods: To try to understand the different placental pathologies, research efforts have focused on examining metabolomic profiles as indicators of the repercussions of these vascular disorders. This study examines changes produced in the metabolomic profiles of chorionic villi in the placentas of women with CVD. In a study population of 12 pregnant women, 6 with and 6 without CVD, we compared through mass spectroscopy coupled to ultra-high performance liquid chromatography (UHPLC-MS), 240 metabolites in chorionic villus samples. Results: This study is the first to detect in the placental villi of pregnant women with CVD, modifications in lysophosphatidylcholines and amino acids along with diminished levels of other lipids such as triglycerides, sphingomyelins, and non-esterified omega 9 fatty acids, suggesting a role of these abnormalities in the pathogenesis of CVD. Conclusions: Our findings are a starting point for future studies designed to examine the impacts of CVD on maternal and fetal well-being., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Aim: To assess the feasibility and technical success of endovenous laser ablation (EVLA) of recurrent varicose veins arising from the former sapheno-femoral junction (SFJ)., Methods: We retrospectively analyzed all EVLA procedures treated in our institution by one surgeon between March 2019 and April 2020 and selected all consecutive cases with SFJ recurrence occuring after surgical high ligation and stripping or endovenous thermal ablation for incompetence of the great saphenous vein (GSV) in superficial venous insufficiency. The feasibility, technical success as determined by duplex ultrasound on the postoperative visit, complications and rate of endothermal heat-induced thrombosis (EHIT) were recorded. A subgroup definition was performed based on sonographic morphology of the recurrence and resulting strategy of ablation., Results: Thirty-five limbs with SFJ recurrence in 34 patients were treated with EVLA in order to shut down the highest refluxing point. In 22 interventions, it was required to switch off a short stump or a neovascularization by direct puncture (Subgroup 1). In 13 treatments, the presence of residual GSV segments, or persistent, varicose transformed major tributaries like the anterior accessory great saphenous vein, enabled cannulation and advancing the laser fiber from distal to the former SFJ (Subgroup 2). The EVLA procedures could be successfully carried out in all 35 cases. There were no major complications, no thromboembolism or EHIT, and no local groin complications. In one case, the patient developed a phlebitic response that required temporary medication. Technical success was achieved with 34/35 treatments (97.1%). When comparing the subgroups, the morphological pattern of the SFJ recurrence and the resulting technique of puncture, cannulation and ablation did not influence the result., Conclusions: The results of this case series suggest that SFJ recurrences can also be successfully treated in situations where there are tortuous or short stumps that require direct puncture and ablation., Competing Interests: The authors have declared that no competing interests exist.

The development of lower extremity venous insufficiency (VI) during pregnancy has been associated with placental damage. VI is associated with increased oxidative stress in venous wall. We have investigated potential disturbance/dysregulation of the production of reactive oxygen species (ROS) in placenta and its eventual systemic effects through the measurement of malondialdehyde (MDA) plasma levels in women with VI. A total of 62 women with VI and 52 healthy controls (HCs) were studied. Levels of nicotinamide adenine dinucleotide phosphate-oxidase 1 (NOX1), 2 (NOX2), inducible nitric oxide synthase (iNOS), endothelial (eNOS), poly(ADP-ribose) polymerase PARP (PARP) and ERK were measured in placental tissue with immunohistochemistry and RT-qPCR. Plasma and placental levels of MDA were determined by colorimetry at the two study times of 32 weeks of gestation and post-partum. Protein and gene expression levels of NOX1, NOX2, iNOS, PARP and ERK were significantly increased in placentas of VI. eNOS activity was low in both study groups, and there were no significant differences in gene or protein expression levels. Women with VI showed a significant elevation of plasma MDA levels at 32 weeks of gestation, and these levels remained elevated at 32 weeks post-partum. The MDA levels were significantly higher in placentas of women with VI. Placental damage that was found in the women with VI was characterized by overexpression of oxidative stress markers NOX1, NOX2, and iNOS, as well as PARP and ERK. Pregnant women with VI showed systemic increases in oxidative stress markers such as plasma MDA levels. The foetuses of women with VI had a significant decrease in their venous pH as compared to those from HC women. The situation of oxidative stress and cellular damage created in the placenta is in coexpression with the production of a pH acidification., (© 2020 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

