Two-Year Results of a First-In-Human Study in Patients Surgically Implanted With a Bioprosthetic Venous Valve, the VenoValve in Patients With Severe Chronic Venous Insufficiency.

OBJECTIVE: Two-year follow-up results from a first-in-human study of patients implanted with the VenoValve are evaluated for supporting the long-term clinical safety and performance of the device. BACKGROUND: Chronic Venous Insufficiency (CVI) involves improper functioning of lower limb vein valves and inability of these valves to move blood back towards the heart. CVI symptoms include swelling, varicose veins, pain, and leg ulcers. Currently, there is no cure for this condition and treatment options are limited. This study provides 2-year outcomes for 8 patients who were implanted with the bioprosthetic VenoValve for treating severe CVI with deep venous reflux measured at the mid-popliteal vein. The 6-month and 1-year results were previously published. METHODS: Eleven patients with C5 & C6 CVI were implanted with VenoValve into the midthigh femoral vein and followed for 2 years. Assessed clinical outcomes include device-related adverse events, reflux time, disease severity, and pain scores. RESULTS: All 11 implant procedures were successful. Two-year follow-up data was obtained for 8 subjects: 1 patient died of non-device related causes, 1 was lost to follow-up, and 1 refused to follow-up due to the COVID-19 pandemic. No device-related adverse events occurred between the first and second years of follow-up. Reported 2-year clinical performance outcomes included significant decreases in mean reflux times of the mid-popliteal vein (61%), and significant improvements in mean scores for disease severity rVCSS (56%) and VAS pain (87%). CONCLUSIONS: Results from this study support long-term safety and effectiveness of the VenoValve for improving CVI severity by reducing reflux and thereby venous pressures in the lower extremities. With limited treatments for valvular incompetence involved in severe, deep venous CVI, the device may be considered as a novel therapy. A pivotal trial in the United States is currently being conducted to assess the device in a larger number of patients.

Mutations in EPHB4 cause human venous valve aplasia.

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 analyzed developmental phenotypes after 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.

Saphenous vein valve assessment utilizing upright CT to potentially improve graft assessment for bypass surgery.

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 < 0.0001, Left: 4 (IQR: 3-5) vs. 2 (IQR: 1-2), p < 0.0001]. The number of tributaries and vessel areas per leg were also higher for upright compared with supine CT. Upright CT enables non-invasive detection of SV valves, tributaries, and vessel size. Although not tested here, it is expected that upright CT may potentially improve graft assessment for bypass surgery.

Functional ultrasound imaging of the venous valve of the great saphenous vein in the area around the crosse using the novel vector flow technique.

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.

[Functional assessment of primary lesion of the great saphenous vein when deciding upon stripping]. / Funktsional'naia otsenka pervichnogo porazheniia bol'shoi podkozhnoi veny pri reshenii voprosa o stripinge.

The purpose of the study was to examine a possibility of functional assessment of the great saphenous vein (GSV) with the help of a day orthostatic loading test for prognosis of restoration of the function of the GSV afterremoving its varicose tributaries in patients with primary varicose veins. Our prospective study included a total of sixty-five 29-to-53-year-old patients (15 men and 50 women, mean age - 36.7 years). The total number of the lower limb examined amounted to 87. All patients underwent ultrasonographic examination (duplex scanning) prior to operation, 1 and 12 months thereafter. The study was carried out using a day orthostatic loading test consisting in duplex scanning performed twice during 24 hours: in the evening after 18:00 hours and in the morning before 10:00 hours after a good night's rest. It was demonstrated that the day orthostatic loading test characterized the degree of preservation of the muscular-tonic properties of the GSV, making it possible to predict reversibility of reflux along it after removing the varicose tributaries, hence it may be used as a criterion for individualization of the choice of the scope of surgical intervention. A high orthostatic gradient prior to operation suggests preservation of the potential of the muscular-tonic function of the GSV; its decrease after surgery demonstrates reduction of the volemic loading on the GSV.

A pilot study of venous duplex ultrasound parameters in healthy children.

