Monocyte infiltration into venous valves

Purpose: Greater saphenous veins removed at surgery for correction of venous dysfunction have few valves. Those that are present may be shrunken, deformed, or monocuspid. This study was carried out to determine whether leukocyte infiltration is associated with valve damage. Methods: Seventeen specimens were removed at surgery from five men and eight women (age, 29 to 80 years). These consisted of the proximal 15 cm of the duplex-confirmed, refluxing proximal greater saphenous vein, one proximal lesser saphenous vein, and one midportion of greater saphenous vein. The severity of venous stasis in each patient limb was classified by the CEAP formula.¹ Twelve were class 2, two were class 3, and three were class 4. Control specimens were obtained from patients who underwent coronary artery bypass grafting. These were two men and two women, ages 72, 66, 62, and 60 years, free of venous insufficiency, with the specimens obtained from the proximal saphenous vein. Two of the control specimens contained venous valves corresponding to the test specimens. Longitudinal 10 μm paraffin sections were labeled with anti-CD64 monoclonal antibody, specific for tissue monocytes and macrophages, and studied by light microscopy. Five regions were chosen for quantification of the leukocyte infiltrate. Cells were categorized and counted directly. Volume proportions were calculated using stereologic techniques. Results: Three of seven specimens studied for morphologic changes had clearly shortened valve leaflets. Collagen degeneration was noted in all seven specimens. Leaflets had essentially disappeared in three and were shortened to 100 to 2100 μm in five. Specific leukocyte staining was accomplished on 10 additional specimens. All specimens showed monocyte/macrophage infiltration in valve leaflets and venous wall. These were more numerous in the valve sinus and proximal wall both on and under the endothelium. Control specimens showed no monocyte/macrophage infiltration. Conclusions: These observations suggest that venous valve damage in refluxing saphenous veins is associated with a leukocyte (monocyte/macrophage) infiltrate. Cell activation and fluid dynamic factors, such as eddies recirculation, and stasis in the valve sinus may be a part of the process of leukocyte penetration of the endothelium. The magnitude of leukocyte infiltration in the vein wall and in the base of the valve leaflet may be important in the genesis of primary venous dysfunction. (J Vasc Surg 1998;27:158-66.)     

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.     

Immunocytochemical characterisation of the inflammatory cell infiltrate of varicose veins.

OBJECTIVES: To characterise the inflammatory cell infiltrate in varicose vein wall, and its relationship to the valve complex. DESIGN: A comparative study of the distribution of inflammatory cells in normal and varicose vein. MATERIALS: Specimens of proximal human long saphenous vein were obtained from patients with duplex Doppler confirmed long saphenous vein reflux (n=14). Control vein was obtained from patients undergoing coronary artery bypass without clinical evidence of venous insufficiency (n=6). Longitudinal 7 microm frozen sections of vein, displaying valve, were prepared. METHODS: Using immunohistochemistry, T-lymphocytes (CD3), macrophage/monocytes (CD68), neutrophils (CD15s) and mast cells (anti-mast cell tryptase) were identified. The number of cells per unit length vein were counted using light microscopy. RESULTS: There were significantly more mast cells and macrophage/monocytes in varicose vein as compared to control. There was a non-significant trend towards more T-lymphocytes in varicose vein. Few neutrophils were present in varicose or normal vein. The distribution of inflammatory cells with respect to the valve was not found to be significant. CONCLUSIONS: Varicose veins display a greater inflammatory cell infiltrate than normal vein. The key role of macrophage/monocytes and mast cells in tissue damage and remodelling should stimulate further research into whether they play a significant role in the development of chronic venous insufficiency.     

Venous hypertension, inflammation and valve remodeling.

