RASA1-driven cellular export of collagen IV is required for the development of lymphovenous and venous valves in mice.

RASA1, a negative regulator of Ras-MAPK signaling, is essential for the development and maintenance of lymphatic vessel valves. However, whether RASA1 is required for the development and maintenance of lymphovenous valves (LVV) and venous valves (VV) is unknown. In this study, we show that induced disruption of Rasa1 in mouse embryos did not affect initial specification of LVV or central VV, but did affect their continued development. Similarly, a switch to expression of a catalytically inactive form of RASA1 resulted in impaired LVV and VV development. Blocked development of LVV was associated with accumulation of the basement membrane protein, collagen IV, in LVV-forming endothelial cells (EC), and could be partially or completely rescued by MAPK inhibitors and drugs that promote collagen IV folding. Disruption of Rasa1 in adult mice resulted in venous hypertension and impaired VV function that was associated with loss of EC from VV leaflets. In conclusion, RASA1 functions as a negative regulator of Ras signaling in EC that is necessary for EC export of collagen IV, thus permitting the development of LVV and the development and maintenance of VV.

Comparative Study of Morphology and Distribution of Valves in Human Retromandibular Vein.

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.

Using two-dimensional ultrasound imaging to examine venous pressure.

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.

Understanding basic vein physiology and venous blood pressure through simple physical assessments.

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.

Human Femoral Vein Diameter and Topography of Valves and Tributaries: A Post Mortem Analysis.

The femoral vein (FV) is a clinically important vessel. Failure of its valves can lead to chronic venous insufficiency (CVI) with severe manifestations such as painful ulcers. Although they are crucial for identifying suitable implant sites for therapeutic valves, studies on the topography of FV tributaries and valves are rare. Moreover, the femoral vein diameter (FVD) must be known to assess the morphometric requirements for valve implants. To reassess the anatomical requirements for valve implants, 155 FVs from 82 human corpses were examined. FVDs and tributary and valve topographies were assessed using a laboratory straightedge. The FVD increased from 6 mm in the distal femoropopliteal vein to 11 mm in the iliofemoral vein proximal to the saphenofemoral junction (SFJ). Diameters were significantly bigger in males than females. Height correlated positively with FVD. Distal to the SFJ, within a distance of 38 cm, one to eight valves were present. Up to two valves were present within 10 cm proximal to the SFJ. Individual tributary and valve topography must be considered to ensure appropriate design and successful implantation of a venous valve for CVI therapy in the FV. A suitable implant site would be proximal to the SFJ via an infrainguinal transfemoral access. Clin. Anat. 31:1065-1076, 2018. © 2018 Wiley Periodicals, Inc.

The internal anatomy of the inferior vena cava with specific emphasis on the entrance of the renal, gonadal and lumbar veins.

Major tributaries such as the renal and adrenal veins have been studied extensively; however, tributaries of the infra-renal segment of the inferior vena cava (IVC) have not been given much attention. Accurate knowledge of the anatomy of these veins is necessary for improved efficacy of surgical interventions in the retroperitoneum. The aim of this study therefore was to provide a comprehensive picture of the internal anatomy of the tributaries of the infra-renal segment of the IVC. Dissection of the posterior abdominal wall was performed on 30 formalin-fixed cadavers. Endoscopic study was carried out followed by a midline venotomy on the anterior wall of the isolated IVC, the location and orientation of its tributaries and their ostia were observed and measurements taken. The results showed that while there was great variation in the drainage pattern of the lumbar veins, most lumbar veins had ostia located between L2 and L3 vertebrae irrespective of the location of renal and gonadal tributaries. Valves were found in 81.81 % of gonadal veins, in 56.60 % of all lumbar veins and discrete ostial valves in 14.81 % of renal veins. The location of the tributaries of the IVC was correlated with the vertebral levels. Empirical data regarding their ostio-valvular complexes were established, which put into question widely accepted concept of valveless tributaries. Our results may implicate surgical procedures in and around the retroperitoneal region.

Persistent jugulocephalic vein: case report including commentaries on distribution of valves, blood flow direction and embryology.

