0
Clinical Cardiology |

Antiatherothrombotic Properties of Statins:  Implications for Cardiovascular Event Reduction FREE

Robert S. Rosenson, MD; Christine C. Tangney, PhD
[+] Author Affiliations

From the Preventive Cardiology Center, Departments of Medicine (Dr Rosenson) and Clinical Nutrition (Dr Tangney), Rush-Presbyterian-St Luke's Medical Center, Chicago, Ill.


Clinical Cardiology section editors: Bruce Brundage, MD, University of California, Los Angeles School of Medicine; Margaret A. Winker, MD, Senior Editor, JAMA.


JAMA. 1998;279(20):1643-1650. doi:10.1001/jama.279.20.1643.
Text Size: A A A
Published online

Clinical trials of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors or statin therapy have demonstrated that baseline or treated low-density lipoprotein (LDL) cholesterol levels are only weakly associated with net coronary angiographic change or cardiovascular events. The beneficial effects of statins on clinical events may involve nonlipid mechanisms that modify endothelial function, inflammatory responses, plaque stability, and thrombus formation. Experimental animal models suggest that statins may foster stability through a reduction in macrophages and cholesterol ester content and an increase in volume of collagen and smooth muscle cells. The thrombotic sequelae caused by plaque disruption is mitigated by statins through inhibition of platelet aggregation and maintenance of a favorable balance between prothrombotic and fibrinolytic mechanisms. These nonlipid properties of statins may help to explain the early and significant cardiovascular event reduction reported in several clinical trials of statin therapy.

Figures in this Article

CLINICAL TRIALS of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors or statin therapy demonstrate an improvement in cardiovascular end points and coronary stenosis that is incompletely explained by the baseline or treated low-density lipoprotein (LDL) cholesterol level.15 The beneficial effects of statins on clinical events may involve nonlipid mechanisms that modify endothelial function, inflammatory responses, plaque stability, and thrombus formation (Table 1, Figure 1). This article discusses several nonlipid mechanisms that may contribute to the cardiovascular event reduction observed in clinical trials of statin therapy.

Table Graphic Jump LocationTable 1.—Potential Differential Mechanisms Beyond Lipid Lowering

Graphic Jump Location
Coronary plaque disruption and major pathophysiological pathways as influenced by various statin therapies. This schematic diagram depicts an acute plaque disruption and resultant thrombus formation. Recirculation zones increase blood viscosity, which foster rapid plaque formation. NO indicates nitric oxide; PAI-1, plasminogen activator inhibitor 1; PGI2, prostacyclin; MCP-1, monocyte chemotactic protein 1; M-CSF, monocyte colony-stimulating factor; LDL, low-density lipoprotein; Ox-LDL, oxidized low-density lipoprotein; MM-LDL, minimally modified low-density lipoprotein; A, atorvastatin; C, cerivastatin; F, fluvastatin; L, lovastatin; P, pravastatin; and S, simvastatin.

The LDL cholesterol levels serve as the focus of cholesterol treatment guidelines that were established to prevent coronary heart disease (CHD) in patients with hypercholesterolemia who are initially free of CHD and for those with established CHD.69 Treatment guidelines target LDL cholesterol levels on the basis of epidemiological associations rather than clinical trial outcomes and, thus, promulgate the concept that the magnitude of LDL cholesterol reduction equates directly with a proportionate reduction in atherosclerotic burden and clinical cardiovascular events. The LDL cholesterol level is an important target of cardiovascular prevention; however, elevated LDL cholesterol levels identify less than one half of individuals who will die from CHD.10,11 The LDL cholesterol concentrations had a sensitivity of 47% in predicting 10-year CHD death rates in the Lipid Research Clinics Prevalence Study.12 Similar data are available from the Finnish cohort (n=444) of the Seven Countries Study for which only a modest correlation between serum cholesterol and 30-year CHD mortality was observed (r=0.42).11 The revised National Cholesterol Education Program (NCEP II) guidelines7 that stratify risk by LDL cholesterol levels and conventional risk factors are no better in predicting risk.12 The importance of LDL cholesterol levels on the prediction of CHD can be improved by concomitant measurements of high-density lipoprotein cholesterol levels,13 fibrinogen,14,15 plasma viscosity,16 and C-reactive protein.15

Clinical trials with statin therapy are accompanied by comparable changes in LDL cholesterol levels, but varying reductions in cardiovascular events35,1730 (Table 2). The relationship between baseline and treated LDL cholesterol levels and cardiovascular end points has been evaluated in several clinical trials.35 The Regression Growth Evaluation Statin Study (REGRESS) demonstrated that the effect of pravastatin on change in mean coronary artery segment diameter, minimum obstruction diameter, and clinical events was not influenced by baseline LDL cholesterol level.3 Similarly, the Scandinavian Simvastatin Survival Study reported that major coronary events were reduced by a similar amount regardless of the baseline LDL cholesterol level.4 The West of Scotland Coronary Prevention Study (WOSCOPS) evaluated the relationship between on-treatment LDL cholesterol levels or total cholesterol change and CHD risk5 using the Framingham CHD-risk model.31 The CHD event rate in pravastatin-treated patients was not related to the magnitude of LDL cholesterol level lowering when the LDL cholesterol level reduction ranged from 19% to 54%.5 The Framingham model accurately predicted the CHD event risk rate in the placebo group but underestimated the CHD risk reduction in the pravastatin therapy group by 35%. These analyses suggest that nonlipid mechanisms32,33 may contribute to the cardiovascular event reduction in WOSCOPS21 and explain the early clinical benefit in this trial and several others.3,17,18,20,21,34

Table Graphic Jump LocationTable 2.—Effect of Statins on Cardiovascular (CV) Event Reduction and LDL-Cholesterol Levels*

Coronary plaque rupture and erosions are recognized precipitants of thrombosis in acute myocardial infarction, unstable angina pectoris, and sudden death.3540 The vast majority of acute myocardial infarctions arise from atherosclerotic lesions that are minimal to moderate in severity as quantified by arteriography.38,41 The rapid progression of subclinical coronary stenosis has led to an appreciation of the vulnerable plaque.35,36

The characteristics of the typical vulnerable plaque include increased numbers of inflammatory cells, such as macrophages and T lymphocytes at the shoulder region of the plaque, a large lipid pool, few smooth muscle cells and collagen fibers, and a thin fibrous cap3739,4244 (Figure 1). The content of macrophages and T lymphocytes within the plaque is an important determinant of plaque disruption. The macrophages release proteolytic enzymes that weaken a thin overlying fibrous cap and accelerate collagen degradation. T lymphocytes release interferon gamma (IFN-γ) at sites of human plaque disruption.43 Interferon gamma inhibits smooth muscle cells from expressing interstitial collagen genes and provides a molecular basis for impaired collagen synthesis and inhibition of smooth muscle cell proliferation.4547 In addition to impaired synthesis of structural proteins, catabolism of the extracellular matrix by metalloproteinases (interstitial collagenase, gelatinases, stromelysins) can weaken the fibrous cap.37 These matrix-degrading proteinases are expressed by macrophage-derived foam cells and smooth muscle cells that are exposed to inflammatory cytokines (interleukin 1 or tumor necrosis factor). Plaque erosion is characterized by endothelial cell loss, sparsely distributed inflammatory cells, clusters of smooth muscle cells, and proteoglycans at the luminal surface.40

Experimental animal models demonstrate that statin therapy can stabilize atherosclerotic plaques.48,49 These compositional changes include a reduction in extracellular lipid deposits and the area of macrophages in the intima and media, increase in collagen area and the ratio of collagen area to the area of extracellular lipid deposits, increase in smooth muscle cells, and less calcification and neovascularization in the intima. Lipid-lowering therapies may reduce cardiovascular risk not only through altering the arterial wall (endothelial dysfunction, atherogenesis, plaque stability), but also through their thrombogenic effects and effects on blood flow properties(Table 3).

