Acute venous occlusion enhances matrix metalloprotease activity: Implications on endothelial dysfunction.

Venous hypertension is associated with microvascular inflammation, restructuring, and apoptosis, but the cellular and molecular mechanisms underlying these events remain uncertain. In the present study, we tested the hypothesis that elevated venous pressure and reduction of shear stress induce elevated enzymatic activity. This activity in turn may affect endothelial surface receptors and promote their dysfunction. Using a rodent model for venous hypertension using acute venular occlusion, microzymographic techniques for enzyme detection, and immunohistochemistry for receptor labeling, we found increased activity of the matrix metalloproteases (MMPs) -1, -8, and -9 and tissue inhibitors of metalloproteases (TIMPs) -1 and -2 in both high- and low-pressure regions. In this short time frame, we also observed that elevated venule pressure led to two different fates for the vascular endothelial growth factor receptor-2 (VEGFR2); in higher-pressure upstream regions, some animals exhibited higher VEGFR2 expression, while others displayed lower levels upstream compared to their downstream counterparts with lower pressure. VEGFR2 expression was, on average, more pronounced upon application of MMP inhibitor, suggesting possible cleavage of the receptor by activated enzymes in this model. We conclude that venous pressure elevation increases enzymatic activity which may contribute to inflammation and endothelial dysfunction associated with this disease by influencing critical surface receptors.

Phlebolymphemeda: usually unrecognized, often poorly treated.

Phlebolymphedema is a condition of mixed venous and lymphatic insufficiency. It is usually not recognized and it is usually not treated. The lymphatic and venous systems are intimately interrelated. In the presence of venous hypertension, which is characteristic of most venous disorders, the increase in lymphatic flow becomes much greater than the lymph transport capacity. The diagnosis of phlebolymphedema is based on a detailed history and physical examination. Patients with phlebolymphedema have skin changes of venous insufficiency, which are easy to recognize. Treatment for chronic phlebolymphedema consists of treating the venous abnormality and watching regression of the lymphatic problem.

Foam sclerotherapy: techniques and uses.

Sclerosant foam has been increasing in use in recent times. It has certain advantages over liquid sclerosants and is quite safe to use, despite the fact that there are adverse events that have been reported. The history of sclerosant foam goes back in time many years. Tessari developed the current method of creating sclerosant foam in 2001, and his technique has been modified. In our experience, the sclerosant foam has totally replaced other methods of treating venous insufficiency, and the results of treatment are superior to other methods. It is apparent that treatment of a variety of venous disorders can be accomplished using foam sclerotherapy. Our experience and that of others has shown that there are early advantages in the use of foam in the management of varicose veins compared with surgery and other methods.

Sclerotherapy: a truly minimally invasive technique.

Foam sclerotherapy offers a treatment strategy with great potential. Recently, general and vascular surgery have become less invasive; so too, has the treatment of venous disorders. Sclerosants cause irreversible damage to the vascular endothelium by disrupting cell membranes resulting in sustained vasospasm and denudation of the venous monolayer. Prospective randomized outcome data support the hypothesis that foam sclerotherapy is superior to liquid sclerotherapy. All published reports of varicose vein treatment with foam describe efficacy in terms of immediate and primary venous occlusion of better than 80%. Severe complications of foam sclerotherapy are rare. Recurrent varices are in the 10% to 20% range. Use of foam sclerotherapy in our experience has proven to be effective, essentially pain-free, and durable in the short term. The treatment is quick, efficient, and cheap.

Inelastic compression legging produces gradient compression and significantly higher skin surface pressures compared with an elastic compression stocking.

The purposes of this study were to (1) investigate compression levels beneath an inelastic legging equipped with a new pressure-adjustment system, (2) compare the inelastic compression levels with those provided by a well-known elastic stocking, and (3) evaluate each support's gradient compression production. Eighteen subjects without venous reflux and 12 patients with previously documented venous reflux received elastic and inelastic compression supports sized for the individual. Skin surface pressures under the elastic (Sigvaris 500, 30-40 mm Hg range, Sigvaris, Inc., Peachtree City, GA) and inelastic (CircAid C3 with Built-in-Pressure System [BPS], CircAid Medical Products, San Diego, CA) supports were measured using a calibrated Tekscan I-Scan device (Tekscan, Inc., Boston, MA). The elastic stocking produced significantly lower skin surface pressures than the inelastic legging. Mean pressures (+/- standard error) beneath the elastic stocking were 26 +/- 2 and 23 +/- 1 mm Hg at the ankle and below-knee regions, respectively. Mean pressures (+/- standard error) beneath the inelastic legging with the BPS were 50 +/- 3 and 38 +/- 2 mm Hg at the ankle and below-knee regions, respectively. Importantly, our study indicates that only the inelastic legging with the BPS produces significant ankle to knee gradient compression (p = .001).