Insurmountable evidence has demonstrated a strong association between Alzheimer's disease (AD) and cerebral amyloid angiopathy (CAA), along with various other cerebrovascular diseases. One form of CAA, which is the accumulation of amyloid-beta peptides (Aβ) along cerebral vessel walls, impairs perivascular drainage pathways and contributes to cerebrovascular dysfunction in AD. To date, CAA research has been primarily focused on arterial Aβ, while the accumulation of Aβ in veins and venules were to a lesser extent. In this review, we describe preclinical models and clinical studies supporting the presence of venular amyloid and potential downstream pathological mechanisms that affect the cerebrovasculature in AD. Venous collagenosis, impaired cerebrovascular pulsatility, and enlarged perivascular spaces are exacerbated by venular amyloid and increase Aβ deposition, potentially through impaired perivascular clearance. Gaining a comprehensive understanding of the mechanisms involved in venular Aβ deposition and associated pathologies will give insight to how CAA contributes to AD and its association with AD-related cerebrovascular disease. Lastly, we suggest that special consideration should be made to develop Aβ-targeted therapeutics that remove vascular amyloid and address cerebrovascular dysfunction in AD.

Background: Athletes are generally young, high-functioning individuals. Pathology in this cohort is associated with a decrease in function and consequently has major implications on quality of life. Venous disorders can be attributed to a combination of vascular compression with a high burden of activity., Objective: This article promotes increased awareness of these uncommon conditions specific to the athlete by summarizing pathophysiology, clinical features, investigation, and treatment protocols for use in clinical practice. Prognostic outcomes of these management regimens are also discussed, allowing for clinicians to counsel these high-functioning individuals appropriately. With the aim of providing an overview of sport-related venous pathology, a literature review was undertaken identifying articles that were independently reviewed by the authors., Results: Lower limb venous thrombosis has been identified in young, high-functioning athletes attributed to both compression-related venous trauma, associated with repetitive movements resulting in intimal damage, and blunt trauma. The diagnosis and treatment follow the same protocols as for the general population. Of note, early ambulation is advocated, with an aim to return to premorbid (noncontact) function within 6 weeks. Athletes performing high-intensity repetitive upper limb movement, such as baseball players, are predisposed to upper limb deep venous thrombosis (DVT). Diagnosis follows the same protocols as for lower extremity DVT; however, the optimal treatment strategy remains debated. Current guidelines advocate the use of anticoagulation alone. A specific subset of primary upper limb DVT is effort thrombosis, where there is compression at the level of the thoracic outlet. Thrombolysis with first rib resection is indicated in the acute setting within 14 days. In cases of complete occlusion, surgical decompression with venous reconstruction may be required. Popliteal vein entrapment syndrome is also discussed. This entity has been identified as an overuse injury associated with popliteal vein compression. Duplex ultrasound examination is indicated as a first-line investigation, with conservative noninvasive options considered as an initial management strategy. Chronic venous insufficiency or persistent symptoms may require subsequent surgical decompression., Conclusions: Key conditions including upper extremity and lower extremity venous thrombosis, venous aneurysms, Paget-Schroetter syndrome (effort thrombosis), and popliteal vein entrapment syndrome are discussed. Further studies evaluating long-term outcomes on morbidity for current treatment regimens in upper extremity DVT, effort thrombosis, venous thoracic outlet syndrome, and popliteal venous entrapment syndrome are required., (Copyright © 2019 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.)

The term varicose vein refers to the twisted and swollen vein visible under the skin surface which occurs most commonly in the leg. Epidemiological studies report a varying percentage of incidences from 2 to 56% in men and <1-60% in women. Venous insufficiency is most often caused by the damage to the valves and walls of the veins. The mechanism of varicose vein formation is complex. It is, however, based on hypotensive blood vessels, hypoxia, and other mechanisms associated with inflammation. This work describes mechanisms related to the formation and development of the varicose vein. It discusses risk factors, pathogenesis of chronic venous disease, markers of the epithelial and leukocyte activation, state of hypoxia and inflammation, reactive oxygen species (ROS) generation, and oxidative stress. Additionally, this paper describes substances of plant origin used in the treatment of venous insufficiency. It also considers the structure of the molecules, their properties, and their mechanisms of action, the structure-activity relationship and chemical properties of flavonoids and other substances. The flavonoids include quercetin derivatives, micronized purified flavonoid fraction (Daflon), natural pine bark extract (Pycnogenol), and others such as triterpene saponine, extracts from Ruscus aculeatus and Centella asiatica, Ginkgo biloba extract, coumarin dereivatives that are used in chronic venous insufficiency. Flavonoids are natural substances found in plants, including fruits, vegetables, flowers, and others. They are important to the circulatory system and critical to blood vessels and the blood flow. Additionally, they have antioxidant, antiinflammatory properties., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)

