A nitinol "U-Clip" versus sutured arteriovenous anastomosis: local tissue response and intimal hyperplasia development in a sheep model.

OBJECTIVES: This study sought to compare the local tissue response and subsequent volume of intimal hyperplasia (IH) that develops throughout the maturation of an arteriovenous fistula created using continuous/interrupted polypropylene with that of a novel, metal-alloy, penetrating anastomotic clip device. MATERIALS AND METHODS: Forty-six fistulae were created in 23 sheep under a paired design using the nitinol U-Clip (n = 23) in one hind limb and continuous (n = 20) or interrupted (n = 3) polypropylene suture for the other. Animals were killed at 4 (n = 3), 14 (n = 3), 28 (n = 10), 42 (n = 3), and 180 (n = 4) days. Histological sections were evaluated for quantitative histology and immunohistochemistry. RESULTS: Compared with continuous polypropylene, U-Clip specimens demonstrated less intima-media area per unit length (IMA/L), proliferating cells, and tissue necrosis at all time points (MANOVA, F = 9.8-24.1, all p ≤ .005; observed power >82%). Specifically, values of IMA/L were reduced by 5% (p = .97), 37% (p = .02), 33% (p < .01), 9% (p = .42), and 14% (p = .22) at the time points of 4, 14, 28, 42, and 180 days respectively. Proliferating cells were reduced by 75% (p < .01), 72% (p = .03), 76% (p = .03), 27% (p = .31), and 60% (p = .01) and tissue necrosis by 67% (p < .01), 58% (p = .02), 40% (p = .33), 21% (p = .43), 77% (p = .11). In a 28-day comparison between U-Clip and interrupted polypropylene the U-Clip group demonstrated a 4% (p = .65) reduction in IMA/L, 74% (p < .01) in proliferating cells and 49% (p < .05) in tissue necrosis. CONCLUSIONS: These results provide evidence of reduced local tissue necrosis, proliferating cells, and IH, favouring arteriovenous fistulae created using the U-Clip anastomotic device over conventional polypropylene suture techniques most evident over the first 4 weeks.

Current and evolving strategies for the treatment of atherosclerotic disease of the popliteal artery.

The popliteal artery (PA) may well be the most challenging of all infra-inguinal vessels to treat. Not only is it anatomically unique but it's also exposed to some of the most brutal forces seen in the lower limb, during normal knee flexion. Management may be challenging and with few randomized trials dedicated to answering questions of technical success and durability the correct approach remains contentious. Herein we seek to describe and evaluate the growing number of options for treatment in this vascular territory.

Drug eluting stents in the treatment of below the knee arterial occlusive disease.

The use of endovascular techniques for the treatment of occlusive arterial disease below the knee has gained widespread acceptance and is considered by many as the first line treatment for patients with critical limb ischaemia. Tibial angioplasty and stenting have a high rate of technical success and are relatively low risk procedures, which has widened their applicability to include treatment for the elderly and those with comorbidities unsuitable for open bypass surgery. Despite these advantages the durability of the percutaneous revascularisation remains inferior to that of open surgery for diffusely diseased arteries. In the search to improve their long term performance we have sought to investigate the role of coronary drug eluting stents (DES) in the tibial vasculature in the hope that they may reduce recurrent stenosis, the leading threat to interventional patency. Ample data now exists in the form of registries and randomised trials designed to evaluate the use of DES in the crural arteries below the knee. This article reviews this body of research, explores the use of these devices in more complex lesions, speculates on their future development and examines their cost-effectiveness.

Re-entry device use in the endovascular treatment of aorto-iliac occlusive disease.

The treatment of peripheral arterial occlusive disease with endovascular therapy is rapidly becoming the standard of care. Akin to the movement towards percutaneous coronary interventions that occurred with gusto throughout the 1980s and 1990 s, treatment for the peripheral vasculature has undergone its own paradigm shift. Such that many feel that a first-line catheter-based approach is justified for the majority of patients in 2012. Extensive occlusive disease of the aorto-iliac segment is an area where open surgery has historically been preferred over endovascular therapy. This is partly because the open surgical standard of aorto-bi-femoral bypass has durability unrivalled by other forms of peripheral revascularisation surgery. Furthermore, some have avoided endovascular interventions in this region because of fears of perforation, bleeding and limited technical success in an area where the blood vessels carry a heavy burden of disease and a large thrombotic load. Throughout surgical history we have seen advances in technology emerge to provide a medium through which the proceduralist may extend their indications for treatment. A number of re-entry devices which provide a reliable method of wire passage beyond chronic occlusions of the aorta and iliac arteries have emerged and for the first time are safely facilitating high technical success rates in the treatment of aorto-iliac occlusive disease (AIOD). What follows is a summary of both open and endovascular treatment options for AIOD. Moreover, this review will provide an evidence based description of the emerging litany of devices which aid in wire passage through this most challenging of vascular territories.