OBJECTIVES: To identify possible mechanisms for destruction of valves in chronic venous hypertension and the results of treatment with an anti-inflammatory micronized purified flavonoid fraction. MATERIAL AND METHODS: The saphenous vein valves in a rat model of venous hypertension caused by a femoral arterial-venous fistula were studied. Studies included femoral venous pressure, valve morphology, femoral venous reflux and selected molecular inflammatory markers as examined by immunohistochemistry. The effects of treatment with the anti-inflammatory micronized purified flavonoid fraction (S 5628, Servier, 50 and 100 mg/kg/day) were investigated. RESULTS: The femoral venous pressure was elevated close to arterial values for a period of 3 weeks. We then examined the morphology of the veins and selected molecular inflammatory markers were assessed. The results show that in this model venous reflux develops in response to venous hypertension. This can be inhibited by the administration of the anti-inflammatory micronized purified flavonoid fraction (S 5628, Servier, 50 and 100 mg/kg/day). The valve becomes incompetent by a combination of venous dilation and shortening of the valve leaflets. This is not inhibited by treatment with S 5628. The valve leaflets are infiltrated with granulocytes, monocytes and T-lymphocytes, and the endothelial cells express enhanced levels of P-selectin and ICAM-1. Cells in the valves are subject to extensive apoptosis although no enhancement of MMP 2,9 expression could be detected at the three-week time point examined in this study. CONCLUSIONS: These results indicate that in this model chronic elevation of venous pressure is associated with an inflammatory reaction in venous valves, a process that may lead to their dysfunction, reflux, and upstream elevation of venous pressure. These effects are mitigated by the anti-inflammatory micronized purified flavonoid fraction in a dose dependent manner.     

戴戒术与单纯浅静脉剥脱术治疗原发性下肢深静脉瓣膜功能不全的比较

目的:比较股浅静脉戴戒术与单纯性浅静脉剥脱术治疗下肢深静脉瓣膜功能不全的疗效。方法:将2010年03月—2011年1月收治的48例下肢深静脉瓣膜功能不全伴静脉曲张患者随机分为观察组(股浅静脉戴戒术联合大隐静脉高位结扎剥脱术)和对照组(传统大隐静脉高位结扎剥脱术),通过彩色多普勒检测两组术前及术后股总静脉血管内径、平均血流速度及Valsalva试验下反流持续时间的变化。结果:与术前比较,术后两组患者的静脉瓣膜功能及血流动力学均明显改善,表现为股总静脉管径缩小、平均血流速度增快、静脉血流反流时间缩短(均P<0.05),但观察组上述3个变量手术前后变化程度(差值)均明显大于照组(均P<0.05)。结论:两种手术方式均是治疗下肢深静脉瓣膜功能不全的有效手段,但戴戒术的治疗效果优于单纯性浅静脉剥脱术。     

Update of endovenous treatment modalities for insufficient saphenous veins—A review of literature

Lower-limb venous insufficiency resulting from saphenous vein incompetence is a common disorder, increasing with age. For decades, surgical stripping of the great saphenous vein has been the gold standard in varicose vein treatment. The desire to optimize outcomes of treatment and reduce surgical trauma has led to the development of endovenous techniques. Today, several endovenous techniques are available to ablate the saphenous vein segments with abnormal vein valve function. In this review, we discuss the techniques, mechanisms of action, outcomes, and complications of all endovenous treatment modalities for the treatment of symptomatic lower-limb varicose veins.     

Valvular obstruction of blood flow through saphenous veins

To measure effects of vein valves upon blood flow through venous bypass conduits, 15 human saphenous veins (mean length 40.6 cm, 5.3 valves/vein) were perfused with normal saline at constant pressure (100 mm Hg). Flow through vein was measured before and after valve bisection. Vein valves were bisected using Leather's techniques. After valve bisection, flow in antegrade and retrograde directions was measured in seven veins. These data were analyzed using paired t tests. Antegrade flow through seven veins with intact valves averaged 317.1 cc/min. With valve bisection this increased significantly (P < 0.001) to 474.3 cc/min. Retrograde flow through veins with valves bisected increased significantly (P < 0.0001) to 428.3 cc/min. Eleven veins (mean length 42.2 cm, 5.6 valves/vein) perfused simulated capillary beds with banked blood using pulsatile flow (mean pressure 92 mm Hg). Flow, again, was measured before and after valve bisection. Data were analyzed using the paired t test. Antegrade flow increased from 124.4 cc/min in veins with valves intact to 142.5 cc/min once valves were bisected (P = 0.02). These data demonstrate that saphenous vein valves cause significant obstruction to blood flow under conditions similar to those in the arterial system. Bisection of vein valves significantly increases flow through vein. Improved patency of vein grafts using valve bisection techniques may be explained by increased blood flow alone.     