Table Graphic Jump LocationTable 3.—Comparison of Statins on Potential Mechanisms Influencing Plaque Stabilization and Thrombosis*

Elevated LDL cholesterol levels are a major predisposing factor to atherosclerosis. Oxidized LDL impairs endothelial-dependent vasodilation, induces apoptosis of human endothelial cells via activation of a CPP32-like protease, a member of the interleukin 1β–converting enzyme-like protease family,50 and generates an inflammatory response. Oxidized LDL modifies the functional response of vascular smooth muscle cells to angiotensin II stimulation.51

Oxidized LDL inhibits nitric oxide synthase activity of platelets,52,53 which promotes thrombus formation through an enhancement of fibrinogen binding to platelets.54 Oxidized LDL binds to platelet activation factor, which is an intracellular proinflammatory regulator.55 Modified LDL promotes tissue factor expression by monocytes, but LDL inhibits activation of the extrinsic coagulation pathway through binding to the tissue factor pathway inhibitor (TEPI).56,57 The LDL levels correlate with vitamin K–dependent coagulation factors (and inhibitors) and fibrinogen levels58; however, the significance of these relationships is unresolved.59 In subjects with hypobetalipoproteinemia (LDL cholesterol level, <1.81 mmol/L [69.99 mg/dL]), levels of fibrinogen and fibrinolytic markers (plasminogen activator inhibitor 1 [PAI-1] antigen), tissue plasminogen activator inhibitor 1 antigen) are low and this association further supports the relationship between LDL and these hemostatic factors.60 In addition, LDL contributes to atherothrombogenesis through an increase in plasma and blood viscosity as shown in in vitro experiments and supported by epidemiological studies.59

Endothelial Function

Endothelial-mediated vasodilatation is impaired in hypercholesterolemia and atherosclerosis.61,62 In coronary arteries of patients with atherosclerosis, cholesterol lowering with pravastatin and lovastatin improves endothelial function as evidenced by limiting acetylcholine-induced vasoconstriction (Table 3). 6365 While this improvement in endothelial function was not seen with simvastatin,66 the LDL cholesterol–lowering therapy with simvastatin improves peripheral nitric oxide–mediated vascular relaxation.6770 The improved coronary blood flow and vasodilatory response with statin therapy alleviates transient ischemia in patients with stable angina pectoris71,72 and improves myocardial perfusion.73,74 In patients with mild hypertension, cardiovascular reactivity to angiotensin II and norepinephrine is diminished after 3 weeks of therapy with pravastatin.75 Statin therapy can ameliorate endothelial dysfunction and contribute to the observed clinical benefits of those agents, and this improvement may be ascribed to LDL cholesterol lowering and antioxidant properties of statins.

Inflammation

An early step in atherogenesis involves monocyte adhesion to the endothelium and penetration into the subendothelial space. Oxidized LDL binds to the scavenger cell receptor on monocyte-derived macrophages and contributes to foam cell formation. Inflammatory cytokines secreted by macrophages and T lymphocytes can modify endothelial function, smooth muscle cell proliferation, collagen degradation, and thrombosis.46,47,7678 Cholesterol level lowering in experimental models is accompanied by a reduction of inflammatory cells within atherosclerotic plaque.48,49,7981 Subjects with hypercholesterolemia have increased adhesiveness of isolated monocytes to fixed endothelial cells in vitro, and this response is diminished with lovastatin and simvastatin.81 Hypercholesterolemic rats treated with fluvastatin have significantly attenuated leukocyte-adherence responses to platelet activation factor and leukotriene B4.81

In patients with cardiac transplants, pravastatin may suppress the inflammatory response and inhibit natural killer cell activity in cyclosporin-treated patients.82 Although transplant vasculopathy is a distinct pathological entity from atherosclerotic vascular disease, the same inflammatory mediators may determine plaque vulnerability.

Effect of Lipid Composition on Plaque Stability

The relative content of cholesterol esters in plaque is an important factor influencing plaque stability. The pools of lipid-laden macrophage foam cells are nondistensible and do not absorb transmitted energy. Circumferential shear stress is concentrated on the fibrous cap that separates blood from the thrombogenic lipid core,83,84 and plaque disruption exposes the underlying plaque components to blood components that initiate thrombogenesis.85,86

Statins inhibit cholesterol ester accumulation in monocyte-derived macrophages either by reducing the availability of free cholesterol toward the enzyme acyl-coenzyme A cholesterol acyltransferase by trapping it in phospholipid-containing pools, or by inhibiting LDL endocytosis related to reduced synthesis of mevalonate or mevalonate by-products required for cholesterol esterification.87 Kempen et al88 reported a dose-dependent inhibition of cholesterol accumulation in macrophages that was greater with lovastatin and simvastatin than with pravastatin (Table 3). Lowering blood LDL cholesterol levels may facilitate plaque stability either through a reduction in size89,90 or by an alteration of the physiochemical properties of lipid cores.91,92 Hydrolysis of liquid cholesterol esters to solid cholesterol crystals can yield firmer plaques.

Another factor obscuring the relationship between LDL cholesterol levels and clinical events is the distribution of LDL subspecies within the plaque and the susceptibility of select LDL particles to oxidative modification. Small, dense LDL particles are more atherogenic than larger, buoyant particles, in part, because of enhanced oxidative susceptibility93 and reduced total antioxidant defense.94 The small LDL particle diameter is an independent predictor of myocardial infarction,95,96 and a predominance of dense LDL particles (density, >1.0378 g/mL) predicted coronary arteriographic benefit in the Stanford Coronary Risk Intervention Project.97

In the Kuopio Atherosclerosis Prevention Study (KAPS),26 3 years of pravastatin therapy prolonged the lag time of LDL lipoproteins (a measure of oxidation resistance), increased plasma and LDL vitamin E levels, and improved overall LDL antioxidant capacity (Table 3). 98 Lovastatin and simvastatin have been shown to inhibit LDL oxidation and uptake by macrophages in studies of shorter duration.99105 Simvastatin treatment for 6 months maintains total antioxidant capacity of LDL particles; however, measurements of plasma antioxidants (ubiquinone, dolichol, α-tocopherol, β-carotene, and lycopene) were either reduced103,104 or unchanged.105 Tissue concentrations of ubiquinone may be reduced with certain statins as reported in animal studies.106,107 In contrast, plasma ubiquinone levels fall with simvastatin therapy, whereas the concentration of ubiquinone in skeletal muscle biopsy specimens remains unchanged.105 Overall, these data suggest that statin therapy does not alter tissue antioxidant balance but increases total antioxidant capacity of plasma.

