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.

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.

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.

Severe chronic venous insufficiency: primary treatment with sclerofoam.

Venous insufficiency, for practical purposes, can be divided into primary venous insufficiency and chronic venous insufficiency. The latter is characterized by advanced skin changes of hyperpigmentation, edema, ulceration, scarring from healed ulcers or open ulcerations. These are summarized in the CEAP classification as Classes 4, 5 and 6. Pretreatment evaluation is done with a standing ultrasound reflux examination. Thorough mapping of the extremity reflux is desirable. Physiologic tests of venous function, such as plethysmography, are unnecessary. Treatment is directed at closing refluxing axial veins as well as controlling those perforating veins with outward flow. Varicose veins contribute to axial reflux and must be obliterated. Arterial occlusive disease may complicate venous ulceration in as many as 15% of cases. Initial treatment of severe chronic venous insufficiency is usually carried out by controlling the edema with elastic bandaging or nonelastic support, such as the Unna boot or the CircAid dressing. Surgical intervention has been successful but the advent of foam sclerotherapy has proven to be an attractive alternative to surgery and has added a new tool for the treatment of severe chronic venous insufficiency. In this preliminary experience, the results are quite satisfactory and the technique has been shown to be effective, pain-free, inexpensive, with very little morbidity. Guidelines for obtaining sclerosants for use in foam sclerotherapy legally are provided.

Lower extremity superficial venous aneurysms.

Venous aneurysms are not rare. But most attention has been paid to deep venous aneurysms. Because of their propensity to thrombose and cause pulmonary embolization. Increased availability of duplex Doppler ultrasound has allowed total evaluation of all venous segments in patients undergoing surgery for chronic venous insufficiency. In this study, patients were recorded consecutively and the venous reflux examination was carried out with the patient standing. The superficial venous system was studied with special interrogation of the great and small saphenous veins and their tributaries. Reflux >0.5 sec was recorded as positive. Data were analyzed using the Spearman's correlation index and the student's t-test. A strong correlation was considered for values of rho > 0.6. A total of 65 superficial venous aneurysms of the saphenous vein systems were found in 43 patients (33 women and 10 men) with an average age of 53 years (range, 34-70). The mean body mass index (BMI) overall was 25 +/- 4.6. The BMI in men was 29.5 +/- 2.5. The BMI in women was 23.6 +/- 4 (p < 0.05). Aneurysms of the saphenous systems were classified into four types. Type I aneurysms (52%) were located in the proximal third of the saphenous vein, not at the saphenofemoral junction but instead just distal to the subterminal valve. Type II aneurysms were located in the shaft of the saphenous vein in the distal third of the thigh (35%). The third classification (type III) of superficial saphenous vein aneurysms was an occurrence of types I and II in the same lower extremity (3 patients/43 patients). Superficial venous aneurysms of the short saphenous system were found and were classified as type IV (6%.) Strong correlations were found with female gender and a very strong correlation of larger aneurysms was found with an elevated BMI in men. There was a so a strong correlation between type III aneurysms of the proximal and distal thigh greater saphenous vein and greater saphenous vein reflux. Aneurysms of the saphenous veins are common and this may have an impact on choice of surgical treatment.

Revision of the CEAP classification for chronic venous disorders: consensus statement.

The CEAP classification for chronic venous disorders (CVD) was developed in 1994 by an international ad hoc committee of the American Venous Forum, endorsed by the Society for Vascular Surgery, and incorporated into "Reporting Standards in Venous Disease" in 1995. Today most published clinical papers on CVD use all or portions of CEAP. Rather than have it stand as a static classification system, an ad hoc committee of the American Venous Forum, working with an international liaison committee, has recommended a number of practical changes, detailed in this consensus report. These include refinement of several definitions used in describing CVD; refinement of the C classes of CEAP; addition of the descriptor n (no venous abnormality identified); elaboration of the date of classification and level of investigation; and as a simpler alternative to the full (advanced) CEAP classification, introduction of a basic CEAP version. It is important to stress that CEAP is a descriptive classification, whereas venous severity scoring and quality of life scores are instruments for longitudinal research to assess outcomes.

Hypertension-induced venous valve remodeling.