This paper is a detailed case study of the persistent anastomotic channel between the cephalic vein and the external jugular vein, running anterior to the clavicle, corresponding to the jugulocephalic vein present at early stages of the ontogenesis in humans. This connection is not only a relic of early foetal development seldom occurring in adults, but it may also be of clinical significance, increasing the risk of complications during the cephalic vein catheterisation, clavicular fractures or head and neck surgery. The novelty in this paper was to determine the presence and distribution of valves within the persistent jugulocephalic vein. Three bicuspid venous valves were found that allowed the blood to flow only in one direction - from the cephalic vein to the external jugular vein. The anastomosis between the persistent jugulocephalic vein and the thoracoacromial veins was additionally present. Due to lack of similar data in the literature, further research should be performed on the presence and distribution of the venous valves in various types of the persistent jugulocephalic vein in humans.

More great saphenous vein valves - less varicose veins?

BACKGROUND: In patients with chronic venous disease (CVD) the number of venous valves and the degree of valve deterioration have not been extensively investigated and are poorly understood. The aim of this prospective study was to quantitatively and qualitatively investigate the venous valves in CVD patients in view of their clinical classification. PATIENTS AND METHODS: Within two years a consecutive series of 152 patients (223 limbs) undergoing primary surgery for great saphenous vein varicose veins was investigated. In all patients the 'C' class according to the basic CEAP-classification was registered preoperatively (C2 to C6) for each limb. Both the quantity and quality of venous valves were assessed in the GSV's after removal. Qualitative evaluation of the valves was based on macroscopic appearance using a classification from 0 to 5 and described as 'valve disease class'. RESULTS: A negative correlation between age and the number of valves was detected (p = 0.0035). There was an increase of C-class with increasing age. No significant correlation between the average number of valves per meter and the C-class was detected. For all C-classes an average of between four and five valves per meter was counted. Valve disease class was positively correlated with the C-class although the valve disease class was never higher than the C-class (p < 0.05). CONCLUSIONS: The valve disease class of the great saphenous vein correlates with the C-class of the CEAP-classification. The number of valves did not correlate with the 'C'-class. With each increase in the CEAP class the age increased as well.

Pathophysiology of deep vein thrombosis.

Deep venous thrombosis is a frequent, multifactorial disease and a leading cause of morbidity and mortality. Most of the time deep venous thrombosis is triggered by the interaction between acquired risk factors, such as hip fracture, pregnancy, and immobility, and hereditary risk factors such as thrombophilias. The mechanisms underlying deep venous thrombosis are not fully elucidated; however, in recent years, important advances have shed light on the role of venous flow, endothelium, platelets, leukocytes, and the interaction between inflammation and hemostasis. It has been described that the alteration of venous blood flow produces endothelial activation, favoring the adhesion of platelets and leukocytes, which, through tissue factor expression and neutrophil extracellular traps formation, contribute to the activation of coagulation, trapping more cells, such as red blood cells. Thus, the concerted interaction of these phenomena allows the formation and growth of the thrombus. In this work, the main mechanisms involved in the pathophysiology of deep vein thrombosis will be described.

Supporting evidence for an "arterial pump" venous return mechanism in humans.

Blood flow in large veins is dependent on arterial-atrial pressure gradients and pumping mechanisms in concert with valve recruitment. Classic descriptions of muscle and respiratory pumps describe venous transmural pressure changes that cause flow. Not often considered is the transmission of pulsatile energy from arteries to veins directly adjacent to each other. Recently, an ex vivo study demonstrated a novel arterial pump effect in venoarterial bundles when valves were active in managing venous flow. We sought to show in vivo evidence of this arterial pump mechanism in 16 healthy young adults. Venous blood flow was measured in the venoarterial bundled deep femoral vein (DFV) and the greater saphenous vein (GSV), which is not bundled with an artery. Veins were studied through randomized body positions of -6° head-down tilt (HDT), supine, 20° head-up tilt (HUT), and 40° HUT, with the assumption that greater HUT postures increased valve dependence to observe the arterial pump effect. Between 20° and 40° HUT conditions, bundled DFV blood flow did not change (68 ± 36 vs. 71 ± 56 mL·min-1; Padj > 0.99), whereas nonbundled GSV blood flow decreased (6.1 ± 4.8 vs. 3.5 ± 3.9 mL·min-1; P = 0.01). Diameters between 20° and 40° HUT conditions increased in DFV (0.90 ± 0.16 vs. 1.04 ± 0.19 cm; P < 0.01), but not in GSV (0.33 ± 0.10 vs. 0.32 ± 0.08 cm; P = 0.60). These data support previous ex vivo observations that when venous pressure gradients rely on valve recruitment, presence of an adjacent artery may protect against further decreases in blood flow. The arterial pump mechanism is an underappreciated contributor to venous return and warrants further investigation.NEW & NOTEWORTHY Venous return mechanisms have classically considered muscle and respiratory pumps; however, recent ex vivo evidence suggests that pulsatile energy imparted from arteries to adjacent bundled veins can increase venous flow under certain driving pressures. We tested this concept in humans by manipulating hydrostatic pressures and measuring flow in bundled and nonbundled veins. The bundled vein exhibited flow preservation at the highest hydrostatic pressure. We suggest a novel conservation of energy mechanism within the circulatory system.