Smooth Muscle Cell Proliferation and Collagen Synthesis

Smooth muscle cells foster plaque stabilization39,108 through synthesis of macromolecules that strengthen the fibrous cap37 and absorption of energy transmitted to the vessel wall, which reduces circumferential shear stress along the endothelial surface.83,84 Mechanical stress serves as a stimulus for smooth muscle cell synthesis.109 The smooth muscle cell also is involved in the normal healing process.39,108 After a plaque ulcerates, the normal reparative process requires proliferation of vascular smooth muscle cells. Vascular smooth muscle cells regulate synthesis of interstitial collagens that are stimulated by transforming growth factor β and platelet-derived growth factor and inhibited by IFN-γ.47

The influence of statins on smooth muscle cell proliferation has been evaluated in cell cultures of human femoral and rat myocytes and carotid arteries of rabbits.110114 Balloon-mediated injury of rabbit carotid arteries caused intimal proliferation that was not inhibited in placebo- and pravastatin-treated rabbits, whereas this process was inhibited by treatment with all other statins.110,112 In cell culture experiments, most statins (atorvastatin, cerivastatin, fluvastatin, simvastatin) except pravastatin inhibit smooth muscle cell proliferation and migration induced by the platelet-derived growth factor and fibrinogen.111,112 The permissive action of pravastatin on smooth muscle cell proliferation may be an advantage for the reparative process that follows plaque ulceration.108 The concentration of statin needed to inhibit smooth muscle cell proliferation in vivo is comparable to plasma levels observed in humans administered conventional doses of these agents.114

Whether plaque disruption leads to an acute ischemic event depends, in part, on the propensity for thrombus to form on the damaged vessel wall. The thrombogenic response may be influenced by the thrombogenicity of the vessel wall components,86 interaction of blood components with the lipid pool or smooth muscle cell and proteoglycan complexes, local blood flow properties, and circulating hemostatic factors. The prothrombotic factors that have been evaluated with the statins include tissue factor expression, platelet aggregation, fibrinogen, plasma viscosity, and fibrinolytic factors (Table 3).

Tissue Factor

Tissue factor and corresponding messenger RNA have been localized in macrophages of human atherosclerotic plaque.85 Tissue factor serves as a cofactor for plasma factor VII and cellular receptor for factor VIIa and, thus, plays a central role as the initiator of the extrinsic coagulation pathway.115 Lipophilic statins (fluvastatin, simvastatin) suppress tissue factor expression by cultured human macrophages through inhibition of a geranylgeranylated protein involved in tissue factor biosynthesis.116 This effect on tissue factor was not observed with pravastatin.

The extrinsic coagulation activation pathway is counterbalanced by a serine protease inhibitor known as TEPI. TEPI binds to factor Xa, and this complex inhibits tissue factor–mediated coagulation through binding to the tissue factor—factor VIIa complex.56,57 Circulating TEPI is transported by dense subspecies of LDL, lipoprotein(a) (Lp[a]), and high-density lipoprotein.117 TEPI activity is increased in subjects with heterozygous familial hypercholesterolemia,118,119 and types IIa (by 70%, P<.001) and IIb (by 36%, P<.001) hyperlipoproteinemias.120 Cholesterol level lowering with simvastatin reduces LDL and TEPI without a significant change in factor VIIc.118

Platelet Aggregation

Platelets from patients with elevated LDL levels are more sensitive to aggregating agents than are platelets of normocholesterolemic subjects.121 The LDL causes intracellular acidification through inhibition of Na+/H+ antiport in human platelets, which mobilizes intracellular calcium in the resting state and after stimulation with agonists.122 The adenosine diphosphate–induced fibrinogen binding to platelets is increased in a dose-dependent manner by LDL (0.5-2.0 g of protein per liter).123 Simvastatin reduces platelet aggregation and thromboxane production after 4 to 24 weeks of therapy, whereas lipid lowering was observed by 2 weeks of treatment.124,125 Lovastatin therapy has been accompanied by both an increase and a decrease in platelet count and adenosine diphosphate–induced platelet aggregation.126,127 Pravastatin normalizes platelet-dependent thrombin generation in hypercholesterolemic subjects, but this effect is unaccompanied by a change in prostaglandin production.128 Pravastatin also has been shown to reduce cytosolic calcium and platelet aggregation.129

Statins may reduce platelet aggregation by changing the cholesterol content of platelet membranes, which alters membrane fluidity.129 In an experimental model that simulates primary hemostasis, hypercholesterolemic patients treated with aspirin (325 mg/d) deposit more platelet aggregates on damaged porcine aorta than normocholesterolemic subjects, and this response was reduced by pravastatin therapy.130 In hypercholesterolemic subjects treated with aspirin (325 mg/d) and randomized to either pravastatin or simvastatin at equivalent LDL cholesterol-lowering doses, pravastatin inhibited platelet-thrombus formation on an injured artery. This was not observed in simvastatin-treated patients.131 These latter studies suggest a differential effect of statins on tissue-dependent platelet aggregation.

Fibrinogen and Viscosity

Fibrinogen levels and plasma viscosity may be used to stratify cardiovascular risk in hypercholesterolemic patients with and without established CHD.1416 Elevated plasma viscosity may contribute to atherothrombosis through impaired microcirculatory flow, shear stress damage at the blood-endothelial interface, facilitation of plasma protein interaction with the endothelium in poststenotic recirculation zones, and increased propensity for thrombosis.132

Several studies examining the influence of statins on fibrinogen levels in hypercholesterolemic patients have shown mixed results.133 Lovastatin has been accompanied by 19% to 24% increases in fibrinogen levels in two 6-month studies of 26 and 49 patients, respectively,126,134 and by 5% in a 12-month study of 260 patients.135 Two other small, short-term studies of 15 and 35 patients reported no change in fibrinogen concentration.136,137 In contrast, Mayer et al127 found a significant 10% reduction in fibrinogen levels in 20 hypercholesterolemic patients treated with lovastatin after 16 weeks of therapy, with further reductions throughout the 12-month interval of the study. This study was limited by fibrinogen measurements made at monthly intervals without adjustment for multiple observations and selection of a second fibrinogen value at baseline that was 4% higher than the initial value.133

Lovastatin has been accompanied by an increase in whole blood viscosity,126 while plasma viscosity is either reduced136 or does not change.126,137 Pravastatin has been accompanied by a 7% to 9% lowering of fibrinogen levels in 3 studies of 16 to 24 patients treated from 10 to 24 weeks.138140 Three studies reported no change in fibrinogen concentration with pravastatin.26,141,142 However, KAPS reported a nonsignificant 7% elevation in fibrinogen in patients treated with either pravastatin and placebo for 3 years, but the increase in fibrinogen was 20% lower in the pravastatin group than in the placebo group.26 Unlike the Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial,143 KAPS did not age adjust fibrinogen levels.26 In addition, 2 pravastatin studies reported a reduction in whole blood viscosity at shear rates ranging from 75 to 375 seconds−1, corrected blood viscosity at 112.5 seconds−1 and 225 seconds−1, and plasma viscosity.138,140 Simvastatin does not change fibrinogen as shown in 4 studies of 12 to 111 subjects followed up for 10 weeks to 2 years.140,142,144,145 Additionally, blood, plasma and serum viscosity measurements were unchanged with simvastatin therapy.144 Two comparative studies that randomized subjects to either pravastatin or simvastatin reported a favorable or neutral change in fibrinogen with pravastatin and a neutral change with simvastatin.140,142 No published studies have evaluated the effect of fluvastatin on fibrinogen levels. Atorvastatin (80 mg daily) was accompanied by a 46% increase in fibrinogen levels in 22 heterozygous familial hypercholesterolemic subjects treated for 6 weeks.146 The fibrinogen elevation was greater in subjects randomized to atorvastatin administered as a twice-daily dose compared to a single dose (P<.05). In 789 subjects, a lower dose of atorvastatin (10 mg daily) was accompanied by a smaller (4%) elevation in plasma fibrinogen levels.135 Other investigators evaluated multiple dosages of atorvastatin (10-80 mg daily) on fibrinogen levels in 95 subjects and reported an increase in fibrinogen levels that ranged from 19% to 24%.147

The variable effect of statins on fibrinogen may result from different actions on fibrinogen-regulating cytokines,78 study populations with genetic variation at the fibrinogen gene locus,148 or measurement variability.149 Another factor to consider is age adjustment of fibrinogen levels in long-term studies.143

