Pathophysiology Of Chronic Venous Disease Research Articles

Chronic Venous Disease: Pathophysiological Aspects, Risk Factors, and Diagnosis.

Chronic venous disease (CVD) is highly prevalent in the general population and encompasses a range of pathological and hemodynamic changes in the veins of the lower extremities. These alterations give rise to a variety of symptoms, with more severe forms resulting in venous ulceration, which causes morbidity and high socioeconomic burden. The origins and underlying mechanisms of CVD are intricate and multifaceted, involving environmental factors, genetics, hormonal factors, and immunological factors that bring about structural and functional alterations in the venous system. This review offers the latest insights into the epidemiology, pathophysiology, and risk factors of CVD, aiming to provide a comprehensive overview of the current state of knowledge. Furthermore, the diagnostic approach for CVD is highlighted and current diagnostic tools are described.

Treatment of early-stage chronic venous disease – management standards for 2023

Chronic venous disease (CVD) is one of the most prevalent diseases in the world. Most patients with early-stage CVD willeventually deteriorate, which will result in an increase in treatment costs, but most importantly, a decrease in quality of life.The advances made with regard to the knowledge of the natural history and pathophysiology of CVD as well as the results ofresearch on effects of different drugs depending on the severity of the disease suggest the likely cost-effectiveness of CVDpatients being treated at an early stage of the disease. Recommendations in this group of patients may include lifestylechanges, compression therapy and venoactive drugs (VADs). Combination of ruscus, hesperidin methyl chalcone, andvitamin C is a well-established VAD presenting with anti-inflammatory effects, reducing endothelial activation and leukocyteadhesion, increasing capillary resistance and integrity and improving venous tone and performance of the lymphatic vesselsthus leading to a reduction in CVD symptoms in patients and an improvement in quality of their lifes. This article is based onthe latest guidelines regarding the management of chronic venous disease.

Molecular Determinants of Chronic Venous Disease: A Comprehensive Review.

Chronic Venous Disease (CVD) refers to several pathological and hemodynamic alterations of the veins of lower limbs causing a wide range of symptoms and signs with a high prevalence in the general population and with disabling consequences in the most severe forms. The etiology and pathophysiology of CVD is complex and multifactorial, involving genetic, proteomic, and cellular mechanisms that result in changes to the venous structure and functions. Expressions of several genes associated with angiogenesis, vascular development, and the regulation of veins are responsible for the susceptibility to CVD. Current evidence shows that several extracellular matrix alterations (ECM) could be identified and in some cases pharmacologically targeted. This review shows the most up to date information on molecular determinants of CVD in order to provide a complete overview of the current knowledge on this topic. In particular, the article explores the genetic influence, the hormonal influence, ECM imbalance, and histopathology of CVD and the role of endothelial dysfunction in CVD.

New pathophysiological aspects in chronic venous disease

"Chronic venous disease has been pathology of great interest over time. With its large prevalence among the world population (10-33% adult woman and 10-20% of men) through profound socio-professional implications that affect the quality of life of patients, chronic venous disease is a real public health problem, being an important cause of morbidity and disability, a permanent area of research in the medical-pharmaceutical field. Special attention is now given to identifying the mechanisms and stages of disease development. From studies that have highlighted the importance of venous hypertension as an essential element in the development of the disease, to this day it has come up to demonstrating the fundamental role of the venous endothelium and glycocalyx in triggering and progressing of chronic venous disease. Biochemical, immunohistochemical, and functional investigations have allowed the evaluation of changes that occur in cellular metabolism and evidence of some immune-vascular factors responsible for vascular alterations in chronic venous disease: specialized receptors, adhesion molecules, cytokines, matrix and metalloproteinases. The analysis of the pathophysiology of chronic venous disease is still a vast area open to scientific research."

The influence of compression therapy on the level of inflammatory biomarkers in patients with chronic venous disease.