An arteriovenous fistula model of intimal hyperplasia for evaluation of a nitinol U-Clip anastomosis.

OBJECTIVES: The aim of this study was to create an ovine arteriovenous fistula (AVF) model which would closely replicate a human forearm fistula and use this to quantify the degree of intimal hyperplasia in those created with the U-Clip compared to a conventional sutured anastomosis. MATERIALS AND METHODS: Twenty AVFs were created in 10 Border Leicester-Merino sheep between the superficial femoral artery and vein of each hind limb. On one side the U-Clip and on the other a continuous polypropylene suture was used to perform the anastomosis. The animals were sacrificed at 2 (n = 3), 4 (n = 4), 6 (n = 3) weeks and histological slices were taken of each AVF in cross section to determine the intimal media area per unit length (IMA/L). RESULTS: Intimal hyperplasia (IH) was observed at all time points with one AVF found occluded with thrombus at the time of harvest. The IMA/L was significantly lower in the U-Clip groups by 24% at 2 weeks, 32% at 4 weeks and 23% at 6 weeks (Two-way ANOVA, p = 0.019, observed power = 0.825, time or side p ≥ 0.766, type p = 0.001; Paired t-test, p < 0.001 between matched anastomotic types). Time taken to perform the anastomosis was similar between the two anastomotic techniques (Polypropylene 14(8-18) vs. U-Clip 15.3(11-23) min; p = 0.47). CONCLUSION: This ovine AVF model results in IH similar to that seen in a human AVF. The IH that occurs with the U-Clip is less than that of continuous polypropylene suture.

P2X receptor characterization and IL-1/IL-1Ra release from human endothelial cells.

BACKGROUND AND PURPOSE: The pro-inflammatory cytokine, interleukin-1beta (IL-1beta), has been implicated in the pathogenesis of atherosclerosis, potentially via its release from vascular endothelium. Endothelial cells (EC) synthesize IL-1beta in response to inflammatory stimuli, but the demonstration and mechanism of release of IL-1 from ECs remains unclear. In activated monocytes, efficient release of bioactive IL-1beta occurred via activation of ATP-gated P2X(7) receptors (P2X(7)Rs). Activation of P2X(7)R in ECs from human umbilical vein (HUVECs) released IL-1 receptor antagonist (IL-1Ra). The purpose of this study was to provide a quantitative investigation of P2XR expression and function, in parallel with IL-1beta and IL-1Ra synthesis, processing and release, in HUVECs under pro-inflammatory conditions. EXPERIMENTAL APPROACH: Quantitative RT-PCR, immunoblotting, ELISA, flow cytometry, and whole-cell patch clamp recordings were used to determine protein expression and receptor function. IL-8-luciferase-reporter was used as an IL-1 sensitive bioassay. KEY RESULTS: HUVECs expressed P2X(4)R and P2X(7)R subtypes and both were significantly up-regulated under inflammatory conditions. P2X(7)R currents were increased 3-fold by inflammatory stimuli, whereas no P2X(4)R-mediated currents were detected. Caspase-1, but not IL-1beta, was present intracellularly under basal conditions; inflammatory stimuli activated the synthesis of intracellular pro-IL-1beta and increased caspase-1 levels. Activation of P2X(7)Rs resulted in low-level release of bioactive IL-1beta and simultaneous release of IL-1Ra. The net biological effect of release was anti-inflammatory. CONCLUSIONS AND IMPLICATIONS: Endothelial P2X(7)Rs induced secretion of both pro- and anti-inflammatory IL-1 receptor ligands, the balance of which may provide a means for altering the inflammatory state of the arterial vessel wall.

Arm vein as a last autogenous option for infrainguinal bypass surgery: it is worth the effort.

OBJECTIVES: Considerable evidence exists for the use of arm vein conduit in lower limb bypass surgery. The use of arm vein in preference to synthetic conduit as a last autogenous option was assessed for patency and limb salvage outcomes. MATERIALS AND METHODS: A prospective database was interrogated and checked against TQEH operating theatre database to detect all infrainguinal arm vein bypasses performed between 1997 and 2005. Patency, limb salvage and survival data for 37 arm vein bypasses was calculated using the Kaplan-Meier survival estimate method. RESULTS: There were no perioperative deaths. 30 day patency rates were 89% primary, 95% secondary and 95% limb salvage. 12 month patency rates were 56% primary, 79% secondary and 91% limb salvage. 5 year patency rates were 37% primary, 76% secondary and 91% limb salvage. There was no significant patency advantage for primary vs. "redo" grafts (p=0.54), single vessel vs. spliced conduits (p=0.33) or popliteal vs tibial outflow (p=0.80). Patient survival rate was 92% and 65% at 1 and 5 years respectively. CONCLUSION: Lower limb bypasses using arm vein can be performed with favourable patency and limb salvage compared to synthetic conduits. However, secondary interventions are frequently required to maintain patency. We recommend a vigilant surveillance program for early identification of patency threatening disease.