Internal jugular vein (IJV) stenosis and cerebral venous sinus (CVS) stenosis belong to cerebral venous outflow insufficiency. This study aimed to analyze the similarities and differences between IJV stenosis and CVS stenosis. Patients with either IJV stenosis or CVS stenosis confirmed by contrast-enhanced magnetic resonance venography between October 2017 and July 2018 were enrolled in this retrospective study. The similarities and differences between IJV stenosis and CVS stenosis on the aspects of clinical and imaging features were compared. A total of 82 eligible patients entered into the final analysis. The similarities of the two subsets of cerebral venous outflow insufficiency mainly included headache, head noises or tinnitus, visual disorders, and sleeping disorders, as well as cloud-like white matter hyperintensity in T2WI and FLAIR sequences of MRI. However, there were differences in between, the ratio of patients with higher intracranial pressure (ICP) was common in CVS stenosis (p < 0.001). Namely, higher ratios of papilledema (p = 0.001) and visual damage (p = 0.029), as well as poor Frisen papilledema grade scores were more commonly observed in CVS stenosis (p = 0.004), while abnormal collateral-vessels appeared more frequently in IJV stenosis (100.00%) than CVS stenosis (28.57%). Continuous head noises, tinnitus and cloud-like white matter hyperintensity in MRI are the features of both IJV stenosis and CVS stenosis. Whereas, severe headache, visual damage, papilledema, and intracranial hypertension (IH) were more common in CVS stenosis, and the appearance of collateral-vessels is a key feature of IJV stenosis.

Objective: Compression stockings are the primary treatment for lipodermatosclerosis secondary to chronic venous disease, but do not improve the skin condition. The aim of this study was to investigate the impact of copper on lipodermatosclerosis., Methods: A double-blind randomised controlled pilot study was performed including patients with bilateral lipodermatosclerosis. One compression stocking of a pair was impregnated with copper. Symptom score and surface area of lipodermatosclerosis were assessed at baseline, after 2, 4 and 8 weeks., Results: Sixteen patients were included. There was no significant difference in mean symptom scores; however, there was a significant reduction of the surface area in the study group 42,637 to 35,739 mm 2 versus 41,487 to 43,210 mm 2 in the control group (p = 0.04)., Conclusion: This study demonstrates the beneficial effect of copper on lipodermatosclerosis secondary to chronic venous disease with reduction in surface area but no benefit on symptoms. Trials identification number: NCT03283800.

We sought to assess clinical characteristics and pattern of collateral network involvement associated with development of truncal (systematized) versus diffuse/non-truncal (non-systematized) varicose veins (VVs) in patients undergoing endovascular laser photothermolysis for chronic venous insufficiency (CVI). Secondly, we aimed to assess whether the type of VVs influenced the procedural complications of endovascular laser therapy. A total of 508 patients with hydrostatic VVs of the lower limbs who underwent endovenous laser treatment were included, out of which 84.1% (n=427) had truncal VVs (group 1) and 15.9% (n=81) had diffuse (non-systematized) VVs (group 2). Patients with truncal varices were significantly older (47.50±12.80 vs 43.15±11.75 years, P=0.004) and those with associated connective tissue disorders were more prone to present diffuse VVs (P=0.004). Patients in group 1 presented a significantly higher number of Cockett 1 (P=0.0017), Cockett 2 (P=0.0137), Sherman (P<0.0001), and Hunter (P=0.0011) perforator veins compared to group 2, who presented a higher incidence of Kosinski perforators (P<0.0001). There were no significant differences regarding postoperative complications: thrombophlebitis (P=0.773), local inflammation (P=0.471), pain (P=0.243), paresthesia (P=1.000), or burning sensation (P=0.632). Patients with more advanced CEAP (clinical, etiologic, anatomic, pathophysiologic) classes were older (P<0.0001), more were males (39.05 vs 27.77%, P=0.0084), more were prone to present ulcers (P<0.0001) and local hyperthermia (P=0.019), and presented for endovenous phlebectomy after a longer time from symptom onset. In patients with CVI, systematized VVs were associated with a more severe clinical status and a distinct anatomical pattern of perforators network compared to non-systematized VVs, which is more common in advanced stages.

