Statins and cardiovascular diseases: the multiple effects of lipid-lowering therapy by statins

doi:10.1016/S0021-9150(00)00397-X

Atherosclerosis

Volume 153, Issue 1, November 2000, Pages 181-189

https://doi.org/10.1016/S0021-9150(00)00397-X Get rights and content

Abstract

Cholesterol lowering involving different therapies improves the clinical outcome of patients. To define the underlying pathomechanism, we studied whether treatment with statins was associated with changes in blood thrombogenicity, endothelial dysfunction and soluble adhesion molecule levels. Fifty hypercholesterolemic patients were treated with pravastatin (40 mg/day, n=24) or simvastatin (20 mg/day, n=26). Lipid profile and blood thrombogenicity were assessed in all patients before and after 3 months of cholesterol reducing therapy. Blood thrombogenicity was assessed as thrombus formation, perfusing non-anticoagulated blood directly from the patients' vein through the Badimon perfusion chamber (shear rate 1690/s). Endothelial-dependent vasomotor response was tested by laser-Doppler flowmeter. Soluble adhesion molecule level were measured by ELISA. Total and LDL cholesterol were reduced in the two treatment groups by statin therapy. Statin therapy was associated with a significant reduction in blood thrombogenicity and endothelium-dependent vasoresponse. No differences were observed between simvastatin or pravastatin treatment. Lipid lowering by statins had no effect on plasma levels of fibrinogen, sL-selectin, sP-selectin and sICAM-1 antigen. Cholesterol lowering by both statins reduced the increased blood reactivity and endothelial dysfunction present under hypercholesterolemia. The multiple effects of lipid lowering therapy by statins may explain the benefits observed in recent epidemiological trials.

Introduction

Hypercholesterolemia — the major risk factors for the development of atherosclerotic disease [1], [2], [3], [4] is associated with increased deposition of lipids and monocytes/macrophages within the arterial wall, endothelial dysfunction and vasoconstriction, enhanced platelet reactivity, and hypercoagulability [5], [6]. Reduction of serum cholesterol levels by different interventions including diet, exercise, lifestyle changes or pharmacological approaches is associated with a significant reduction in cardiovascular mortality and morbidity [3], [4], [5], [6]. Recently, the effectiveness of a new class of powerful hypolipidemic agents, the statins, has been tested in several large clinical trials. These trials showed significant improvement in clinical outcomes of patients with and without coronary artery disease [7], [8], [9], [10], [11], [12]. These observations were applicable to primary and secondary prevention of coronary events in both, hyper- and normocholesterolemic populations [4], [6], [7], [8], [9], [10], [11], [12]. Statin treatment was associated with a consistent reduction in coronary events of ≈30–40% [13], [14].

Angiographic trials assessing the effect of lipid lowering treatment on coronary atherosclerosis showed only a small reduction in coronary stenosis [14], [15]. The clinical benefits observed in these trials significantly exceed the expectations based on alterations in vessel lumen diameter. This suggested that lipid-reducing therapy might have additional effects that would explain the discrepancy between clinical benefits and lack of significant lesion regression [3], [4], [5], [6]. Experimental and clinical studies have indicated a relationship between hyperlipidemia and increased blood thrombogenicity [15], [16], [17], [18], [19], [20], [21]. It was suggested that correction of hypercholesterolemia by pravastatin could normalize blood thrombogenicity [20]. However, conflicting findings on the effect of different statins on thrombosis have been reported by other authors [22], [23]. In addition, hyperlipidemia has been associated with an impaired endothelium-dependent vasoresponse [24] and cholesterol lowering by the use of specific statins has been reported to improve endothelial dysfunction [3], [24]. The goal of our study was to delineate whether lipid lowering by statins, irrespective of the specific statin used, was associated with changes in blood thrombogenicity and endothelial dysfunction in the same hyperlipidemic patient population. Furthermore, we studied whether changes in thrombogenicity and endothelial function were associated with alterations in circulating soluble adhesion molecule levels.

