Replacement venous valve prosthesis in primary chronic venous disease: is it likely to be developed in the future?



by A. D. Giannoukas, K. Spanos,
A. E. Giannakopoulos, Greece

D. GIANNOUKAS,
MD, MSc, PhD, FEBVS
Konstantinos SPANOS,
MD, MSc
Vascular Surgery Department
University Hospital of Larissa
Faculty of Medicine
School of Health Sciences
University of Thessaly, Larissa
GrEEcE
Antonios E. GIANNAKOPOULOS,
PhD
Laboratory of Strength of
Materials and Micromechanics
Department of civil Engineering
School of Polytechnics
University of Thessaly, Volos
GREECE

Venous reflux is a clinical sign associated with the inability to control the return of venous flow. Chronic venous insufficiency is subject to change over time. Different factors, such as hypoxia and inflammation, can induce changes in the cytoarchitecture of vein walls, the grade of clinical reflux, and its interaction with aging. The presence of the hypoxia markers—HIF-1α and HIF-2α—and inflammatory markers—IL-6, MMP2, MMP9, and CD206— revealed that patient age affected the severity of reflux in young people (less than 50 years old) and that clinical reflux was related to hypoxic and inflammatory activity in older patients (50 years old or more). Our findings also demonstrated that markers of hypoxia and inflammation increased in the vein walls of patients without apparent clinical reflux, which indicates that histopathological changes occur prior to venous reflux. The presence of HIF-2α, an early marker of hypoxia, was noted in the young population when clinical reflux was not evident. The inflammatory markers exhibited a strong relationship with the severity of vein reflux in the older population.

Medicographia. 2016;38:162-168 (see French abstract on page 168)

Primary chronic venous disease imposes an important socioeconomical burden on the adult population, especially in developed countries.1-3 Primary chronic deep venous insufficiency (cDVI) affects one third of these patients.3 Over a long-term period, this condition may lead to varicose veins, chronic venous ulcers, and persistent, related pathological conditions.4 Because of this, various reconstructions of the deep vein system have been developed and evaluated not only in animal models, but in clinical studies too. Since the description of the first successful repair of a deep vein by Kistner et al and the Straub clinic team,5,6 the introduction of prosthetic valves via an open surgical approach has broadened this field. Prosthetic valves implanted using an endovenous approach have recently been evaluated as a treatment option in cDVI, with the advent of endovascular techniques in venous disease.7,8 In the near future, patients with cDVI are expected to benefit from minimally invasive procedures. In the first part of this article, we will review currently available prosthetic vein valves used in deep venous surgery and see how they were evaluated in animal models and clinical studies. The second part of the article will be devoted to describing implantable valves in primary cDVI, their indications, and the difficulties in designing and developing them.

Surgical reconstruction with prosthetic valves

Prosthetic venous valves provide an alternative option to cDVI treatment, when conservative treatment has failed and symptoms remain persistent.9 Since the mid-1960s, several potential off-the-shelf implantable valves have been tested as a substitute for autogenous venous valves. Prosthetic valves have been designed with single, double, or triple cusp leaflets from allografts, xenografts, or synthetic material attached to a carrier or a frame. However, most of these efforts yielded poor results in animal studies and have thus not been pursued further in clinical trials.

Animal studies

In 1988, Taheri et al10 implanted a center-hinged bileaflet valve constructed from platinum or a pyrolite carbon-covered titanium frame into the femoral vein of dogs. Prior to implantation, the valves were tested for fatigue and wear for 5 months, with only one valve developing a crack next to a cusp hinge. Additionally, flow and hydrodynamic pressure studies demonstrated that regurgitation was almost 48%. However, after 2 years of follow-up, it was reported that all the implanted valves had growths of dense intima hyperplasia that rendered them nonfunctional.11

Although, the long-term results of this study were poor, one could argue that there was promising evidence that modification could extend the life of the valves sufficiently to be clinically useful.

An early clinical experiment with a cryopreserved decellularized allograft, when used as a conduit for arteriovenous fistula (AVF), was shown to be promising, inciting very little antigen response, as determined by panel reactive antibody.12 Thus a decellularized venous valve allograft could minimize the immunologic burden of donor cells. Additionally, this material has also been used in heart valve replacement, where it demonstrated a similar lack of antigen response and acceptable valve function.13

However, in 2003, when Teebken et al14 designed a prosthetic valve using a decellularized allogenic ovine vein and subsequently implanted this valve into the external jugular vein of sheep, the results were disappointing. Twenty four grafts were used without any anticoagulation, and all of them were completely occluded after 6 weeks.

