Do pleiotropic effects of statins beyond lipid alterations exist in vivo? What are they and how do they differ between statins?

The inhibition of cellular proliferation, the restoration of endothelial activity, the inhibition of platelet reactivity, and an antioxidant potential are only a few examples of pleiotropic effects of statins. This review analyzes the current knowledge on the pleiotropic properties of this class of drugs and examines the relevant data that support the presence of these effects in vivo. The favorable outcome of major trials of statins has indicated that pleiotropic factors indeed play a role in cardiovascular protection.

[The treatment and outlook of atherosclerosis today].

Nowadays, the success of atherosclerosis therapy and the efficacy of cardiovascular disease prevention can rely on a comprehensive strategy. New algorithms derived from large population studies have improved the risk evaluation for the single individual and, consequently, the therapeutic approach can be better adapted to the specific needs of the patient. Improvements of noninvasive techniques, such as B-mode ultrasound and magnetic resonance imaging, allow for the reproducible and precise monitoring of lesion evolution that can be easily applied to large population samples.

State-of-the-Art lecture. Statins and blockers of the renin-angiotensin system: vascular protection beyond their primary mode of action.

In addition to their primary mode of action, statins and blockers of the renin-angiotensin system possess common additional properties that are under active investigation. The inhibition of cellular proliferation, the restoration of endothelial activity, the inhibition of platelet reactivity, and an antioxidant potential are only a few examples of shared effects that target the arterial wall. These and other properties may eventually become exploited for the improved treatment of cardiovascular diseases and of other diseases apparently unrelated to the cardiovascular field, including inflammation and cancer.

Antioxidants and coronary artery disease.

Data on the protective role of antioxidants in models of atherosclerosis are only partially confirmed in man. Observational and epidemiological data, as well as randomized trials, provide no clear cut indications, because of positive and disappointing results on the use of antioxidants in cardiovascular protection. Despite the lack of a general consensus, recent data reinforce the concept that the regular intake of antioxidants present in food limits the progression of atherosclerosis.

Cerivastatin: pharmacology of a novel synthetic and highly active HMG-CoA reductase inhibitor.

The pyridine derivative cerivastatin is a new entirely synthetic and enantiomerically pure inhibitor of 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase. As a sodium salt cerivastatin is present in the active, open ring form. Cerivastatin inhibited the membrane-bound (non-solubilized) HMG-CoA reductase of the native microsomal fraction isolated from rat liver with a Ki value of 1.

Increased J774 macrophage cytotoxicity of late postprandial triglyceride-rich lipoproteins from normolipidemic young men expressing an apolipoprotein epsilon 4 allele.

It has been demonstrated that normolipidemic young men with apolipoprotein E4/3 phenotype have a prolonged postprandial clearance of triglyceride-rich lipoproteins following a high-fat diet. In the present study, we isolated fasting and postprandial (3 and 8 h) lipoprotein fraction from normolipidemic young men with E3/3 and E4/3 phenotypes and examined the in vitro cytotoxicity of these lipoproteins towards J774 macrophages. 8 h E4/3 very low density lipoprotein (VLDL) were significantly more cytotoxic than either 8 h E3/3 VLDL or fasting and 3 h E4/3 VLDL (lactate dehydrogenase (LDH) released: 161 +/- 21, 107 +/- 9, 88 +/- 16 and 101 +/- 12 I.

Effect of the new HMG-CoA reductase inhibitor cerivastatin (BAY W 6228)on migration, proliferation and cholesterol synthesis in arterial myocytes.

The major relation existing between cell growth, migration and cholesterol homeostasis prompted us to investigate the effect of the new 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor cerivastatin (BAY W 6228) on these cellular events. The molecule inhibited in a dose-dependent manner the migration and the replication (evaluated as cell number and nuclear incorporation of 3H-thymidine) of rat arterial SMC with IC50 values of 2.7 microM and 0.

Antiatherogenic action of nitrendipine in hypercholesterolemic rabbits: changes in aortic macrophage accumulation and smooth muscle cell phenotype.

Intimal accumulation of macrophages and changes in the phenotype and growth properties of vascular smooth muscle cells (SMCs) represent key events in the development of atherosclerotic lesions. Here we report on the in vivo effect exerted by nitrendipine on aortic tissue of cholesterol-fed rabbits. We have focused especially on the myosin heavy chain (MyHC) pattern expressed by aortic SMC, taken as a marker of cell differentiation.

Reduction of myocardial leukocyte accumulation and myocardial infarct size following administration of BAY u3405, a thromboxane A2 receptor antagonist, in myocardial ischaemia-reperfusion injury.

We investigated the effect of BAY u3405, a thromboxane A2 receptor antagonist in pentobarbital anaesthetized rats subjected to left main coronary artery ligation (1 h) followed by reperfusion (1 h; MI/R). Sham operated rats were used as controls (Sham MI/R). Survival rate, myocardial necrosis, myocardial myeloperoxidase activity (investigated as an index of leukocyte adhesion and accumulation) and serum creatine phosphokinase activity were studied.

[Experimental atherogenesis].

The arterial wall possesses homeostatic mechanisms which are fundamental to the maintenance of its anatomical and functional integrity. The relative or absolute insufficiency of such mechanisms can lead with time to vascular disease, not the least of which is atherosclerosis. The understanding of the physiology of the arterial wall seems therefore necessary to a better approach to the study of several pathological processes.

The role of endothelial injury and platelet and macrophage interactions in atherosclerosis.

Atherosclerotic lesions take two forms, the fatty streak and the fibrous plaque or complicated lesion. The former is a flat, lipid-rich lesion containing variable numbers of foam cells in the form of macrophages and/or smooth muscle. In contrast, the fibrous plaque is a proliferative lesion of smooth muscle containing variable numbers of macrophages.

Studies of hypercholesterolemia in the nonhuman primate. II. Fatty streak conversion to fibrous plaque.

This report presents the second portion of the morphologic studies on chronic, diet-induced hypercholesterolemia in nonhuman primates (Macaca nemestrina) examined sequentially between 5 and 13 months. A direct relationship was observed between the rate of cholesterol increase, the level and duration of hypercholesterolemia, and the changes in the artery wall that led to the formation of fatty streaks and their conversion to fibrous plaques. A loss of endothelial continuity was first observed in the iliac arteries between 3 and 4 months of atherogenic diet and appears to be a critical step in the conversion of many fatty streaks to fibrous plaques.

Studies of hypercholesterolemia in the nonhuman primate. I. Changes that lead to fatty streak formation.

Morphologic studies resulting from events that occur during the development of the lesions of atherosclerosis were studied in chronic, diet-induced hypercholesterolemia in a series of nonhuman primates. Within 12 days of hypercholesterolemia in Macaca nemestrina, monocytes became adherent to the surface of the endothelium. These monocytes appeared to migrate subendothelially, accumulate lipid, and become lipid-laden macrophages (foam cells).

Platelet aggregation measured by the screen filtration pressure method in hypertensive patients.

In this study platelet aggregation was measured by the screen filtration pressure method in 2 groups of hypertensives separated according to age. They were perfectly matched for levels of various "risk factors", with normotensive "controls". No significant difference in platelet aggregate filtration pressure (PAFP) was found between hypertensives and normotensives.

Abnormal platelet aggregation measured by screen filtration pressure (sfp) in coronary heart disease: a new risk factor?

Platelet aggregate filtration pressure PAFP) has been measured in 38 male coronary heart disease patients (CHD) free from "risk factors" for the development of arteriosclerosis. Significantly (p less than 0.05) higher mean PAFP values (mmHg) were found in the CHD group as compared to the "control" group.