In infants, traumatic surface contusions of the brain are rare but subcortical clefts or cysts, variously labelled "contusional tears", "contusional clefts", "cortical tears" or "parenchymal lacerations" have been ascribed to trauma, and are even said to be characteristic of shaking and abuse. We describe the pathology of subcortical clefts or haemorrhages in seven infants. In none were the axonal swellings characteristic of traumatic axonal injury seen in relation to the clefts. Subpial bleeding was associated with clefts in all the cases of recent onset. We hypothesize that subcortical clefts are not due to direct mechanical forces of trauma but are part of a secondary cascade caused by impaired venous drainage which may or may not follow trauma. The finding of subcortical and subpial haemorrhages should prompt a search for CVT. We consider the term "contusion" is not accurate and is misleading., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Objective: Chronic venous leg ulcers (VLUs) affect up to 2% of the general population, resulting in a significant socioeconomic burden. Placental tissue that contains mesenchymal stem cells and active growth factors has been shown to be beneficial in healing of chronic wounds. We compared the efficacy of a human viable wound matrix (hVWM) of cryopreserved placental tissue for the treatment of refractory VLUs with standard therapy., Methods: This prospective single-center open-label single-arm study enrolled patients with Clinical, Etiology, Anatomy, and Pathophysiology clinical class C6 VLUs. The ulcers of all enrolled patients had failed to heal after a trial of standard therapy of at least 12 weeks, which included weekly multilayer compression therapy along with local wound care. The same patients subsequently received application of hVWM (Grafix; Osiris Therapeutics, Columbia, Md) every 1 to 2 weeks in addition to standard therapy. Healing with hVWM therapy was then compared with standard therapy, with each patient serving as his own control., Results: There were 30 VLUs in 21 consecutive eligible patients who were enrolled in the study. All patients were men with an average age of 67 years (standard deviation [SD], ±10.8 years), and the average area of venous ulcers before hVWM initiation was 12.2 cm 2 (SD, ±14.6 cm 2 ; range, 3.3-12.3 cm 2 ). Duplex ultrasound confirmed superficial or deep system venous reflux in all patients. Complete ulcer healing was achieved in 53% (16/30) of VLUs refractory to standard therapy after application of hVWM. There was a mean reduction in wound surface area by 79% (SD, ±27.3%; P < .001 compared with standard therapy) after a mean treatment time of 10.9 weeks. Eighty percent of VLUs were reduced in size by half compared with 25% with standard therapy (P < .001). The mean rate of reduction in ulcer area after hVWM applications was 1.69% per day vs 0.73% per day with standard therapy (P = .01)., Conclusions: Cryopreserved placental tissue (hVWM) improves healing processes to achieve complete wound closure in a significant proportion of chronic VLUs refractory to standard therapy. Adjunctive therapy with hVWM provides superior healing rates in refractory VLUs., (Copyright © 2018 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.)

Venous insufficiency is a common disease arising when veins of the lower limb become incompetent. A conventional surgical strategy consists in stripping the incompetent veins. However, this treatment option is invasive and carries complication risks. In the present study, we propose noninvasive high-intensity focused ultrasound (HIFU) to treat lower limbs venous insufficiency, in particular incompetent perforating veins (mean diameter between 2-6 mm). Sonication parameters were designed by numerical simulations using the k-Wave toolbox to ensure continuous coagulation of a vein with a diameter superior or equal to 2 mm. The selected ultrasound exposures were 4 s pulses in continuous wave mode. Two types of sonication were studied: (1) fixed pulses and (2) moving pulses at constant speed (0.75 mm s -1 ) across the vein. The potential of these exposures to thermally occlude veins were investigated in vivo on rabbit saphenous veins. The impact of vein compression during ultrasonic exposure was also investigated. Fifteen rabbits were used in these trials. A total of 27 saphenous veins (mean diameter 2.0  ±  0.6 mm) were sonicated with a transducer operated at 3 MHz. After a mean 15 d follow-up, rabbits were euthanized and venous samples were extracted and sent for histologic assessment. Only samples with the vein within the HIFU lesion were considered for analysis. Simulated thermal damage distribution demonstrated that fixed pulses and moving pulses respectively placed every 1.5 and 0.5 mm along the vein and delivered at an acoustic power of 85 W and for 4 s were able to induce continuous thermal damages along the vein segments. Experimentally, both treatment parameters (1) and (2) have proven effective to occlude veins with a success rate of 82%. Occlusion was always observed when compression was applied. Our results demonstrate that HIFU can durably and non-invasively occlude veins of diameters comparable to human veins.

