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SUMMARY OBJECTIVE: In deep venous valve repair, transcommissural external valvuloplasty (TEV) is the commonly used technique. In some cases, external banding (EB) is combined with this procedure to improve the patency and durability of the surgical procedure. METHODS: We retrospectively analyzed patients who underwent deep venous valve repair from 1998 through 2018. Patients were divided according to the surgical procedure: Group A: TEV alone and Group B: TEV+EB. Early postoperative outcomes of the procedure were compared between the groups. RESULTS: There were 265 patients in Group A and 165 patients in Group B. The mean follow-up period was 4.2±3.7. The rate of recurrence of venous reflux, ulcer, and reoperation were 31.9 versus 30.9, 21.2 versus 21.8, and 16.7 versus 13.9 in Group A and Group B, respectively. There were 67 reoperations in the follow-up period. At reoperation, external valvuloplasty was performed in 64% of the reoperations in Group A, while this rate was 13% for Group B. CONCLUSIONS: There is no more need for EB during the venous valve repair with the increased experience of valvuloplasty techniques. TEV might be enough with acceptable long-term outcomes during deep venous reconstruction.

Saphenous veins (SVs) are frequently employed as bypass grafts. The SV graft failure is predominantly seen at the valve site. Avoiding valves during vein harvest would help reduce graft failure. We endeavored to detect SV valves, tributaries, and vessel size employing upright computed tomography (CT) for the raw cadaver venous samples and in healthy volunteers. Five cadaver legs were scanned. Anatomical analysis showed 3.0 (IQR: 2.0–3.0) valves and 13.50 (IQR: 10.00–16.25) tributaries. The upright CT completely detected, compared to 2.0 (IQR: 1.5–2.5, p = 0.06) valves and 9.5 (IQR: 7.5–13.0, p = 0.13) tributaries by supine CT. From a total of 190 volunteers, 138 (men:75, women:63) were included. The number of valves from the SF junction to 35 cm were significantly higher in upright CT than in supine CT bilaterally [upright vs. supine, Right: 4 (IQR: 3–5) vs. 2 (IQR:1–2), p p

Background Venus ulcers developed mainly due to reflux of incompetent venous valves in perforating veins. Patients and methods In this randomized controlled trial, 119 patients recruited over two years, with post-phelebtic venous leg ulcers, were randomly assigned into one of two groups: either to receive radiofrequency ablation of markedly incompetent perforators (Group A, n = 62 patients) or to receive conventional compression therapy (Group B, n = 57 patients). Follow-up duration required for ulcer healing continued for 24 months post randomization. Results Statistically significant shorter time to healing (ulcer complete healing or satisfactory clinical improvement) between both groups (56 patients, 90.3% of cases in Group A versus 44 patients 77.2% of cases in Group B) over the follow-up period of 24 months was attained ( p = 0.001). Also, significantly different ulcer recurrence was recorded between both groups, 8 patients (12.9%) in Group A versus 19 patients (33.3%) in Group B ( p = 0.004). Conclusion In absence of deep venous obstruction, the monopolar radiofrequency ablation for incompetent perforators is a feasible and effective method that surpasses the traditional compression protocol for incompetent perforator-induced venous ulcers in terms of time required for healing even in the presence of unresolved deep venous valvular reflux.

The objective of this study was to analyze the distribution and morphology of the valves in the human retromandibular vein. The retromandibular, internal thoracic, azygos, femoral, and brachial veins were harvested from 46 cadavers donated to the Department of Anatomy at Tokyo Dental College for dissection. The frequency of the valves in each vein, the length of the cusps, and the thickness of the vein itself were measured. Valves were present at high frequency (92.1%) in the veins of the limbs and had cusps at least twice as long as the internal diameter of the vein. Veins in the trunk contained a lower frequency of valves, with cusps that tended to be shorter (1.60±0.77) than those of the venous valves in the limbs (2.12±0.60). The valves of the retromandibular vein tended to resemble venous valves in the trunk in terms of both frequency and morphology. The main function of venous valves in the limbs is to prevent retrograde flow. Conversely, valves in the veins of the trunk and retromandibular vein play a role in retaining blood in the veins, and their relationship to other veins means that they can cause major hemorrhage.

The relationship between coronary slow flow (CSF) and coronary sinus (CS) reflux has not been previously studied. This study aimed to investigate the relationship between CSF and CS reflux and Thebesian valve presence as well as the relationship between CS reflux and serum annexin-V and ICAM-1 levels.In this case-control study, patients were divided into two groups: CSF (n = 13) and control (n = 7) groups. CS flow parameters and Thebesian valve presence were evaluated by cardiac magnetic resonance (CMR). Moreover, serum ICAM-1 and annexin-V levels were measured.Regurgitation volume and regurgitation fraction, indicators of reflux flow in CS, were higher in the CSF group than in the control group (p = 0.039 and p = 0.019). Fewer Thebesian valves were observed in the CSF group than in the control group (p = 0.022). Furthermore, a positive correlation was found between regurgitation volume and regurgitation fraction and serum annexin-V and ICAM-1 levels (r = 0.813, p 0.001 and r = 0.996, p 0.001; r = 0.817, p 0.001 and r = 0.993, p 0.001, respectively).This study revealed the significant relationship between CSF and reflux flow in CS. The fact that the patients in the CSF group have fewer Thebesian valves suggests the importance of the valve in preventing backward flow from the coronary vein. A positive correlation between serum ICAM-1 and annexin-V levels with regurgitation volume and regurgitation fraction indicates that after a certain threshold, CS reflux should be considered an abnormal condition.

Objective Bioprosthetic venous valves have yet to achieve long-term patency due to issues with calcification following implantation that is influenced by current xenograft fixation methods, most notably glutaraldehyde. The goal of this study was to investigate the effects of glutaraldehyde fixation on the functional properties of venous tissue to establish a benchmark for the evaluation of alternative fixation methods. Methods The degree of crosslinking was evaluated by determining shrink temperature and the stability of tissue with pronase and collagenase digestion. Results Glutaraldehyde fixation of venous tissue was confirmed by a significant difference in the shrink temperature between fresh and glutaraldehyde treated samples. Significant differences in the amount of tissue remaining following digestion were observed for venous versus cardiac tissue. Conclusions This study demonstrates the importance of tissue-specific evaluation in the development of alternative xenograft fixation methods to improve outcomes with bioprosthetic venous valves.

PURPOSE: The aim of our pilot study is to consider if the new flow presentation of the vector flow (V-flow) allows an assessment of the valve morphology of the crosses with respect to an insufficiency. MATERIAL AND METHODS: We performed a total of 50 investigations in which we documented a complete valve closure at the so called “crosse” at the valve of the large saphenous vein, a delayed valve closure or an incomplete valve closure with consecutive insufficiency at the crosse. The valve function of the crosse is crucial for the development of varicosis. For our study we recorded age and gender of the patients. One patient in the study was suffering from Covid19. For the examinations we used a 3–9 MHz probe and a high-end ultrasound device. The examination was performed in a lying position and under quiet conditions. Before examination we practiced inhalation and exhalation as well as “pressing” or coughing with the patients, which resulted in a physiological closure of the venous valves. To rule out thrombosis, we carried out compression sonography on the legs. During the examination we documented the B-scan, the Color-Coded Duplex Sonography, the HR-flow and the V-flow for 3 seconds at the estuary of the crosses and incorporated these parameters into our measurements. Via V-flow, vectors can be imaged by representing the flow of erythrocytes and visually indicate a possible insufficiency due to delayed or incomplete valve closure. RESULTS: 31 of 50 patients (age 19–81years) showed a complete valve closure of the crosses, three of them suffered from thrombosis. In eight of the 50 study participants (age 45–79 years) a delayed valve closure could be diagnosed by V-flow within 1–2 seconds. None of them had a thrombosis, but six of them suffered from cancer. In eleven patients we derived an incomplete valve closure with insufficiency (age 51–88 years). With reflux it took >2 seconds to close the valve. The patient with Covid19 also showed an incomplete valve closure with insufficiency. At the same time this patient showed a Covid19-associated deep vein thrombosis. Eight additional patients also had a thrombosis. Six of them suffered from cancer. Overall, the results were best visualized by V-Flow. CONCLUSION: The crosse as a significant venous structure can be well investigated by V-flow with respect to hemodynamic changes and a resulted reflux. Also associated changes close to the valve can be visualized well.