Chronic venous disease (CVD) is defined as any morphological and functional abnormalities of long duration manifested either by symptoms and/or signs indicating the need for investigation and/or care. The pathophysiological mechanism of CVD can be characterized by reflux, obstruction, or a combination of both, which leads to increased venous pressure. Compression therapy remains the gold standard of the conservative treatment of CVD in all stages. The possible forms of compression therapy are elastic stocking, non-elastic and elastic bandages, and intermittent pneumatic compression. Compression bandages have been proven to improve the healing of venous ulcers, in comparison with standard care without compression therapy. In the last years, inflammation has been shown to play an important role in the pathophysiology of CVD. The influence of the altered shear stress on the endothelial cells (EC) causes EC to release inflammatory molecules, chemokines, vasoactive agents, express selectins, and prothrombotic precursors such as ICAM-1, MCP-1, MIP 1β, VCAM, L-selectin, E-selectin, IL-1β, IL-4, IL-6, IL-8, IL-12p40, IL-13, G-CSF, GM-CSF, IFN-γ, TNF-α, MIP-1α. Several studies were performed to investigate the influence of compression therapy on the level of various inflammatory biomarkers in patients with CVD. In these studies level of the most inflammatory molecules, such as IL-1β, IL-6, IL-8, IL-12p40, G-CSF, GM-CSF, IFN-γ, TNF-α, VEGF, MMP 3, 8, 9 and TIMP-1 decreased after the therapy.

Monitoring of endostatin, TNF-a VEGFs, MMP-9, and cathepsin-L during three months of diosmin treatment in patients with chronic venous disease (CVD)

Introduction: Primary CVD as a result of increased venous hypertension caused mostly by reflux from valvular incompetence as an indication for venoactive drug treatment. The objective of the study was the association between three months of treatment with diosmin and changes to the angiogenic factors involved in the pathophysiology and clinical symptoms of CVD. Material and methods: 41 patients were included in the study. Plasma levels of tumour necrosis factor a (TNF-a), vascular endothelial growth factor (VEGF-A and VEGF-C), matrix metalloproteinase 9 (MMP-9), Cathepsine-L and endostatin were measured using an ELISA assay at baseline and after three months of diosmin administration. Clinical evaluation was performed using duplex Doppler, the VAS scale, leg circumference measurement and BMI score. Results: Three-month treatment with diosmin was associated with a statistically significant decrease in TNF-a, VEGF-A, VEGF-C, MMP-9, Cathepsin-L and endostatin plasma levels with p < 0.01 and p < 0.05 respectively. The average ankle circumference decreased significantly from 30.45 (± 2.05) to 29.0 (± 1.43) (p < 0.05). Conclusion: Diosmin influence on the inflammatory and proteolytic mechanisms involved in the pathology of CVD, could modify endostatin release and angiogenic processes.

Pathophysiology of Chronic Venous Disease and Venous Ulcers.

Chronic venous disease and venous leg ulceration are a common disease affecting millions of individuals. The fundamental problem is venous hypertension with resultant clinical manifestations of venous disease including varicose veins, skin changes, and venous leg ulceration. The pathophysiology leading to venous hypertension is complex and multifactorial, involving genetic predisposition, environmental factors, hormones, endothelial dysfunction, inflammatory cells and molecules and activation on the endothelium and vein wall, and disturbances in the balance of cytokines and matrix metalloproteinases. Understanding the pathophysiology of chronic venous disease and venous leg ulcers identifies cellular pathways, biomarkers, metabolic signatures, and cellular cross-talk for targeted therapy.

The place of Ruscus extract, hesperidin methyl chalcone, and vitamin C in the management of chronic venous disease

Despite continuous improvement in our knowledge and management of chronic venous disease (CVD), certain areas, such as the role of muscarinic receptors in the pathology and treatment of CVD, remain unexplored. The symposium "The place of Ruscus extract, hesperidin methyl chalcone, and vitamin C in the management of CVD", held at the Annual Meeting of the European Venous Forum on 7-9 July 2016 in London, presented an update on the pathophysiology of CVD and highlighted how the combination of Ruscus extract, hesperidin methyl chalcone, and vitamin C (Ruscus/HMC/VitC; Cyclo 3® Fort), may counteract the deleterious processes underlying CVD. The data presented during this symposium are reported here. The pathophysiology of CVD is driven by a complex process involving numerous factors, with the two key players being venous hypertension and the inflammatory response. The cascade of reactions induced by disturbed venous flow, inflammation, and tissue alterations results in the early appearance of symptoms and progressive development of clinical signs of disease. Previous studies have shown that Ruscus extract acts at three levels: on the veins, capillaries and lymphatics, and has anti-inflammatory properties. A series of recent experiments has shed new light on the mechanism of action of the combination of Ruscus/HMC/VitC. The efficacy of Ruscus/HMC/VitC in CVD is supported by clinical studies, while two meta-analyses have confirmed a significant decrease of several symptoms and ankle circumference in response to treatment with this agent, leading to the conclusion that Ruscus/HMC/VitC deserves a Grade A rating.