Even though this, the only existing animal study using decellularized venous valve allograft, had a negative outcome, this method still seems to hold promise. The method has been used successfully in other vascular beds,12,13 and further studies examining its use with anticoagulation are needed.

Burkhart et al evaluated the patency rate and hemodynamic behavior of a cryopreserved allograft venous valve in dogs in 1997.15 In this study, the dog recipients had pre-established lower limb venous insufficiency and were transplanted with cryopreserved veins containing valve allografts that were matched with dog erythrocyte antigen. The whole process was aided by the construction of a distal AVF. After subsequent ligation of this high-flow distal AVF that had been functioning for 3 to 6 weeks, all the transplants remained patent and competent for 3 more weeks, after which the recipients were sacrificed for histological examination. The histological results showed that endothelial cells were identified on the luminal surface only, and there was no presence of thrombus even in the cusp sinuses.

Clinical studies

These promising results triggered the initiative for a phase 1 multicenter feasibility study.16 During the first 6 months of follow- up, the primary patency and competency rates were 67% and 56%, respectively, indicating that a low-grade rejection phenomenon might be affecting the function of the valves. In 2003, Neglen et al17 reported the long-term results of this clinical study: after 2 years of follow-up, the percentage of cryovalves that remained both patent and competent was 27%. The authors concluded that cryovalve insertion was associated with high morbidity, high occlusion rate, poor cumulative midterm rate of patent graft with competent valve, and poor clinical results. The procedure should not be used as a primary technique for valve reconstruction, and it is questionable whether it is useful even in patients in whom autologous reconstruction techniques have been exhausted. However, if cryovalves are to become a viable alternative for valve repair, improved cryopreservation techniques, immunologic modifications, or better matching must be achieved.

A cryopreserved valve allograft (cryovalve), available from cryoLife Inc (Kennesaw, Georgia, USA), can remain competent with up to 125 mm Hg of retrograde pressure. However, there are two important issues to address for optimal competency outcome with the cryovalve: firstly, at the time of implantation, a primary valvuloplasty would be necessary17; and, secondly, someone has to manage the potential issue of rejection with the valve substitute.16,17 Since patients suffering from primary cDVI are not critically ill, immunosuppression should be minimal so it is well-tolerated and complication-free. There are no protocols for the administration of immunosuppression after cryovalve implant for cDVI treatment.

Figure 1 (left). Artificial monocusp venous valve consisted of a thin polyether urethane
membrane inside a single body Z-stent.
Copied from reference 20: Pavcnik et al. Vasc Med. 2008;13(1):75-84.© 2008, SAGE Publications.

Figure 2 (below). Segment of bovine jugular vein with leaflets (A), vein segments
trimmed and sutured to a nitinol stent (B), and bioprosthesis compressed and loaded
within an 18-Fr introducer (C). Copied from reference 20.

Implantable endovenous valves

In 1981, charles Dotter was the first person to perform a transcatheter delivery of prosthetic venous valve for the treatment of venous reflux.18 This study triggered many attempts to develop various valves for percutaneous implantation in the following decades. Uflacker et al19 inserted a percutaneously delivered, stent-based, membrane-like venous valve into the inferior vena cava of a pig. This artificial monocusp venous valve, which consisted of a thin polyether urethane membrane inside a single body Z-stent, could be inserted percutaneously through a 10-Fr sheath (Figure 1).20 However, the valve only functioned for a week, and after that a partial thrombus appeared inside the valve cusps. A later development was the bovine glutaraldehyde-preserved, valve-containing jugular vein segment, which was also percutaneously delivered in a pig model.21 This segment was sutured inside a self-expanding nitinol stent (Boston Scientific, Boston, MA, USA), which could be introduced through an 18-Fr sheath (Figure 2).20 Although the xenografts were patent and competent in the surviving animals after 2 weeks of follow-up, the implant itself caused complications due to a foreign body reaction.

One of the glutaraldehyde-preserved bovine prosthetic valves was included in a clinical trial and assessed by de Borst et al.22 This was a percutaneously delivered bovine jugular valve– bearing venous xenograft sutured inside a memory coded nitinol frame (VenPro Inc, Irvine, CA, USA) (Figure 3).20 When phase 1 of the trial was completed, the prosthesis was improved; the bovine jugular venous valve was replaced by pericardial tissue, with a heparin coating, and the nitinol stent’s radial stiffness was increased.23 currently, phase 2 of the clinical trial is awaiting launch in Europe and in the US.