Chronic Venous Disease is estimated at 83.6% of the global population. Patients experience pain, discomfort and severe complications with few effective therapies being available. Current strategies for the treatment of malfunctioning venous valves are invasive with a high recurrence rate. A prosthetic venous valve replacement is imminent, possibly providing better outcomes and improved general quality of life. In this review, prosthetic venous valves history is presented and assesses the advantages and disadvantages of developed venous valves. Articles that discussed potential designs of prosthetic venous valves were examined. A systematic search produced thirty-five papers fitting the inclusion criteria. Our understanding of the ideal abilities required in prosthetic valves has evolved. Developed valves are reported for regurgitation, migration and leakage. Issues have been resolved, but we are still away from the ideal valve. Improvements within the last eight years provided information on the importance of sinuses and prosthetic to venous wall-size mismatch.

Ultrasound imaging is being used increasingly to aid in the teaching of human physiology and anatomy. Here we describe how its use can be integrated into the teaching of concepts surrounding venous circulation, specifically 1) venous valves and the muscle pump, 2) the effects of hydrostatic pressure on venous pressure, and 3) central venous pressure. The imaging procedures described are relatively simple but add a dimension that helps deliver the teaching points clearly and is enjoyable for students. They also aid in the link of basic physiology to clinical aspects of venous circulatory physiology.

Chronic venous disease (CVD) is the most common reported chronic condition in the United States, affecting more than 25 million Americans. Regardless of its high occurrence, current therapeutic options are far from ideal due to their palliative nature. For best treatment outcomes, challenging cases of chronic venous insufficiency (CVI) are treated by repair or replacement of venous valves. Regrettably, the success of venous valve transplant is dependent on the availability of autologous venous valves and hindered by the possibility of donor site complications and increased patient morbidity. Therefore, the use of alternative tissue sources to provide off-the-shelf venous valve replacements has potential to be extremely beneficial to the field of CVI. This manuscript demonstrates the capability of producing off-the-shelf fully functional venous valved extracellular matrix (ECM) scaffold conduits from bovine saphenous vein (SV), using an antigen removal (AR) method. AR ECM scaffolds maintained native SV structure-function relationships and associated venous valves function. Conversely, SDS decellularization caused significant changes to the collagen and elastin macromolecular structures, resulting in collagen fibril merging, elimination of fibril crimp, amalgaming collagen fibers and fragmentation of the inner elastic lamina. ECM changes induced by SDS decellularization resulted in significant venous valve dysfunction. Venous valved conduits generated using the AR approach have potential to serve as off-the-shelf venous valve replacements for CVI. STATEMENT OF SIGNIFICANCE: Retention of the structure and composition of extracellular matrix (ECM) proteins within xenogeneic scaffolds for tissue engineering is of crucial importance, due to the undeniable effect ECM proteins can impose on repopulating cells and function of the resultant biomaterial. This manuscript demonstrates that alteration or elimination of ECM proteins via commonly utilized decellularization approach results in complete disruption of venous valve function. Conversely, retention of the delicate ECM structure and composition of native venous tissue, using an antigen removal tissue processing method, results in preservation of native venous valve function.

BACKGROUND: Almost 95% of the venous valves are micron scale found in veins smaller than 300μm diameter. The fluid dynamics of blood flow and transport through these micro venous valves and their contribution to thrombosis is not yet well understood or characterized due to difficulty in making direct measurements in murine models. OBJECTIVE: The unique flow patterns that may arise in physiological and pathological non-actuating micro venous valves are predicted. METHODS: Computational fluid and transport simulations are used to model blood flow and oxygen gradients in a microfluidic vein. RESULTS: The model successfully recreates the typical non-Newtonian vortical flow within the valve cusps seen in preclinical experimental models and in clinic. The analysis further reveals variation in the vortex strengths due to temporal changes in blood flow. The cusp oxygen is typically low from the main lumen, and it is regulated by systemic venous flow. CONCLUSIONS: The analysis leads to a clinically-relevant hypothesis that micro venous valves may not create a hypoxic environment needed for endothelial inflammation, which is one of the main causes of thrombosis. However, incompetent micro venous valves are still locations for complex fluid dynamics of blood leading to low shear regions that may contribute to thrombosis through other pathways.

Background Chronic deep venous insufficiency is caused by incompetent vein valves, blockage of large-calibre leg veins, or both; and causes a range of symptoms including recurrent ulcers, pain and swelling. Most surgeons accept that well-fitted graduated compression stockings (GCS) and local care of wounds serve as adequate treatment for most people, but sometimes symptoms are not controlled and ulcers recur frequently, or they do not heal despite compliance with conservative measures. In these situations, in the presence of severe venous dysfunction, surgery has been advocated by some vascular surgeons. This is an update of the review first published in 2000. Objectives To assess the effects of surgical management of deep venous insufficiency on ulcer healing and recurrence, complications of surgery, clinical outcomes, quality of life (QoL) and pain. Search methods The Cochrane Vascular Information Specialist searched the Cochrane Vascular Specialised Register, CENTRAL, MEDLINE, Embase and CINAHL databases, and the WHO ICTRP and ClinicalTrials.gov trials registries to 23 June 2020. Selection criteria We considered randomised controlled trials (RCTs) of surgical treatment versus another surgical procedure, usual care or no treatment, for people with deep venous insufficiency. Data collection and analysis Two review authors independently assessed trials for inclusion, extracted data and assessed the risk of bias with the Cochrane risk of bias tool. We evaluated the certainty of the evidence using GRADE. We were unable to pool data due to differences in outcomes reported and how these were measured. Outcomes of interest were ulcer healing and recurrence, complications of surgery, clinical changes, QoL and pain. Main results We included four RCTs (273 participants) comparing valvuloplasty plus surgery of the superficial venous system with surgery of the superficial venous system for primary valvular incompetence. Follow-up was two to 10 years. All included studies investigated primary valve incompetence. No studies investigated other surgical procedures for the treatment of people with deep venous insufficiency or surgery for secondary valvular incompetence or venous obstruction. The certainty of the evidence was downgraded for risk of bias concerns and imprecision due to small numbers of included trials, participants and events. None of the studies reported ulcer healing or ulcer recurrence. One study included 27 participants with active venous ulceration at the time of surgery; the other three studies did not include people with ulcers. There were no major complications of surgery, no incidence of deep vein thrombosis and no deaths reported (very low-certainty evidence). All four studies reported clinical changes but the data could not be pooled due to different outcome measures and reporting of the data. Two studies assessed clinical changes using subjective and objective measurements, as specified in the clinical, aetiological, anatomical and pathophysiological (CEAP) classification score (low-certainty evidence). One study reported mean CEAP severity scores and one study reported change in clinical class using CEAP. At baseline, the mean CEAP severity score was 18.1 (standard deviation (SD) 4.4) for limbs undergoing external valvuloplasty with surgery to the superficial venous system and 17.8 (SD 3.4) for limbs undergoing surgery to the superficial venous system only. At three years post-surgery, the mean CEAP severity score was 5.2 (SD 1.6) for limbs that had undergone external valvuloplasty with surgery to the superficial venous system and 9.2 (SD 2.6) for limbs that had undergone surgery to the superficial venous system only (low-certainty evidence). In another study, participants with progressive clinical dynamics over the five years preceding surgery had higher rates of improvement in clinical condition in the treatment group (valvuloplasty plus ligation) compared with the control group (ligation only) (80% versus 51%) after seven years of follow-up. Participants with stable preoperative clinical dynamics demonstrated similar rates of improvement in both groups (95% with valvuloplasty plus ligation versus 90% with ligation only) (low-certainty evidence). One study reported disease-specific QoL using cumulative scores from a 10-item visual analogue scale (VAS) and reported that in the limited anterior plication (LAP) plus superficial venous surgery group the score decreased from 49 to 11 at 10 years, compared to a decrease from 48 to 36 in participants treated with superficial venous surgery only (very low-certainty evidence). Two studies reported pain. Within the QoL VAS scale, one item was 'pain/discomfort' and scores decreased from 4 to 1 at 10 years for participants in the LAP plus superficial venous surgery group and increased from 2 to 3 at 10 years in participants treated with superficial venous surgery only. A second study reported that 'leg heaviness and pain' was resolved completely in 36/40 limbs treated with femoral vein external valvuloplasty plus high ligation and stripping of the great saphenous vein (GSV) and percutaneous continuous circumsuture and 22/40 limbs treated with high ligation and stripping of GSV and percutaneous continuous circumsuture alone, at three years' follow-up (very low-certainty evidence). Authors' conclusions We only identified evidence from four RCTs for valvuloplasty plus surgery of the superficial venous system for primary valvular incompetence. We found no studies investigating other surgical procedures for the treatment of people with deep venous insufficiency, or that included participants with secondary valvular incompetence or venous obstruction. None of the studies reported ulcer healing or recurrence, and few studies reported complications of surgery, clinical outcomes, QoL and pain (very low- to low-certainty evidence). Conclusions on the effectiveness of valvuloplasty for deep venous insufficiency cannot be made.