Does extracellular matrix of the varicose vein wall change according to clinical stage?

The etiology and pathophysiology of chronic venous disease is not fully understood. This study aimed to determine the variation of the extracellular matrix proteins in varicose vein wall according to clinical stage. Forty varicose and 10 control veins were sampled from the saphenofemoral junction. The Clinical Etiologic Anatomic Pathophysiologic (CEAP) classification was used in patients with varicose veins. Samples were stained with hematoxylin-eosin, Masson's trichrome, EVG (Elastica-van Gieson) stain and with laminin, fibronectin, tenascin antibodies. Stained samples were examined immuno-histochemically. Changes in extracellular matrix were determined semi-quantitatively using light microscopy. It was observed that in the early stages (C2-C3) of chronic venous disease, fibrosis is increased in the intima and media layers, with fragmentation in lamina elastica interna, and increased tenascin expression in the intima layer. In advanced stages (C4-C6), the accumulation of tenascin in the intima continued along with fibrosis in the media layer, the thickness of the media layer increased and fibronectin deposition was observed. This study showed that changes first occur in the intima during the early stages of the disease with addition of alterations in the media layer at later stages.

Veno-active drugs for chronic venous disease: A randomized, double-blind, placebo-controlled parallel-design trial

Our current understanding of the pathophysiology of chronic venous disease (CVD) suggests that veno-active drugs (VAD) can provide effective symptom relief. Few studies have conducted head-to-head comparisons of VAD and placebo while also assessing objective measures (such as water plethysmography findings and tibiotarsal joint range of motion) and patient-reported quality of life outcomes. To compare the effects of different VAD on limb volume reduction, tibiotarsal range of motion, and quality of life. 136 patients with CVD (CEAP grades 2-5) were randomly allocated into four groups to receive micronized diosmin + hesperidin, aminaphthone, coumarin + troxerutin, or placebo (starch). Patients were administered a questionnaire consisting of a quality of life (QoL) measure designed specifically for persons with CVD, and underwent tibiotarsal joint angle measurement and water plethysmography of the lower extremity before and 30 days after pharmacological intervention. Assessors were blind to the treatment groups. Nine patients dropped out of the trial. Data collected from the 127 remaining patients was considered for statistical analysis. There were no differences in tibiotarsal joint range of motion. Volume reductions ≥100 mL were more frequent in the diosmin + hesperidin group than in any other group. QoL scores were best in the aminaphthone group, and between-group differences were found on individual analysis of questionnaire items. Use of VAD was associated with significant improvements in QoL as compared with placebo. VAD may be effective for providing symptom relief in patients with CVD.

Endothelial PDGF-BB produced ex vivo correlates with relevant hemodynamic parameters in patients affected by chronic venous disease

Surgical specimens of vein were obtained from the tertiary venous network and/or saphenous vein from patients (n=20) affected by chronic venous disease (CVD). Into the venous segments, which subsequently were surgically ablated, the following hemodynamic parameters were assessed by echo-color-doppler (ECD): peak systolic velocity, end diastolic velocity, whose combination allowed the calculation of the resistance index (RI) and the reflux time (RT). Highly purified venous endothelial cell (VEC) cultures derived from venous segments of these CVD patients were then characterized for the profile of cytokines and chemokines released in the culture supernatants. Among the 27 cytokines and chemokines examined, we found a positive and significant correlation (R=0.5; p=0.03) only between the spontaneous release of PDGF-BB by VEC cultures and the RT values of the patients from which the VEC were isolates. In addition, the release of PDGF-BB in the VEC culture supernatants was significantly (p<0.01) increased upon in vitro treatment with recombinant TNF-α. By using pharmacological inhibitors, specific for the main pathways, NF-kB, ERK1/2 and p38 MAPK, activated by exposure of endothelial cells to TNF-α, we found that only NF-kB appeared to be significantly involved in mediating the PDGF-BB induction by TNF-α. Of interest, the release of PDGF-BB in response to the in vitro inflammatory stimulation, maintained a positive and significant correlation with RT (R=0.6; p=0.01), while showing a negative correlation with RI (R=−0.5; p=0.03). The potential implications of our findings for the pathophysiology of CVD are discussed.