Pathogenesis of primary chronic venous disease: Insights from animal models of venous hypertension.

BACKGROUND: Reflux of blood through incompetent venous valves is a major cause of the venous hypertension that underlies clinical manifestations of chronic venous disease, including varicose veins, lipodermatosclerosis, and venous ulcers. OBJECTIVE: To review published literature relating to animal models in which venous hypertension has been produced and which have yielded information on the mechanisms by which venous hypertension may trigger inflammation and cause changes in the skin and venous valves. METHODS: Medline searches, with additional papers identified from reference lists in published papers. RESULTS: At least three types of animal model were identified that have contributed to a better understanding of the trigger mechanisms and role of inflammatory processes in chronic venous disease. These models involve venous hypertension induced either by acute venular occlusion, placement of a chronic arteriovenous fistula, or ligation of several large veins. Model results suggest that elevated venous pressure and altered flow can trigger inflammatory cascades in the vein wall and venous valves which can cause progressive valvular incompetence and eventual valvular destruction, and which are also important in the skin changes associated with venous disease. Treatment with agents that reduce oxidative stress by scavenging free radicals and that inhibit the inflammatory cascade can prevent the progressive deterioration of function in valves exposed to elevated venous pressure and can prevent the development of reflux blood flow. CONCLUSIONS: Understanding these processes suggests potential therapeutic targets that could be effective in slowing or preventing progression, and could help promote a more positive and proactive attitude towards treatment of the underlying disease process, rather than the later manifestations of chronic venous disease.

Foam sclerotherapy for the treatment of varicose veins.

Treatment of venous insufficiency with liquid sclerotherapy is considered by some to be an unfulfilled promise. It was heralded in the first half of the last century to be a replacement for surgery, but as recurrences of varicose veins appeared in limbs treated with injection techniques, surgery reappeared and was dominant in the last half of the century. Just as saphenous stripping was proved to be superior to proximal ligation, both were replaced by use of electromagnetic energy, such as radiofrequency and laser venous ablation, as a means of taking the saphenous veins out of the circulation. Now reports of recurrent varices in 20 to 50% of operated cases are making some physicians look to alternatives in treating varicose veins. Foam sclerotherapy must be looked upon as an entirely new method of treatment. It is useful in all types of varices and is proven to be safe, simple, cheap, reliable, and repeatable.

Risk factors for chronic venous disease: the San Diego Population Study.

BACKGROUND: The etiology of chronic venous disease in the lower limbs is unclear, and very limited data are available on potential risk factors from representative population studies. METHODS: Participants in the San Diego Population Study, a free-living adult population randomly selected from age, sex, and ethnic strata, were systematically assessed for risk factors for venous disease. Categorization of normal, moderate, and severe disease was determined hierarchically through clinical examination and ultrasonography imaging by trained vascular technologists, who also performed anthropometric measures. An interviewer administered a questionnaire and an examination assessed potential risk factors for venous disease suggested by previous reports. RESULTS: In multivariable models, moderate venous disease was independently related to age, a family history of venous disease, previous hernia surgery, and normotension in both sexes. In men, current walking, the absence of cardiovascular disease, and not moving after sitting were also predictive. Additional predictors in women were weight, number of births, oophorectomy, flat feet, and not sitting. For severe disease, age, family history of venous disease, waist circumference, and flat feet were predictive in both sexes. In men, occupation as a laborer, cigarette smoking, and normotension were also independently associated with severe venous disease. Additional significant and independent predictors in women were hours standing, history of leg injury, number of births, and cardiovascular disease, but African American ethnicity was protective. Multiple other postulated risk factors for venous disease were not significant in multivariable analysis in this population. CONCLUSIONS: Although some risk factors for venous disease such as age, family history of venous disease, and findings suggestive of ligamentous laxity (hernia surgery, flat feet) are immutable, others can be modified, such as weight, physical activity, and cigarette smoking. Overall, these data provide modest support for the potential of behavioral risk-factor modification to prevent chronic venous disease.