Objective This study evaluated a special category of arteriovenous fistula outflow stenosis caused by venous valve hyperplasia and explored the effectiveness of surgical repair in dealing with this kind of stenosis. Study design This retrospective cohort study was conducted from February 2016 to January 2020 in our center. Patients with arteriovenous fistula dysfunction, including flow rate insufficiency, venous hypertension, thrombosis, and aneurysm dilation enlargement, were selected. Stenosis lesions presenting with venous valve hyperplasia were selected after ultrasound screening. All patients underwent surgical repair and were followed up every 6 months after surgery. Results Forty-three patients (median age, 54.5 ± 11.2 years; 65.1% men) were included. All procedures were technically successful. Based on intraoperative exploration, 56.5% were reconstructed via autologous vein patch, 17.4% of patients were reconstructed with end-to-end reconstruction after cutting the stenotic segment, 13.0% of cases simply had the valve resected, and 13.0% of cases involved a longitudinal incision and transverse suture. All patients returned to routine dialysis the following day and avoided catheter insertion. The mean follow-up time was 22.5 ± 14.0 (range, 1.3–49.8) months. The patency rates at 2 and 4 years were 92.2% and 79.0%, respectively. Valves harvested from patients were analyzed via Masson staining and immunohistochemical staining, indicating collagen fiber and myofibroblast hyperplasia in outflow venous valve hyperplasia (OVVH). Conclusions Outflow venous valve hyperplasia can lead to fistula dysfunction. Ultrasound is the main method to diagnosis OVVH. Special surgical repair can preserve valuable vascular resources and relieve stenosis, is safe and effective, and has a high patency rate.

Anatomic variants in the right atrium are under-recognized and under-reported phenomena in cardiac imaging. In the fetus, right atrium serves as a conduit for oxygenated blood to be delivered to the left heart bypassing the right ventricle and the nonfunctional lungs. The anatomy in the fetal right atrium is designed for such purposeful circulation. The right and left venous valves are prominent structures in the fetal heart that direct inferior vena caval flow towards the foramen ovale. These anatomic structures typically regress and the foramen ovale closes after birth. However, the venous valves can persist leading to a range of anatomic, physiological, and pathological consequences in the adult. We describe various presentations of persistent venous valves, focusing on the right venous valve in this illustrated multimodality imaging article.

An understanding of the complexity of the cardiovascular system is incomplete without a knowledge of the venous system. It is important for students to understand that, in a closed system, like the circulatory system, changes to the venous side of the circulation have a knock-on effect on heart function and the arterial system and vice versa. Veins are capacitance vessels feeding blood to the right side of the heart. Changes in venous compliance have large effects on the volume of blood entering the heart and hence cardiac output by the Frank-Starling Law. In healthy steady-state conditions, venous return has to equal cardiac output, i.e., the heart cannot pump more blood than is delivered to it. A sound understanding of the venous system is essential in understanding how changes in cardiac output occur with changes in right atrial pressure or central venous pressure, and the effect these changes have on arterial blood pressure regulation. The aim of this paper is to detail simple hands-on physiological assessments that can be easily undertaken in the practical laboratory setting and that illustrate some key functions of veins. Specifically, we illustrate that venous valves prevent the backflow of blood, that venous blood pressure increases from the heart to the feet, that the skeletal muscle pump facilitates venous return, and we investigate the physiological and clinical significance of central venous pressure and how it may be assessed.

Objective/background Valve incompetence is a progressive disease of the venous system that may eventually lead to venous hypertension, pain, and ulcers. There is a need for a venous valve prosthesis to replace incompetent valves. Computational and experimental investigations on venous valve design and associated haemodynamics will undoubtedly advance prosthesis design and treatments. Here, the objective is to investigate the effect of venous valve on the fluid and solid mechanics. The hypothesis is that there exists a valve geometry that maximises leaflet shear stress (LSS) but minimises leaflet intramural stress (LIS; i.e., minimise stress ratio = LIS/LSS). Methods To address the hypothesis, fully dynamic fluid–structure interaction (FSI) models were developed. The entire cycle of valve opening and closure was simulated. The flow validation experiments were conducted using a stented venous valve prosthesis and a pulse duplicator flow loop. Results Agreement between the output of FSI simulations and output of pulse duplicator was confirmed. The maximum flow rates were within 6% difference, and the total flow during the cycle was within 10% difference. The simulated high stress ratio region at the leaflet base (five times the leaflet average) predicted the disease location of the vast majority of explanted venous valves reported in clinical literature. The study found that the reduced valve height and leaflet dome shape resulted in optimal performance to provide the lowest stress ratio. Conclusion This study proposes an effective design of venous prostheses and elaborates on the correlations of venous valve with clinical observations.

Risk factors for the development of progression chronic venous disease (CVD) and varicose veins are widespread and include advanced age, excess body weight, sedentary lifestyles and occupations, family history, and pregnancy. Varicose veins and CVD are associated with venous hypertension, venous reflux, dysfunctional venous valves, and vein wall inflammation, though the precise etiologies are unclear. Once venous pathology develops, it can progress through a vicious cycle of inflammation and leukocyte recruitment that leads to further deterioration of vein walls and valves, increased hypertension, and release of additional proinflammatory mediators. Early treatment of symptomatic varicose veins and CVD as well as lifestyle changes can help break the inflammatory cycle and alleviate symptoms. Physicians and patients should be aware of the risk factors for CVD, the treatments and measures available to slow disease progression, and the serious consequences of allowing the disease to progress unchecked. Funding: Servier (France).