The valvular anatomy of the iliac venous system and its clinical implications

Clinical and phlebographic evidence exists that correlates the presence of varices of the vulva, posterior thigh, and the pelvic congestion syndrome with insufficiency of the internal iliac venous system (pelvic dumping syndrome). Information in the modern medical literature regarding the valvular anatomy of the internal iliac veins and its tributaries is limited. We dissected 82 iliac venous system specimens in 42 human cadavers (29 men, 13 women) to gain information on the relationship between the disease described and the anatomy of the region. Each specimen contained common, external, and internal iliac veins, including the tributaries of the latter. We recorded the anatomic variations of the internal iliac vein trunk and the location of valves in the complete iliac venous system, including 485 tributaries of the internal iliac veins. Five specimens of internal iliac vein had calcified thrombosis or were extensively involved with pelvic carcinoma and were not suitable for valve study, which left 79 specimens for analysis. The internal iliac vein drained into the external iliac venous system by means of a single trunk in 73% of the specimens and by two well-formed and separated trunks in 27% of the specimens. In one specimen (1.2%) the internal iliac vein drained directly into the inferior vena cava (parallel internal and external iliac veins). One specimen had a well-developed valve in the common iliac vein (1.2%). The external iliac vein had one valve in 26.2% of the specimens. This vein had three times as many valves on the right side as in the left (39.6% vs 14.6%: p = 0.0106).(ABSTRACT TRUNCATED AT 250 WORDS)     

复发性下肢静脉曲张再手术原因分析

目的:探讨分析复发性下肢静脉曲张再手术的原因。方法:总结63例复发性下肢静脉曲张患者的临床资料,应用彩色多普勒和顺行静脉造影了解下肢深静脉和交通支瓣膜功能。结果:63例中52例为下肢深静脉瓣膜功能不全,11例为交通支瓣膜功能不全伴隐静脉主干及其部分属支残留。结论:有效修复深静脉瓣膜功能,结扎和离断相应属支及交通支,阻断静脉的反流,纠正3个静脉系统及溃疡周围的血液滞留,是防治下肢静脉曲张术后复发的主要措施。     

Autogenous Valve Reconstruction Technique for Post-Thrombotic Reflux

Post-thrombotic reflux in deep veins of the lower extremities cannot be treated by in situ valvuloplasty because of valve degeneration. The outcome of transplantation and transposition of segments with valves is controversial. From feasibility tests in animals and fresh human cadavers we have developed an autogenous valve reconstruction technique. The valve is fashioned from the proximal end of the greater saphenous vein that is left attached to the femoral vein, invaginated, and fixed to the venous wall. This technique provides a competent bicuspid valve. In a series of 19 patients operated on in 1995 we performed 20 valve reconstruction procedures at the level of the femorosaphenous junction by invagination of a fragment from the proximal end of the greater saphenous vein in the common femoral vein. Mean follow-up time was 10 months. No complications were observed. All femoral veins were patent and competent except one in which mild reflux was observed because of insufficient valve size. Further follow-up is needed to confirm the efficacy of this simple, new technique.     

下肢静脉曲张术后复发的原因分析(附46例报告)

目的分析下肢静脉曲张术后复发的原因。方法总结中山大学附属第二医院2002年6月至2004年8月收治的46例（52条患肢）下肢静脉曲张术后复发病人的临床资料，其中合并下肢静脉性溃疡20例（24条患肢）。所有病人均行深、浅静脉及交通静脉彩色多普勒超声检查和患肢顺行性深静脉造影。结果复发的原因有大隐静脉主干及其部分属支残存（11条患肢），合并交通静脉功能不全（35条患肢），合并深静脉瓣膜功能不全（20条患肢）。出现小隐静脉曲张（10条患肢），深静脉血栓形成后遗症（5条患肢），同时存在3个静脉系统病变（15条患肢）。结论下肢静脉曲张术后复发的原因较为复杂，通常累及3个静脉系统。交通静脉功能不全是导致下肢静脉曲张术后复发的主要原因。术前全面的影像学检查和选择正确的手术方式是避免术后静脉曲张复发的关键。     

Autogenous venous valve transplantation in the dog

Incompetence of femoral vein valves has been causally linked to venous insufficiency of the lower extremities. Attempts to transplant competent venous valves into the femoral region have historically been associated with a high rate of early thrombosis. Using modern vasclar surgical techniques, 10 mongrel male dogs had 20 competent valves from the external jugular veins transplanted to both femoral veins. Five dogs (Group I) received no perioperative pharmacological therapy, while 5 dogs (Group II) received low-dose aspirin (2 mg/kg) daily. The surgical technique involved gentle, no-touch dissection of the external jugular veins, systematic anticoagulation with a single bolus of heparin (5000 units), excision of a valve-containing segment of the femoral vein, and transplantation of a valve-containing segment of external jugular vein using interrupted 7-O monoflament sutures. Early patency was confirmed by venography at 2, 7, and 14 days postoperatively. Five animals were sacrificed at 43, 65, 69, 91, and 105 days. Valve competency was evaluated by retrograde flushing. Group I had 100% early and late graft patency and valve competency. Group II had two thrombosed grafts (80% patency) with irreversible valve destruction. Both graft failures were associated with wound hematomas. These results suggest that autotransplantation of competent venous valves into the femoral region can be accomplished using modern vascular surgical techniques. Adjunctive measures such as distal arteriovenous fistulae or anti-platelet therapy do not appear necessary to maintain graft patency or valve competence.     

