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Facts and fiction surrounding the discovery of the venous valves.

Venous valves are delicate structures, the integrity of which is crucial for the normal function of the venous system. Their abnormalities lead to widespread disorders, ranging from chronic venous insufficiency to life-threatening thromboembolic phenomena. The discovery of the venous valves, however, has been the subject of hot controversy. Even though Fabricius ab Aquapendente is credited with the discovery by most historians, we demonstrate in this paper that other anatomists described them many years before Fabricius ab Aquapendente publicly demonstrated them in Padua in 1579. A thorough review of the historical literature surrounding the discovery of the venous valves was carried out from 1545 to the present under the supervision of the Medical History Department of our institution. Research was performed at the History of Medicine Division of the National Library of Medicine and through MEDLINE access to the medical literature. The Parisian Charles Estienne first mentioned the venous valves in his 1545 publication when he described "apophyses membranarum" in the veins of the liver. Lusitanus and Canano publicly demonstrated them in the azygos vein during cadaver dissections performed in Ferrera, Italy. The Parisian Jacques Sylvius described valves in the veins of the extremities in 1555. The work of these anatomists, however, could not achieve full recognition, because Andreas Vesalius, the leading anatomist at that time, was unable to confirm their findings and strongly denied the existence of venous valves. Vesalius's influence was so powerful that research on the subject was idle until 1579, when Fabricius ab Aquapendente "discovered" the venous valves. About the same time, the German Salomon Alberti published the first drawings of a venous valve (in 1585). William Harvey, a disciple of Fabricius ab Aquapendente, finally postulated the function of the venous valves, providing anatomical support for one of the greatest discoveries in medicine: the blood circulation. Therefore, our investigations revealed that Estienne and Canano discovered the venous valves in the 1530s. Fabricius ab Aquapendente's achievement was their full recognition 64 years later. However, it was not until 1628 that their function was fully understood, with the discovery of the blood circulation by William Harvey.

Anatomy↗

[Functional insufficiency of the venous valve apparatus and venous return from the lower extremities in humans during the standing test].

The studies were performed with participation of 16 normal subjects with the US Doppler evidence of functional insufficiency of the deep vein valves in a lower extremity. Valve insufficiency was of the latent clinical form without symptoms of chronic venous insufficiency. Functioning of the contralateral leg venous valves was normal in all subjects. Linear velocities of blood flow in the femoral vein in both extremities in the horizontal and vertical position were compared. In the horizontal position, outflow from the deep vein with valve disfunction was 1.5 times (p<0.01) higher comparing with the other leg as the control. In vertical subjects, outflow from the compromised vein was, on the contrary, reduced almost by half as compared with the healthy leg. These features of local phlebohemodynamics at the outlet of insufficient vein appear to determine the intensity of passive mechanic blood redistribution driven by the gravity.

Adult↗

TuJ1 (class III beta-tubulin) as phenotypic marker of lymphatic and venous valves.

Lymphatic and venous valves are essential for unidirectional circulation; however, no specific marker has been described for these valves. Here, we show that TuJ1 (class III beta-tubulin) is expressed strongly in valve endothelium but not in nonvalvular endothelium lining of lymphatics. TuJ1 is also expressed in venous valves mainly at the tip of leaflets. In contrast, endothelial markers CD31, CD34, and factor 8-related antigen did not distinguish valves from vascular endothelium. TuJ1 is also expressed irregularly in the vascular endothelium of hemangiomas. The data suggest that TuJ1 may be a phenotypic marker of lymphatic and venous valves, discriminating lymphatic and venous valvular endothelial cells from nonvalve lymphatic and vascular endothelial cells.

Adult↗

Ultrasonographic evaluation of vertebral venous valves.

To date, vertebral venous valves have not been studied clinically or by sonography. This report reveals that these valves could be studied noninvasively by using sonographic techniques. Real-time sonography clearly showed the opening and closing of the two cusps of vertebral venous valves at the junction of the vertebral vein and the brachiocephalic vein, which move synchronously with the internal jugular venous valves. This is the first time the vertebral venous valves have been studied by using clinical sonography. This might provide a new point of view for evaluating the clinical significance of vertebral venous valves.