The working hypothesis of this study was that (1) the reduction of plasma lipid levels reduces blood thrombogenicity and endothelial dysfunction and (2) that the decreased thrombogenicity of blood and endothelium is associated with a reduction in circulating soluble adhesion molecule levels. Given the number of pathogenic processes modulated by plasma lipid levels, we further hypothesized that the significant benefits observed in clinical trials with statins might rather be a result of the significant reduction of plasma cholesterol level than a specific effect associated with the administration of one specific statin. To prove this hypothesis, hyperlipidemic patients were randomized into two groups receiving one of two most frequently prescribed statins for lipid reduction.

This study demonstrates multiple effects of cholesterol reducing therapy by the statin class on blood thrombogenicity and endothelial dysfunction in the same patient group under hyperlipidemic conditions. The combined reduction of blood thrombogenicity and endothelial dysfunction observed after lipid lowering by statins may be responsible for the clinical improvements reported in several large epidemiological trials.

Section snippets

Patient population

The study population included hypercholesterolemic patients (n=50). Hypercholesterolemia was defined as LDL-cholesterol level >120 mg/dl. Twenty-six of the patients had documented coronary artery disease and/or peripheral artery disease. The presence of coronary artery disease was documented by coronary angiography (stenosis >50%), history of previous myocardial infarction or typical angina pectoris with typical changes in treadmill ECG. Exclusion criteria included malignant diseases,

Study population

No significant differences between both groups were present in the anthrophometric, routine laboratory and other clinical risk factors at baseline (Table 1). The medication profile pre-treatment was also comparable in the two groups of patients. The serum lipid profile comprising total cholesterol, LDL cholesterol, HDL cholesterol, and triglycerides was similar in both groups at baseline. Total cholesterol and LDL cholesterol level were significantly reduced in both groups of patients after

Discussion

This study demonstrates that the reduction of plasma cholesterol levels by statins reduces the high blood thrombogenicity observed in the same group of patients under hyperlipidemic conditions. We conclude that the reduction of blood thrombogenicity and endothelial activity may be mechanisms by which cholesterol lowering through statins accounts for the beneficial effects on CHD observed in several large epidemiological trials.

Epidemiological evidence has shown the relationship between plasma

Acknowledgements

This work was supported in part by grants from the Spanish Society of Cardiology (to Dr. J Osende) and the followings grants from the National Institutes of Health (NIH P50 HL54469 to Dr J.J. Badimon and Dr J.T. Fallon) and (NIH 5 MO1 RR 00071) to the Mount Sinai General Clinical Research Center. The authors would like to express their appreciation to the excellent work, care and dedication of the nurse coordinators Stella Palencia and Ida Guzman.

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Citation Excerpt :
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Statins and cardiovascular diseases: the multiple effects of lipid-lowering therapy by statins

Abstract

Introduction

Section snippets

Patient population

Study population

Discussion

Acknowledgements

J Am Coll Cardiol.

Lancet

New views on the relationship of plasma lipids to cardiovascular disease

Circulation

National cholesterol education program: second report of the expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (adult treatment panel II)

Circulation

The national cholesterol education program: progress and prospects

J. Am. Med. Acad.

Cholesterol lowering and coronary artery disease: mechanisms of risk reduction

Heart

Cholesterol reduction yields clinical benefit. Impact of statin trials

Circulation

Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia

N Engl. J. Med.

The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels

N. Engl. J. Med.

AM for the AFCAPS/TexCAPS Research Group. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS

J. Am. Med. Am.

Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels

N. Engl. J. Med.

Effect of lipid lowering by pravastatin on progression and regression of coronary disease in symptomatic men with normal to moderately elevated cholesterol levels. The Regression Growth Evaluation Statin Study. (REGRESS)

Circulation

Cholesterol lowering with statin drugs, risk of stroke, and total mortality: an overview of randomized trials

J. Am. Med Acad.

Cholesterol management in theory and practice

Circulation

Regression or stabilization of atherosclerosis means regression or stabilization of what we don't see in the arteriogram

Eur. Heart J.

Platelet function in hyperlipoproteinemia

New Engl. J. Med.

Platelet deposition at high shear rates is enhanced by high plasma cholesterol levels: in vivo study in the rabbit model

Arterioscler. Thromb.