Objective We sought to describe the leaflet morphology variation in the Melody Transcatheter Pulmonary Valve (TPV) and evaluate associated outcomes. The Melody TPV is constructed from harvested bovine jugular venous valves which have been rigorously tested. Natural anatomic leaflet variations are seen in the Melody TPV but have not been evaluated. Design A Melody TPV leaflet morphology classification system was devised after reviewing a subset of photographed and implanted TPVs. All images were blindly reviewed by implanters and classified. Midterm hemodynamic outcomes and complications of the Melody TPVs were compared by leaflet morphology. Results Photographed Melody TPVs implanted between 2011 and 2016 (n = 62) were categorized into the following leaflet morphology types: A-symmetric trileaflet (47%); B-asymmetric trileaflet with a single small leaflet (32%); C-asymmetric trileaflet with a single large leaflet (16%); D-rudimentary leaflet with near bicuspid appearance (5%). Acceptable hemodynamic function at 6 months postimplantation was seen in 97.5% of valves. Over a median follow-up of 1.5 years (range 0-4.4 years), two TPVs (Type A) had > mild regurgitation. Nine TPVs developed complications (endocarditis, 3; stent fracture, 2; refractory arrhythmia, 1; conduit replacement, 2; death, 1), of which 6 required reintervention. There was no significant difference in outcomes based on Melody TPV leaflet morphology type. Conclusions The Melody TPV can be classified into one of four categories based on leaflet morphology. Study outcomes were not associated with leaflet morphology. Further documentation and evaluation of Melody TPV morphology may lead to better understanding of this technology.

Venous valve (VV) failure causes chronic venous insufficiency, but the molecular regulation of valve development is poorly understood. A primary lymphatic anomaly, caused by mutations in the receptor tyrosine kinase EPHB4, was recently described, with these patients also presenting with venous insufficiency. Whether the venous anomalies are the result of an effect on VVs is not known. VV formation requires complex 'organization' of valve-forming endothelial cells, including their reorientation perpendicular to the direction of blood flow. Using quantitative ultrasound we identified substantial VV aplasia and deep venous reflux in patients with mutations in EPHB4. We used a GFP reporter, in mice, to study expression of its ligand, ephrinB2, and analysed developmental phenotypes following conditional deletion of floxed Ephb4 and Efnb2 alleles. EphB4 and ephrinB2 expression patterns were dynamically regulated around organizing valve-forming cells. Efnb2 deletion disrupted the normal endothelial expression patterns of the gap junction proteins connexin37 and connexin43 (both required for normal valve development) around reorientating valve-forming cells, and produced deficient valve-forming cell elongation, reorientation, polarity, and proliferation. Ephb4 was also required for valve-forming cell organization, and subsequent growth of the valve leaflets. These results uncover a potentially novel cause of primary human VV aplasia.

Lymphatic vasculature is an integral part of digestive, immune and circulatory systems. The homeobox transcription factor PROX1 is necessary for the development of lymphatic vessels, lymphatic valves (LVs) and lymphovenous valves (LVVs). We and others previously reported a feedback loop between PROX1 and vascular endothelial growth factor-C (VEGF-C) signaling. PROX1 promotes the expression of the VEGF-C receptor VEGFR3 in lymphatic endothelial cells (LECs). In turn, VEGF-C signaling maintains PROX1 expression in LECs. However, the mechanisms of PROX1/VEGF-C feedback loop remain poorly understood. Whether VEGF-C signaling is necessary for LV and LVV development is also unknown. Here, we report for the first time that VEGF-C signaling is necessary for valve morphogenesis. We have also discovered that the transcriptional co-activators YAP and TAZ are required to maintain PROX1 expression in LVs and LVVs in response to VEGF-C signaling. Deletion of Yap and Taz in the lymphatic vasculature of mouse embryos did not affect the formation of LVs or LVVs, but resulted in the degeneration of these structures. Our results have identified VEGF-C, YAP and TAZ as a crucial molecular pathway in valve development., Summary: YAP and TAZ mediate the positive feedback loop between PROX1 and VEGF-C signaling in the developing lymphatic and lymphovenous valves.

High-ligation and stripping (HL/S) and external valvuloplasty (eVP) with the implantation of an external device to restore the valve's function, are surgical methods to eliminate reflux at the saphenofemoral junction. Furthermore, redo-surgery (RedoS) can be performed in terms of same side groin recurrences. It is unclear, if there is a difference in quality of life (QoL) between these 3 surgical treatment options. Therefore, it was the aim of our study to elucidate QoL in patients before and after surgical treatment at the saphenofemoral junction by comparing HL/S, eVP, and RedoS.A total of 303 participants (156 HL/S, 81eVP, 64 RedoS) were recruited during the daily clinical routine. QoL was measured at admission and 6 weeks after the surgical procedure by means of SF-12 (12 item short form health survey) and Aberdeen Varicose Vein Questionnaire.The mean value of Aberdeen Varicose Vein Questionnaire was 14.5 (SD 2.1) preoperatively and 4.9 (SD 3.3) postoperatively in the HL/S group, 16.4 (SD 1.4) preoperatively and 6.8 (SD 2.5) postoperatively in the eVP group and 15.5 (2.2) preoperatively and 5.8 (SD 4.2) postoperatively in the RedoS group, which was statistically significant (P0.05) in all groups. Postoperatively, the mean values were statistically significant within the groups. Concerning physical aspects of the SF-12 we found a significant improvement in the RedoS group, while mental aspects were significantly better in the HL/S and eVP group postoperatively. Nevertheless, the clinical relevance of these SF-12 differences is questionable under consideration of the minimal important difference.Varicose vein surgery leads to a significant improvement of QoL in all groups. The implantation of an external patch could have a negative influence in QoL.

Biologically-engineered matrix - a tissue that is grown in vitro from donor cells, decellularized, and stored prior to use as off-the-shelf allografts - offers a promising alternative to current cardiovascular biomaterials. This perspective reviews preclinical studies and clinical trials of vascular grafts and valves comprising biologically-engineered matrix, with a focus on those based on donor dermal fibroblast remodeling of fibrin gel with the capacity to heal and grow following recellularization, via animation of the matrix. It concludes with a discussion of related key clinical considerations.

Native venous valves enable proper return of blood to the heart. Under pathological conditions (e.g., chronic venous insufficiency), venous valves malfunction and fail to prevent backward flow. Clinically, this can result in painful swelling, varicose veins, edema, and skin ulcerations leading to a chronic wound situation. Surgical correction of venous valves has proven to drastically reduce these symptoms. However, the absence of intact leaflets in many patients limits the applicability of this strategy. In this context, the development of venous valve replacements represents an appealing approach. Despite acceptable results in animal models, no venous valve has succeeded in clinical trials, and so far no single prosthetic venous valve is commercially available. This calls for advanced materials and fabrication approaches to develop clinically relevant venous valves able to restore natural flow conditions in the venous circulation. In this study, we critically discuss the approaches attempted in the last years, and we highlight the potential of tissue engineering to offer new avenues for valve fabrication.Impact statementVenous valves prosthesis offer the potential to restore normal venous flow, and to improve the prospect of patients that suffer from chronic venous disease. Current venous valve replacements are associated with poor outcomes. A deeper understanding of the approaches attempted so far is essential to establish the next steps toward valve development, and importantly, tissue engineering constitutes a unique toolbox to advance in this quest.