Fibrinolytic Balance

Fibrinolytic mechanisms evaluated with statins include measurements of Lp(a) and PAI-1, the principal inhibitor of the fibrinolytic system. Impaired fibrinolysis as measured by an elevation in PAI-1 is predictive of ischemic heart disease in free-living subjects150 and survivors of myocardial infarction.150152 Pravastatin reduces PAI-1 antigen levels by 26% to 56%,139,141 and this appears to facilitate fibrinolysis. Lovastatin has been shown to both decrease PAI-1 by 22%134 and elevate PAI-1 by 34% in 260 subjects.135 Atorvastatin therapy increased PAI-1 by 36% after 12 months.135 Simvastatin increased PAI-1 by 18% in 111 patients treated for 2 years.145 Fluvastatin has a neutral effect on PAI-1 antigen.153

Lipoprotein(a) interferes with fibrinolysis by competing with plasminogen binding to plasminogen receptors, fibrinogen, and fibrin.154 The net effect is impaired plasminogen activation and plasmin generation at the thrombus surface.155 The Lp(a) levels can increase by as much as 34% with statin therapy156160 and potentially impair clot lysis. Since the importance of Lp(a) on cardiovascular risk diminishes with LDL cholesterol–lowering therapy,155 the importance of this modest evaluation in Lp(a) levels on overall cardiovascular risk is unclear. The opposing effects of statins on the different mediators of fibrinolysis may offset each other.

Statins influence critical pathways that regulate plaque stability and thrombosis, and these properties extend beyond LDL lowering. The spectrum of direct antiatherogenic properties of statins includes maintenance of endothelial function, anti-inflammatory actions, and a permissive action on smooth muscle cell proliferation that allows for synthesis of extracellular matrix proteins involved in the reparative response. Following plaque disruption, statins influence thrombosis through variable inhibitory actions on platelet deposition and aggregation, coagulation factors, rheology, and fibrinolysis. The qualitative differences among statins may influence the effectiveness in the prevention of cardiovascular events and atherosclerosis disease progression.

Knowledge about the intricacies of atherosclerosis and thrombosis continues to expand rapidly, and these mechanisms should be used to support the evidence from randomized clinical trials. Since the nonlipid properties of statins differ despite comparable LDL cholesterol level lowering, the net clinical efficacy of these agents requires validation by randomized clinical trials.