Adult↗

Histopathology of veins and venous valves of patients with venous insufficiency syndrome: ultrastructure.

Vein and vein valve biopsies were obtained from venous insufficiency syndrome (VIS) patients undergoing venous valve transplants. Normal control biopsies were obtained from other non-VIS procedures. The specimens were examined using light and transmission electron microscopy (TEM). Biopsies from VIS patients showed a variety of changes from what was considered normal structure. Most histopathologic changes were noted in the endothelium and subendothelial layer of the vein valve and wall, and in the media of the vein wall. These changes included 1) erosion of the endothelium with consequent adherence of blood elements, 2) intact endothelium with a thickened subendothelial zone which was populated with migrated smooth muscle and perhaps other cell types, 3) occurrence of abnormal or over-abundant collagen, and 4) thickening of the media with changes in the smooth muscle population therein.

Biopsy↗

A percutaneous approach to deep venous valve insufficiency with a new self-expanding venous frame valve.

PURPOSE: To ascertain if a percutaneously delivered venous valve bioprosthesis (PVVB) can be implanted in the porcine venous system and function without complications. METHODS: The PVVB is a glutaraldehyde-preserved, valve-bearing venous xenograft sutured inside a memory-coded nitinol frame (diameter 10, 12, or 14 mm). In 10 50-kg pigs, the external jugular vein was exposed, and a 16-F introducer sheath was positioned in the common iliac vein. One PVVB was inserted and deployed in each iliac vein under fluoroscopic control. After PVVB implantation, all animals were randomly given either vitamin K antagonists (1-2 mg/d) (group I) or a combination of aspirin (150 mg/d) and clopidogrel (75 mg/d) (group II), which were shown in a preliminary pilot study to be the most effective anticoagulation regimens in the pig model. Ascending and descending completion phlebograms were performed. PVVBs were evaluated with phlebography at 4 weeks to assess patency and competence; all PVVBs were explanted and processed for histological analysis. RESULTS: In 8 animals, the PVVB was successfully deployed in both the left and right iliac veins. In 2 pigs, only 1 PVVB was inserted due to vascular anomalies. Completion phlebography demonstrated 18 patent and competent valves. At 2 weeks, bleeding complications occurred in 3 group I pigs; all 5 animals were terminated to prevent further complications. Of the 8 valves in this group, 7 were patent (3 competent) by phlebography; 1 PVVB had migrated due to known undersizing of the stent frame. At 4 weeks, group II (5 pigs, 10 valves) analysis revealed 5 patent (3 competent) valves; no bleeding complications occurred in this group. Histology showed thrombosis as the cause of occlusion in all 5 non-patent valves from group II. CONCLUSIONS: Deployment of a glutaraldehyde-fixed bovine vein sutured to a self-expanding nitinol stent in the porcine iliac vein is technically feasible. Development of a venous bioprosthesis that can be placed percutaneously may have important clinical applications as an endovascular treatment for chronic venous insufficiency when it is due to valvular incompetence.

Animals↗

Valve competence following experimental venous valve autotransplantation.

In canine experiments, venous patency and valvular competence were evaluated following transposition of a valve-containing vein segment, with an without a distal arteriovenous (AV) fistula. The effects of distal fistula size on valvular function were also examined. Autogenous valve-containing venous segment grafts were placed in the femoral position. With no adjuncts, 90% of the grafts showed either occlusion, severe extrinsic narrowing, or intraluminal filling defects on early venograms, although 75% of valves were eventually competent at death. Veins that had undergone thrombosis and recanalization were routinely incompetent. With a distal AV fistula, all veins remained patent and 86% demonstrated valve competence. With both an AV fistula and dextran 40, all veins remained patent and all valves were component. Separately, graded size of AV fistulas did not result in loss of valve competence. Following venous segment transposition, continuous venous patency appears necessary for eventual valvular function, and this is enhanced by both a distal AV fistula and dextran.

