New mouse model of vein bypass graft atherosclerosis

Animal models of vein graft disease are used as preliminary tools to study and understand the pathogenesis of the disease in humans and improve its diagnosis, prevention and therapy. Several animal models that manifest lesions resembling neointimal hyperplasia of human vein grafts have been developed, but there are limitations in studying the mechanism of this disease in these models. We previously established a mouse model of vein bypass graft atherosclerosis that allows us to take advantage of transgenic and knockout techniques. Using this model, we studied the pathogenesis of vein graft atherosclerosis. The lesion in the grafts was characterised by mononuclear cell infiltration followed by smooth muscle cell (SMC) proliferation and matrix protein deposition, which is similar to the human lesion. Studies of the molecular mechanism of pathogenesis in this model revealed that physical force initiated signal pathways, particularly mitogen-activated protein kinases (MAPK), leading to vascular cell death and an inflammatory response, followed by SMC proliferation, which contributed to the development of arteriosclerosis. Suramin inhibited SMC migration and proliferation in vivo and in vitro by blocking platelet-derived growth factor (PDGF)-initiated PDGF receptor activation and MAPK-AP-1 signalling, and was also effective in inhibition of neointima hyperplasia in mouse vein bypass grafts. This new mouse model of vein bypass graft atherosclerosis affords us with a valuable new approach to attain further understanding of the mechanism of vein graft disease with the use of transgenic mice, and in evaluating the effects of drugs and gene therapy on vascular diseases.     

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.     

Dendritic cells in aortocoronary saphenous vein bypass grafts

Dendritic cells are specialised leucocytes responsible for capturing and presenting antigens to T lymphocytes, which in turn mediate immune responses in various pathological conditions. The observations in this study demonstrate that dendritic cells are present in stenotic aortocoronary saphenous vein bypass grafts, which suggest that these cells may be involved in inflammatory actions which may subsequently contribute to graft failure.     

Prognostic factors for atherosclerosis progression in saphenous vein grafts: the postcoronary artery bypass graft (Post-CABG) trial. Post-CABG Trial Investigators

OBJECTIVES: The study was done to assess patients in the Post-Coronary Artery Bypass Graft (Post-CABG) trial to determine prognostic factors for atherosclerosis progression. BACKGROUND: Saphenous vein grafts (SVGs) are effective in relieving angina and, in certain patient subsets, in prolonging life. However, the progression of atherosclerosis in many of these grafts limits their usefulness. METHODS: The Post-CABG trial studied moderate versus aggressive lipid-lowering and low-dose warfarin versus placebo in patients with a history of coronary artery bypass surgery and found that more aggressive lipid lowering was effective in preventing progression of atherosclerosis in SVGs, but warfarin had no effect. Using variables measured at baseline, we sought the independent prognostic factors for atherosclerosis progression in SVGs, employing the statistical method of generalized estimating equations with a logit-link function. RESULTS: Twelve independent prognostic factors for atherosclerosis progression were found. In the order of their importance they were: maximum stenosis of the graft at baseline angiography, years post-SVG placement; the moderate low-density lipoprotein-cholesterol (LDL-C) lowering strategy; prior myocardial infarction; high triglyceride level; small minimum graft diameter; low high-density lipoprotein-cholesterol (HDL-C); high LDL-C; high mean arterial pressure; low ejection fraction; male gender; and current smoking. CONCLUSIONS: This study identified Post-CABG patient and SVG characteristics associated with saphenous vein graft atherosclerosis progression. These data provide a basis for rational risk factor management to prevent progression of SVG atherosclerosis.     

Transluminal atherectomy of saphenous vein aortocoronary bypass grafts

Angioplasty of stenotic saphenous vein aortocoronary bypass grafts is often unsatisfactory because of the relatively high incidence of acute complications and restenosis. During an initial evaluation of transluminal coronary atherectomy, 14 patients had atherectomy of saphenous vein graft lesions (15 grafts). Atherectomy was successful in 13 of 14 patients, decreasing the mean diameter of stenosis from 85 to 15%. In 1 patient, the lesion could not be crossed by the atherectomy device. The following 3 minor complications occurred: 1 embolus of atheromatous material; 1 air embolism; and 1 transient thrombosis leading to subendocardial myocardial infarction. Of the 14 patients, 8 underwent angiography 4 to 6 months after atherectomy; 5 patients had restenosis and 3 had widely patent grafts. Four other patients were clinically evaluated at 3 months after atherectomy. Two were asymptomatic, 1 had class II angina and 1 had class III angina. Transluminal atherectomy achieved excellent immediate results with a low incidence of major complications in the treatment of stenosed saphenous vein bypass grafts. However, preliminary follow-up results suggest a high incidence of restenosis.     

Relationship between plasma homocysteine levels and saphenous vein graft disease after coronary artery bypass grafts.

The long-term efficacy of coronary artery bypass graft (CABG) surgery is limited by saphenous vein graft (SVG) disease. Elevated levels of plasma homocysteine are a known independent risk factor for cardiovascular disease. However, its influence on the patency of SVG is unknown. To determine whether plasma homocysteine levels are related to SVG disease after CABG we measured homocysteine levels in 80 patients who underwent CABG (age: 64+/-8, interval after bypass surgery: 6.4+/-3.1, range: 1-13 years). The patients were divided into a vein graft disease group (more than 50% angiographical stenosis in any vein graft, n=40) and a no-vein graft disease group (<50% stenosis in any vein graft, n=40). The presence of a mutation in the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene was also determined by polymerase chain reaction. Homocysteine levels in the vein graft disease group were significantly higher than in the no-vein graft disease group (11.2 vs. 9.1 micromol/l, p=0.01). Multiple regression analysis showed that the interval after CABG was an independent factor for SVG disease (odds ratio: 1.014, 95% confidence intervals: 1.003-1.025, p=0.013) and elevated levels of homocysteine tended to be an independent factor for SVG disease (odds ratio: 1.098, 95% confidence intervals: 0.994-1.213, p=0.067). There was no significant difference in MTHFR genotypes between the two groups. These findings indicate that elevated levels of plasma homocysteine are related to SVG disease after CABG.     

Propranolol vs. saphenous vein graft bypass for impending infarction (preinfarction syndrome)

The prognosis in impending infarction is good on a medical regime of bed rest and sedation. In a series of 18 cases treated also with propranolol the results were even better; there were no deaths or transmural infarction. Surgical intervention is not indicated in impending infarction and should be considered an experimental procedure at this time.