Mouse strain differential neointimal response in vein grafts and wire-injured arteries.

BACKGROUND: Neointimal development is seen clinically after both vein grafting and balloon catheterization, but may not represent the same pathology under these 2 conditions. This study compared the degree of neointimal hyperplasia after vein grafting or arterial-injury grafts in 2 strains of mice: C57Bl/6 and FVB. METHODS AND RESULTS: Jugular vein branches were interpositioned as grafts in the femoral artery of syngenic-matched mice, with graft harvest at 30 days. Wire-injured carotid arteries were grafted to the carotid arteries of syngenic-matched mice, with graft harvest at 14 days. Histomorphometry revealed no strain differences in vein grafts in the extent of position-dependent neointimal thickening or lumen cross-sectional area. Both strains showed significantly thicker neointima and less lumen area at the proximal graft site (vs the mid-graft; p<0.05). In contrast, a significantly greater neointimal thickness was found in the wire-injured carotid grafts of FVB mice vs those of C57Bl/6 mice (p<0.05). CONCLUSIONS: Neointimal formation shows a vessel-dependent, strain-dependent difference, with greater arterial neointimal thickening in FVB mice. These data suggest that different mechanisms operate for arterial-injury- vs vein-graft-associated neointimal development and that the difference has a genetic basis.     

Targets for gene therapy of vein grafts

Poor long-term patency and a lack of suitable systemic pharmacologic therapy for the prevention of vein graft failure have prompted the search for effective local gene therapy. Vein grafts are particularly well suited for gene transfer in the clinic because direct access to vein is available during surgical preparation for grafting. In this review, the available animal models are discussed and a new mouse model is highlighted. Recent advances in gene transfer technology are reviewed, including the use of adeno-associated virus and modified adenoviruses that can prolong in vivo transgene expression for months. Gene therapy is intended to reduce early thrombosis, reduce neointima formation, and prevent atherosclerosis in vein grafts. Promising antithrombotic targets include tissue plasminogen activator and thrombomodulin. Nitric oxide synthase, prostacyclin synthase, and tissue inhibitors of metalloproteinases have been used to reduce neointima formation, and vein graft atheroma remains a challenge for the future.     

Beta-galactosidase-tagged adventitial myofibroblasts tracked to the neointima in healing rat vein grafts

OBJECTIVE: Myofibroblasts are present transiently in normal healing wounds. However, they have been found to persist in the stroma of neoplasms, fibrotic conditions and other pathological settings. In rat vein grafts, we have observed the prolonged presence of myofibroblasts. Our aim was to determine the origin of myofibroblasts in vein grafts. METHODS: Epigastric vein to femoral artery grafts were microsurgically placed in male Lewis rats and harvested. Neointimal development, cellular death and proliferation, and cell phenotypes were analyzed using immunohistochemistry and light and electron microscopy. To follow cellular movement in the vessel wall, vein grafts were transfected with replication-defective adenovirus containing the gene encoding beta-galactosidase (n = 50), and harvested at 1, 2, 3, 4, 5, 6, 7, 14 and 28 days. Grafts were analyzed after X-gal staining. RESULTS: Myofibroblasts were detected in the outer adventitia at 4 days, in the media at 1 week and in the developing neointima at 2 weeks. Cells tagged using adenoviral beta-galactosidase demonstrated adventitia to neointima cell migration. CONCLUSIONS: Although there may be other sources of myofibroblasts in this model, the adventitia has been shown to be an origin of myofibroblasts which subsequently migrate through the vessel wall to the neointima during graft remodeling and contribute to neointimal formation.     

Percutaneous intervention for atherosclerotic disease in saphenous vein grafts

The long term benefit of coronary artery bypass surgery (CABG) is limited by development of atherosclerotic disease in the bypass conduits. Percutaneous revascularisation is frequently the preferred method of treated symptomatic saphenous vein graft (SVG) atherosclerotic disease. The immediate and long term results of percutaneous intervention for SVGs is reviewed. Therapeutic considerations as well as novel technical advances are overviewed     

Macro-porosity is necessary for the reduction of neointimal and medial thickening by external stenting of porcine saphenous vein bypass grafts