Advances in Engineering Venous Valves: The Pursuit of a Definite Solution for Chronic Venous Disease.

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 statement Venous 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.

[Peripheral intravenous lines : A multifaceted topic]. / Periphere Venenverweilkanülen : Ein facettenreiches Thema.

Peripheral intravenous lines are indispensable for emergency and intensive medical care. They have a high importance, especially in the context of primary care as well as in the early stages of treatment initiation. This requires in-depth knowledge of the persons being treated. This article describes the most important aspects of the indications, puncture and fixation techniques as well as special features in terms of management and hygiene.

Fluid-structure interaction simulations of venous valves: A monolithic ALE method for large structural displacements.

Venous valves are bicuspidal valves that ensure that blood in veins only flows back to the heart. To prevent retrograde blood flow, the two intraluminal leaflets meet in the center of the vein and occlude the vessel. In fluid-structure interaction (FSI) simulations of venous valves, the large structural displacements may lead to mesh deteriorations and entanglements, causing instabilities of the solver and, consequently, the numerical solution to diverge. In this paper, we propose an arbitrary Lagrangian-Eulerian (ALE) scheme for FSI simulations designed to solve these instabilities. A monolithic formulation for the FSI problem is considered, and due to the complexity of the operators, the exact Jacobian matrix is evaluated using automatic differentiation. The method relies on the introduction of a staggered in time velocity to improve stability, and on fictitious springs to model the contact force of the valve leaflets. Because the large structural displacements may compromise the quality of the fluid mesh as well, a smoother fluid displacement, obtained with the introduction of a scaling factor that measures the distance of a fluid element from the valve leaflet tip, guarantees that there are no mesh entanglements in the fluid domain. To further improve stability, a streamline upwind Petrov-Galerkin (SUPG) method is employed. The proposed ALE scheme is applied to a two-dimensional (2D) model of a venous valve. The presented simulations show that the proposed method deals well with the large structural displacements of the problem, allowing a reconstruction of the valve behavior in both the opening and closing phase.

Aging of the venous valves as a new risk factor for venous thrombosis in the elderly: the BATAVIA study.

Essentials Risk of venous thrombosis (VT) related to valve thickness and valvular reflux in unknown. Venous valves and reflux were measured by ultrasonography in cases and controls aged 70+. Risk of VT was associated with increased valve thickness and valvular reflux >1second. Thickening of valves is a generic process: there was no difference between right and left legs. SUMMARY: Background Increasing age is the strongest risk factor for venous thrombosis (VT). Increasing age has been related to a thickening of the venous valves and a decreased valvular function. The association between valve thickness and the risk of VT is not known. Objectives To assess the association between increased valve thickness and valve closure time (VCT) and the risk of VT. Methods Analyses were performed in the BATAVIA study, including 70 cases aged 70 + with a first VT and 96 controls. We performed an ultrasound examination of the valves in the popliteal veins. The valves were imaged with a 9 MHz linear probe using B-mode ultrasonography. VCT was measured as an indicator for valve function using an automatic inflatable cuff. To estimate the risk of VT, valve thickness was dichotomized at the 90th percentile as measured in controls and VCT was dichotomized at 1 s. Results Mean valve thickness of controls was similar in the left (0.36 mm, 95% CI 0.34-0.37) and right (0.36 mm, 95% CI 0.35-0.38) leg. In 45 cases a valve was observed in the contralateral leg with a mean valve thickness of 0.39 mm (95% CI 0.36-0.42). Cases had an increased valve thickness compared with controls: mean difference 0.028 mm (95%CI 0.001-0.055). Valve thickness > 90th percentile increased the risk of VT 2.9-fold. Mean VCT in controls was 0.38 s, in contralateral leg of cases 0.58 s. VCT > 1 s increased the risk of VT 2.8-fold (95% CI 0.8-10.4). Conclusions Risk of VT was associated with increased valve thickness and valvular reflux of > 1 s.