Molecular mechanisms in chronic venous insufficiency.

Chronic venous disease (CVD) is common. Its manifestations include varicose veins; skin changes such as dermatitis, hyperpigmentation, and lipodermatosclerosis; and chronic leg ulcers. Recent advances in the understanding of its pathophysiology have shown how molecular mechanisms in the inflammatory cascade are involved in these diverse findings. Venous hypertension and associated fluid shear stress alterations on the endothelial surface may initiate this cascade and may lead to adverse changes in the venous wall, venous valves, and skin that can eventually result in varicose veins and in venous ulcers.

Primary chronic venous disorders.

Primary chronic venous disorders, which according to the CEAP classification are those not associated with an identifiable mechanism of venous dysfunction, are among the most common in Western populations. Varicose veins without skin changes are present in about 20% of the population while active ulcers may be present in as many as 0.5%. Primary venous disorders are thought to arise from intrinsic structural and biochemical abnormalities of the vein wall. Advanced cases may be associated with skin changes and ulceration arising from extravasation of macromolecules and red blood cells leading to endothelial cell activation, leukocyte diapedesis, and altered tissue remodeling with intense collagen deposition. Laboratory evaluation of patients with primary venous disorders includes venous duplex ultrasonography performed in the upright position, occasionally supplemented with plethysmography and, when deep venous reconstruction is contemplated, ascending and descending venography. Primary venous disease is most often associated with truncal saphenous insufficiency. Although historically treated with stripping of the saphenous vein and interruption and removal of major tributary and perforating veins, a variety of endovenous techniques are now available to ablate the saphenous veins and have generally been demonstrated to be safe and less morbid than traditional procedures. Sclerotherapy also has an important role in the management of telangiectasias; primary, residual, or recurrent varicosities without connection to incompetent venous trunks; and congenital venous malformations. The introduction of ultrasound guided foam sclerotherapy has broadened potential indications to include treatment of the main saphenous trunks, varicose tributaries, and perforating veins. Surgical repair of incompetent deep venous valves has been reported to be an effective procedure in nonrandomized series, but appropriate case selection is critical to successful outcomes.

Severe chronic venous insufficiency treated by foamed sclerosant.

Our objective was to chronicle our experience in using sclerosant foam to treat severe chronic venous insufficiency (CVI). Forty-four patients with 60 limbs severely affected by severe CVI were entered into the study. They had lipodermatosclerosis, CEAP 4 (seven limbs); atrophie blanche or scars of healed venous ulcerations, CEAP 5 (18 limbs); and frank, open venous ulcers, CEAP 6 (35 limbs). Patients and limbs were collected into three groups. In group I, all limbs were treated with compression without intervention. Group II consisted of crossover patients who failed compression treatment. Group III consisted of patients treated promptly with sclerosant foam therapy without a waiting period of compression. A standing Doppler duplex reflux examination was done in all cases. Compression was by Unna boot or long stretch elastic bandaging. Foam was generated from Polidocanol 1%, 2%, or 3% by the two-syringe technique and administered under ultrasound guidance. Posttreatment compression was used for 14 days. In addition to clinical and ultrasound evaluation at 2, 7, 14, and 30 days, venous severity scoring was noted at entry and discharge. In group I, 12 patients were discharged from care within 6 weeks of initiating compression. All eight of the class 6 limbs had healed. Group II consisted of four CEAP class 5 limbs and eight class 6 limbs that had failed to heal with compression. Five of eight venous ulcers healed within 2 weeks, two more healed by 4 weeks, and one required 6 weeks to heal. In group III, 7 of 11 venous ulcers healed within 2 weeks and four more within 4 weeks. Venous severity scores reflected the success of treatment, with the greatest change occurring in group III and the least in group I. Limbs treated with foam had a statistically better outcome than those without (p = 0.041). One patient failed foam sclerotherapy, another had pulmonary emboli 4 months after foam treatment, and a single medial gastrocnemius thrombus was discovered 24 hr after treatment. Treatment of severe CVI with compression and foam sclerotherapy causes more rapid resolution of the venous insufficiency complications and does so without an increase in morbidity.

Microcirculation and venous ulcers: a review.