BACKGROUND: placing external non-restrictive macro-porous stents around porcine vein grafts prevents neointima formation and medial thickening in both the short and long term. Whether the porosity of the stent material influences this effect, however, has not been determined. Therefore, the effect on neointimal and medial thickening of external macro-porous (polyester) and micro-porous (polytetrafluorethylene) stents of equal diameter were compared. The effect on expression of platelet-derived growth factor (PDGF), a potent mediator of vascular smooth muscle cell migration and proliferation and its receptors was also investigated. METHODS AND RESULTS: saphenous vein-carotid artery interposition grafting was performed in Landrace pigs with external placement of 8 mm diameter macro- and micro-porous stents contralaterally. One month after surgery, graft wall dimensions, PDGF and PDGF receptor expression and cell proliferation using proliferating cell nuclear antigen (PCNA) were measured on histological sections. Macro-porous stents significantly reduced neointimal and medial thickening compared with micro-porous stents (0.1+/-0.02 vs. 0.25+/-0.03 mm, P<0.002, and 0.10+/-0.02 vs. 0.17+/-0.02 mm, P<0.014, respectively). Macro-porous stents significantly reduced the percentage of cells expressing PDGF and PCNA, compared with micro-porous stents (36+/-9 vs. 80+/-7, P < 0.002, and 11+/-3 vs. 21+/-2, P < 0.02, respectively). The percentage of cells expressing PDGF receptors was similar with both the stent types. Adventitial microvessel formation occurred across macro-porous stents but was markedly suppressed by micro-porous stents. CONCLUSIONS: porosity is crucial to the efficacy of external stents in reducing neointima formation in porcine vein grafts. Decreases in PDGF expression and cell proliferation accompany the reduction in neointima formation. In addition, macro-porous stents allow adventitial microvessels to connect with the vasculature outside the stent, thereby potentially improving oxygenation. Although external stenting is highly effective in reducing neointima formation after vein grafting, the properties of the stent material necessary for this effect have not been defined. This study establishes that macro-porosity is one essential feature required to reduce PDGF expression cell proliferation and neointima formation.     

Expansive remodeling in venous bypass grafts: novel implications for vein graft disease

ObjectiveTo date, intimal hyperplasia has been regarded as the principle mechanism responsible for subsequent vein graft disease. Lumen remodeling has not been previously considered as an additional mechanism. The objectives of this study were to determine changes in lumen remodeling in arterialized vein grafts, the accompanying cellular and extracellular matrix events contributing to remodeling, and the effects of a high cholesterol diet.Methods and resultsReversed jugular vein-to-common carotid artery interposition grafts were constructed in 70 normocholesterolemic and 11 hypercholesterolemic male New Zealand white rabbits. The lumen area initially remained unchanged between 1 and 4 weeks but significantly increased by 40% at 12 weeks. This phase of expansive positive remodeling was accompanied by significantly increased cell apoptosis, collagen synthesis (1.7-fold), collagen content (3.7-fold), gelatinase (MMP-2 and MMP-9) levels and decreased tissue inhibitor of metalloproteinase (TIMP) levels. Expansive remodeling temporally corresponded to high macrophage infiltration and increased low density lipoprotein (LDL) retention (fourfold) in the vein grafts. A high cholesterol diet stimulated early macrophage infiltration and increased MMP-12 (metalloelastase) levels, which was associated with earlier onset of expansive remodeling.ConclusionExpansive lumenal remodeling is a novel mechanism of vein graft response to the arterial circulation, which is accelerated by a high cholesterol diet.     

Late thrombotic occlusion of saphenous vein grafts: successful recanalization using thrombolytic therapy

We report two cases in which thrombosis was the primary cause of vein graft occlusion many years after bypass surgery. Both displayed minimal thrombolysis immediately after a selective infusion of streptokinase but were patent when reimaged hours later. Such therapy may be helpful when graft occlusions are associated with a large volume of thrombus.     

Atherosclerosis in vascular grafts for peripheral vascular disease. Part 1. Autogenous vein grafts

29 autogenous vein grafts, from 26 patients with peripheral arterial disease, were studied. 4 grafts of Group I (less than 3 months duration) were patent and removed for reasons other than graft failure. These showed 'arterialisation' only; 4 grafts of Group II (duration 5-18 months) showed thrombotic occlusion; 21 grafts of Group III (duration greater than 2 years) showed impaired graft patency and lipid identifiable as apolipoprotein B-containing-lipoproteins (LpB), and fibrinogen-related antigens (FRA) were seen as intramural deposits in the thickened grafts. LpB was also seen in a perifibrous distribution on the collagen of organised thrombi. Complicated lesions in some Group III grafts showed stenosis or occlusion, ulceration, calcification or aneurysm formation. These features suggest that a process indistinguishable from 'true' atherosclerosis affects vein grafts of long duration. The ways in which such changes may: contribute to graft failure; and improve our understanding of the basic processes involved in atherogenesis, are discussed.     