Figure 3. Gluteraldehyde preserved bicuspid bovine valve sutured
inside a memory coded nitinol frame of a self-expanding stent.
Copied from reference 20: Pavcnik et al. Vasc Med. 2008;13(1):75-84. © 2008,
SAGE Publications.

Pavcnik et al have been heavily involved in the technological development of prosthetic venous valves.20,24-29 They have developed three generations of bioprosthetic venous valves (BVVs) and assessed their performance and their characteristics in animals; their bioprosthesis is currently part of clinical trials (Figure 4, page 172).30 The BVVs consist of a small leaflet of porcine small intestinal submucosa (cook Biotech, West Lafayette, IN, USA) attached to different types of square stent frames.

Porcine submucosa is a relatively acellular, nonimmunogenic, biodegradable, xenogenic, collagen-based extracellular matrix material that provides a temporary scaffold for cellular colonization.31 For their experimental animal work, they used an ovine jugular vein due to anatomical and functional similarities of the sheep jugular vein to the human femoral vein.20,24-29

Figure 4. Three generations of bioprosthetic venous valves. Front (A) and side (B) views of the original, first-generation design of the
square stent-based bioprosthetic venous valve (BVV), a side view of a second-generation BVV (C), and side view of a third-generation
BVV (D).
Copied from reference 30: Pavcnik et al. Ces Radiol. 2007;61(2):129-137. © 2007, all rights reserved.

The first-generation prosthesis was developed using nitinol or stainless steel wires for the frames and led to promising patency rates in animals. It was demonstrated at six months that patency and competency rates were 88% for the implanted valves, with host cell integration into the submucosa collagen matrix.28 In 2003, in the first clinical use, three patients with severe deep chronic valvular insufficiency who received anticoagulation pre- and postoperatively were treated with a square stent, submucosa BVV in the safety part of the trial, with a mixed outcome.28 Based on these previous studies, improved second-generation prostheses were developed to eliminate occasional tilting of the original BVV. The new valve was a sturdier version of the device described previously, and researchers had to assess several stent frame modifications to improve valve positioning during placement and to ensure its centering in the vein without tilting. The new BVV was composed of two overlapping frames made from nitinol (Figure 4),30 which provided four extra points at which the device could make contact with the inner wall of the vessel. Two sizes of BVV were tested in veins with diameters of 10 mm to 12 mm and 12 mm to 14 mm.26,27 The results were even better than those previously described; venograms at 6 weeks follow-up demonstrated no reflux in most (92.3%) of the valves.27 Third generation valves were designed to prevent potential contact of the free leaflet portions with the inner venous wall and to ensure continued leaflet coaptation, even with their possible shortening. This time, the frame of the valve was made from nitinol tubing, which was cut by a laser device and again had four barbs for valve stabilization. The round geometry of the BVV allowed the leaflets to coapt and improved blood flow in the larger pockets of the valve, which prevented potential thrombus formation. In addition, two gold markers were placed on the nitinol frame to ensure precise anatomical orientation during valve deployment. The desired spatial orientation was achieved after deployment for all the valves, and all remained stable and completely functional on venography after implantation over a 5-week follow-up. On gross examination, the remodeled submocosa leaflets were free from the vein wall except at their distal parts, where the submucosa was thickened and attached to the vein.20,27,29 In an one-year clinical feasibility study, the third-generation BVVs had no migration and a 73% patency rate, but none remained competent.29

Another group used a self-expanding stent (Wallstent, Schneider Inc., USA) with an autograft valve-bearing segment of vein secured within; overexpansion was utilized to hold the device in place. In this animal study, after one week of follow-up, residual nonocclusive thrombus was found attached to the exposed stent struts on the downstream end of the valvestent in all animals, despite the universal use of anticoagulation in the first week post implantation.32 At six weeks, a manual strip test showed that all valves were patent and most of them competent. Overall findings suggested that less exposed metal would be better; however, no clinical paper has been published on the valve-stent design yet.

