Inhibition of thrombin generation by simvastatin and lack of additive effects of aspirin in patients with marked hypercholesterolemia.
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OBJECTIVES: To assess the effects of aspirin compared with simvastatin on thrombin generation in hypercholesterolemic men, and to establish whether the reduction of elevated blood cholesterol by simvastatin would affect the action of aspirin on thrombin formation. BACKGROUND: Aspirin inhibits thrombin formation, but its performance is blunted in hypercholesterolemia. By virtue of altering lipid profile, statins could be expected to influence thrombin generation. METHODS: Thirty-three men, aged 34 to 61 years, with minimal or no clinical symptoms, serum total cholesterol >6.5 mmol/liter and serum triglycerides <4.6 mmol/liter, completed the study consisting of three treatment phases. First, they received 300 mg of aspirin daily for two weeks (phase I), which was then replaced by simvastatin at the average dose of 24 mg/d for three months (phase II). In phase III, aspirin, 300 mg/day, was added for two weeks to simvastatin, the dose of which remained unchanged. Thrombin generation was assessed: 1) in vivo, by measuring levels of fibrinopeptide A (FPA) and prothrombin fragment 1+2 (F1+2) in venous blood; and 2) ex vivo, by monitoring the rates of increase of FPA and F1+2 in blood emerging from standardized skin incisions of a forearm. A mathematical model was used to describe the kinetics of thrombin formation at the site of microvascular injury. RESULTS: Two-week treatment with aspirin had no effect on thrombin markers in vivo, while ex vivo it depressed the total amount of thrombin formed, though not the reaction rate. After simvastatin treatment, serum cholesterol decreased by 31% and LDL cholesterol by 42%, while thrombin generation became markedly depressed. In venous blood, FPA was significantly reduced. Concomitantly, the initial thrombin concentration and total amount of thrombin generated decreased significantly. Addition of aspirin to simvastatin (phase III) had no further effect on any of these parameters. CONCLUSIONS: In men with hypercholesterolemia, lowering serum cholesterol level by a three-month simvastatin treatment is accompanied by a marked reduction of thrombin generation both at basal conditions in venous blood and after activation of hemostasis by microvascular injury. Once blood cholesterol became reduced, adding aspirin to simvastatin did not enhance dampening of thrombin formation. (+info)
Cholesterol and lipoprotein metabolism in aging: reversal of hypercholesterolemia by growth hormone treatment in old rats.
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Plasma cholesterol levels increase with age, as does the incidence of coronary heart disease. The mechanisms responsible for the age-related hypercholesterolemia are not well understood. An interesting hypothesis suggests that the relative deficiency in growth hormone (GH), which occurs with aging, contributes to the development of the age-related hypercholesterolemia, because GH has beneficial effects on cholesterol metabolism. In the present work, we tested this hypothesis by the administration of GH to normal rats of varying ages. Plasma lipids and hepatic cholesterol metabolism were characterized in 2-, 12-, and 18-month-old male Sprague-Dawley rats. In 2-month-old rats, GH specifically stimulated the hepatic low density lipoprotein (LDL) receptor expression in a dose-dependent way, both at the protein level and at the mRNA level. Concomitantly, plasma cholesterol increased by approximately 30% within the large high density lipoprotein and LDL fractions. In 12-month-old animals, cholesterol 7alpha-hydroxylase (C7alphaOH) activity was reduced, whereas hepatic LDL receptors and plasma total cholesterol were unchanged. GH treatment (1 mg. kg-1. d-1) normalized the activity of C7alphaOH and had effects on plasma cholesterol and LDL receptors similar to those seen in 2-month-old animals. In 18-month-old rats, plasma cholesterol was increased 2-fold, whereas hepatic LDL receptor expression and C7alphaOH activity were similar to those of the 12-month-old animals. Infusion of GH to 18-month-old rats had similar effects on hepatic C7alphaOH and LDL receptors as seen in 12-month-old rats. However, GH treatment strongly reduced the hypercholesterolemia in 18-month-old animals. We conclude that the age-dependent increase of plasma cholesterol in rats can be reversed by the administration of GH, presumably through the pleiotropic effects of this hormone on lipoprotein metabolism. (+info)
Effects of the National Cholesterol Education Program's Step I and Step II dietary intervention programs on cardiovascular disease risk factors: a meta-analysis.