Objective Definitive treatment techniques for symptomatic deep venous reflux have been relegated to complex and invasive open surgery which is rarely performed today. The BlueLeaf System provides an endovenous method for the formation of deep venous valves without an implant, avoiding the complications associated with permanent foreign materials. The system has the adaptability to form valves within the femoral and popliteal veins at multiple levels in a single procedure. The aim was to determine the midterm safety and efficacy of this novel device in an early feasibility study. Methods Feasibility of endovenous deep venous valve formation was assessed in patients with chronic venous insufficiency (Clinical, Etiologic, Anatomic, Pathophysiologic [CEAP] 4-6). Follow-up was completed through 1 year, assessing vein patency and reflux time (RT) with duplex ultrasound examination. Venous clinical improvement was evaluated using the revised Venous Clinical Severity Scale. Results Of the 14 patients, 13 (93%) had successful formation of at least one monocuspid valve, with a mean number of 1.4 valves (range, 0-3 valves) per patient. There were no device-related serious adverse events during the index procedure. There were no deep venous thromboses reported at any time point, including 10 patients through the 1-year follow-up. In patients with at least one valve formed, site reported duplex ultrasound examination measured the average RT in the popliteal vein below valve formations, was 3.0 ± 1.0 seconds at baseline, 3.9 ± 3.1 seconds at 30 days, and 3.6 ± 2.1 seconds at 360 days. The revised Venous Clinical Severity Scale improved in all 13 successfully treated patients, decreasing from 15.0 ± 6.0 at baseline to 11.6 ± 5.5 at 30 days, 10.7 ± 5.3 at 210 days, and 9.4 ± 5.0 at 360 days (P = .0002; baseline to 360 days). Among the five patients with an ulcer who reached the 360-day follow-up visit, all (100%) healed at least one ulcer. Two patients (40%) healed all ulcers and three patients (60%) had a decrease in ulcers number but remained at C6 at 360 days. The five patients with a total of nine active ulcers at baseline had four active ulcers at 360 days. Conclusions The BlueLeaf System holds promise as a minimally invasive means to safely form fully autogenous deep venous valves. Reconstructed deep veins remained patent, without deep venous thrombosis and symptomatic improvement was consistently observed; however, a decrease in the RT was not. Incremental device design improvements have been undertaken to improve valve function. The results of these iterations await further clinical evaluation.

After acute treatment of deep vein thrombosis, not only the risk but also associated side effects of postthrombotic syndrome (PTS) are often underestimated.There are essentially two main types of PTS.1. Obstructive type—no sufficient recanalization of the deep vein.2. Refluctive type—sufficient recanalization of the deep vein, but insufficient venous valves in conjunction with venous reflux.A statement regarding deep vein recanalization and venous valve function can be made at the earliest after 6 months.PTS is often diagnosed without appropriate medical history. However, the assessment of the degree of recanalization and venous reflux is paramount to the medical prognosis. In our opinion, beside proximal thrombosis, sufficient recanalization combined with a strong venous reflux, especially in the popliteal vein, works as a powerful predictor for an unfavorable and fast progression of PTS and chronic venous insufficiency. Thus, the obstructive type is prognostically more favorable. For PTS in general, consistent compression therapy represents the first-line treatment option.With concomitant varicosis, one should assess whether the varicose veins represent primary varicosis with reflux or secondary varicosis without reflux. Especially in the presence of venous ulcers, the elimination of concomitant primary varicosis leads to an improved prognosis. Moist wound treatment is considered to be the standard treatment for all wounds undergoing secondary healing. A standardized set of topical therapeutic agents also facilitates the treatment. In individual cases “ulcershaving” and mesh graft transplantation proved to be successful.

PURPOSE Doppler ultrasound imaging has been used widely for diagnosing vascular diseases. Recently, vector Doppler imaging (VDI) has been proposed for visualizing the blood flow in all directions to yield more detailed information for estimating flow conditions. Increasing the resolution of VDI is important for the structural mapping of superficial vessels with microstructure. However, VDI that operates under a high-frequency ultrasound (HFUS; >30 MHz) is rare. In this study, a 40-MHz high-frequency VDI (HFVDI) based on ultrafast ultrasound imaging was developed to obtain the vector information of blood flow around the superficial venous valve. METHODS The use of HFUS imaging system causes an overload of data acquisition easily. In order to provide sufficient recording time, the frame rate should be reduced. Because the aliasing problem worsens due to a low frame rate when operating Doppler imaging, phase-unwrapping processing methods based on spatial and temporal continuities were applied. Flow phantom experiments were performed to validate the accuracy. In vivo experiments were performed on the valve of superficial veins of healthy volunteers. RESULTS The experimental results from the phantom study indicated that the error of velocity estimation was

Abstract. Background: The aim of this study was to investigate the influence of age on the ultrastructure of venous valve morphology in patients with C2 classified chronic venous disorders according to the CEAP classification. Patients and methods: The study population consisted of 16 consecutive patients with varicose veins (C2). The mean age was 49.8 years (30–66). The (pre-) terminal valve including the vessel wall was harvested within the proximal 2 centimetres of the great saphenous vein. The mean thickness (volume-to-surface ratio = V/S ratio) of elastin, collagen, endothelium and of the entire valve was determined. A blinded morphologist performed the examination by transmission electron microscopy and stereology. Analyses by Pearson’s product moment correlation, Kendall’s tau and Spearman’s rank correlation were performed to investigate whether there is a correlation between age and the ultrastructural morphology. Results: Stereological analysis of the valves demonstrated a mean V/S ratio (signifying a thickness estimation) for elastin of 0.87 μm3/μm2, for collagen of 18.0 μm3/μm2, for endothelium of 0.65 μm3/μm2, and for the entire valve of 25.2 μm³/μm². Statistical analyses showed no statistically significant correlation between age and the ultrastructural morphology in this patient group. Conclusions: The ultrastructural morphology of the venous valves in chronic venous disorders may not depend on age in patients presenting with C2 disease. This conclusion may or may not apply to all C classes as we investigated a homogenous group of patients with C2 limbs.

Objective This study measured patient outcomes among symptomatic patients with superficial chronic venous insufficiency who were treated with retrograde ultrasound-guided polidocanol microfoam 1% in a community setting. Methods Between March 2015 and June 2017, 250 symptomatic patients with C2-C6 chronic venous insufficiency received polidocanol microfoam 1% and were followed for 16 ± 7 months. Sixteen of the 250 patients (6.4%) had skin ulcers, and 56 (22.4%) were treated previously with thermal or surgical interventions. All patients underwent a duplex ultrasound venous incompetence study to map perforators and veins to be treated. Incompetent veins were accessed with a micropuncture needle distal to the midthigh perforator, approximately 10 cm above the knee fold. The leg was then elevated 45°. Under ultrasound guidance, the incompetent greater saphenous vein was closed with polidocanol microfoam 1%. A second injection was administered through the same catheter directing the microfoam to flow in a retrograde fashion through the incompetent venous valves to the ankle. Results All patients completed the initial treatment; 55 (22.0%) required planned secondary treatment during the follow-up period for residual venous reflux in the below-knee greater saphenous vein. Complete elimination of venous valvular reflux and symptom improvement was documented in 236 patients (94.4%). Minor adverse events included asymptomatic deep vein thrombi (n = 2), common femoral vein thrombus extension (n = 1), and superficial venous thrombi (n = 4). Of the 16 patients with skin ulcers, 10 were C6 patients and 80% experienced wound closure within 4 weeks of treatment. Conclusions Retrograde administration of polidocanol microfoam 1% is a safe and effective treatment with important clinical benefit for superficial venous insufficiency in community practice.