Developing venous gangrene in deep vein thrombosis: intraarterial low-dose burst therapy with urokinase--case reports

Two patients with developing venous gangrene of the lower extremity and contraindications to systemic thrombolytic therapy are presented. Low-dose intraarterial burst therapy with urokinase provided rapid amelioration of symptoms and avoided amputation without any serious bleeding complications in both patients.     

Mucosal healing in inflammatory bowel disease: Maintain or de-escalate therapy

In the past decade, thanks to the introduction of biologic therapies, a new therapeutic goal, mucosal healing(MH), has been introduced. MH is the expression of an arrest of disease progression, resulting in minor hospitalizations, surgeries, and prolonged clinical remission. MH may be achieved with several therapeutic strategies reaching success rates up to 80% for both, ulcerative colitis(UC) and Crohn's disease(CD). Various scoring systems for UC and for the transmural CD, have been proposed to standardize the definition of MH. Several attempts have been undertaken to de-escalate therapy once MH is achieved, thus, reducing the risk of adverse events. In this review, we analysed the available studies regarding the achievement of MH and the subsequent treatment de-escalation according to disease type and administered therapy, together with non-invasive markers proposed as predictors for relapse. The available data are not encouraging since de-escalation after the achievement of MH is followed by a high number of clinical relapses reaching up to 50% within one year. Unclear is also another question, in case of combination therapies, which drug is more appropriate to stop, in order to guarantee a durable remission. Predictors of unfavourable outcome such as disease extension, perianal disease, or early onset disease appear to be inadequate to foresee behaviour of disease. Further studies are warranted to investigate the role of histologic healing for the further course of disease.     

Covered stent grafts: role in intervention of coronary arteries and degenerated vein grafts

Covered stent grafts, metal stents covered by a polytetrafluoroethylene (PTFE) membrane, were developed in order to prevent restenosis, which is due to proliferation of tissue through the stent mesh. However, observational studies suggest that the cardiovascular event rate is elevated, when stent grafts are used electively in native vessels. In contrast, stent grafts appeared to be safe in the larger vessels of degenerated vein grafts. Potentially, microembolism of atherosclerotic debris might be reduced when used in saphenous vein grafts. Therefore, a randomized prospective study (STING) was performed to compare conventional stents with stent grafts in this indication. However, preliminary results do not support the hypothesis that stent grafts are superior. Further ongoing studies have to be awaited before a final conclusion can be drawn. Nevertheless, stent grafts are very helpful and reduce cardiovascular event rates and the need to perform emergency surgery in the case of a coronary rupture during a percutaneous intervention. Thus, having a stent graft available in the catheterization laboratory provides the interventionalist an important anchor for bail out situations.     

Role of endothelial cell denudation and smooth muscle cell dedifferentiation in neointimal formation of human vein grafts after coronary artery bypass grafting: therapeutic implications

OBJECTIVE—To provide better insights into the genesis of neointimal thickening in human vein grafts early after surgery.
DESIGN—Retrospective study.
SETTING—Tertiary referral centre.
SUBJECTS—18 distal anastomotic sites of patent grafts, obtained at necropsy from eight patients who died over differing periods (ranging from two days to nine months) after the procedure.
MAIN OUTCOME MEASURES—Immunohistochemical evaluation of smooth muscle cell phenotype modulation in relation to proliferative activity.
RESULTS—The earliest changes are characterised by loss of surface lining endothelial cells and insudation of blood corpuscular elements admixed with fibrin-platelet thrombus. At sites of injury vimentin positive and actin negative spindle shaped cells appear in the intima, while the related pre-existent media shows focal absence of actin positive smooth muscle cells. Proliferative activity colocalises at these sites. With time distinct neointimal thickening occurs, associated with disappearance of proliferative activity and a phenotypic shift of the smooth muscle cells.
CONCLUSIONS—The observation that luminal endothelial cell denudation, with insudation of the intima with blood elements, occurs in the very early stages suggests that these phenomena are responsible for the observed dedifferentiation of pre-existent smooth muscle cells, known to be a prerequisite for cell proliferation and the evolution of intimal thickening. It is likely, therefore, that platelet released growth factors play a pivotal role, which thus may provide a target for preventive pharmacological intervention.


Keywords: smooth muscle cell proliferation; vein graft stenosis; platelet derived growth factor; platelet receptor inhibitors