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BACKGROUND: Plasma lipid and lipoprotein responses have been variable in dietary intervention studies. OBJECTIVE: The objective of this study was to evaluate the effects of the National Cholesterol Education Program's Step I and Step II dietary interventions on major cardiovascular disease risk factors using meta-analysis. DESIGN: MEDLINE was used to select 37 dietary intervention studies in free-living subjects published from 1981 to 1997. RESULTS: Step I and Step II dietary interventions significantly decreased plasma lipids and lipoproteins. Plasma total cholesterol (TC), LDL cholesterol, triacylglycerol, and TC:HDL cholesterol decreased by 0.63 mmol/L (10%), 0.49 mmol/L (12%), 0.17 mmol/L (8%), and 0.50 (10%), respectively, in Step I intervention studies, and by 0.81 mmol/L (13%), 0.65 mmol/L (16%), 0.19 mmol/L (8%), and 0.34 (7%), respectively, in Step II intervention studies (P < 0.01 for all). HDL cholesterol decreased by 7% (P = 0.05) in response to Step II but not to Step I dietary interventions. Positive correlations between changes in dietary total and saturated fatty acids and changes in TC and LDL and HDL cholesterol were observed (r = 0.59, 0.61, and 0.46, respectively; P < 0.001). Multiple regression analyses showed that for every 1% decrease in energy consumed as dietary saturated fatty acid, TC decreased by 0.056 mmol/L and LDL cholesterol by 0.05 mmol/L. Moreover, for every 1-kg decrease in body weight, triacylglycerol decreased by 0.011 mmol/L and HDL cholesterol increased by 0.011 mmol/L. Exercise resulted in greater decreases in TC, LDL cholesterol, and triacylglycerol and prevented the decrease in HDL cholesterol associated with low-fat diets. CONCLUSION: Step I and Step II dietary interventions have multiple beneficial effects on important cardiovascular disease risk factors. (+info)
Impaired aerobic capacity in hypercholesterolemic mice: partial reversal by exercise training.
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The present study assessed whether impaired aerobic capacity previously observed in hypercholesterolemic mice is reversible by exercise training. Seventy-two 8-wk-old female C57BL/6J wild-type (+, n = 42) and apolipoprotein E-deficient (-, n = 30) mice were assigned to the following eight interventions: normal chow, sedentary (E+, n = 17; E-, n = 8) or exercised (E+ex, n = 13; E-ex, n = 7) and high-fat chow, sedentary (E+chol, n = 6; E-chol, n = 8) or exercised (E+chol-ex, n = 6; E-chol-ex, n = 7). Mice were trained on a treadmill 2 x 1 h/day, 6 days/wk, for 4 wk. Cholesterol levels correlated inversely with maximum oxygen uptake (r = -0.35; P < 0. 02), which was blunted in all hypercholesterolemic sedentary groups (all P < 0.05). Maximum oxygen uptake improved in all training groups but failed to match E+ex (all P < 0.05). Vascular reactivity and nitric oxide (NO) synthesis correlated with anaerobic threshold (r = 0.36; P < 0.025) and maximal distance run (r = 0.59; P < 0.007). We conclude that genetically induced hypercholesterolemia impairs aerobic capacity. This adverse impact of hypercholesterolemia on aerobic capacity may be related to its impairment of vascular NO synthesis and/or vascular smooth muscle sensitivity to nitrovasodilators. Aerobic capacity is improved to the same degree by exercise training in normal and genetically hypercholesterolemic mice, although there remains a persistent difference between these groups after training. (+info)
Intracranial arteries of human fetuses are more resistant to hypercholesterolemia-induced fatty streak formation than extracranial arteries.
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BACKGROUND: Atherosclerotic lesions in intracranial arteries occur later and are less extensive than in extracranial arteries. To investigate potential mechanisms responsible for this difference, in particular the atherogenic response to hypercholesterolemia and LDL oxidation, we compared the extent of fatty streak formation and the composition of these very early lesions in intracranial arteries of human fetuses from normocholesterolemic and hypercholesterolemic mothers with those in extracranial arteries. METHODS AND RESULTS: Lesions were quantified by computer-assisted image analysis of 30 oil red O-stained sections, each from the middle cerebral, basilar, and common carotid arteries and the abdominal aorta of human fetuses (spontaneous abortions and premature newborns who died within 12 hours of birth; both of fetal age 6.2+/-1.3 months) from 43 hypercholesterolemic mothers and 34 normocholesterolemic mothers. Macrophages, apolipoprotein B, and 2 epitopes of oxidized LDL in lesions were determined immunocytochemically. Activities of superoxide dismutase, catalase, and glutathione peroxidase in the arterial wall were also determined. Lesion numbers and sizes were dramatically greater in the abdominal aorta (area of the largest lesion per section: 66.5+/-10.9 x10(3) microm2) and the carotid (11. 6+/-5.3 x10(3) microm2) than in the basilar and middle cerebral artery (0.4+/-0.1 and 0.8+/-0.2 x10(3) microm2, respectively; P<0. 0001). Hypercholesterolemia resulted in a significant increase of lesion size in extracranial arteries but only a marginal increase in intracranial arteries. In analogy, hypercholesterolemia induced a much greater increase in the intimal presence of macrophages, apolipoprotein B, and oxidized LDL (oxidation-specific epitopes) in extracranial than in intracranial arteries. Immunocytochemistry did not indicate that lesions of intracranial arteries contain relatively less oxidized LDL than similar-size lesions of extracranial arteries. Activities of Mn-superoxide dismutase but not of Zn-superoxide dismutase, catalase, or glutathione peroxidase were significantly higher in both intracranial arteries. CONCLUSIONS: Exposure to hypercholesterolemia during fetal development results in extensive formation of fatty streaks in extracranial but not intracranial arteries. The fact that such a difference in lesion formation occurs in the absence of many other atherogenic risk factors found later in life suggests that differences in the atherogenic response to hypercholesterolemia are an important contributor to the slower onset of the disease in intracranial vessels in adults. Fetal arteries may allow elucidation of the mechanisms responsible, for example, better protection of intracranial arteries against free radical-mediated atherogenic processes. (+info)
Increased NADH-oxidase-mediated superoxide production in the early stages of atherosclerosis: evidence for involvement of the renin-angiotensin system.