Thompson GR, Hollyer J, Waters DD. Percentage change rather than plasma level of LDL-cholesterol determines therapeutic response in coronary heart disease.  Curr Opin Lipidol.1995;6:386-388.
Sacks FM, Gibson CM, Rosner B, Pasternak RC, Stone PH.and the Harvard Atherosclerosis Reversibility Project Research Group.  The influence of pretreatment low density lipoprotein cholesterol concentrations on the effect of hypercholesterolemic therapy on coronary atherosclerosis in angiographic trials.  Am J Cardiol.1995;76:78C-85C.
Jukema JW, Bruschke AVG, van Boven AJ.  et al.  Effects of lipid lowering by pravastatin on progression and regression of coronary artery disease in symptomatic men with normal to moderately elevated serum cholesterol levels: the Regression Growth Evaluation Statin Study (REGRESS).  Circulation.1995;91:2528-2540.
Scandinavian Simvastatin Survival Study Group.  Baseline serum cholesterol and treatment effect in the Scandinavian Simvastatin Survival Study (4S).  Lancet.1995;345:1274-1275.
West of Scotland Coronary Prevention Study Group.  Influence of pravastatin and plasma lipids on clinical events in the West of Scotland Coronary Prevention Study (WOSCOPS).  Circulation.1998;97:1440-1445.
The Expert Panel on Detection Evaluation, and Treatment of High Blood Cholesterol in Adults.  Expert Panel Report of the National Cholesterol Education Program.  Arch Intern Med.1986;148:36-69.
The Expert Panel on Detection Evaluation, and Treatment of High Blood Cholesterol in Adults.  Summary of the second report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel II).  JAMA.1993;269:3015-3023.
Study Group of the European Atherosclerosis Society.  The recognition and management of hyperlipidemia in adults: a policy statement of the European Atherosclerosis Society.  Eur Heart J.1988;9:571-600.
The Canadian Consensus Conference on Cholesterol.  Final report.  Can Med Assoc J.1988;26:369-388.
Pekkannen J, Linn S, Heiss G.  et al.  Ten-year mortality from cardiovascular disease in relaxation to cholesterol level among men with and without preexisting cardiovascular disease.  N Engl J Med.1990;322:1700-1707.
Pekkannen J, Tervahuata M, Nissinen A, Karvonen MJ. Does the predictive value of baseline coronary risk factors change over a 30-year follow-up?  Cardiology.1993;82:181-190.
Grover SA, Coupal L, Hu XP. Identifying adults at increased risk of coronary disease: how well do the current cholesterol guidelines work?  JAMA.1995;274:801-806.
Castelli WP, Garrison RJ, Wilson PWF, Abbott RD, Kalousdian S, Kannel WB. Incidence of coronary heart disease and lipoprotein cholesterol levels: the Framingham Study.  JAMA.1986;256:2835-2838.
Heinrich J, Ballaisen L, Schulte H, Assmann G, van de Loo J. Fibrinogen and factor VII in the prediction of coronary risk: results from the PROCAM Study in healthy men.  Arterioscler Thromb.1994;14:54-59.
Thompson SG, Kienast J, Pyke SDM, Haverkate F, van de Loo JCW.for the European Concerted Action on Thrombosis and Disabilities Angina Pectoris Study Group.  Hemostatic factors and the risk of myocardial infarction or sudden death in patients with angina pectoris.  N Engl J Med.1995;332:635-641.
Sweetnam PM, Thomas HF, Yarnell JWG, Beswick AD, Baker IA, Elwood PC. Fibrinogen, viscosity, and the 10-year incidence of ischaemic heart disease.  Eur Heart J.1996;17:1814-1820.
Tonkin A.for the Long-term Intervention With Pravastatin in Ischemic Disease (LIPID).  Not Available. Paper presented at: 70th Scientific Sessions of the American Heart Association; November 12, 1997. Orlando, Fla.
Downs JR, Clearfield M, Weis S.  et al.  Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS.  JAMA.1998;279:1615-1622.
Pitt B, Mancini GBJ, Ellis SG, Rosman HS, Park JS, McGovern ME. Pravastatin Limitation of Atherosclerosis in the Coronary Arteries (PLAC I): reduction in atherosclerosis progression and clinical events.  J Am Coll Cardiol.1995;26:1133-1139.
The Pravastatin Multinational Study Group for Cardiac Risk Patients.  Effects of pravastatin in patients with serum total cholesterol levels from 5.2 to 7.8 mmol/Liter (200 to 300 mg/dl) plus two additional atherosclerotic risk factors.  Am J Cardiol.1993;72:1031-1037.
Shepherd J, Cobb SM, Ford I.  et al.  Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia.  N Engl J Med.1995;333:1301-1307.
Crouse JR, Byington RP, Bond MG.  et al.  Pravastatin, Lipids, and Atherosclerosis in the Carotid Arteries (PLAC II).  Am J Cardiol.1995;75:455-459.
Furberg CD, Adams Jr HP, Applegate WB.  et al.  Effect of lovastatin on early carotid atherosclerosis and cardiovascular events.  Circulation.1994;90:1679-1687.
Sacks FM, Pfeffer MA, Moye LA.  et al.  The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels.  N Engl J Med.1996;335:1001-1009.
Waters D, Higginson L, Gladstone P.  et al.  Effects of monotherapy with an HMG-CoA reductase inhibitor on the progression of coronary atherosclerosis as assessed by serial quantitative arteriography: the Canadian Coronary Atherosclerosis Intervention Trial.  Circulation.1994;89:959-968.
Salonen R, Nyyssonen K, Porkkala E.  et al.  Kuopio Atherosclerosis Prevention Study (KAPS): a population based primary preventive trial of the effect of LDL lowering on atherosclerotic progression in carotid and femoral arteries.  Circulation.1995;92:1758-1764.
MAAS Investigators.  Effect of simvastatin on coronary atheroma: the Multicentre Anti-atheroma Study (MAAS).  Lancet.1994;344:633-638.
Scandinavian Simvastatin Survival Study Group.  Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S).  Lancet.1994;344:1383-1389.
Blankenhorn DH, Azen SP, Kramsch DM.  et al.  Coronary angiographic changes with lovastatin therapy: the Monitored Atherosclerosis Regression Study (MARS).  Ann Intern Med.1993;119:969-976.
The Post Coronary Artery Bypass Graft Trial Investigators.  The effect of aggressive lowering of low-density lipoprotein cholesterol levels and low-dose anticoagulation on obstructive changes in saphenous-vein coronary-artery bypass grafts.  N Engl J Med.1997;336:153-162.
Grover SA, Abrahamowicz M, Joseph L, Brewer C, Coupal L, Suissa S. The benefits of treating hyperlipidemia to prevent coronary heart disease: estimating changes in life expectancy and morbidity.  JAMA.1992;267:816-822.
Vaughan CJ, Murphy MB, Buckley BM. Statins do more than lower cholesterol.  Lancet.1996;348:1079-1082.
Kinlay S, Selwyn AP, Delagrange D, Creager MA, Libby P, Ganz P. Biological mechanisms for the clinical success of lipid-lowering in coronary artery disease and the use of surrogate end points.  Curr Opin Lipidol.1996;7:389-397.
Byington RP, Jukema JW, Salonen JT.  et al.  Reduction in cardiovascular events during pravastatin therapy: pooled analysis of clinical events of the Pravastatin Atherosclerosis Intervention Program.  Circulation.1995;92:2419-2425.
Davies MJ, Thomas A. Thrombosis and acute coronary-artery lesions in sudden cardiac ischemic death.  N Engl J Med.1984;310:1137-1140.
Davies MJ, Thomas AC. Plaque fissuring: the cause of acute myocardial infarction, sudden ischaemic death and crescendo angina.  Br Heart J.1985;53:363-373.
Libby P. Molecular basis of acute coronary syndromes.  Circulation.1995;91:2844-2850.
Falk E, Shah PK, Fuster V. Coronary plaque disruption.  Circulation.1995;92:657-671.
Davies MJ. Stability and instability: two faces of coronary atherosclerosis: the Paul Dudley White Lecture, 1995.  Circulation.1996;94:2013-2020.
Farb A, Burke AP, Tang AL.  et al.  Coronary plaque erosion without rupture into a lipid core: a frequent cause of coronary thrombosis in sudden coronary death.  Circulation.1996;93:1354-1363.
Hackett D, Davies G, Maseri A. Preexisting coronary stenoses in patients with first myocardial infarction are not necessarily severe.  Eur Heart J.1988;9:1317-1323.
Berliner JA, Navab M, Fogelman AM.  et al.  Atherosclerosis: basic mechanisms: oxidation, inflammation, and genetics.  Circulation.1995;91:2488-2496.
Hansson GK, Holm J, Jonasson L. Detection of activated T lymphocytes in the human atherosclerotic plaque.  Am J Pathol.1989;135:169-175.
van der Wal AC, Becker AE, van der Loos CM, Das PK. Site of intimal rupture or erosion of thrombosed coronary atherosclerotic plaques is characterized by an inflammatory process irrespective of the dominant plaque morphology.  Circulation.1994;89:36-44.
Rekhter M, Zhang K, Narayanan A, Phan S, Schork M, Gordon D. Type I collagen gene expression in human atherosclerosis: localization to specific plaque regions.  Am J Pathol.1993;143:1634-1648.
Warner SJC, Friedman GB, Libby P. Immune interferon inhibits proliferation and induces 2‘-5‘-oligoadenylate synthetase gene expression in human vascular smooth muscle cells.  J Clin Invest.1989;83:1174-1182.
Amento EP, Ehsani N, Palmer H, Libby P. Cytokines positively and negatively regulate interstitial collagen gene expression in human vascular smooth muscle cells.  Arterioscler Thromb.1991;11:1223-1230.
Shiomi M, Ito T, Tsukada T.  et al.  Reduction of serum cholesterol levels alters lesional composition of atherosclerotic plaques: effect of pravastatin sodium on atherosclerosis in mature WHHL rabbits.  Arterioscler Thromb Vasc Biol.1995;15:1938-1944.
Williams JK, Sukhova GK, Herrington DM, Libby P. Pravastatin has cholesterol-lowering independent effects on the artery wall of atherosclerotic monkeys.  J Am Coll Cardiol.1998;31:684-691.
Dimmeler S, Haendeler J, Galle J, Zeiher AM. Oxidized low-density lipoprotein induces apoptosis of human endothelial cells by activation of CPP32-like proteases: a mechanistic clue to the "response to injury" hypothesis.  Circulation.1997;95:1760-1763.
Nickenig G, Sachinidis A, Michaelsen F, Bohm M, Seewald S, Vetter H. Upregulation of vascular angiotensin II receptor gene expression by low-density lipoprotein in vascular smooth muscle cells.  Circulation.1997;95:473-478.
Pedreno J, de Castellarnau C, Cullare C.  et al.  LDL binding sites on platelets differ from the "classical" receptor of nucleated cells.  Arterioscler Thromb.1992;12:1353-1362.