BACKGROUND High prevalence of valve absence was found in the internal jugular vein (IJV) of healthy volunteers by means of M-mode high-resolution Echo Colour Doppler (ECD). However, the prevalence of valve in neurovascular disorders linked to Chronic Cerebrospinal Venous Insufficiency (CCSVI) is still unknown. METHODS A cohort of 83 Healthy Controls (HC), 71 Multiple Sclerosis (MS), 99 Inner Ear Disorders (IED) underwent ECD investigation of the IJV valve, including M-mode evaluation and related hemodynamics. The primary outcome measure was characterization of valve presence, morphology and motility, whereas the secondary outcome was the rate of flow alteration. RESULTS Bilateral valve presence was found in 38% of HC, 58% of MS and 25% of IED, whereas, bilateral valve absence was recorded in 16% of HC, 10% of MS and 31% of IED (p

Chronic venous disease is caused by chronic venous insufficiency (CVI), which results in significant symptoms such as venous ulcers, ankle eczema, leg swelling, etc. Venous valve incompetence is a major cause of CVI. When the valves of veins in the leg become incompetent (i.e., do not close properly), blood is able to flow backwards (i.e., reflux), which results in blood pooling in the lower extremities, distal venous hypertension, and CVI. Current clinical therapies, such as surgical venous valve reconstruction and bioprosthetic venous valve replacement, are highly invasive and only moderately successful. This is due, in part, to the scanty information available about venous valve leaflet structure and mechanical properties. To date, only one previous study by our research group has reported on the mechanical properties of venous valve leaflet tissue, and specifically in the case of jugular vein valves. In this study, we conducted equibiaxial tensile tests on bovine saphenous vein valve leaflet tissues to better understand their nonlinear, anisotropic mechanical behavior. By stretching the valvular tissues to 60% strain in both the circumferential and radial directions, we generated stress-strain curves for proximal (i.e., those closest to the heart) and distal (i.e., those furthest from the heart) valve leaflets. Histology and collagen assays were also conducted to study corresponding leaflet microstructures and the biochemical properties of the tissues. Results showed: (1) saphenous venous valve tissues possessed overall anisotropic properties. The tissues were stiffer in the circumferential direction than in the radial direction (p

Various conduits and stent-mounted valves are used as pulmonary valve graft tissues for right ventricular outflow tract reconstruction with good hemodynamic results. Valve replacement carries an increased risk of infective endocarditis (IE). Recent observations have increased awareness of the risk of IE after transcatheter implantation of a stent-mounted bovine jugular vein valve. This study focused on the susceptibility of graft tissue surfaces to bacterial adherence as a potential risk factor for subsequent IE.Adhesion of Staphylococcus aureus, Staphylococcus epidermidis, and Streptococcus sanguinis to bovine pericardium (BP) patch, bovine jugular vein (BJV), and cryopreserved homograft (CH) tissues was quantified under static and shear stress conditions. Microscopic analysis and histology were performed to evaluate bacterial adhesion to matrix components.In general, similar bacteria numbers were recovered from CH and BJV tissue surfaces for all strains, especially in flow conditions. Static bacterial adhesion to the CH wall was lower for S sanguinis adhesion (P .05 vs BP patch). Adhesion to the BJV wall, CH wall, and leaflet was decreased for S epidermidis in static conditions (P .05 vs BP patch). Bacterial adhesion under shear stress indicated similar bacterial adhesion to all tissues, except for lower adhesion to the BJV wall after S sanguinis incubation. Microscopic analysis showed the importance of matrix component exposure for bacterial adherence to CH.Our data provide evidence that the surface composition of BJV and CH tissues themselves, bacterial surface proteins, and shear forces per se are not the prime determinants of bacterial adherence.

Recently, transcatheter therapy has expanded the treatment options for patients with heart valve disease. With the growing understanding of tricuspid regurgitation and its natural history, it becomes increasingly obvious that this patient population is a heterogeneous cohort presenting for treatment in different stages of a continuous disease process. It is still unclear which interventional approach will result in functional and clinical success and in which subtype of patient population. This article reviews the pathophysiologic background and current evidence for caval valve implantation and examines the potential role of this approach for the treatment of severe tricuspid regurgitation.

Venous thromboembolism (VTE) is a significant problem in the perioperative period, increasing patient morbidity, mortality, and health care costs. It is also considered the most preventable of the major postoperative complications. Despite widespread adoption of prophylaxis guidelines, it appears that morbidity from the disease has not substantially changed within the past 2 decades. It is becoming clear that current prophylaxis efforts are not sufficient. Using more potent anticoagulants may decrease the incidence of VTE, but increase the risk for bleeding and infection. Much has been learned about the pathophysiology of venous thrombogenesis in recent years. Beyond the "traditional coagulation cascade," which anticoagulants modulate, there is a growing appreciation for the roles of tissue factor, monocytes, neutrophils, neutrophil extracellular traps, microvesicles, and platelets in thrombus initiation and propagation. These recent studies explain to some degree why aspirin appears to be remarkably effective in preventing thrombus propagation. Endothelial dysfunction, traditionally thought of as a risk factor for arterial thrombosis, plays an important role within the cusps of venous valves, a unique environment where the majority of venous thrombi originate. This suggests a role for newer treatment modalities such as statins. Not all patients have an equal likelihood of experiencing a VTE, even when undergoing high-risk procedures, and better tools are required to accurately predict VTE risk. Only then will we be able to effectively individualize prophylaxis by balancing the risks for VTE against the risks associated with treatment. Given the different cell types and pathways involved in thrombogenesis, it is likely that multimodal treatment regimens will be more effective, enabling the use of lower and safer doses of hemostatic modulating therapies such as anticoagulants, antithrombotics, and antiplatelet medications.

Background Primary cough headache (PCH) is precipitated by coughing or the Valsalva manoeuver (VM), and its underlying pathophysiology remains unclear. Case report We report a case of recurrent cough headaches precipitated by VM with transient increase of intracranial pressure (ICP) diagnosed by measuring left sigmoid sinus pressure. Bilateral internal jugular vein valve incompetence (IJVVI) was also diagnosed by Doppler ultrasonography during a VM. Indomethacin was administered for over four months, and the headache had completely disappeared at the four-month follow-up. Conclusions Cough headache might be associated with a transient increase of ICP induced by IJVVI, which might partially explain the pathophysiology of VM-induced headache. Detecting the internal jugular vein during a VM might be used as diagnostic procedure for patients who have PCH during resting and VM. If it is necessary, monitoring the ICP could be considered.

Objective To identify which deep anatomical anomalies can explain variable hemodynamic outcomes in patients with superficial reflux associated with primary deep axial reflux who underwent isolated superficial vein ablation without improvement. Methods This is a retrospective study of deep venous valve anomalies in patients who underwent superficial vein ablation for superficial and associated deep reflux. A group of 21 patients who were diagnosed with saphenous reflux associated with primary deep axial reflux, were submitted to great saphenous vein ablation. In 17 patients the deep reflux was not abolished. In this subgroup, surgical exploration of the deep valve was carried out using venotomy for possible valve repair. Results Among the 17 subgroup patients, four post-thrombotic lesions were discovered intra-operatively in four patients; they underwent different surgical procedures. In 13 of the subgroup patients, primary valve incompetence was confirmed intra-operatively. In 11 cases the leaflets were asymmetrical and in only two were they symmetrical. After valvuloplasty, deep reflux was abolished in all 13 patients. Clinical improvement was obtained in 12/13 patients (92%). It is noteworthy that abolition of deep reflux was associated with significant improvement in air plethysmography data as well as with improvement in clinical status measured on CEAP class, VCSS and the SF-36 questionnaire. Conclusion Failure to correct deep axial reflux by superficial ablation in patients with superficial and associated primary deep axial reflux may be related to asymmetry in the leaflets of the incompetent deep venous valve.