Animals↗

Catheter directed thrombolysis for treatment of ilio-femoral deep venous thrombosis is durable, preserves venous valve function and may prevent chronic venous insufficiency.

OBJECTIVES: To investigate the results of catheter directed thrombolysis offered to patients with acute femoro-iliac deep venous thrombosis (DVT). DESIGN: Retrospective analysis of all patients treated with this modality at Gentofte Hospital until December 2003. MATERIAL: Forty-five consecutive patients treated between June 1999 and December 2003 with a median age of 31 years. All patients had femoro-iliac DVT with an average anamnesis of 6 days. METHODS: All patients were treated by catheter directed infusion of alteplase into the popliteal vein. After thrombolysis residual venous stenoses were treated by percutaneous balloon angioplasty (PTA) and stenting. Patients were followed with color-duplex scanning for assessment of venous patency and reflux. RESULTS: Forty-two of 45 (93%) of cases were treated successfully with reopening of the thrombosed vein segments. In 30 of 45 cases a residual stenosis was treated by PTA and stenting. Only one serious complication was observed: Compartment syndrome of the forearm where arterial punctures had been taken. After an average of 24 months follow-up were no cases of re-thrombosis among the 42 patients discharged with open veins. Only two of 41 with presumed normal venous valve function prior to DVT developed reflux during follow-up. CONCLUSION: In this selected patient group, catheter directed thrombolysis seems effective in treating acute DVT, it appears durable and preserves venous valve function in the majority. The method needs to be tested in a randomised controlled trial.

Adolescent↗

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.

Animals↗

An anomalous muscle bundle inside the right atrium possibly related to the right venous valve.

The right and left venous valves of the sinoatrial orifice regulate the flow of blood from the sinus venosus to the atrium in pisces, amphibians, and reptiles. In aves, mammals and humans, the venous valve loses its hemodynamic function and hence has become the 'Cinderella' among heart valves, receiving attention only when congenital anomalies occur that are related to it. The right venous valve persists in humans as the crista terminalis, Eustachian and Thebesian valves. An intraluminal muscle band is described located inside the right atrium, and coursing in the line of the crista terminalis between the septum spurium and inferior vena cava. This abnormal band is possibly derived from the right venous valve.

Adolescent↗

[Substitute valve at popliteal vein in treating deep venous valve insufficiency of lower extremities].

OBJECTIVE: To study the effectiveness of substitute valve at the popliteal vein in treatment of deep venous valve insufficiency of lower extremities. METHODS: From January 1996 to August 2002, 27 patients were diagnosed having deep venous valve insufficiency of lower extremities by color Doppler and radiography with an average disease course of 17.4 years. All 27 patients had varicose vein, 25 pain, 22 swelling, 25 pigmentation in ankle area and 19 chronic ulcerations. Two cases had been treated with great saphenous vein ligation and striping. Average vein pressure in resting position was (11.00 +/- 0.73) kPa, and the ambulatory venous pressure was (9.14 +/- 0.68) kPa. All patients were treated with substitute valve at the popliteal vein, and great saphenous vein ligation and stripping, some were treated with subfascial endoscopic perforating veins ablation. RESULTS: The average ambulatory venous pressure after operation was (5.94 +/- 0.82) kPa, were significantly different from that before operation(P < 0.01). The curative results were satisfactory, and all symptom and physical sign disappeared. After a mean follow-up period of 2-6 years, 21 cases had satisfactory results. CONCLUSION: Substitute valve at the popliteal vein have the value of widespread application.

Adult↗

Ultrasonic evaluation of jugular venous valve competence.

Jugular venous valve competence has been studied in the past only by invasive venography. The authors demonstrate that this valve can be noninvasively studied using real-time and pulsed Doppler ultrasound techniques and relate this to possible clinical implications. Visualization of the jugular valve with real-time ultrasound is reported and its competence documented using pulsed Doppler and M-mode techniques. The clinical relevance to the etiology of the respirator brain syndrome is discussed.

Adult↗

Morphological study of the human maxillofacial venous vasculature: examination of venous valves using the corrosion resin cast technique.

