Cross-sectional studies of cardiac, cerebral and peripheral macroangiopathy (MA) were conducted in 842 subjects with type-2 diabetes. Prevalence of ischemic heart disease (IHD), cerebral infarction (CI) and arteriosclerosis obliterans (ASO) was 33.8, 31.9 and 10.5%, respectively. Although half of the diabetic subjects had at least one of these MA, many cases were clinically asymptomatic. Most of the subjects complicated with ASO had IHD and/or CI, suggesting that ASO may serve as an index for advanced systemic atherosclerosis. Multivariate analysis indicated aging, duration of diabetes, co-existance of hypertension and low HDLcholesterol as common risk factors of these 3 MA. In addition, high total cholesterol levels and smoking could be independent risk factors of IHD and ASO, respectively. Diabetic MA, especially ASO, tended to associate with endstage renal disease and autonomic neuropathy. The degree of MA which complicated was closely correlated with the mortality rate. The mortality rate of subjects with all 3 MA surpassed that of MA-free cases by 21 fold. These data suggest that evaluation of MA using noninvasive approach is important for subjects with longstanding diabetes and/or advanced microangiopathy.

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McCully first proposed the idea that, in patients with homocysteinemia, high plasma levels of homocysteine (Hcy) resulted in severe and premature atherosclerosis. Epidemiologic studies indicate that hyperhomocysteinemia is an independent risk factor for atherosclerosis. Meta analysis revealed that for every 5μmol/l increase in homocysteine, men had a 1.6-fold increase in the coronary heart disease risk. A 5μmol/l increase in plasma homocysteine is equivalent to an increase in blood cholesterol of 0.5μmol/l. Increasing in the dietary intake of folic acid by 200μg should reduce homocysteine levels by 4μmol/l. Studies investigating the mechanism of action of homocysteine suggest that an increased level of plasma homocysteine may be a physiological risk factor for thrombosis and arterial injury as well as for increased risk of fibrous plaque formation.
A key enzymes for homocysteine metabolism is cystathionine β-synthase and methylenetetrahydrofolate reductase (MTHFR). Recently, polymorphism of these enzymes has been reported to play an important role in the genesis of hyperhomocysteinemia. There is a polymorphysm of the MTHFR (C677T), Ala/Val and Val/Val genotype associated with coronary artery disease.

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Thrombus formation is frequently associated with atherosclerotic lesions, and thrombus formation on coronary plaque rupture or erosion plays a key role in the pathogenesis of acute coronary syndrome. Tissue factor (TF) is a major initiator of the blood coagulation cascade. Overexpression of the TF antigen and mRNA has been found in atherosclerotic plaques and atherectomy specimens. We examined the morphology of intimal injury and localization of the TF antigen in human aortic and coronary atherosclerotic lesions, and in the rabbit aorta. In human atherosclerotic lesions (diffuse intimal thickening, fatty streak, and atheroma), intimal smooth muscle cells (SMCs), macrophages and some endothelial cells were positive for TF. In addition, in atheromatous plaques, the TF antigen was also detected in the extracellular matrix. These atheromatous lesions showed a high TF activity by a chromogenic assay using S-2222. In coronary atherosclerotic lesions, SMCs and endothelial cells were strongly and macrophages were weakly positive for TF. We experimentally made three types of atherosclerotic lesions (diffuse intimal thickening, fatty intimal thickening and fibrofatty plaque) in rabbit aortas by balloon catheter and cholesterol diet. In these atheromatous lesions, SMCs, endothelial cells and extracellular matrix were strongly and macrophages were weakly positive for TF. When the diffuse intimal thickening and fibrofatty plaques were injured by a balloon catheter, fibrin-rich thrombus formation was observed. On the other hand, when fatty intimal thickening lesions were injured, platelet rich thrombus formation was observed. These findings suggest that TF in atherosclerotic lesions plays an important role in thrombus formation not only at the plaque rupture site but also at the plaque erosion site.

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Late graft failure of autogenous vein grafts is a critical problem, particularly in the presence of poor runoff vessels. Intimal hyperplasia is considered to be the main cause of graft failure.
The nitric oxide(NO) is not only a vasodilator but also inhibits platelet aggregation, adherence and vascular smooth muscle proliferation. However, little information is available on such endothelial functions of autogenous vein grafts. We examined to clarify the relationship between the vein graft intimal thickening and NO.
Results: 1) In rabbit jugular vein grafts, Acetylcholine (ACh)-induced endothelium-dependent relaxations and ACh-induced endothelium-mediated production of c-GMP were significantly impaired compared to those of control vein, while SIN-I(the active metabolite of molsidomine)-induced relaxations and production of c-GMP were comparable between the two groups. 2) Hypercholesterolemia accelerated the intimal thickening compared to that of normolipidemia. In cases of poor distal runoff, the enhancement of the intimal thickening by hypercholesterolemia is augmented. 3) Intimal thickening of rabbit juglar vein grafts under hypercholesterolemia was reduced by chronic administration of dietary L-arginine, which is a precursor of nitric oxide by enhancing the NO production of the endothelium. 4) HVJ-liposomes containing encapsulated bovine ecNOS cDNA or control vector plasmid was implanted into the autogenous vein grafts under hypercholesterolemic rabbits. At four weeks after, the average value of intimal thickening was significantly reduced by ecNOS in comparison with vector group.
Conclusions: These results suggest that the production of NO in the endothelium of the vein grafts was significantly impaired. This dysfunction of the endothelium may accelerate intimal thickening of the vein graft and result in late graft failure. The preservation or enhancement of NO production in the endothelium of the autogenous vein grafts may be beneficial for preventing the late graft failure. The gene transfer warrants further study as a possible approach to prevent late graft failure.

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