Correlative Fluorescence and Scanning Electron Microscopy to Study Lymphovenous Valve Development.

Lymph collected from throughout the body is exclusively returned to blood circulation via two pairs of bilaterally located lymphovenous valves. Lymphovenous valves share numerous similarities with lymphatic and venous valves and are defective in multiple mouse models of lymphedema or lymphatic dysfunction. Here we describe a protocol that combines the strengths of fluorescence microscopy and scanning electron microscopy to precisely locate and analyze the topography of developing lymphovenous valves at high resolution.

Dilemma during ultrasound-guided internal jugular venous catheterization.

The presence of Internal Jugular Valves can pose a diagnostic and procedural challenge during ultrasound-guided cannulation. After ruling out dissection, thrombus, or ultrasound artifacts, it can still be accessed and successfully cannulated with appropriate precautions including use of Live ultrasound, positioning, use of soft-tipped catheters, and minimizing duration of catheter placement.

Bioengineered valves for the venous circulation.

INTRODUCTION: 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.

Global sensitivity analysis of a model for venous valve dynamics.

Chronic venous disease is defined as dysfunction of the venous system caused by incompetent venous valves with or without a proximal venous obstruction. Assessing the severity of the disease is challenging, since venous function is determined by various interacting hemodynamic factors. Mathematical models can relate these factors using physical laws and can thereby aid understanding of venous (patho-)physiology. To eventually use a mathematical model to support clinical decision making, first the model sensitivity needs to be determined. Therefore, the aim of this study is to assess the sensitivity of the venous valve model outputs to the relevant input parameters. Using a 1D pulse wave propagation model of the tibial vein including a venous valve, valve dynamics under head up tilt are simulated. A variance-based sensitivity analysis is performed based on generalized polynomial chaos expansion. Taking a global approach, individual parameter importance on the valve dynamics as well as importance of their interactions is determined. For the output related to opening state of the valve, the opening/closing pressure drop (dpvalve,0) is found to be the most important parameter. The venous radius (rvein,0) is related to venous filling volume and is consequently most important for the output describing venous filling time. Finally, it is concluded that improved assessment of rvein,0 and dpvalve,0 is most rewarding when simulating valve dynamics, as this results in the largest reduction in output uncertainty. In practice, this could be achieved using ultrasound imaging of the veins and fluid structure interaction simulations to characterize detailed valve dynamics, respectively.

Bioengineered living cardiac and venous valve replacements: current status and future prospects.

Valvular heart disease remains to be a major cause of death worldwide with increasing prevalence, mortality, and morbidity. Current heart valve replacements are associated with several limitations due to their nonviable nature. In this regard, heart valve tissue engineering has shown to represent a promising concept in order to overcome these limitations and replace diseased cardiac valves with living, autologous constructs. These bioengineered valves hold potential for in situ remodeling, growth, and repair throughout the patient's lifetime without the risk of thromboembolic complications and adverse immune responses. For the fabrication of tissue-engineered heart valves, several concepts have been established, the "classical" in vitro tissue engineering approach, the in situ tissue engineering approach, and alternative approaches including three-dimensional printing and electrospinning. Besides first attempts have been conducted in order to produce a tissue-engineered venous valve for the treatment of deep venous valve insufficiency. Here we review basic principals and current scientific status of valvular tissue engineering, including a critical discussion and outlook for the future.