Recent histological and immunocytochemical analyses of venous leg ulcers suggest that lesions observed in the different stages of chronic venous insufficiency (CVI) may be related to an inflammatory process. This inflammatory process leads to fibrosclerotic remodeling of the skin and then to ulceration. The vascular network of the most superficial layers of the skin appears to be the target of the inflammatory reaction. Hemodynamic forces such as venous hypertension, circulatory stasis, and modified conditions of shear stress appear to play an important role in an inflammatory reaction accompanied by leukocyte activation which clinically leads to CVI: venous dermatitis and venous ulceration. The leukocyte activation is accompanied by the expression of integrins and by synthesis and release of many inflammatory molecules, including proteolytic enzymes, leukotrienes, prostaglandin, bradykinin, free oxygen radicals, cytokines, and possibly other classes of inflammatory mediators. The inflammatory reaction perpetuates itself, leading to liposclerotic skin and subcutaneous tissue remodeling. In light of the mechanisms of venous ulcer formation cited above, therapy in the future might be directed against leukocyte activation in order to diminish the magnitude of the inflammatory response. With this in mind, the attention of many investigators has been drawn to two different drugs with an anti-inflammatory effect: pentoxifylline and flavonoids.

Chronic venous insufficiency and the therapeutic effects of Daflon 500 mg.

Chronic venous insufficiency is linked to venous hypertension and forces of shear stress on the endothelium. Venous hypertension depends upon two forces: the weight of a column of blood from the right atrium transmitted through the valveless vena cava and iliac veins to the femoral vein, and pressure generated by contracting skeletal muscles of the leg transmitted through failed perforating veins. When valve failure occurs in superficial axial veins and perforating veins, the venous pressure in the veins and venules of the skin and subcutaneous tissue is raised. The skin changes in chronic venous insufficiency are directly related to the severity of the venous hypertension. Also, pathologic changes in the valves are linked to venous hypertension and leukocyte infiltration and activation. It is hypothesized that acute venous pressure elevations cause a shift in the venous hemodynamics with changes in wall shear stress. This initiates the inflammatory cascade. Daflon 500 mg ameliorates the effects of chronic inflammation. In randomized trials, 60 days of therapy with Daflon at a dosage of 500 mg 2 tablets daily was effective, in addition to elastic compression, in accelerating venous ulcer healing. Because venous insufficiency is linked to venous hypertension and an inflammatory reaction, it appears that Daflon 500 mg 2 tablets daily shows a great potential for accomplishing blockade of the inflammatory cascade.

Venous angiomata: treatment with sclerosant foam.

Venous angiomata, or venous malformations, are often present at birth, although they may not be evident until later. They consist of a spongy tangle of veins, and these lesions usually vary in size. Treatment of venous angiomata is often requested for cosmetic reasons, but painful ulcerations, nerve compression, functional disability can command care. This presentation describes management using sclerosant foam as the treating agent. During a 30-month period ending March 2004, 1,321 patients were investigated for venous disorders at the Vein Institute of La Jolla. Fourteen (incidence 1%) were found to have venous angiomata (: nine women). The age range was 15-76 years (mean 30.8 +/- 18.6). Lesions were classified by the Hamburg system and were primarily venous, extratruncular in 12 patients and combined extratruncular and truncular in two patients. Eight patients, three males, had manifestations of lower extremity Klippel-Trenaunay (syndrome; six had only venous angiomas. Only 10 of the 14 patients were treated. All patients were studied by Doppler duplex examination. Selected lesions were chosen for helical computed tomographic studies. Magnetic resonance venography was also used to image the lesions, define the deep circulation, note connections with normal circulation, identify vessels for therapeutic access, and determine infiltration of the lesion into adjacent soft tissue. Foam was produced by the Tessari two syringes one three-way stopcock teclinique, with the air to Polidocanol ratio being 4 or 5 to 1. This was used at 1% or 2% concentration, specific for each patient. The SonoSite 190 plus Duplex Doppler was used for ultrasound guidance, whenever deep access was required and to monitor progress and effects of treatment. A goal was set for each patient before treatment was begun. Ten patients were treated, and four await treatment. The mean number of treatments was 3.6 +/- 2.8 (range 1-10). A primary goal of pain-free healing was set in patients with nonhealing, painful ulceration or symptomatic varicose veins. This was achieved in all treated patients. Cosmetically, all of the patients were improved, and symptomatic patients were relieved of pain. The single complication was formation of a cutaneous ulcer following injection of telangiectasias. Sclerosant foam is a satisfactory tool to use in treating venous angiomata including the Klippel-Trenaunay syndrome. Use of foam sclerotherapy in this experience has proven the technique to be effective, essentially pain-free, and durable in the short term.