Chen LY, Mehta P, Mehta JL. Oxidized LDL decreases L-arginine uptake and nitric oxide synthase protein expression in human platelets: relevance of the effect of oxidized LDL on platelet function.  Circulation.1996;93:1740-1746.
Hassall DG, Owens JS, Bruckdorfer KR. The aggregation of isolated human platelets in the presence of lipoproteins and prostacyclin.  Biochem J.1983;216:43-49.
Dentan C, Lesnik P, Chapman MJ, Ninio E. PAF-acether-degrading acetylhydrolase in plasma LDL is inactivated by copper- and cell-mediated oxidation.  Arterioscler Thromb.1994;14:353-360.
Broze Jr GJ. The role of tissue factor pathway inhibitor in a revised coagulation cascade.  Semin Hematol.1992;29:159-169.
Sanders NL, Bajaj SP, Zivelin A, Rapaport SI. Inhibition of tissue factor/factor VII activity in plasma requires factor X and an additional plasma component.  Blood.1985;66:204-212.
Woodward M, Lowe GDO, Rumley A.  et al.  Epidemiology of coagulation factors, inhibitors and activation markers, the Third Glasgow MONICA Survey II: relationships to cardiovascular risk factors and prevalent cardiovascular disease.  Br J Haematol.1997;97:785-797.
Rosenson RS, Lowe GDO. Effects of lipids and lipoproteins on thrombosis and rheology.  Atherosclerosis.1998;140:271-280.
Balleisen L, Assmann G, Bailey J, Epping P-H, Schulte H, van de Loo J. Epidemiological study on factor VII, factor VIII and fibrinogen in an industrial population, II: baseline data on the relation to blood pressure, blood glucose, uric acid, and lipid fractions.  Thromb Haemost.1985;54:721-723.
Leung WH, Lau CP, Wong CK. Beneficial effect of cholesterol-lowering therapy on coronary endothelium-dependent relaxation in hypercholesterolaemic patients.  Lancet.1993;341:1496-1500.
Anderson TJ, Gerhard MD, Meredith IT.  et al.  Systemic nature of endothelial dysfunction in atherosclerosis.  Am J Cardiol.1995;75:71B-74B.
Egashira K, Hirooka Y, Kai H.  et al.  Reduction in serum cholesterol with pravastatin improves endothelium-dependent coronary vasomotion in patients with hypercholesterolemia.  Circulation.1994;89:2519-2524.
Treasure CB, Klein JL, Weintraub WS.  et al.  Beneficial effects of cholesterol-lowering therapy on the coronary endothelium in patients with coronary artery disease.  N Engl J Med.1995;332:481-487.
Anderson TJ, Meredith IT, Yeung AC, Frei B, Selwyn AP, Ganz P. The effect of cholesterol-lowering and antioxidant therapy on endothelium-dependent coronary vasomotion.  N Engl J Med.1995;332:488-493.
Winniford M, Hodgson J, Yeung A.  et al.  CARAT Study: the effect of cholesterol lowering on coronary blood flow. Study presented at: 66th Congress of the European Atherosclerosis Society; July 1996; Florence, Italy.
Stroes ESG, Koomans HA, deBruin TWA, Rabelink TJ. Vascular function in the forearm of hypercholesterolaemic patients off and on lipid-lowering medication.  Lancet.1995;346:467-471.
Vogel RA, Corretti MC, Plotnick GD. Changes in flow-mediated brachial artery vasoactivity with lowering of desirable cholesterol levels in healthy middle-aged men.  Am J Cardiol.1996;77:37-40.
Hayoz D, Weber R, Rutschmann B.  et al.  Postischemic blood flow response in hypercholesterolemic patients.  Hypertension.1995;26:497-502.
O'Driscoll G, Green D, Taylor RR. Simvastatin, an HMG-coenzyme A reductase inhibitor, improves endothelial function within 1 month.  Circulation.1997;95:1126-1131.
van Boven AJ, Jukema JW, Zwinderman AH, Crijns HJ, Lie KI, Bruschke AVG. Reduction of transient myocardial ischemia with pravastatin in addition to the conventional treatment in patients with angina pectoris.  Circulation.1996;94:1503-1505.
Andrews TC, Raby K, Barry J.  et al.  Effect of cholesterol reduction on myocardial ischemia in patients with coronary disease.  Circulation.1997;95:324-328.
Eichstadt HW, Eskotter H, Hoffmann I, Amthauer HW, Weidinger G. Improvement of myocardial perfusion by short-term fluvastatin therapy in coronary artery disease.  Am J Cardiol.1995;76:122A-125A.
Aengevaeren WRM, Uijen GJH, Jukema JW, Bruschke AVG, Werf T. Functional evaluation of lipid-lowering therapy by pravastatin in the Regression Growth Evaluation Statin Study.  Circulation.1997;96:429-435.
Straznicky NE, Howes LG, Lam W, Louis WJ. Effects of pravastatin on cardiovascular reactivity to norepinephrine and angiotensin II in patients with hypercholesterolemia and systemic hypertension.  Am J Cardiol.1995;75:582-586.
Vallance P, Collier J, Bhagat K. Infection, inflammation, and infarction: does acute endothelial dysfunction provide a link?  Lancet.1997;349:1391-1392.
Neumann FJ, Marx N, Gawaz M.  et al.  Induction of cytokine expression in leukocytes by binding of thrombin-stimulated platelets.  Circulation.1997;95:2387-2394.
Green F, Humphries S. Control of plasma fibrinogen levels.  Baillieres Clin Haematol.1989;2:945-959.
Padgett RC, Heistad DD, Mugge A, Armstrong ML, Piegors DJ, Lopez JAG. Vascular responses to activated leukocytes after regression of atherosclerosis.  Circ Res.1992;70:423-429.
Weber C, Erl W, Weber KSC, Weber PC. HMG-CoA reductase inhibitors decrease CD11b expression and CD11b-dependent adhesion of monocytes to endothelium and reduce increased adhesiveness of monocytes isolated from patients with hypercholesterolemia.  J Am Coll Cardiol.1997;30:1212-1217.
Kimura M, Kurose I, Russell J, Granger DN. Effects of fluvastatin on leukocyte-endothelial cell adhesion in hypercholesterolemic rats.  Arterioscler Thromb Vasc Biol.1997;17:1521-1526.
Kobashigawa JA, Katznelson S, Laks H.  et al.  Effect of pravastatin on outcomes after cardiac transplantation.  N Engl J Med.1995;333:621-627.
Richardson PD, Davies MJ, Born GVR. Influence of plaque configuration and stress distribution on fissuring of coronary atherosclerotic plaques.  Lancet.1989;2:941-944.
Cheng GC, Loree HM, Kamm RD, Fishbein MC, Lee RT. Distribution of circumferential stress in ruptured and stable atherosclerotic lesions: a structural analysis with histopathological correlation.  Circulation.1993;87:1179-1187.
Wilcox JN, Smith KM, Schwartz SM, Gordon D. Localization of tissue factor in the normal vessel wall and in the atherosclerotic plaque.  Proc Natl Acad Sci U S A.1989;86:2839-2843.
Fernandez-Ortiz A, Badimon JJ, Falk E.  et al.  Characterization of the relative thrombogenicity of atherosclerotic plaque components: implications for consequences of plaque rupture.  J Am Coll Cardiol.1994;23:1562-1569.
Bernini F, Didoni G, Bonfadini G, Bellosta S, Fumagalli R. Requirement for mevalonate in acetylated LDL induction of cholesterol esterification in macrophages.  Atherosclerosis.1993;104:19-26.
Kempen HJM, Vermeer M, deWit E, Havekes LM. Vastatins inhibit cholesterol ester accumulation in human monocyte-derived macrophages.  Arterioscler Thromb.1991;11:146-153.
Armstrong ML, Warner E, Connor W. Regression of coronary atheromatosis in rhesus monkeys.  Circ Res.1970;27:59-67.
Clarkson TB, Bond MG, Bullock BC, Marzetta CA. A study of atherosclerosis regression in Macaca mulatta Exp Mol Pathol.1981;34:345-368.
Small DM, Bond MG, Waugh D, Prack M, Sawyer JK. Physiocochemical and histological changes in the arterial wall of nonhuman primates during progression and regression of atherosclerosis.  J Clin Invest.1984;73:1590-1605.
Small DM. Progression and regression of atherosclerotic lesions: insights from lipid physical biochemistry.  Arteriosclerosis.1988;8:103-129.
deGraaf J, Hak-Lemmers HLM, Hectors MPC, Demaker PCM, Hendriks JCM, Stalenhoef AFH. Enhanced susceptibility to in vitro oxidation of the dense low density lipoprotein subfraction in healthy subjects.  Arterioscler Thromb.1991;11:298-306.
Navab M, Berliner JA, Watson AD.  et al.  The yin and yang of oxidation in the development of the fatty streak: a review based on the 1994 George Lyman Duff Memorial Lecture.  Arterioscler Thromb Vasc Biol.1996;16:831-842.
Gardner CD, Fortmann SP, Krauss RM. Association of small low-density lipoprotein particles with the incidence of coronary artery disease in men and women.  JAMA.1996;276:875-881.
Stampfer MJ, Krauss RM, Ma J.  et al.  A prospective study of triglyceride level, low-density lipoprotein particle diameter, and risk of myocardial infarction.  JAMA.1996;276:882-888.
Miller BD, Alderman EL, Haskell WL, Fair JM, Krauss RM. Predominance of dense low-density lipoprotein particles predicts angiographic benefit of therapy in the Stanford Coronary Risk Intervention Project.  Circulation.1996;94:2146-2153.
Salonen R, Nyyssonen K, Porkkala-Sarataho E.  et al.  The Kuopio Atherosclerosis Prevention Study (KAPS): effect of pravastatin treatment on lipids, oxidation resistance of lipoproteins, and atherosclerotic progression.  Am J Cardiol.1995;76:34C-39C.
Hoffman R, Brook GJ, Aviram M. Hypolipidemic drugs reduce lipoprotein susceptibility to undergo lipid peroxidation: in vitro and ex vivo studies.  Atherosclerosis.1992;93:105-113.
Aviram M, Dankner G, Cogan U, Hochgraf E, Brook JG. Lovastatin inhibits low-density lipoprotein oxidation and alters its fluidity and uptake by macrophages: in vitro and in vivo studies.  Metabolism.1992;41:229-235.
Brosche T, Kral C, Summa JD, Platt D. Effective lovastatin therapy in elderly hypercholesterolemic patients—an antioxidative impact?  Arch Gerontol Geriatr.1996;22:207-221.
Ghirlanda G, Oradei A, Manto A.  et al.  Evidence of plasma CoQ10-lowering effect by HMG-CoA reductase inhibitors: a double-blind, placebo-controlled study.  J Clin Pharmacol.1993;33:226-229.
Watts GF, Castelluccio C, Rice-Evans C, Taub NA, Baurn H, Quinn PF. Plasma coenzyme Q (ubiquinone) concentrations in patients treated with simvastatin.  J Clin Pathol.1993;46:1055-1057.
Giroux LM, Davignon J, Naruszewicz M. Simvastatin inhibits the oxidation of low-density lipoproteins by activated human monocyte-derived macrophages.  Biochim Biophys Acta.1993;1165: 335-338.
Laaksonen R, Jokelainen K, Laakso J.  et al.  The effect of simvastatin treatment on natural antioxidants in low-density lipoproteins and high-energy phosphates and ubiquinone in skeletal muscle.  Am J Cardiol.1996;77:851-854.