Venous hemodynamics in a chronic venous valvular insufficiency model

To develop a large-animal model of chronic venous valve incompetence, 13 greyhound dogs underwent unilateral hindlimb venous valve lysis with a valve cutter apparatus pulled retrograde through the iliac, femoral, and lateral saphenous veins. Bilateral venous pressures in the lateral saphenous vein were recorded before valve lysis, immediately after valve lysis, and at intervals from 1 to 14 weeks after valve lysis, with the dogs in the supine position and elevated 80 degrees semierect, as well as after stimulated hindlimb muscle contraction to empty the hindlimb veins. Passive venous filling time with elevation and 90% venous refilling time after muscle contraction were calculated. From immediately after through 14 weeks after valve lysis, a shortened venous filling time and 90% venous refilling time as well as an elevated poststimulation venous pressure were noted. This valve lysis method successfully produced a hemodynamically verified model of venous valvular insufficiency.     

The Valvular Apparatus in Venous Insufficiency: A Problem of Quantity?

n = 51) with symptomatic venous insufficiency undergoing saphenectomy (VI) were compared with the number of GSV valves in patients (n= 26) without venous insufficiency undergoing in situ GSV bypass under angioscopic surveillance who served as a control group. The two groups differed, as expected, in age and sex distribution. The VI group had a mean of 25.7 ± 11.0 centimeters of GSV between valves, while the control group had 19.0 ± 9.7 centimeters of GSV between valves (F = 6.99; p= 0.01). The mean number of valves in the saphenous veins of the two groups also differed significantly: VI = 2.3 ± 0.83 versus control (CTRL) = 4.8 ± 2.01 (F = 61.86; p < 0.0001). That properly functioning valve leaflets help maintain physiologic antegrade venous flow is indisputable. This study, however, suggests that the relative lack of valves may be related to the development of venous insufficiency. This report documents that patients with symptomatic reflux in the GSV have significantly fewer valves than patients with apparently normal functioning saphenous veins.     

In vitro observations of greater saphenous vein valves during pulsatile and nonpulsatile flow and following lysis

A significant number of saphenous vein femoral-popliteal bypass graft failures have been attributed to flow abnormalities caused by venous valves. Seventy-seven greater saphenous vein valves were observed and photographed through a 0-degree choledochoscope during pulsatile and nonpulsatile flow. No valve was seen to lie flat against the vein wall. With pulsatile flow the valves were noted to close during diastole. Stasis was noted within the valve cusps. Twenty-three valves produced photographs of sufficient quality to allow measurement of the luminal obstruction caused by the valves. This valvular obstruction represented 61% ± 12% of the total vein lumen. Fifty venous valves were lysed by five different techniques: the microscissors, the Connolly vein stripper, the Mills valvulotome, the venotomy valvulectomy of Hall, and eversion valvulectomy. The first three methods created valvular incompetence, but flaps of valve cusps were observed to disturb flow and place potentially thrombogenic surfaces within the vein lumen. Valvulectomy, whether by venotomy or eversion, removed the valve cusps satisfactorily. (J VASC SURG 1984;1:356-61.)     

应用股浅静脉瓣膜环形缩窄术治疗原发性下肢深静脉瓣膜功能不全的疗效评价

目的用CEAP分类记分法 (clinical,etiologic ,anatomic ,andpathophysiologic ,CEAP)评价股浅静脉瓣膜环形缩窄术治疗原发性下肢深静脉瓣膜功能不全 (PDVI)的疗效和应用价值。方法将 97例 (97侧肢体 )经顺行性静脉造影证实PDVI的患者分为A组 79侧 ,B组 18侧。A组行大隐静脉高位结扎剥脱 交通支结扎术同时行股浅静脉瓣膜环形缩窄术 ,B组仅行大隐静脉高位结扎剥脱 交通支结扎术。以CEAP临床分类与临床记分评价疗效。结果A、B两组术后临床记分均明显下降 (A组由 6 4± 3 7降至 1 7± 1 8,P <0 0 1;B组由 3 8± 3 6降至 1 4± 1 5 ,P <0 0 5 ) ,A组较B组下降程度更大 (P <0 0 1)。结论从CEAP临床记分结果看 ,股浅静脉瓣膜环形缩窄手术有助于PDVI患者临床症状缓解。因此术前明确诊断为PDVI的患者 ,应行股浅静脉瓣膜环形缩窄手术。     