OBJECTIVE: The spectrum of chronic venous disease (CVD) in adults is well documented, whereas there is a paucity of data published commenting on pediatric CVD. We previously identified that there is often venous reflux present in cases of pediatric lower extremity edema despite an alternative confirmed diagnosis. To further assess the clinical significance of this venous reflux, this study aimed to elicit venous parameters in healthy pediatric controls. METHODS: Healthy pediatric volunteers aged 5 to 17 years were recruited for venous reflux study. A comprehensive venous reflux study was performed with the patient standing. Vein diameter, patterns of valvular reflux, and accessory venous anatomy were examined in the deep and superficial venous systems. RESULTS: Eighteen children including 10 boys and 8 girls were studied. Five volunteers were aged 5 to 8 years, six volunteers were aged 9 to 12 years, and seven volunteers were aged 13 to 17 years. Great saphenous vein (GSV) diameter at the saphenofemoral junction significantly increased with age. Deep vein valve closure time (VCT) did not differ significantly between groups, whereas GSV VCT was significantly higher in the 9- to 12-year age group. Incidental venous insufficiency was identified in 60% of children aged 5 to 8 years (n = 3), 50% of children aged 9 to 12 years (n = 3), and 57% of children aged 13 to 17 years (n = 4). All superficial venous reflux was confined to the GSV; there were no cases of isolated deep venous reflux. Reflux was identified at multiple GSV stations in 60% of children. There was no significant difference in incompetent GSV VCT in comparing children with and without deep venous reflux. Accessory superficial veins were identified in 20% of children aged 5 to 8 years (n = 1), 50% of children aged 9 to 12 years (n = 3), and 43% of children aged 13 to 17 years (n = 3). The presence of an accessory saphenous vein was not associated with deep venous reflux in any patient, and only 29% of those with accessory saphenous venous anatomy had evidence of superficial venous (GSV) reflux. CONCLUSIONS: The GSV continues to grow in diameter through the teenage years. Incidental valvular incompetence and GSV reflux are common. The presence of accessory saphenous veins is similarly common and not associated with venous reflux. The clinical significance and natural history of this incidental venous reflux remain unclear. Future research should determine whether these changes seen in the pediatric age group lead to CVD during later years of life.

[Method of preventive ultrasound diagnosis of venous thrombosis]. / Metod preventivnoi ul'trazvukovoi diagnostiki venoznykh trombozov.

AIM: The purpose of the study was to work out a method of preventive diagnosis of venous thromboses by means of ultrasonographic duplex scanning (USDS). PATIENTS AND METHODS: A total of 306 people were examined. Of these, 146 patients presented with acute venous thrombosis, 108 subjects suffered from varicose veins, and 52 were apparently healthy people composing the control group. All those enrolled into the study were examined by means of USDS, with the D-dimer level determined. RESULTS: The obtained findings made it possible to discover and duly describe an ultrasonographic phenomenon of the presence of echo-positive inclusions in the zone of valvular sinuses, which was called the phenomenon of spontaneous echo contrast (SEC). This was followed by working out a classification of this phenomenon, describing two degrees thereof. Degree 1 SEC reflects the fact that the area of valvular sinuses is the most thrombogenic zone. Degree 2 SEC is characterised as a pathological, being simultaneously pre-thrombotic, condition and may serve as one of the earliest predictors of the development of venous thrombosis. A close correlation was established between the degree 2 SEC phenomenon, the presence of venous thrombosis and the values of the D-dimer level (r=0.89, p<0.01). CONCLUSION: Ultrasonographic examination of valvular sinuses is a simple, readily available and reproducible method of screening and may thus be used for preventive diagnosis of acute venous thromboses. The findings of this study make it possible to form risk groups by the development of deep vein thrombosis, as well as to initiate timely measures on prevention of the pathology concerned.

Determining the origin of superficial venous reflux in the groin with duplex ultrasound and implications for varicose vein surgery.

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.

[Perforating veins insufficiency in patients with varicose disease].

MATERIAL AND METHODS: It was analyzed the results of complex survey and treatment of 181 patients with varicose disease CEAP degrees C3-C6. Ultrasonic scanning was applied to define localization, severity and extension of blood reflux in venous system. RESULTS: Superficial reflux was revealed in all patients, perforating--in 59.7%, deep--in 22.8% of cases. We concluded that high-intensive total-subtotal blood reflux in superficial veins was main hemodynamic factor resulted perforating insufficiency in 42% of patients, high-intensive deep reflux--in 17.7% of cases additionally. In patients with subcompensated course of disease superficial reflux removal and large perforating veins (diameter 4.5±0.5 mm) ligation are advisable. Small perforating veins insufficiency (diameter 3.5±0.5 mm) is eliminated independently after superficial reflux removal. Two-staged treatment should be used in patients with decompensated course of disease and trophic disorders ofshin. Perforating veins sclerotherapy under ultrasonic control is advisable secondarily after superficial reflux removal.