Sulodexide in the Treatment of Chronic Venous Disease

Chronic venous disease encompasses a range of venous disorders, including those involving the lower limbs resulting from venous hypertension. The spectrum of chronic venous disease signs and symptoms shows variable severity, ranging from mild (aching, pain, and varicose veins) to severe (venous ulcers). The pathophysiology of chronic venous disease is characterized by venous hypertension, which triggers endothelial dysfunction and inflammation leading to microcirculatory and tissue damage, and eventually to varicose veins and venous ulcers. Sulodexide is an orally active mixture of glycosaminoglycan (GAG) polysaccharides with established antithrombotic and profibrinolytic activity. The agent is used in the treatment of a number of vascular disorders with increased risk of thrombosis, including intermittent claudication, peripheral arterial occlusive disease and post-myocardial infarction. Sulodexide differs from heparin because it is orally bioavailable and has a longer half-life and a smaller effect on systemic clotting and bleeding. An increasing body of preclinical evidence shows that sulodexide also exerts anti-inflammatory, endothelial-protective, and pleiotropic effects, supporting its potential efficacy in the treatment of chronic venous disease. Clinical studies of sulodexide have shown that the agent is associated with significant improvements in the clinical signs and symptoms of venous ulcers, and is therefore a recommended therapy in combination with local wound care and bandages for patients with persistent venous leg ulcers. Preliminary evidence supports the use of sulodexide in the prevention of recurrent deep venous thrombosis. Sulodexide was generally safe and well tolerated in clinical trials, without hemorrhagic complications. Sulodexide therefore appears to be a favorable option for the treatment of all stages of chronic venous disease and for the prevention of disease progression.

Treatment of Primary Varicose Veins Has Changed with the Introduction of New Techniques

New technologies have produced a revolution in primary varicose vein treatments. Duplex ultrasound is now used for preoperative diagnosis, postoperative surveillance, and during many procedures. Ultrasound has also altered our understanding of the pathophysiology of chronic venous disease. Laser and radiofrequency saphenous ablations are common. Classic techniques, such as sclerotherapy, high ligation, stripping, and phlebectomy, have been improved. Magnetic resonance venography, computed tomographic venography, and intravascular ultrasound have improved diagnostic capabilities. New strategies like ambulatory selective varices ablation under local anesthesia (ASVAL) and conservative hemodynamic treatment for chronic venous insufficiency (CHIVA) raise important questions about how to manage these patients.

Venous haemodynamics: What we know and don't know

The presence of haemodynamic abnormalities in chronic venous disease (CVD) has been well established. The relationships between these abnormalities and clinical manifestations, or natural history of CVD, are complex and remain to be investigated. Flow-mediated processes and mechanisms unrelated to blood flow may play an important role in the pathophysiology of CVD. Current state of knowledge makes questionable a possibility of building treatment strategies based on a single simplified model of the disease. As an example of such simplified approach, CHIVA introduces an opportunity to critically assess the gaps in knowledge in venous pathophysiology.

Hyperemic maximal venous outflow unmasks symptomatic lower extremity venous obstruction

Venous obstruction is an underappreciated and often unrecognized component of the pathophysiology of symptomatic chronic venous disease (CVD). Moreover, standard methods used to detect venous obstruction, such as maximal venous outflow, are inadequate as they typically test patients at rest and in the supine position when the pathophysiology of CVD is defined in the upright patient performing exercise. This report describes a patient with incapacitating venous claudication in whom standard noninvasive venous function tests were normal and whose phlebography was interpreted as showing no evidence of venous obstruction. A postocclusive reactive hyperemic technique was used to unmask significant outflow obstruction, leading to operative correction and subsequent symptom resolution.