Sulodexide is a glycosaminoglycan extracted from porcine intestinal mucosa. The purpose of this review is to discuss sulodexide's complex pharmacological profile and its clinical applications for venous disease. Sulodexide has wide-ranging biological effects on the vascular system, including antithrombotic, profibrinolytic, anti-inflammatory, endothelial protective and vasoregulatory effects. Sulodexide has emerged as a potential therapeutic option for the management of chronic venous insufficiency, including venous ulceration, and the prevention of recurrent venous thromboembolism, with a low rate of major bleeding complications. Sulodexide's pleiotropic vascular effects may facilitate the management of common venous disorders., (© 2018 International Society on Thrombosis and Haemostasis.)

Background and Purpose: Cloudy white matter lesions are associated imaging features of internal jugular venous stenosis (IJVS). However, the mechanism of the IJVS associated cloudy white matter lesions is still unclear. This study aims to evaluate blood-brain barrier integrity of the patients with IJVS., Materials and Methods: A total of 45 eligible patients with IJVS confirmed by computed tomography venography (CTV) and 45 healthy controls were enrolled into this study. The levels of serum MMP-9 and the markers of tight junctions, including occludin and ZO-1 obtained from IJVS patients and control group were tested by enzyme-linked immune-sorbent assay and compared., Results: Both the levels of serum MMP-9 (0.2ng/ml) and occludin (0.05ng/ml) in IJVS group were higher than in the control group (0.01ng/ml vs. 0 ng/ml, all p<0.001). While, the levels of serum ZO-1 showed no statistical significance between the two groups (0.55ng/ml vs 0.735ng/ml, P=0.34). The levels of serum MMP-9 between the subset with or without white matter lesions in IJVS group showed a significant difference (0.22 [0.06, 0.43] vs. 0.01 [0.01, 0.06], P =0.019)., Conclusion: BBB disruption may participate in the formation of IJVS-associated white matter lesions; the mechanism of BBB disruption may involve MMP-9 and occludin., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Oxidative stress plays an important role in the pathophysiology of many human disorders, while antioxidants prevent the development of various adverse symptoms. Diosmin is a natural flavonoid applied in vascular system disorders, especially in chronic venous insufficiency (CVI), and it plays a significant part in the alleviation of CVI symptoms. Due to antioxidant activity, it also has the ability to scavenge the oxygen free radicals and hence decreases the level of oxidative stress biomarkers, such as prostaglandins and their precursors-isoprostanes. In the study, the influence of diosmin treatment on the level of isoprostanes in plasma samples of patients suffering from CVI was examined. The qualitative analysis was performed using high-performance liquid chromatography with spectrometry detection (LC-MS). The statistically significant decrease of isoprostane content after 3 months of treatment was observed within the studied group; however, the most significant changes were observed in patients who smoke.

Objective: This study aims to correlate the demographic data, different clinical degrees of chronic venous insufficiency (CEAP), ultrasound findings of saphenofemoral junction (SFJ) reflux, and anatomopathological findings of the proximal segment of the great saphenous vein (GSV) extracted from patients with primary chronic venous insufficiency (CVI) submitted to stripping of the great saphenous vein for the treatment of lower limb varicose., Method: This is a prospective study of 84 patients (110 limbs) who were submitted to the stripping of the great saphenous vein for the treatment of varicose veins of the lower limbs, who were evaluated for CEAP clinical classification, the presence of reflux at the SFJ with Doppler ultrasonography, and histopathological changes. We study the relationship between the histopathological findings of the proximal GSV withdrawal of patients with CVI with a normal GSV control group from cadavers., Results: The mean age of the patients was higher in the advanced CEAPS categories when comparing C2 (46,1 years) with C4 (55,7 years) and C5-6(66 years), as well as C3 patients (50,6 years) with C5-6 patients. The normal GSV wall thickness (mean 839,7 micrometers) was significantly lower than in the saphenous varicose vein (mean 1609,7 micrometers). The correlational analysis of reflux in SFJ with clinical classification or histopathological finding did not show statistically significant findings., Conclusions: The greater the age, the greater the clinical severity of the patients. The GSV wall is thicker in patients with lower limb varicose veins, but those histopathological changes are not correlated with the disease's clinical severity or reflux in the SFJ on a Doppler ultrasound.