Willis RA, Folkers K, Tucker JL, Ye CQ, Xia LJ, Tamagawa H. Lovastatin decreases coenzyme Q levels in rats.  Proc Natl Acad Sci U S A.1990;87:8928-8930.
Marinari UM, Pronzato MA, Dapino D.  et al.  Effects of simvastatin on liver and plasma levels of cholesterol, dolichol and ubiquinol in hypercholesterolemic rats.  Ital J Biochem.1995;44:1-9.
Weissberg PL, Clesham GJ, Bennett MR. Is vascular smooth muscle cell proliferation beneficial?  Lancet.1996;347:305-307.
Cheng GC, Libby P, Grodzinsky AJ, Lee RT. Induction of DNA synthesis by a single transient mechanical stimulus of human vascular smooth muscle cells: role of fibroblast growth factor-2.  Circulation.1996;93:99-105.
Soma MR, Donetti E, Parolini C.  et al.  HMG CoA reductase inhibitors: in vivo effects on carotid intimal thickening in normocholesterolemic rabbits.  Arterioscler Thromb.1993;13:571-578.
Corsini A, Raiteri M, Soma M, Fumagalli R, Paoletti R. Simvastatin but not pravastatin inhibits the proliferation of rat aorta myocytes.  Pharmacol Res.1991;23:173-180.
Negre-Aminoux P, van Vliet AK, van Erck M.  et al.  Inhibition of proliferation of human smooth muscle cells by various HMG-CoA reductase inhibitors: comparison with other human cell types.  Biochim Biophys Acta.1997;1345:259-268.
Igarashi M, Takeda Y, Mori S.  et al.  Suppression of neointimal thickening by a newly developed HMG-CoA reductase inhibitor, BAYw6228, and its inhibitory effect on vascular smooth muscle cell growth.  Br J Pharmacol.1997;120:1172-1178.
Corsini A, Pazzucconi F, Pfister P, Paoletti R, Sirtori CR. Inhibitor of proliferation of arterial smooth-muscle cells by fluvastatin.  Lancet.1996;348:1584.
Nemerson Y. Tissue factor and haemostasis.  Blood.1988;71:1-8.
Colli S, Eligini S, Lalli M, Camera M, Paoletti R, Tremoli E. Vastatins inhibit tissue factor in cultured human macrophages.  Arterioscler Thromb Vasc Biol.1997;17:265-272.
Lesnik P, Vonica A, Guerin M, Moreau M, Chapman MJ. Anticoagulant activity of tissue factor pathway inhibitor in human plasma is preferentially associated with dense subspecies of LDL and HDL and with Lp(a).  Arterioscler Thromb.1993;13:1066-1075.
Sandset PM, Lund H, Norseth J, Abildgaard U, Ose L. Treatment with hydroxymethylglutaryl-coenzyme A reductase inhibitors in hypercholesterolemia induces changes in the components of the extrinsic coagulation system.  Arterioscler Thromb.1991;11:138-145.
Hansen JB, Huseby NE, Sandset PM, Svensson B, Lyngmo V, Nordoy A. Tissue factor pathway inhibitor and lipoproteins: evidence for association with and regulation by LDL in human plasma.  Arterioscler Thromb.1994;14:223-229.
Zitoun D, Bara L, Basdevant A, Samama MM. Levels of factor VIIc associated with decreased tissue factor pathway inhibitor and increased plasminogen activator inhibitor-1 in dyslipidemias.  Arterioscler Thromb Vasc Biol.1996;16:77-81.
Carvalho AC, Colman RW, Less RS. Platelet function in hyperlipoproteinemia.  N Engl J Med.1974;290:434-438.
Nofer JR, Tepel M, Kehrel B.  et al.  Low-density lipoproteins inhibit the Na+/H+ antiport in human platelets: a novel mechanism enhancing platelet activity in hypercholesterolemia.  Circulation.1997;95:1370-1377.
van Willigan G, Gorter G, Akkerman JWN. LDLs increase the exposure of fibrinogen binding sites on platelets and secretion of dense granules.  Arterioscler Thromb.1994;14:41-46.
Davi G, Averna M, Novo S.  et al.  Effects of synvinolin on platelet aggregation and thromboxane B2 synthesis in type IIa hypercholesterolemic patients.  Atherosclerosis.1989;79:79-83.
Notarbartolo A, Davi G, Averna M.  et al.  Inhibition of thromboxane biosynthesis and platelet function by simvastatin in type IIa hypercholesterolemia.  Arterioscler Thromb Vasc Biol.1995;15:247-251.
Beigel Y, Fuchs J, Snir M, Green P, Lurie Y, Djaldetti M. Lovastatin therapy in hypercholesterolemia: effect on fibrinogen, hemorrheologic parameters, platelet activity, and red blood cell morphology.  J Clin Pharmacol.1991;31:512-517.
Mayer J, Eller T, Brauer P.  et al.  Effects of long-term treatment with lovastatin on the clotting system and blood platelets.  Ann Hematol.1992;64:196-201.
Aoki I, Aoki A, Kawano K.  et al.  Platelet-dependent thrombin generation in patients with hyperlipidemia.  J Am Coll Cardiol.1997;30:91-96.
Le Quan Sang KH, Levenson J, Megnien JL, Simon A, Devynck MA. Platelet cytosolic Ca2+ and membrane dynamics in patients with primary hypercholesterolemia: effects of pravastatin.  Arterioscler Thromb Vasc Biol.1995;15:759-764.
Lacoste L, Lam JYT, Hung J.  et al.  Hyperlipidemia and coronary disease: correction of the increased thrombogenic potential with cholesterol reduction.  Circulation.1995;92:3172-3177.
Lacoste L, Lam JYT. Comparative effect of pravastatin and simvastatin on platelet-thrombus formation in hypercholesterolemic coronary patients.  J Am Coll Cardiol.1996;27:413A.
Rosenson RS. Viscosity and ischemic heart disease.  J Vasc Med Biol.1993;4:206-212.
Rosenson RS, Tangney CC. Beneficial effects of statins.  Lancet.1996;348:1583.
Isaacsohn J, Setaro JF, Nicholas C.  et al.  Effects of lovastatin therapy on plasminogen activator inhibitor-1 antigen levels.  Am J Cardiol.1994;74:735-737.
Davidson M, McKenney J, Stein E.  et al.  Comparison of one-year efficacy and safety of atorvastatin versus lovastatin in primary hypercholesterolemia.  Am J Cardiol.1997;79:1475-1481.
Koenig W, Hehr R, Ditschuneit HH.  et al.  Lovastatin alters blood rheology in primary hyperlipoproteinemia: dependence on lipoprotein(a)?  J Clin Pharmacol.1992;32:539-545.
Koppensteiner R, Minar E, Ehringer H. Effect of lovastatin on hemorheology in type II hyperlipoproteinemia.  Atherosclerosis.1990;83:53-58.
Jay RH, Ramply MW, Betteridge DJ. Abnormalities of blood rheology in familial hypercholesterolemia: effects of treatment.  Am J Cardiol.1993;72:1031-1037.
Avellone G, Di Garbo V, Cordova R, Raneli G, De Simone R, Bompiani G. Changes induced by pravastatin treatment on hemostatic and fibrinolytic patterns in patients with type IIB hyperlipoproteinemia.  Curr Ther Res Clin Exp.1994;55:1335-1344.
Tsuda Y, Satoh K, Kitadai M.  et al.  Effects of pravastatin sodium and simvastatin on plasma fibrinogen level and blood rheology in type II hyperlipoproteinemia.  Atherosclerosis.1996;122:225-233.
Wada H, Mori Y, Kaneko T.  et al.  Hypercoagulable state in patients with hypercholesterolemia: effects of pravastatin.  Clin Ther.1992;14:829-834.
Branchi A, Rovellini A, Sommariva D, Gugliandolo AG, Fasoli A. Effect of three fibrate derivatives and of two HMG-CoA reductase inhibitors on plasma fibrinogen level in patients with primary hypercholesterolemia.  Thromb Haemost.1993;70:241-243.
The Writing Group for the PEPI Trial.  Effects of estrogen or estrogen/progestin regimens on heart disease risk factors in postmenopausal women: the Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial.  JAMA.1995;273:199-208.
Bo M, Bonino F, Neirotti M.  et al.  Hemorheologic and coagulative pattern in hypercholesterolemic subjects treated with lipid-lowering drugs.  Angiology.1991;42:106-113.
Mitropoulos KA, Armitage JM, Collins R.  et al.  Randomized placebo-controlled study of the effects of simvastatin on haemostatic variables, lipoproteins and free fatty acids.  Eur Heart J.1997;18:235-241.
Marais AD, Firth JC, Bateman ME, Byrnes P, Martens C, Mountney J. Atorvastatin: an effective lipid-modifying agent in familial hypercholesterolemia.  Arterioscler Thromb Vasc Biol.1997;17:1527-1531.
Wierzbicki AS, Lumb PJ, Semra YK, Crook MA. Effect of atorvastatin on plasma fibrinogen.  Lancet.1998;351:569-570.
Behague I, Poirier O, Nicaud V.  et al.  β Fibrinogen gene polymorphisms are associated with plasma fibrinogen and coronary artery disease in patients with myocardial infarction: the ECTIM Study.  Circulation.1996;93:440-449.
Rosenson RS, Tangney CC, Hafner JM. Intraindividual variability of fibrinogen levels and cardiovascular risk profile.  Arterioscler Thromb.1994;14:1928-1932.
Meade TW, Ruddock V, Stirling Y, Chakrabarti R, Miller GJ. Fibrinolytic activity, clotting factors, and long-term incidence of ischaemic heart disease in the Northwick Park Heart Study.  Lancet.1993;342:1076-1079.
Hamsten A, Wiman B, De Faire U, Blomback M. Increased plasma levels of a rapid inhibitor of tissue plasminogen activator in young survivors of myocardial infarction.  N Engl J Med.1985;313:1557-1563.
Juhan-Vague I, Pyke SDM, Alessi MC, Jespersen J, Haverkate F, Thompson SG.for the ECAT Study Group.  Fibrinolytic factors and the risk of myocardial infarction or sudden death in patients with angina pectoris.  Circulation.1996;94:2057-2063.
Bevilacqua M, Bettica P, Milani M.  et al.  Effect of fluvastatin on lipids and fibrinolysis in coronary artery disease.  Am J Cardiol.1997;79:84-87.
Stein JH, Rosenson RS. Lipoprotein(a) and coronary heart disease.  Arch Intern Med.1997;157:1170-1176.
Harpel PC, Gordon BR, Parker TS. Plasmin catalyzes binding of lipoprotein(a) to immobilized fibrinogen and fibrin.  Proc Natl Acad Sci U S A.1989;86:3847-3851.
Leren TP, Hjermann I, Berg K, Leren P, Foss OP, Viksmoen L. Effects of lovastatin alone and in combination with cholestyramine on serum lipids and apolipoproteins in heterozygotes for familial hypercholesterolemia.  Atherosclerosis.1988;73: 135-141.
Kostner GM, Gavish D, Leopold B, Bolzano K, Weintraub MS, Breslow JL. HMG CoA reductase inhibitors lower LDL cholesterol without reducing Lp(a) levels.  Circulation.1989;80:1313-1319.
Slunga L, Johnson O, Dahlen GH. Changes in Lp(a) lipoprotein levels during the treatment of hypercholesterolemia with simvastatin.  Eur J Clin Pharmacol.1992;43:369-373.
Haffner S, Orchard T, Stein E, Schmidt D, LaBelle P. Effect of simvastatin on Lp(a) concentrations.  Clin Cardiol.1995;18:261-267.
Hunninghake DB, Stein EA, Mellies MJ. Effects of one year of treatment with pravastatin, an HMG-CoA reductase inhibitor, on lipoprotein(a).  J Clin Pharmacol.1993;33:574-580.