The relative position of paired valves at venous junctions suggests their role in modulating three-dimensional flow pattern in veins.

PURPOSE: The aim of the study is to investigate the relative position of orifices of two valves within the most proximal segments of the great saphenous vein (GSV), and the femoral vein (FV). METHODS: A total of 15 volunteers with no signs or symptoms of venous disease and 13 unaffected limbs of patients with unilateral primary chronic venous disease (CVD) were included. Two most proximal valves of the GSV and the FV were identified. The angle between the two valves, and the distance between the valves were measured. RESULTS: The mean distance between the two valves in the GSV was 3.8 ± 0.4 cm, and in the FV was 4.6 ± 0.3 cm. In one limb, the distance between the FV valves was 1 cm less than GSV valves, and in two limbs the distances were equal. In the remaining 12 limbs available for comparison, the valves in the FV were 1-2 cm further apart compared to the GSV (P = 0.002, paired t-test). All studied pairs of valves were positioned at a minimum 60° angle to each other. The mean angle between the two valves was 84.3 ± 8.4° in the GSV, and 88.3 ± 6.7° in the FV (P = 0.24). The angle between the two valves correlated with the distance between the valves (r = 0.68, P = 0.000005). No significant relations were found between the diameter of the studied vein, and the angle between the two valves. There was no difference in valve orientation between volunteers and unaffected limbs of the patients with CVD. CONCLUSION: When two valves are present in the areas of venous junctions, they consistently positioned at a significant angle to each other. A hypothesis that venous valves at the junctions increase efficiency of venous return by creating a helical flow pattern can be postulated and deserves further investigation.

Physical stress testing of bovine jugular veins using magnetic resonance imaging, echocardiography and electrical velocimetry.

Bovine jugular veins (BJVs) (Contegra) are valve-bearing pulmonary artery substitutes. Their valves have higher profiles than human pulmonary valves; this might result in less optimal performance. Therefore, we investigated the impact of stress and undersizing on conduit performance with ergometry, echocardiography and magnetic resonance imaging (MRI). Between April 2007 and June 2008, 20 BJV recipients (age 7.9-19.6 years) underwent spiroergometry and subsequent echocardiography; after due rest, ergometry was repeated and followed by MRI during recovery. A year later, exams were repeated. Data was evaluated as follows: comparison of stress related maximal individual valve performance changes (magnetic resonance: exercise induced average stroke volume changes by 61+/-49%; mean insufficiency increased by 2% in patients with <1% rest insufficiency and by 8% after rest insufficiency of >10%; the average rest gradient of 24+/-11 mmHg rose to 40+/-20 mmHg), and stratification of pooled observations by regurgitation fraction, insufficiency grades and z-values (insufficiency rose with increasing heart rate and decreasing stroke volume; undersizing increased gradients during recovery by 7+/-0.7 mmHg/z-value). Contegras high-profile valves tolerate stress without performance drop. Stress induced changes of insufficiency and gradient were clinically not significant, but sufficient to distort examination results; therefore, constant examination conditions are indispensable for a correct follow-up.

Use of intraoperative venography to guide the distal portion of a ventriculoatrial shunt past an obstruction in the central veins: technical case report.