Chronic venous insufficiency (CVI) is a multifactorial disease, commonly caused by valvular incompetence (clinically diagnosed by venous reflux) and venous hypertension. The incidence of these factors clearly increases with patient age, and aging is one of the risk factors involved. The activity of the PI3K/Akt/mTOR pathway is considered fundamental in vascular pathologies, and understanding its involvement would help in the development of possible therapeutic targets. This is an observational, analytical, and prospective cohort study that reviewed 110 patients with CVI scheduled to undergo stratified saphenectomy. They were distributed according to the presence (R = 81) or absence (NR = 29) of valvular incompetence (venous reflux) diagnosed clinically. Each of the groups was further divided according to age, with a cutoff point of 50 years (NR < 50 = 13, NR ≥ 50 = 16, R < 50 = 32, and R ≥ 50 = 49). The involvement of the PI3K/Akt/mTOR pathway, as well as that of HIF-1 α and HIF-2 α and of CD4+, CD8+, and CD19+ cells and mastocytes, was assessed. Saphenous vein tissue samples obtained during surgery were processed for RT-qPCR and immunohistochemistry. Patients with venous reflux showed a significant increase in mRNA and protein expression levels for PI3K/mTOR and HIF-1 α /HIF-2 α . The number of mast cells was significantly elevated in the R group. In distribution by age, PI3K/Akt/mTOR and HIF-1 α were significantly higher in R < 50 patients. Furthermore, these patients had a significant increase in the number of CD4+, CD8+, and CD19+ cells and mastocytes in the saphenous vein wall. These findings provide a basis for the possible existence of changes in PI3K/Akt/mTOR pathway expression in young patients, with potential accelerated asynchronous aging that is enhanced by CVI.

Lower extremity venous insufficiency (VI) is a complication of pregnancy. The potential association of this venous disease with structural damage of the placenta has not been described. We analyzed the pattern of histopathologic lesions and the gene and protein expression of HIF1-α and apoptosis regulatory proteins. A prospective study was carried out on placenta samples from 43 women with pregnancy-associated VI and 24 age-matched pregnant healthy controls (HCs). Women with VI showed a significant increase in the number of villi (150.77 ± 42.55 VI versus 122.13 ± 27.74 HC) and in syncytial knots compared with those found in the placentas from HCs (67.15 ± 31.08 VI versus 42.49 ± 17.36 HC), and an increase in the number of bridges (32.40 ± 2.67 VI versus 22.73 ± 2.37 HC; P < .05). The mean number of syncytial nodes per villus is 1.37 ± 0.90 in the VI group and 0.49 ± 0.58 in the HC group (P < .001). Significant increases in the expression of Bax and caspase-3 and caspase-9 in the placentas from women with VI were observed compared with those found in HC. The expression of HIF-1α at both the messenger RNA and protein levels was also significantly increased in the placentas from women with VI. Our study demonstrates that placentas from women with pregnancy-associated VI show structural remodeling, with an increase in the number of villi and syncytial knots and enhanced apoptotic cellular death. Interestingly, this placental damage is associated with an increased expression of hypoxia-triggered molecular pathways, such as HIF-1α., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Extensive research exists on arterial mechanical properties and how they change in disease conditions, but substantially less is known about venous mechanics in healthy and disease states. Although the mechanics of both vessel types are determined by the unique layered composition of the vessel wall, the precise distribution of the layers differs greatly between arteries and veins. Thus, vein mechanics must be analyzed and understood independently from those of arteries. This review discusses the compositional attributes that are unique to veins, how these attributes contribute to venous mechanics, and the alterations that occur to both composition and material properties during venous thrombosis and insufficiency. In general, changes to the venous wall during thrombosis increase wall stiffness and decrease extensibility. During venous insufficiency, however, both the stiffness and the extensibility of the venous wall decrease. Characterizing these changes is essential to better understand disease progression and build vein-specific devices for treating venous disease., Competing Interests: Conflict of Interest Disclosure: The authors have completed and submitted the Methodist DeBakey Cardiovascular Journal Conflict of Interest Statement and none were reported.

