Elevated levels of serum lipoprotein (a) [Lp (a)] are reported to be associated with risk of atherosclerosis and thrombosis. Little is known about the influence of Lp (a) on the progression of coronary artery disease. We evaluated the association of serum Lp (a) and the longterm changes of angiographic severity in patients who underwent repeated coronary angiography at intervals of more than 2 years. We evaluated 70 patients, and divided them into 3 groups by angiographic findings. Median Lp (a) concentration was significantly higher in the progression group (N=36) than in the no-change group (N=23) or the regression group (N=11) (32.4 vs 22, 19.3 mg/dl, p < 0.05). Furthermore, the progression group had more patients whose Lp (a) levels were greater than 30 mg/dl (p=0.006), while in the regression group all patients were under 30 mg/dl. Stepwise logistic regression analysis for progression of lesions showed that Lp (a) 30 mg/dl remained significant, giving an estimated odds ratio (OR) of 2.46 (p=0.005). In the subgroup analysis, OR in patients with mild lesions was reduced to 2.05 (p < 0.05) while in patients with severe lesions OR was increased to 3.39 (p = 0.003). The serum Lp (a) level has a close correlation with angiographic progression, and may be an important predictor for progression.

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We investigated the effect of nephropathy on the composition of apolipoprotein-containing particles in non-obese NIDDM patients with normocholesterolemia. Sixty-seven normal control subjects (group A), 48 NIDDM patients without nephropathy (group B) and 36 NIDDM patients with nephropathy (group C) were studied. Apolipoprotein Al or B100 containing particles (Apo Al or Apo B100) were isolated by immunoaffinity columns prepared with monoclonal antibodies. The total cholesterol (CH), esterified cholesterol (EC) and free cholesterol (FC) content in these particles was analyzed. Both the EC/FC ratio levels in Apo Al and in Apo B100 in group C were significantly higher than those in group A or B. Both the CH in Apo Al/apolipoprotein Al ratio and in Apo B100/apolipoprotein B100 ratio levels in group C were significantly lower than those in group A or B. The insulin resistance index showed significant positive correlation with the EC/FC ratio levels in Apo Al and in Apo B100, and showed significant negative correlation with the CH levels in Apo Al/apolipoprotein Al ratio and the CH levels in Apo B100/apolipoprotein B100 ratio levels in group C. Those compositional changes of lipoproteins in NIDDM patients with nephropathy may reflect partial insulin resistance and deteriorating atherosclerosis.

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In order to clarify the significance of obesity in atherosclerotic risk at different ages, the relationship between the body-mass index, serum sialic acid concentration, and various atherosclerotic risk factors were investigated for healthy subjects in three different age groups, 35-39, 40-49 and 50-59 years old. The body-mass index correlated significantly with mean arterial blood pressure, fasting blood sugar, serum triglycerides, atherogenic index and serum uric acid in all age groups. The magnitudes of the association of body-mass index with mean arterial blood pressure, fasting blood sugar and serum triglycerides decreased with age, while those of the association with atherogenic index and serum uric acid were not different among the three age groups. Body-mass index did not show significant correlation with white blood cell count, platelet count or smoking in any of the age groups. Simple and multiple regression analyses showed that body-mass index was significantly correlated with serum sialic acid in the 35-39-year-old group, but not in the other two groups. Neither the percentage of obese subjects (body-mass index > 26.4) nor the mean values of body-mass index were different among the three groups. These results suggest that for younger people, the body-mass index is related more closely with some atherosclerotic risk factors (e.g. blood pressure, blood sugar and serum triglycerides), and obesity may be possibly more involved in the progression of atherosclerosis, compared to more elderly people.

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Macrophage or macrophage-derived foam cell death is one of the characteristic events in the development of cell-poor lipid-rich cores of the advanced atherosclerotic plaques. Although the in vivo mechanism for the death of macrophages is unclear, one possible candidate for the agent which induces macrophage cell death is oxidized low density lipoprotein (Ox-LDL). To investigate the mechanism of Ox-LDL-induced macrophage cell death, we have recently employed macrophage cell genetics and isolated mutant cells resistant to the cytotoxic effect of Ox-LDL from mutagenized populations of murine macrophage-derived J774 cells (Hakamata, H., Miyazaki, A., Sakai, M., Matsuda, H., Suzuki, H., Kodama, T., and Horiuchi, S. (1998) J. Lipid Res. 39, 482-494). The results obtained showed that one mutant form, J021b cells, was characterized by reduced expression of type I and type II class A macrophage scavenger receptors (MSR-Al/A11) with a concomitant decrease in the uptake of Ox-LDL. Moreover, peritoneal macrophages obtained from MSRAl/All-knockout mice showed a higher resistance to the cytotoxic effect of Ox-LDL compared to those of their wild-type littermates. From these results, we have concluded that Ox-LDL cytotoxicity to macrophages is enhanced by effective endocytic uptake of Ox-LDL through MSR-Al/All. These findings imply a possibility that formation of the cell-poor lipidrich core is also enhanced by MSR-Al/All-mediated uptake of Ox-LDL and subsequent macrophage cell death in atherosclerotic lesions.

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Obesity is associated with an increased risk of atherosclerotic coronary artery disease. Cytokines and oxygen-centered free radicals implicated in insulin resistance stimulate adipocyte and endothelial production of plasminogen activator inhibitor type-1 (PAI-1), the primary physiologic inhibitor of fibrinolysis, in vitro. In obese hyperinsulinemic animal models simulating insulin resistance, plasma PAI-1 activity is increased. As the cardiovascular risk profile in specific populations may differ, endogenous fibrinolysis in lean and obese subjects was characterized and the mechanisms underlying differences were identified. Obese subjects (body mass index > 26) exhibited increased blood levels of PAI-1 antigen compared with corresponding values in lean controls. Blood t-PA antigen differed as well, yet basal endogenous fibrinolytic activity was decreased because of the high PAI-1 activity. The increased PAI-1 level was associated with increased levels of immunoreactive insulin (IRI). In diabetic subjects, coronary atherectomy specimens exhibited strong positive PAI1 immunostaining, suggesting that in the diabetic vascular wall, intramural fibrinolytic activity is diminished. Using the oral glucose tolerance test, patients with significant stenosis confirmed by coronary angiography exhibited increased ∑IRI, ∑BS, ∑IRI/∑BS, and IRI at 120 min compared to subjects without significant stenosis. IRI at 120 min was closely correlated with the severity of coronary artery disease. These results indicate that adipocyte overproduction of PAI-1 by insulin induces decreased endogenous fibrinolytic activity and contributes to the accelerated coronary macroangiopathy in hyperinsulinemic obese subjects with insulin resistance.

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