BACKGROUND: The venous drainage in the human head and neck, structures located superior to the heart, generally does not counter the force of gravity. Accordingly, venous valves in the human head have been reported to be few or nonexistent, and therefore the direction of venous drainage is variable and obscure. METHODS: We investigated whether venous valves were present in 13 heads of human adult cadavers using scanning electron microscopic observation of corrosive resin casts in the human maxillofacial region. This technique afforded the observation of the venous valves. RESULTS: Venous valves were found throughout the facial region. In particular, there were many valves distributed in the lingual, upper and lower labial, facial and pharyngeal veins. The venous valves were particularly well formed at motile parts of the maxillofacial region. CONCLUSIONS: It is suggested that these valves may aid the venous blood return and permit the blood drainage in one direction.

Aged↗

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.

Animals↗

Development of a prosthetic venous valve.

The pathology of thrombophlebitis primarily results from the obliteration of venous valves in the lower extremities. The objective of this study was to develop a prosthetic venous valve that could be implanted in the human femoral system to ameliorate the deleterious effects of thrombophlebitis. Prosthetic venous valves were produced from two materials: Pellethane valves were fabricated from a dip-casting process; umbilical vein valves were produced by a fixation process. The valves were evaluated as implants within the external jugular veins of 10 research dogs. Each animal was implanted with one Pellethane valve in one external jugular vein and one umbilical vein venous valve in the contralateral jugular vein. Each valve was positioned over a stainless-steel cylinder that had been implanted into the jugular veins in such a manner that there existed no blood-cylinder interaction. Patency of the valves was determined by X-ray venography at 24, 48, and 72 h and at 5 and 8 days postoperatively. All of the umbilical vein venous valves were occluded by the end of 48 h, whereas two of the Pellethane venous valves remained patent for at least 5 days but were occluded at 8 days. The results of this study suggest the possibility of success of Pellethane valve implants in the venous circulation and indicate future directions for study.

Animals↗

Data regarding the typology and functional significance of the venous valves.

Many authors described in detail the morphological features of human venous valves, but less their functional architecture. The present study provides additional information concerning the valvular anatomy, to enable its functional interpretation. The previously reported data and the author's results showed the regional distribution and characteristics of venous valves in different areas of the human body. Certain findings suggested a reorganization after birth of the venous valves which are frequently met in fetus. The close relation between hemodynamic mechanisms and the blood guiding structures may explain the changes (disappearance or persistence) of venous valves in some areas after birth. Significance of the rudimentary folds, resembling valves, is not yet elucidated. Based on his observations, the author attempted a new classification of the veins. The relations between density and morphological peculiarities of venous valves in different vein types showed that the constant valves were always involved in the local hemodynamics. Bardeleben's principles referring to the location and topographical arrangement of venous valves can be applied only to certain areas of the limbs, but not to other regions. In this paper there are described and functionally interpreted the venous valves of all territories of the human body.

Azygos Vein↗

[Reconstructive venous valve surgery].

The indication for venous valves surgery has to consider morphological and functional aspects. 36 reconstructive valve repair procedures and the long-term results are reported. The procedures need surgical skill and a meticulous operation technique. Primary idiopathic valvular incompetence can be treated with a direct valvuloplasty (Kistner). The leaflets of the floppy valve become shortened either by an open repair or with a closed procedure. Patients suffering from post-thrombotic syndrome showing intact valves in the deep femoral vein may undergo a transposition operation. In this case the superficial femoral vein is implanted end to side into the deep femoral vein distally to a proximal valve. The best results in post-thrombotic syndrome are achieved with a free transplantation of a venous valve from the axillary vein into the superficial femoral or into the popliteal vein (Taheri). Postoperatively the patients are anticoagulated and have to wear a compressing stocking (Grade III). The results of direct valvuloplasty (Kistner) and valve transplant (Taheri) are satisfactory, whereas the results of transposition seem to be disappointing. Good results are depending mostly on a correct indication for the operation and on avoiding the contraindications.

Adult↗