Nomenclature of the veins of the lower limb: extensions, refinements, and clinical application.

The relative deficiency of the official Terminologia Anatomica with regard to the veins of the lower limbs was responsible for a nonuniform anatomic nomenclature in the clinical literature. In 2001, an International Interdisciplinary Committee updated and refined the official Terminologia Anatomica regarding the veins of the lower limbs. Recommendations for terminology were included in an updating document that appeared in the Journal of Vascular Surgery (2002;36:416-22). To enhance further the use of a common scientific language, the committee worked on the present document, which includes (1) extensions and refinements regarding the veins of the lower limbs; (2) the nomenclature of the venous system of the pelvis; (3) the use of eponyms; and (4) the use of terms and adjectives of particular importance in clinical vascular anatomy.

An animal model of venous hypertension: the role of inflammation in venous valve failure.

BACKGROUND: Clinical observation suggests that chronic venous insufficiency is related to failure of venous valves. Duplex ultrasound studies of lower extremity superficial veins regularly show valve failure and venous reflux. Gross morphologic observation of venous valves in surgical specimens shows tearing, splitting, scarring, and disappearance of valves. HYPOTHESIS: Venous valve damage is acquired, linked with venous hypertension, and affected by inflammation. OBJECTIVE: The objective of this study was to investigate the inflammatory process in valve remodeling associated with acute and chronic venous hypertension. METHODS: A femoral arteriovenous fistula was created in study animals (Wistar rats, n = 60), and animals without an arteriovenous fistula were studied as controls (n = 5). At 1, 7, 21, and 42 days animals with the femoral arteriovenous fistula were anesthetized, and systemic pressure, the pressure in the femoral vein distal to fistula, and the pressure of the femoral vein in the contralateral hind limb were measured. Timed collection of blood backflow after division of the femoral vein distal to the fistula and in the alive, anesthetized animal was collected, measured, and calculated per unit time to be used as an indicator of valve insufficiency. The femoral vein distal to the fistula was harvested; valvular structures were examined and measured. Specimens were processed, and longitudinal sections were made and challenged with immunostaining antibodies against matrix metalloprotease (MMP)-2 and MMP-9. Sections were examined, and expression of molecular markers was determined by light absorption measurements after image digitization. RESULTS: One week after the procedure, all animals exhibited some degree of hind limb edema ipsilateral to the arteriovenous fistula. Pressure in the femoral vein distal to the fistula was markedly increased on average to 96 +/- 9 mm Hg. Reflux was increased in a time-dependent manner, with the 21-day and 42-day groups showing the highest values. Valves just distal to the fistula showed an increased diameter of the valvular annulus and a shortening of the annular height. Venous wall findings included fibrosis and fusion of the media and adventitia and scarring and disappearance of valves principally in the 21- and 42-day specimens. Immunolabeling for MMP-2 showed an increased level in the 21- and 42-day groups. MMP-9 showed an increased level at 1 day, followed by a more marked level in the 21- and 42-day groups. CONCLUSIONS: In this animal model of venous hypertension the findings of limb edema, increasing valvular reflux, and morphologic changes of increased annulus diameter and valve height are seen. Histologic changes included massive fibrosis of media and fusion with adventitia. Inflammatory markers MMP-2 and MMP-9 are strongly represented, and valve disappearance occurs after these markers are present. The gross morphologic changes seen are quite similar to those observed in human surgical specimens removed in treatment of venous insufficiency. CLINICAL RELEVANCE: When observed angioscopically at the time of vein stripping, saphenous vein valves show severe deformities including shortening, scarring, and tearing. The current model of induced venous hypertension demonstrates early venous valve changes that replicate those observed in humans. This observation provides a link from venous hypertension to an induced inflammatory reaction that stimulates the valve damage. Thus the model could be useful for defining the fundamental mechanisms that cause venous valve failure and varicose veins and in pharmacologic testing to prevent or treat venous insufficiency.