Primary venous valve incompetence of the leg

Chronic venous insufficiency due to stretching of the venous valve cusp in the leg is described. Details of the pre- and postoperative clinical and radiographic features of this entity are presented. Hemodynamic findings are described. The surgical results show that permanent control of ulceration was achieved in all 18 limbs afflicted, severe aching was relieved in 80 percent and severe swelling was controlled in 70 percent. Follow-up extends to 10 years in some cases, and the average is 5 years. The importance of this entity is that it is one cause of the chronic venous insufficiency syndrome that can be corrected by reconstructive venous surgery.The occurrence of primary valve incompetence may be widespread and may be an important cause of varicose veins in the saphenous system. Its occurrence in the deep veins has been recognized by those who have performed descending venography, but the possibility of its pathologic significance was only advocated by Bauer [1] in 1948 and mentioned by Lockhart-Mummery and Smitham [2] in 1951. With the development of a surgical method of repair, the clinical benefit of repair of femoral vein incompetence can be assessed. Its frequency is yet to be determined. By adding surgical repair in the deep system of veins to conventional surgical methods in the saphenous and perforator veins, there is hope for relief of aching and suffering for many of those now afflicted with severe degrees of chronic venous insufficiency and of return of many disabled persons to full- or part-time work. The cost-effectiveness of this approach will depend on savings in both outpatient and inpatient care as well as return of persons to self-supporting work status.     

Anatomie des epifaszialen Venensystems

The superficial venous system is basically different from the deep venous system. The superficial veins run independently from the arteries, they lie on the fascia and are partly separated from the subcutaneous connective tissue by their own fascia. This applies particularly to the great saphenous vein and the small saphenous vein. The great saphenous vein opens into the communicating femoral vein in the region of the saphenous opening of the fascia lata. The small saphenous vein continues into the thigh as the femoro-popliteal vein and finally opens into the great saphenous vein as the posterior accessory saphenous vein. The region of the opening into the great saphenous vein has many valves and side branches the most important of which are an ostial valve which is only sometimes present and the terminal valve. The latter is situated between the actual junction and the most proximal side branch. Even this is not constant and is found in only four out of five cases.     

Percutaneous autologous venous valve transplantation: short-term feasibility study in an ovine model

BACKGROUND: Limited experience with bioprosthetic venous valve percutaneously inserted into femoral veins in 15 patients has been promising in short-term results only to show disappointing long-term results. Percutaneous autogenous venous valve (PAVV) transplantation was explored in an ovine model as a possible alternative treatment. METHODS: PAVV consisted of a vein segment containing a valve that was attached to a stent template. The stent templates (n = 9) were designed and hand made in our research laboratory. They consist of two stainless steel square stents 13 or 15 mm in diameter to fit the ovine jugular veins (JV), which ranges from 10 to 15 mm in diameter. A valve-containing segment of JV was harvested and attached with sutures and barbs inside the stent template (n = 9). The valve devices were then manually folded and front loaded inside the 4 cm chamber of the 13F delivery sheath and delivered into the contralateral JV by femoral vein approach. Transplanted PAVVs were studied by immediate and 3 months venograms. Animals were euthanized at 3 months, and jugular veins harvested to perform angioscopic evaluations in vitro. RESULTS: PAVV transplantation was successful in all nine animals. Good valve function with no reflux was observed on immediate and 3 months venograms in eight valves. The transplanted maximal JV diameter ranged from 10.2 mm to 15.4 mm (mean 13.1 +/- 1.5 mm). Venoscopic examination revealed intact, flexible, nonthickened valve leaflets in eight specimens. One PAVV exhibited normal function of one leaflet only; the other cusp was accidentally cut during the transplantation procedure. All transplanted autologous valves were free of thrombus and incorporated into the vein wall of the host vessel. CONCLUSION: This study demonstrated that autogenous valve transplants remained patent and competent without long-term anticoagulation for up to 3 months. The percutaneous autogenous venous valve may provide in future minimally invasive treatment for patients with chronic deep venous insufficiency, but long-term studies need to be done to document its continued patency and function.