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BACKGROUND: Angiotensin II activates NAD(P)H-dependent oxidases via AT1-receptor stimulation, the most important vascular source of superoxide (O2*-). The AT1 receptor is upregulated in vitro by low-density lipoprotein. The present study was designed to test whether hypercholesterolemia is associated with increased NAD(P)H-dependent vascular O2*- production and whether AT1-receptor blockade may inhibit this oxidase and in parallel improve endothelial dysfunction. METHODS AND RESULTS: Vascular responses were determined by isometric tension studies, and relative rates of vascular O2*- production were determined by use of chemiluminescence with lucigenin, a cypridina luciferin analogue, and electron spin resonance studies. AT1-receptor mRNA was quantified by Northern analysis, and AT1-receptor density was measured by radioligand binding assays. Hypercholesterolemia was associated with impaired endothelium-dependent vasodilation and increased O2*- production in intact vessels. In vessel homogenates, we found a significant activation of NADH-driven O2*- production in both models of hyperlipidemia. Treatment of cholesterol-fed animals with the AT1-receptor antagonist Bay 10-6734 improved endothelial dysfunction, normalized vascular O2*- and NADH-oxidase activity, decreased macrophage infiltration, and reduced early plaque formation. In the setting of hypercholesterolemia, the aortic AT1 receptor mRNA was upregulated to 166+/-11%, accompanied by a comparable increase in AT1-receptor density. CONCLUSIONS: Hypercholesterolemia is associated with AT1-receptor upregulation, endothelial dysfunction, and increased NADH-dependent vascular O2*- production. The improvement of endothelial dysfunction, inhibition of the oxidase, and reduction of early plaque formation by an AT1-receptor antagonist suggests a crucial role of angiotensin II-mediated O2*- production in the early stage of atherosclerosis. (+info)
Cardiovascular risk factors in Mexican American adults: a transcultural analysis of NHANES III, 1988-1994.
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OBJECTIVES: This study examined the extent to which cardiovascular disease risk factors differ among subgroups of Mexican Americans living in the United States. METHODS: Using data from a national sample (1988-1994) of 1387 Mexican American women and 1404 Mexican American men, aged 25 to 64 years, we examined an estimate of coronary heart disease mortality risk and 5 primary cardiovascular disease risk factors: systolic blood pressure, body mass index, cigarette smoking, non-high-density lipoprotein cholesterol, and type 2 diabetes mellitus. Differences in risk were evaluated by country of birth and primary language spoken. RESULTS: Estimated 10-year coronary heart disease mortality risk per 1000 persons, adjusted for age and education, was highest for US-born Spanish-speaking men and women (27.5 and 11.4, respectively), intermediate for US-born English-speaking men and women (22.5 and 7.0), and lowest for Mexican-born men and women (20.0 and 6.6). A similar pattern of higher risk among US-born Spanish-speaking men and women was demonstrated for each of the 5 cardiovascular disease risk factors. CONCLUSIONS: These findings illustrate the heterogeneity of the Mexican American population and identify a new group at substantial risk for cardiovascular disease and in need of effective heart disease prevention programs. (+info)
Economic evaluation of cholesterol-related interventions in general practice. An appraisal of the evidence.
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STUDY OBJECTIVE: To investigate and evaluate published data on cost effectiveness of cholesterol lowering interventions, and how this information could be interpreted in a rational approach of cholesterol management in general practice. DESIGN: A systematic review of the literature. SETTING: No restriction on setting. MATERIALS: Papers reporting on the cost effectiveness or cost utility of prevention of (recurrent) coronary heart disease by reduction of hypercholesterolaemia in adults. MAIN RESULTS: Thirty nine studies, most cost effectiveness analyses, were included. In 24 studies drug interventions only were analysed. Costs of screening to target cholesterol lowering interventions to persons with hypercholesterolaemia were considered in nine studies. Adjustments of the efficacy of the intervention for community effectiveness were described in seven studies. In four studies life years gained were adjusted for quality of life. Despite large variation in the outcomes, there is a constant tendency towards a less favourable cost effectiveness ratio for intervening in persons without coronary heart disease compared with persons with coronary heart disease and for women compared with men. CONCLUSIONS: There is lack of data on cost effectiveness of cholesterol lowering interventions in the general practice setting. The cost effectiveness of cholesterol lowering in general practice deteriorates when all relevant costs are taken into account and when efficacy is corrected for community effectiveness. Cholesterol lowering intervention is more cost effective in men compared with women and in patients with coronary heart disease compared with persons without coronary heart disease. Considerations from cost effectiveness analyses should be incorporated into the development and implementation of national cholesterol guidelines for general practitioners. Standardisation of cost effectiveness studies is important for future economic evaluations. (+info)