Treatment with low drug doses is generally recommended in the elderly. However, the efficacy of low-dose 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitor treatment in elderly hypercholesterolemic patients has never been examined. Therefore, we compared the effect of low-dose with standard-dose pravastatin, an HMG CoA reductase inhibitor, on the incidence of cardiovascular events (CVEs) in elderly patients with hypercholesterolemia in a randomized prospective trial. Subjects aged ≥60 years (73±6 years) with serum total cholesterol (TC) levels of 220-280 mg/dL were randomized to the low-dose (group L, 5 mg/day ; n= 334) or standard-dose (group S, 10-20 mg/day ; n=331). Baseline TC levels were similar in the 2 groups (253±15 mg/dL). Patients were followed for 3-5 years (mean 3.9 years). TC levels decreased from baseline by 11-13% in group L and by 15-17% in group S. TC levels at 1 year in S and L group were 209±2 mg/dL (16±1% decrease) and 221±2 mg/dL (12±1% decrease), respectively. Forty-two and 29 CVEs occurred in group L and S, respectively. The incidence of CVEs was significantly lower in group S than in group L (P=0.046, generalized Wilcoxon test ; P=0.096, log-rank test). The risk ratio for group S compared with group L was 0.674 (95% confidence interval : 0.423-1.074). Subgroup analyses suggested that the difference in the incidence of CVEs between the 2 groups was more clear in subjects without diabetes mellitus, with TC levels of <253 mg/dL, and with TG levels of ≥133 mg/dL. The incidence of CVEs in group S was significantly lower than that in group L in subjects without both diabetes mellitus and previous cardiovascular disease (P=0.026, generalized Wilcoxon test ; P=0.032, log-rank test). These findings suggest that standard-dose pravastatin (10-20 mg/day) is more effective in reducing the incidence of CVEs in the elderly than low-dose pravastatin (5 mg/day), especially in nondiabetic elderly patients with mild hypercholesterolemia or previous cardiovascular disease. J Atheroscler Thromb, 2001 ; 8 : 33-44.
To evaluate the effect of ethyl icosapentaenoate (EPA) on the metabolism of tumor necrosis factor α (TNFα) and interleukin-1β (IL-1β), the concentrations of these cytokines in the carotids of rabbits sheathed in a cuff were studied. Japanese white rabbits were divided into two groups ; the EPA group, in which 600 mg/kg/day EPA was administered forcibly p.o. for 1 week before cuff treatment, and the control group. Carotid artery samples were obtained just before, 3 days and 7 days after cuff treatment, and TNFα and IL-1β were determined separately with the Western blot analysis method. In the control group, there were 43.5 (±3.0) pg/rig protein of TNFα and 53.5 (±4.8) pg/μg protein of IL-1/β just before cuff treatment. Compared to the control group, these concentrations of the EPA group were both significantly low. Three days after cuff treatment, TNFα of the EPA group was still significantly low, while IL-1β showed no difference. There was no significant difference between the two groups 7 days after cuff treatment. These findings suggested that EPA could influence TNFα and IL-1β metabolism in the arterial wall even at baseline. Furthermore, EPA suppressed TNFα and IL-1β production in the early phase of intimal thickening, indicating a mechanism inhibiting the activation of smooth muscle cells such as their proliferation and migration, induced by the cuff-sheath method. J Atheroscler Thromb, 2001; 8 45-49.
In atherosclerotic lesions, matrix metalloproteinases produced by foam cells (macrophages) are thought to increase plaque instability, promote plaque rupture, by degradating extracellular matrix. To investigate the relationship between the expression of these proteinases and the histologic appearance of atheromas, immunohistochemical analysis of matrix metalloproteinase 3 and cell-type markers was performed in atherosclerotic plaques induced in rabbit abdominal aortas by high-cholesterol diets and mechanical injury. In addition to an antibody against matrix metalloproteinase 3, RAM-11 and HHF-35 were used to detect macrophages and smooth muscle cells, respectively. Matrix metalloproteinase 3 was expressed diffusely within the plaques with a fibrofatty histologic pattern. In plaques with foam cell accumulation, matrix metalloproteinase 3 was seen in areas rich in foam cells and the smooth muscle cells near the lumen. In the plaques with fewer macrophages, the proteinase was expressed only in such smooth muscle cells. Matrix metalloproteinase 3 was expressed in the smooth muscle cells in plaques of all histologic types, and macrophages also expressed the metalloproteinase when present in significant numbers. These findings suggest that macrophage accumulation plays an important pathophysiologic role in causing the instability of atherosclerotic lesions by increasing the levels of matrix metalloproteinase 3. J Atheroscler Thromb, 2001 ; 8 : 50-54.
We investigated whether a high glucose condition could affect cholesterol ester (CE) synthesis and accumulation of cholesterol in arterial wall cells by using the human monocytic cell line THP-1. After 24-hour PMA treatment, cells were grown in control (200 mg/dl of glucose) or high glucose concentration (400, 600, 800, or 1, 600 mg/dl) medium for 6 days. CE synthesis was then investigated in cells incubated with 50 μg/ml of native, glycated, acetylated, or oxidized LDL. Cells grown in 400 mg/dl of glucose showed a significant increase of CE synthesis regardless of whether they were incubated with native, glycated or oxidized LDL, compared with cells grown in 200 mg/dl of glucose. In parallel with the studies of CE synthesis, the intracellular accumulation of CE also increased in cells grown in 400 mg/dl of glucose when incubated with oxidized LDL (50 μg/ml), compared with that in cells grown in 200 mg/dl of glucose. The amount of oxidized LDL associated with cells grown in 400 mg/dl of glucose was markedly higher than that in cells grown in 200 mg/dl of glucose. This suggests that there is an optimal glucose concentration (400 mg/dl) which increases the number of some scavenger receptors (receptors for oxidized LDL) expressed on cells, and might increase and stimulate CE synthesis, resulting in intracellular accumulation of CE in macrophage. A high blood glucose concentration could change the metabolism of arterial wall cells and play an important role in the pathogenesis of vascular complications of diabetes mellitus. J Atheroscler Thromb, 2001 ; 8 : 55-62.