Background Recurrent varicose veins occur up to 80% of procedures. The sapheno-femoral junction can be involved in more than 50% of cases. A detailed pathophysiological explanation of the phenomenon is still missing. The aim of the present work is to evaluate the role of femoral vein incompetence as risk factor for sapheno-femoral junction recurrence. Methods Three-hundred-eighty-one patients presenting an incompetent great saphenous vein system and eventually also an incompetent femoral tract (C2-6EpAsdPr) underwent a great saphenous vein high ligation with flush ligation also of the incompetent tributaries along the leg, sparing the saphenous trunk. Pre-operatively, all patients underwent a sonographic evaluation assessing the superficial and deep venous systems, including a detailed analysis of the iliac-femoral vein tract above the sapheno-femoral junction. A retrospective statistical analysis assessed the recurrence risk associated with iliac-femoral vein tract incompetence. Results In a 5.5 ± 1.9 years follow-up, great saphenous vein trunk reflux recurrence was detected in 45/381 (11.8%) cases. The reflux source was found in a reconnected sapheno-femoral stump in 11/45 cases (24.5%), in the pelvic network in 8/45 cases (17.8%), in a neovascularization process in 7/45 (15.5%) and in a newly incompetent great saphenous vein tributary in 19/45 (42.2%). At the pre-operative assessment, iliac-femoral vein tract reflux was present in 7 (26.9%) of the 26 cases who developed a sapheno-femoral junction recurrence and in 25 (7%) of the 355 patients who did not demonstrate sapheno-femoral junction recurrence (odds ratio: 4.8; confidence interval 95%: 1.8-12.6; p < .003). Discussion Despite many technical diagnostic and therapeutic refinements, varicose veins recurrence remains a frequent event. The present investigation points out the association among iliac-femoral vein tract incompetence and sapheno-femoral junction recurrences after high ligation.

In five patients who suffered from chronic venous insufficiency clinical stage C4 (n = 3) and C6 (n = 2) the capillary blood pressure was measured twice by means of invasive direct cannulation of nailfold capillaries of the toe. During one measurement course the patients wore below knee medical compression stockings (40 mmHg) during the other they did not have compression therapy. With the patient in supine position, the CP was investigated by the servo-nulling technique under resting conditions and under dynamic conditions: the calf-muscle/ankle joint venous pump was simulated by means of inflating a blood pressure cuff, which surrounded the mid lower leg, to 60 mmHg for 60 s., Results: The simulated calf-muscle contraction induced a steep increase of CP with 5.65 mmHg/s (Q1 5.27 mmHg/s, Q3 5.92 mmHg/s), which was significantly (p = 0.013) reduced by MCS to 2.47 mmHg/s (Q1 1.65 mmHg/s, Q3 3.0 mmHg/s). Time needed to reach the max. CP was 11.35 s, which was lengthened by MCS to 23.4 s (p = 0.134)., Conclusion: Compression therapy prevents capillary hypertension, the major hemodynamic reason for the development of advanced stages of chronic venous insufficiency which are defined by skin disease like hyperpigmentation, lipodermatosclerosis and ulcer.

Chronic venous insufficiency and varicose veins occur commonly in affluent countries and are a socioeconomic burden. However, there remains a relative lack of knowledge about venous pathophysiology. Various theories have been suggested, yet the molecular sequence of events is poorly understood. Transforming growth factor-beta one (TGF-β1) is a highly complex polypeptide with multifunctional properties that has an active role during embryonic development, in adult organ physiology and in the pathophysiology of major diseases, including cancer and various autoimmune, fibrotic and cardiovascular diseases. Therefore, an emphasis on understanding its signaling pathways (and possible disruptions) will be an essential requirement for a better comprehension and management of specific diseases. This review aims at shedding more light on venous pathophysiology by describing the TGF-β1 structure, function, activation and signaling, and providing an overview of how this growth factor and disturbances in its signaling pathway may contribute to specific pathological processes concerning the vessel wall which, in turn, may have a role in chronic venous insufficiency., Competing Interests: The authors declare no conflict of interest.