OBJECTIVE: Ventriculoatrial (VA) shunting is commonly used to treat hydrocephalus when ventriculoperitoneal shunting has failed. Placement of a VA shunt in patients with narrowing or occlusion of the central veins presents considerable difficulty because few imaging modalities exist to safely and reliably insert a guidewire or atrial catheter past the occlusion. We report the use of intraoperative venography to guide the placement of the distal portion of a VA shunt in a patient with a valve blocking the left brachiocephalic vein. CLINICAL PRESENTATION: A 42-year-old man with pseudotumor cerebri and a left ventriculoperitoneal shunt presented with severe headaches. He was diagnosed with partial distal shunt obstruction. Because of a history of failed attempts at ventriculoperitoneal shunting, conversion to a VA shunt via the left internal jugular vein was planned. TECHNIQUE: Surgery was performed by using the standard technique until resistance was encountered when inserting a guidewire into the internal jugular vein. Intraoperative venography of the central veins was performed, which showed a large valve blocking progression of the guidewire in the left brachiocephalic vein. Using fluoroscopic guidance, a 0.035-inch guidewire was successfully directed through the vein past the obstruction and exchanged for a peel-away introducer. The distal shunt catheter was then inserted, and the correct position in the atrium was confirmed fluoroscopically. CONCLUSION: When obstruction of the central veins is found during a VA shunting procedure, intraoperative venography is a useful method to aid in the placement of the atrial catheter through the central veins.

[Comparison between canine decellularized venous valve stent combined with endothelial progenitor cells and native venous valve on venous valve closure mechanism in normal physiological conditions].

OBJECTIVE: To compare canine decellularized venous valve stent combining endothelial progenitor cells (EPC) with native venous valve in terms of venous valve closure mechanism in normal physiological conditions. METHODS: Thirty-six male hybrid dogs weighing 15-18 kg were used. The left femoral vein with valve from 12 dogs was harvested to prepare decellularized valved venous stent combined with EPC. The rest 24 dogs were randomly divided into the experimental group and the control group (n=12 per group). In the experimental group, EPC obtained from the bone marrow through in vitro amplification were cultured, the cells at passage 3 (5 x 10(6) cells/mL) were seeded on the stent, and the general and HE staining observations were performed before and after the seeding of the cells. In the experimental group, allogenic decellularized valved venous stent combined with EPC was transplanted to the left femoral vein region, while in the control group, the autogenous vein venous valve was implanted in situ. Color Doppler Ultrasound exam was performed 4 weeks after transplantation to compare the direction and velocity of blood flow in the distal and proximal end of the valve, and the changes of vein diameter in the valve sinus before and after the closure of venous valve when the dogs changed from supine position to reverse trendelenburg position. RESULTS: General and HE staining observations before and after cell seeding: the decellularized valved venous stent maintained its fiber and collagen structure, and the EPC were planted on the decellularized stent successfully through bioreactor. During the period from the reverse trendelenburg position to the starting point for the closure of the valve, the reverse flow of blood occurred in the experimental group with the velocity of (1.4 +/- 0.3) cm/s; while in the control group, there was no reverse flow of blood, but the peak flow rate was decreased from (21.3 +/- 2.1) cm/s to (18.2 +/- 3.3) cm/s. In the control group, the active period of valve, the starting point for the closure of the valve, and the time between the beginning of closure and the complete closure was (918 +/- 46), (712 +/- 48), and (154 +/- 29) ms, respectively; while in the experimental group, it was (989 +/- 53), (785 +/- 43), and (223 +/- 29) ms, respectively. There was significant difference between two groups (P < 0.05). After the complete closure of valve, no reverse flow of blood occurred in two groups. The vein diameter in the valve sinus of the experimental and the control group after the valve closure was increased by 116.8% +/- 2.0% and 118.5% +/- 2.2%, respectively, when compared with the value before valve closure (P > 0.05). CONCLUSION: Canine decellularized venous valve stent combined with EPC is remarkably different from natural venous valve in terms of the valve closure mechanism in physiological condition. The former relies on the reverse flow of blood and the latter is related to the decreased velocity of blood flow and the increased pressure of vein in the venous sinus segment.

Giant Eustachian valve and left ventricular systolic dysfunction in a patient with non-dilated amyloid cardiomyopathy.

Amyloid cardiomyopathy is characterized by non-dilated thick-walled left ventricular, thickening of interventricular septum and right ventricular free wall, biatrial enlargement associated with granular 'sparkling' appearance of the myocardium. Typically, decreased left ventricular compliance results in abnormal diastolic functions but left ventricular systolic functions are preserved until late in the course of the illness when left ventricle starts to dilate culminating into dilated cardiomyopathy. We present a 77-year-old patient who had typical echocardiographic features of amyloid heart disease, a giant Eustachian valve resembling cor triatriatum dexter and left ventricular systolic dysfunction without associated left ventricular dilatation.