Stasis dermatitis commonly occurs in older age. It is caused by venous hypertension resulting from retrograde flow due to incompetent venous valves, valve destruction, or obstruction of the venous system. Further tissue changes arise from an inflammatory process mediated by metalloproteinases, which are up-regulated by ferric ion from extravasated red blood cells. Stasis dermatitis presents initially as poorly demarcated erythematous plaques of the lower legs bilaterally, classically involving the medial malleolus. It is one of the spectrum of cutaneous findings that may result from chronic venous insufficiency. Its mimics include cellulitis, contact dermatitis, and pigmented purpuric dermatoses. Duplex ultrasound is useful in demonstrating venous reflux when the clinical diagnosis of stasis dermatitis is inadequate. Conservative treatment involves the use of compression therapy directed at improving ambulatory venous pressure. Interventional therapy currently includes minimally invasive techniques such as endovenous thermal ablation and ultrasound-guided foam sclerotherapy, which have supplanted the use of open surgical techniques.

Objective The purpose of this paper was to describe patterns of superficial reflux in the groin with respect to the terminal valve (TV), which is located at the saphenous opening to the common femoral vein, the great saphenous vein, and its tributary veins. Methods This study included 2019 legs with chronic venous insufficiency that received endoluminal varicose vein treatment because of varicosities with insufficiency of the saphenofemoral junction (SFJ). In a preoperative duplex ultrasound investigation of the superficial vein system, reflux after provocation in the SFJ, great saphenous vein, cranial veins (superficial external pudendal vein, superficial epigastric vein, superficial circumflex iliac vein), and anterior and posterior accessory saphenous veins was recorded and classified on the basis of the origin of reflux. Results In 1348 legs (66.8%), the reflux had its origin exclusively in the common femoral vein. In 170 legs (8.4%), the reflux had its origin in the common femoral and cranial veins. In 430 legs (21.3%), the insufficiency was due to saphenocranial reflux only. In 71 legs (3.5%), the origin of reflux could not be determined. Conclusions Reflux in the SFJ does not involve the TV in 24.8% of the legs, implying that routine high ligation and ablation close to the TV might be overtreatment in these patients.

INTRODUCTION To deliver accurate morphological descriptions of the Vieussens valve (VV) and to investigate whether this structure could be visualized using standard contrast-enhanced electrocardiogram-gated multislice computed tomography (MSCT). METHODS A total of 145 human autopsied hearts and 114 cardiac MSCT scans were examined. RESULTS The VV was observed in both study groups, however, the detection rate was significantly worse in the MSCT examination (18.4% in MSCT vs 62.1% in cadavers, P

This paper hypothesizes, based on fluid dynamics principles, that in multiple sclerosis (MS) non-laminar, vortex blood flow occurs in the superior vena cava (SVC) and brachiocephalic veins (BVs), particularly at junctions with their tributary veins. The physics-based analysis demonstrates that the morphology and physical attributes of the major thoracic veins, and their tributary confluent veins, together with the attributes of the flowing blood, predict transition from laminar to non-laminar flow, primarily vortex flow, at select vein curvatures and junctions. Non-laminar, vortex flow results in the development of immobile stenotic valves and intraluminal flow obstructions, particularly in the internal jugular veins (IJVs) and in the azygos vein (AV) at their confluences with the SVC or BVs. Clinical trials' observations of vascular flow show that regions of low and reversing flow are associated with endothelial malformation. The physics-based analysis predicts the growth of intraluminal flaps and septa at segments of vein curvature and flow confluences. The analysis demonstrates positive correlations between predicted and clinically observed elongation of valve leaflets and between the predicted and observed prevalence of immobile valves at various venous flow confluences. The analysis predicts the formation of sclerotic plaques at venous junctions and curvatures, in locations that are analogous to plaques in atherosclerosis. The analysis predicts that increasing venous compliance increases the laminarity of venous flow and reduces the prevalence and severity of vein malformations and plaques, a potentially significant clinical result. An over-arching observation is that the correlations between predicted phenomena and clinically observed phenomena are sufficiently positive that the physics-based approach represents a new means for understanding the relationships between venous flow in MS and clinically observed venous malformations.

Deep vein thrombosis (DVT) and its consequences are lethal, but current models cannot completely dissect its determinants – endothelium, flow and blood constituents – together called Virchow’s triad. Most models for studying DVT forego assessment of venous valves that serve as the primary sites of DVT formation. Therefore, our knowledge of DVT formed at the venous cusps has remained obscure due to lack of experimental models. Here, organ-on-chip methodology is leveraged to create a Vein-Chip platform integrating fully vascularized venous valves and its hemodynamic, as seen in vivo. These Vein-Chips reveal that vascular endothelium of valve cusps adapts to the locally disturbed microenvironment by expressing a different phenotype from the regions of uniform flow. This spatial adaptation of endothelial function recreated on this in vitro Vein-Chip platform is shown to protect the vein from thrombosis from disturbed flow in valves, but interestingly, cytokine stimulation reverses the effect and switches the valve endothelium to becoming prothrombotic. The platform eventually modulates the three factors of Virchow’s triad and provides a systematic approach to investigate the determinants of fibrin and platelet dynamics of DVT. Therefore, this Vein-Chip offers a new preclinical approach to study venous pathophysiology and show effects of antithrombotic drug treatment.

Chronic insufficiency of lower extremity venous valves represents a frequent structural disorder of the vascular system being responsible for a substantial global disease load. While in the field of superficial valve insufficiency surgical as well as endoluminal interventions represent good therapeutic options with high rates of complete remission of symptoms, only limited options exist in the field of deep venous reflux today. Bioengineered, autologous cell-based, endothelialized valve constructs may open up new therapeutic options in these patients, potentially offering novel treatment options in cases with severe insufficiency of deep venous segments in the future. Areas covered: This review summarizes previous reports focusing on venous valve replacement and bioengineering, also including first preclinical in vivo studies and first clinical trials in patients. In particular, the aspects of current technical and medical limitations of venous valve bioengineering approaches preventing clinical translation and potential solutions by upcoming technologies will be discussed as part of this review. Expert commentary: Bioengineered replacement valves may open up novel options in the treatment of venous valve disease in defined patient groups in the future. However, preventing thromboembolic complications will remain the bottle-neck for clinical translation of the technologies involved.

Objective Venous thromboembolism frequently results in thrombi formation near or within the pocket of a venous valve due to recirculating hemodynamics, which has been largely attributed to hypoxia-induced tissue factor (TF) expression. Numerical models are now capable of assessing the spatiotemporal behavior of the TF-initiated coagulation cascade under nonuniform hemodynamics. The aim of this study was to use such a numerical simulation to analyze the degree and location of thrombin formation with respect to TF position in the presence of disturbed flow induced by an open venous valve. Methods Thrombin formation was simulated using a computational model that captures the hemodynamics, kinetics, and chemical transport of 22 biochemical species. Disturbed flow is described by the presence of a valve in the equilibrium phase of the valve cycle with leaflets in a fully open position. Three different positions of TF downstream of the valve opening were investigated. Results The critical amount of TF required to initiate a thrombotic response is reduced by up to 80% when it is positioned underneath the recirculating regions near the valve opening. In addition, because of the increased surface area of the open valve cusp in conjunction with recirculating hemodynamics, it was observed that thrombin is generated inside the valve pocket even when the exposed region of TF is downstream of the valve. Conclusions The presence of prothrombotic surface reactions in conjunction with recirculating hemodynamics provides an additional mechanism for thrombus formation in venous valves that does not require direct damage or dysfunction to the valve itself.

