Factors Influencing Venous Remodeling in the Development of Varicose Veins of the Lower Limbs.

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.

Pigmentation of lower limbs: Contribution of haemosiderin and melanin in chronic venous insufficiency and related disorders.

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.

Cyanoacrylate glue reactions: A systematic review, cases, and proposed mechanisms.

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.

Dystrophic Calcification of the Lower Leg in a Patient with Chronic Lower Extremity Venous Insufficiency and Diabetes Mellitus: A Case Report and Literature Review.

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.

The relationship between venous insufficiency and serum magnesium level

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.

A pre-clinical animal study of a novel mechanical-only ablation device treatment for superficial venous disease.

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.

The presence of a pathologic perforator may be predictive of central venous pathology and multilevel disease in severe chronic venous insufficiency.

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.

Abnormal proinflammatory and stressor environmental with increased the regulatory cellular IGF-1/PAPP-A/STC and Wnt-1/ß-Catenin canonical pathway in placenta of women with Chronic venous Disease during Pregnancy.

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/ ß-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, ß-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, ß-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/ß-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.

Histopathological study of JNK in venous wall of patients with chronic venous insufficiency related to osteogenesis process.

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.

Comparison Between Cyanoacrylate Embolization and Radiofrequency Ablation for Superficial Venous Incompetence: A Systematic Review and Meta-analysis.

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.

A New Method Involving Percutaneous Application in the Treatment of Deep Venous Insufficiency: An Experimental Study With Internal Compression Therapy in a Porcine Model.

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.

Compression stockings attenuate the expression of proteins associated with vascular damage in human varicose veins.

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 (Gp91phox 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 Gp91phox 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.

Location of reflux in the saphenous vein does not affect outcomes of vein ablation.

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.

Therapeutic potential of flavonoids in the treatment of chronic venous insufficiency.

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.

Lipidomic profiling of chorionic villi in the placentas of women with chronic venous disease.

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.

Detection of skin alterations in mild-to-moderate chronic venous disease using non-invasive techniques.

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.

Role of fibronectin in chronic venous diseases: A review.

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.

Feasibility and technique of endovenous laser ablation (EVLA) of recurrent varicose veins deriving from the sapheno-femoral junction-A case series of 35 consecutive procedures.

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.

Potential Role of Venular Amyloid in Alzheimer's Disease Pathogenesis.

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 (Aß) 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 Aß, while the accumulation of Aß 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 Aß deposition, potentially through impaired perivascular clearance. Gaining a comprehensive understanding of the mechanisms involved in venular Aß 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 Aß-targeted therapeutics that remove vascular amyloid and address cerebrovascular dysfunction in AD.

Pregnancy-associated venous insufficiency course with placental and systemic oxidative stress.

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.