The role of the fibrocyte in intimal hyperplasia.

BACKGROUND: Experimental animal studies have shown that the intimal hyperplasia (IH) responsible for occlusion after successful revascularization procedures may be partially caused by a bone marrow-derived cell that migrates to the site of vascular injury. Concurrent studies have demonstrated an extensive role in wound healing for the circulating fibrocyte. OBJECTIVES: We aimed to trace the path of the circulating cell that contributes to IH and determine if it is the fibrocyte. METHODS AND RESULTS: We established an in vitro model whereby purified monocytes from six healthy human volunteers were cultured into fibrocytes. These cells were morphometrically similar to the vascular smooth muscle cell (VSMC) found in IH and expressed alpha-smooth muscle actin (alpha-SMA) as well as CD34, CD45 and Collagen I (Col I), markers indicative of the fibrocyte. In an in vivo ovine carotid artery synthetic patch graft model, carboxyfluorescein diacetate, succinimidyl ester (CFSE) labeled circulating leukocytes were observed throughout the graft as well as in the neointima in 18 sheep. These cells were shown to produce collagen and alpha-SMA at 1, 2 and 4 weeks. These cells then underwent immunohistochemical analysis and were found to express a set of markers unique to the fibrocyte (CD34, CD45, Vimentin and alpha-SMA) and also to double stain for CD34 and alpha-SMA. CONCLUSIONS: IH in an ovine carotid artery patch graft model is partially derived from a hematopoietic circulating progenitor cell that acquires mesenchymal features as it matures at the site of injury.

Efficiency of utilization of urea nitrogen for albumin synthesis by chronically uraemic and normal man.

1. The relation between endogenous urea metabolism and albumin synthesis has been studied in ten patients with chronic renal failure and in four normal subjects, after single intravenous injections of [14-C]urea,[15-N]urea and 125-I-labelled albumin. 2. The rate of urea synthesis was determined from the dynamics of plasma [14-C]urea specific radioactivity and the rate of urea metabolism was estimated from the relative rates of urea synthesis and urea appearance in urine and body water. Deconvolution analysis of plasma [15N]albumin enrichmevt and 125-i-labelled albumin radioactivity yielded the cumulative incorporation of 15-N into total exchangeable albumin and enabled calculation of the absolute rate of urema nitrogen utilization for albumin synthesis. 3. Although the mean absolute rate of urea degradation in uraemic patients (3-7 mmol/h) was higher than in normal subjects (2-3 mmol/h) there was no significant positive correlation between urea degradation and plasma urea concentration. 4. In uraemic subjects, there was a significant positive correlation between urea synthetic rate and urea degration rate. 5. The rate of utilization of urea nitrogen for albumin synthesis was low, but was very much higher in uraemic subjects (mean 83-8 mumol/h) compared with normal subjects (mean 6-4 mumol/h), as was the provision by urea of the nitrogen required for albumin synthesis in uraemic subjects (2-37%) compared with normal subjects (0-13%). 6. The efficiency of utilization of urea nitrogen for albumin synthesis was higher in the uraemic patients (1-3%) than the normal subjects (0-2%), and was higher in those patients with chronic renal failure who received a 30 g protein diet than those on 70 g of protein. A significant negative correlation was noted between efficiency of urea nitrogen utilization and the rate of synthesis of albumin. 7. These studies suggest the presence of a mechanism for the conservation of urea nitrogen in chronic renal failure which is unrelated to the extent of urea degradation, and which can only be partly explained by the higher proportion of intraluminal gut nitrogen derived from urea.

Utilization of urea nitrogen for albumin synthesis in the stagnant loop syndrome.

A study of urea and albumin metabolism was carried out in a patient with the stagnant loop syndrome and in a control subject using radioisotopic and stable isotopic techniques. The patient had a higher rate of urea synthesis, urea hydrolysis in the gut, and of incorporation of recycled urea nitrogen into albumin. Although only a small proportion (0.4%) of the urea nitrogen available was used for albumin synthesis and this constituted only 0.8% of the daily nitrogen requirement for this purpose, the reutilization of nitrogen was relatively much greater than was observed in the control study.