The valve cusp hypoxia thesis (VCHT) of the aetiology of deep venous thrombosis (DVT) was adumbrated in this journal in 1977 and fully articulated in 2008, the original hypothesis having been strongly corroborated by experiments published in 1981 and 1984. It presents a unitary account of the pathogenesis of venous thrombosis and embolism that is rooted in the pathophysiological tradition of Hunter, Virchow, Lister, Welch and Aschoff, a tradition traceable back to Harvey. In this paper we summarise the thesis in its mature form, consider its compatibility with recent advances in the DVT field, and ask why it has not yet been assimilated into the mainstream literature, which during the past half century has been dominated by a haematology-orientated 'consensus model'. We identify and discuss seven ways in which the VCHT is incompatible with these mainstream beliefs about the aetiology of venous thrombosis, drawing attention to: (1) the spurious nature of 'Virchow's triad'; (2) the crucial differences between 'venous thrombus' and 'clot'; the facts that (3) venous thrombi form in the valve pockets (VVPs), (4) DVT is not a primarily haematological condition, (5) the so-called 'thrombophilias' are not thrombogenic per se; (6) the conflict between the single unitary aetiology of DVT and the tacit assumption that the condition is 'multicausal'; (7) the inability of anticoagulants to prevent the initiation of venous thrombogenesis, though they do prevent the growth of thrombi to clinically significant size. In discussing point (7), we show that the VCHT indicates new approaches to mechanical prophylaxis against DVT. These approaches are then formulated as experimentally testable hypotheses, and we suggest methods for testing them preclinically using animal trials.

Purpose Options for pediatric valve replacement are limited by inability to adapt to child growth. An expandable valve design is presented in which human cryopreserved venous valved conduits are constructed within a bare-metal stent scaffold. We demonstrate functionality in vitro and acute competence in vivo. Description A cryopreserved femoral venous valved conduit was compressed within a bare-metal stent scaffold and sutured at the proximal and distal ends. In vitro testing was performed at low and high pressure after sequential balloon expansion. Valve morphology was measured in the nondistended state. The construct was tested in 2 patients. Evaluation In vitro testing confirmed competence of the 14-mm femoral valve construct at 10-mm to 14-mm diameters. The median leaflet commissural height-to-diameter ratio was 2.2 (range, 1.6 to 4.1) for femoral. The construct was implanted in 2 patients at internal diameters of 6 mm and 8 mm. Echocardiograms demonstrated competence at short-term follow-up. In 1 patient, competence was demonstrated after balloon expansion. Conclusions This study demonstrates the feasibility of this expandable valve design using an allograft venous valved conduit compressed within a stent.

The work was based on the results of examination and treatment of 43 female patients presenting with varicose transformation of pelvic, perineal, and lower-limb veins. The inclusion criteria were as follows: the presence of visually determined varicose transformation of the veins of the external genital organs, perineum, posterior surface of the thighs, as well as valvular insufficiency of the mentioned veins by the findings of ultrasonographic angioscanning (USAS). The following exclusion criteria were applied: the presence of pregnancy, symptoms of pelvic venous plethora (PVP), and varicothrombophlebitis. In 33 women correction of the pelvioperineal reflux (PPR) was performed with the help of local phlebectomy on the large pudendal lips and perineum, with the maximally possible mobilization of the vessel within the limits of the operative wound. Miniphlebectomy with the use of Varady phleboextractors was performed in 10 women presenting with isolated varicose transformation of the subcutaneous veins of the posterior femoral surface. The duration of follow up of patients amounted to 3 years. The criteria for efficiency of the carried out treatment were as follows: freedom from varicose syndrome both in the perineum and on the lower extremities, as well as no PVP symptoms during the whole term of follow up. Varicose syndrome of the external genital organs, perineum and posterior surface of the femurs was successfully eliminated in 100% of patients. Meticulous mobilization and removal of the veins of the labia majora, perineum and subcutaneous femoral veins is a reliable method of removing pathological reflux of blood from the intrapelvic to superficial veins of the perineum and lower limbs. 100% of our patients were found to be free from relapses of either vulvar or perineal varicosity, with no evidence of lower limb varicose veins. Local phlebectomy is an efficient method of elimination of varicose syndrome induced by PVP in patients with dilatation of intrapelvic, vulvar and perineal veins.

Carotid-cavernous fistulas are vascular malformations that pose a risk for intracranial hemorrhage when there is documented cortical venous drainage. When possible, treatment with transvenous embolization has become the technique of choice since the late 1990s.1,2 We present a case of a patient with a carotid-cavernous fistula treated with venous coil embolization via a jugular venous approach. The patient was a 59-year-old female with a history of intense headaches. Initial magnetic resonance imaging showed congestion in the right cavernous sinus, and a diagnostic angiogram revealed a cavernous carotid fistula Thomas type 4.3,4 Given the presence of retrograde cortical venous drainage, we decided to treat the lesion. A femoral route for endovascular treatment was attempted, but it was unsuccessful in traversing the external jugular vein due to venous valves. We accessed the fistula through a direct puncture direct proximal approach,5 from the external jugular vein making our trajectory through the facial-angular-supraorbital vein, ultimately reaching the cavernous sinus. We then filled the sinus with coils to obliterate the fistula. The patient awakened neurologically intact, and a postoperative angiogram demonstrated complete occlusion of the lesion. The patient was discharged at postoperative day 1 without complications. In this video, we narrate the important details of this alternative when a traditional route is inaccessible (Video 1). Informed consent was obtained for the case illustrated; however, neither Institutional Review Board nor patient consent is required for the report of a single case in which no identifiable patient information is shared.

The present study aimed to understand the effect of venous valve lesion on the valve cycle. A modified immersed finite element method was used to model the blood-tissue interactions in the pathological vein. The contact process between leaflets or between leaflet and sinus was evaluated using an adhesive contact method. The venous valve modeling was validated by comparing the results of the healthy valve with those of experiments and other simulations. Four valve lesions induced by the abnormal elasticity variation were considered for the unhealthy valve: fibrosis, atrophy, incomplete fibrosis, and incomplete atrophy. The opening orifice area was inversely proportional to the structural stiffness of the valve, while the transvalvular flow velocity was proportional to the structural stiffness of the valve. The stiffening of the fibrotic leaflet led to a decrease in the orifice area and a stronger jet. The leaflet and blood wall shear stress (WSS) in fibrosis was the highest. The softening of the atrophic leaflet resulted in overly soft behavior. The venous incompetence and reflux were observed in atrophy. Also, the atrophic leaflet in incomplete atrophy exhibited weak resistance to the hemodynamic action, and the valve was reluctant to be closed owing to the large rotation of the healthy leaflet. Low blood WSS and maximum leaflet WSS existed in all the cases. A less biologically favorable condition was found especially in the fibrotic leaflet, involving a higher mechanical cost. This study provided an insight into the venous valve lesion, which might help understand the valve mechanism of the diseased vein. These findings will be more useful when the biology is also understood. Thus, more biological studies are needed.