INTRODUCTION: In human beings, chronic venous insufficiency is linked to venous hypertension. This in turn is associated with venous valve incompetence. This study was designed to test the hypothesis that venous hypertension serves to initiate a process that results in the venous valve and venous wall damage observed in venous insufficiency. Material and methods Acute venous hypertension was produced by creation of an arteriovenous (AV) fistula between the femoral artery and vein in Wistar rats. At specified intervals pressure in the veins was recorded. The proximal valve containing saphenous vein was exposed, and reflux was measured from reverse blood flow through the first proximal valve. The vein was excised, valve parameters were measured, a portion was taken for morphologic investigation, and the remaining specimen was frozen in liquid nitrogen for investigation of leukocyte infiltration, expression of adhesion molecules, matrix metalloproteinase (MMP) levels, and apoptotic markers. Contralateral nonpressurized saphenous veins were used as control specimens. RESULTS: The saphenous and femoral veins were immediately distended by pulsatile blood flow from the arterial system. Pressure was significantly increased from 11 +/- 2 mm Hg to 94 +/- 9 mm Hg. At 2 days no reflux was detected in the saphenous veins. At 1 week, one of four rats exhibited reflux; at 2 weeks, two of four rats had reflux; and at 3 weeks, three of four rats showed reflux. Contralateral saphenous veins were uniformly competent. Compared with control specimens, the veins were dilated; leaflet length and leaflet width were significantly reduced. Granulocytes, monocytes, and macrophages were identified in all regions of the vein wall, and the number was increased by the presence of the AV fistula. The number of T-lymphocytes was increased, and B-lymphocytes were present. P-selectin was upregulated in the saphenous vein walls, as was intercellular adhesion molecules. MMP-2 and MMP-9 expression in the veins was not enhanced. In the nuclear factor kappabeta family, Ikappabeta was not increased in any hypertensive veins. The number of apoptotic cells in the vein wall was increased in the presence of the AV fistula. CONCLUSION: This study indicates that acute venous hypertension is accompanied by significant venous distention and some valve damage as early as 3 weeks after fistula creation. There is development of inflammatory markers, with leukocyte infiltration and increased adhesion molecule expression. We could not detect significant enhancement of MMP levels or nuclear transcription factors. It is uncertain whether this lack of evidence may be partially due to enhanced apoptosis in venous valves and vein walls. A detailed definition of the inflammatory reaction produced by venous hypertension should be the subject of further study. Clinical relevance Saphenous vein valves when observed at the time of vein stripping show deformities of shortening, scarring, and tearing. The current model of induced venous hypertension demonstrates early venous valve changes similar to those observed in human beings and links them to a venous hypertension-induced inflammatory reaction. Thus the model could be useful in pharmacologic testing to prevent or treat venous insufficiency and for defining the fundamental mechanisms that cause varicose veins.

Advanced management of congenital vascular malformations: a multidisciplinary approach.

INTRODUCTION: Management of congenital vascular malformations (CVM) remains a major challenge because treatment carries a substantial risk of morbidity and recurrence of the fundamental problem. The new classification of CVM allows a multidisciplinary approach to the treatment with full integration of the several treatment modalities. The multidisciplinary approach was introduced at our CVM Clinic in 1995 and this report summarizes our results to date. PATIENTS AND METHODS: The CVM Clinic is attended by 15 different specialties. These allow application of advanced diagnosis and treatments. The interdisciplinary consultation allows proper application of the various treatment modalities including embolosclerotherapy and surgical therapy. The embolosclerosants utilized are absolute ethanol and N-butyl cyanoacrylate (NBCA). These are used for venous malformations (VM), arteriovenous shunting malformations (AVM), and hemolymphatic malformations (HLM). These agents are used independently and as preoperative adjuncts. Among the 438 patients treated between September 1995 and September 1999, there were 99 patients treated with combinations of embolosclerotherapy. There were 286 sessions, 252 of which were for ethanol sclerotherapy and 247 of these employed ethanol alone and five were combined with NBCA. Independent embolotherapy with NBCA was instituted more recently and has been used in 28 sessions. Perioperative embolosclerotherapy has been performed in 43 sessions, mostly as preliminary preparation to reduce subsequent surgical morbidity. Followup assessment of immediate and interim results after completion of multisession therapy has been done using combinations of noninvasive diagnostic testing. RESULTS: The immediate success rate of embolosclerotherapy has been 94.7% (271/286 sessions). There has been an immediate 5.2% failure (15/286 sessions). Failures have largely been due to forced abandonment of the sclerosing procedure due to risk of deep venous thrombosis. Interim results though short-term success following completion of multisession therapy, average 3.2 sessions per patient, were satisfactory. Complications, mostly skin damage from embolosclerotherapy were experienced in 31 patients during the 286 sessions performed on 99 patients. These skin complications were discussed and accepted by the multidisciplinary team which recognized unavoidable morbidity accompanying the ethanol therapy when applied to superficially located lesions. The overall morbidity included complication rate per session (14.7%, 42/286) and 31.3% per patient (31/99). Recovery from the skin complications has been mostly spontaneous but one case in which peroneal nerve palsy occurred became permanent. There has been no recurrence of the lesions treated successfully, and this has been confirmed through a battery of noninvasive testing. The average follow-up period after completion of multisession therapy is relatively short with 10.6 months (6.0-32 months) only to meet the condition as interim results. Fourteen patients have undergone surgical ablation after preoperative embolosclerotherapy and the surgical morbidity has been minimal. CONCLUSION: An accurate diagnosis and multidisciplinary treatment strategy for management of CVMs can improve overall treatment success with a reduced morbidity and recurrence over conventional approaches. This study reviews current trends in contemporary diagnosis and clinical management of congenital vascular malformations (CVM) of the peripheral vascular system emphasizing our new multidisciplinary approach.