Following the development of novel endovascular technology, a balloon-expandable stent with a glutaraldehyde xenograft valve mounted within the stent was used for the treatment of primary cDVI. In this animal study, the implanted valves performed quite poorly; occlusion of all six inferior vena cava implants at two months’ follow-up was demonstrated, with collateral circulation present.33 It was not clear whether the presence of xenograft material or metal or the trauma from balloon expansion to either the recipient vein wall or the donor valve was responsible for the poor results. It is possible that each factor could have to some degree contributed to these poor outcomes, and this particular valve-stent arrangement is unlikely to be the focus of investigation in the near future.

In addition, another implantable bioprosthetic valve was developed and evaluated using endothelial progenitor outgrowth cells isolated from whole bovine blood, as a source of in vitro autologous seeding for submucosal endothelialization.34 When examined by immunofluorescent staining, the endothelial monolayer remained intact after loading and delivery and when subjected to flow in the in vitro loop. After histological examination of the valves subjected to the ex vivo shunt loop, retention of the endothelial monolayer was revealed. According to this study, endothelial progenitor outgrowth cells seem to be a promising cell source for autologous endothelialization of bioprosthetic valves for the treatment of cDVI. However, clinical studies should be undertaken to clarify outcomes in the near future.

In the most recent study, autologous endovenous valve transfer stents (EVTSs) were evaluated in animals; a stent was placed around a native vein with a functional valve.8 The EVTSs (9 × 24 mm, including barbs) were developed by AllVascular (St Leonards, NSW, Australia) and the introducing system was produced by cook (Bloomington, IN, USA). For optimal wall fixation, the fine barbs (3 mm in length) penetrated not only the donor’s wall, but also impinged on the recipient wall. In addition, the body of the stent had a zigzag pattern, which created high frictional resistance between the external surface of the stent and the recipient vein wall. A 2-mm expansion oversizing was considered optimal in the assessment of the recipient diameter. The length of the EVTSs were 20 mm to avoid tilting within the recipient vein and to minimize the possibility of endoleak. At harvest, all the transferred valves were competent, with no evidence of thrombosis, tilting, endoleak, or migration. Following these promising results, a clinical study in four patients was undertaken. Four males with recalcitrant ulcers (with a mean age of 22 years) had axillary veins transferred to the popliteal vein and were followed up. All of the ulcers improved and 50% healed completely; furthermore, all the valves were competent and patent.8

Optimal design and development

Primary cDVI is a health problem that is underestimated and that has increased the socioeconomical burden of our era.1-3 It is a fact that the current treatment modalities are unsatisfactory, with poor outcomes despite clear indications. According to the guidelines of the American Venous Forum on surgical repair of deep vein valve incompetence, valve reconstruction is recommended in primary valvular incompetence after less invasive therapies have failed.9 Most of these procedures require considerable surgical skill and experience and, furthermore, these operations are not commonly performed and are associated with significant morbidity and mortality because of the risk of venous thromboemblolism.35

A venous valve delivered remotely with minimally invasive treatment (percutaneously) may remove the difficulties associated with open surgery. As previously mentioned, many animal studies and a few clinical ones have been undertaken to assess the feasibility and efficacy of prosthetic valves in primary cDVI. It has been suggested that the optimal prosthetic valve should be made from either synthetic or biological material attached to the frame of a stent that comes in a variety of diameters, with a proper fixation system to avoid migration.8,36
The venous connections to the stent would need to be fluid sealed to prevent endoleak, and the stent itself should have a minimal blood interface to minimize thrombogenicity as the barbs would be in contact with blood. Additionally, the device should be designed with a small-diameter profile for the system of introduction to be less traumatic and more feasible.8 The prosthetic valve should be durable, stable, and nonthrombogenic and should function properly under a diverse range of physiological conditions. Another review has stated specific design characteristics that future venous valve implants should have such as36:

♦ Biocompatible materials
♦ collapsible to a diameter ♦ Stent length 200 megacycles (equivalent to 5 years).36

Summary

In conclusion, we do not currently have an optimal endovalve available. The latest guidelines of the American Venous Forum refer only to surgical repair of primary deep vein valve incompetence, with valve reconstruction recommended (grade 1, level A) in primary valvular incompetence after less invasive therapies have failed.9 However, the procedures involved are very demanding, the results are not good, and availability restricted to only a few specialized centers. With the development of novel endovascular technologies, patients with primary cDVI are expected to benefit, but we still lack an effective endovalve and we do not know if the indications for its use will be the same as those for surgical repair.

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Keywords: prosthetic venous valve; primary chronic deep venous insufficiency; endovenous; animal study; clinical study