Exploration par ultrasons des veines des membres inférieurs

Combined B mode and Doppler ultrasound techniques is now considered the preferential method for investigating lower limb venous network. It allows direct examination of the vessels and provides anatomic and physiologic information. This non-invasive method has two major clinical indications: the diagnosis of vein-thrombosis and the assessment of chronic venous disease. Detection of lower-limb deep-vein thrombosis has been assessed mainly in three situations: in patients with clinically suspected deep-vein thrombosis or with clinically suspected pulmonary embolism, and in those at high risk of venous thrombo-embolism in screening. Lower-limb venous ultrasound was compared with a reference standard or with clinical outcome. Various diagnostic managements have been recommended combining clinical assessment and D- dimer plasma measurement in venous thrombosis as well as also helical computed tomography in pulmonary embolism. Before they can be used in clinical practice, diagnostic strategies need to be compared in term of cost-effectiveness. Feasibility as well as availability of equipment and expertise must also be taken into consideration. Lower-limb venous ultrasound remains also highly useful as a complementary tool to the clinical assessment for determining the aetiology, the anatomy and the pathophysiology of chronic venous disease.

Overexpression of transforming growth factor–β 1 correlates with increased synthesis of nitric oxide synthase in varicose veins

Transforming growth factor-beta 1 (TGF-beta 1 ) is known to maintain a balance between apoptosis and cellular dysfunction and therefore may have a pivotal role in vessel remodeling during pathogenesis of vascular disorders. We previously demonstrated that inducible nitric oxide synthase (iNOS) mediates signal transduction in vascular wall during the development of varicose veins. Currently, we investigated the expression and correlation of TGF-beta 1 , iNOS, monocyte/macrophage infiltration, and loss of vascular smooth muscle cells (VSMCs), in a series of normal and varicose vein specimens. Twenty varicose vein specimens were retrieved from 20 patients undergoing lower-extremity varicose vein excision, and 27 normal greater saphenous vein segments (controls) were obtained from 27 patients undergoing infrainguinal arterial bypass surgery. Principal risk factors (diabetes mellitus, hypertension, tobacco abuse) were also compared. Varicose vein segments were separated into tortuous and nontortuous regions based on their macroscopic and microscopic morphology. VSMC actin, CD68 + monocytes/macrophages, iNOS, and TGF-beta 1 , were examined by immunohistochemistry, immunoblotting, and real-time reverse transcriptase polymerase chain reaction. According to the CEAP classification for chronic lower extremity venous disease, most of the patients were in class 2 for clinical signs of the disease (n = 11). Mean ages were 53.6 +/- 4.7 years for the varicose vein group and 56.5 +/- 4.4 years for the controls. The gender distribution was same in both groups. Immunoreactivity to TGF-beta 1 and iNOS was significantly different in the tortuous regions of the varicose veins compared with nontortuous regions (P < .01). Not only was a significantly higher expression of iNOS noted in the varicose vein group (P < .001), but a differential expression of iNOS was also observed in the tortuous and nontortuous portions of the varicose veins. Significant overexpression of TGF-beta 1 (P < .01) that correlated with overproduction of iNOS and with increased presence of CD68 + monocytes/macrophages was observed in the varicose vein walls compared with normal veins. This is the first evidence of TGF-beta 1 , as well as iNOS, being differentially upregulated in nontortuous and tortuous segments of varicose veins. The increased expression of TGF-beta 1 and presence of macrophages, correlating with overproduction of iNOS, may be associated with varicosity development and deserves further study. The pathogenesis of varicose veins, the most common manifestation of chronic venous disease, is debatable. Elucidation of mechanisms involved in the disease process is the first step to improved therapeutic modulations. Towards this goal, the relationship between NO production and TGF-beta 1 in the molecular pathophysiology of chronic venous disease was investigated. The data identify for the first time, an important role for TGF-b1-iNOS-monocyte/macrophage signaling in the etiology of varicosities. Furthermore, we determine if there are any significant differences within the varicose vein group itself based on regional differences, by classifying the varicose tissues into tortuous and non-tortuous segments.