Nomenclature of the veins of the lower limbs: an international interdisciplinary consensus statement.

An agreement on anatomic terminology is the foundation for a common language in medical science and for an effective exchange of information. A thorough review of the literature has shown need for revision and extension of the official terminologia anatomica with regard to the veins of the lower limb. The foundation of this consensus document was laid by the faculty at a precongress meeting of The Fourteenth World Congress of the International Union of Phlebology (IUP), held in Rome on September 8-9, 2001, under the auspices of the IUP, the International Federation of Associations of Anatomists (IFAA), and the Federative International Committee on Anatomical Terminology (FICAT). The official names of some veins have been changed according to the guidelines of the FICAT. In addition, previously unnamed veins have received names relevant to their anatomy and clinical significance. Some of the terminology recommendations are innovative, but were judged to be correct by members of the committee.

Surgical and endovascular treatment of lower extremity venous insufficiency.

Lower extremity venous insufficiency is a highly prevalent condition. Now it is understood that telangiectasias, reticular varicosities, and true varicose veins are physiologically similar and etiologically identical. The four main influences causing these abnormalities are heredity, female sex, gravitational hydrostatic forces, and hemodynamic muscular compartment pressure. There are clear indications and goals for intervention. A cornerstone in the treatment of venous insufficiency is elimination of sources of venous hypertension. One of these is the refluxing greater saphenous vein. Minimally invasive saphenous ablation can be achieved by radiofrequency energy and laser light energy. These new techniques eliminate the psychologic barrier to treatment caused by the term "stripping" and allow the objectives of surgery to be achieved with minimal invasion and quick recovery. Endovenous techniques show great promise. They provide minimal invasion, often under local anesthesia and intravenous sedation, thereby eliminating the need for general anesthesia. Objectives of venous insufficiency have been established and the endoluminal minimally invasive techniques developed in recent years appear to accomplish their goals.

Advances in venous surgery: SEPS and phlebectomy for chronic venous insufficiency.

Chronic venous insufficiency (CVI) and its complications of chronic pain, intractable ulceration, and infection are important conditions to treat by modern surgical techniques. As early as the 1930s, perforating veins with outward flow were implicated in the pathogenesis of this condition. Recognition that such outward flow promotes leukocyte adhesion and activation as the principal microcirculatory cause for the cutaneous changes has explained the importance of perforating vein interruption? Because of disability of CVI, surgeons and patients reluctantly tolerated the open Linton perforator interruption operation with its morbid knee-to-ankle incisions. It was tolerated because it worked. Modifications to reduce the morbidity of the procedure eliminated two of the three incisions used in the explorations of the 1930s. Other modifications such as DePalma's modification of the incisions further reduced wound complications. However, the most significant surgical alteration was to utilize the endoscopic techniques introduced in Europe by Fischer and Hauer. Very quickly it was obvious that the endoscopic technique minimized postoperative complications. Application of endoscopic perforator interruption to varicose vein surgery validated the safety of the procedure but did not contribute to knowledge about treating CVI.