Figures

Graphic Jump Location
Coronary plaque disruption and major pathophysiological pathways as influenced by various statin therapies. This schematic diagram depicts an acute plaque disruption and resultant thrombus formation. Recirculation zones increase blood viscosity, which foster rapid plaque formation. NO indicates nitric oxide; PAI-1, plasminogen activator inhibitor 1; PGI2, prostacyclin; MCP-1, monocyte chemotactic protein 1; M-CSF, monocyte colony-stimulating factor; LDL, low-density lipoprotein; Ox-LDL, oxidized low-density lipoprotein; MM-LDL, minimally modified low-density lipoprotein; A, atorvastatin; C, cerivastatin; F, fluvastatin; L, lovastatin; P, pravastatin; and S, simvastatin.

Tables

Table Graphic Jump LocationTable 1.—Potential Differential Mechanisms Beyond Lipid Lowering
Table Graphic Jump LocationTable 2.—Effect of Statins on Cardiovascular (CV) Event Reduction and LDL-Cholesterol Levels*
Table Graphic Jump LocationTable 3.—Comparison of Statins on Potential Mechanisms Influencing Plaque Stabilization and Thrombosis*

References

Thompson GR, Hollyer J, Waters DD. Percentage change rather than plasma level of LDL-cholesterol determines therapeutic response in coronary heart disease.  Curr Opin Lipidol.1995;6:386-388.
Sacks FM, Gibson CM, Rosner B, Pasternak RC, Stone PH.and the Harvard Atherosclerosis Reversibility Project Research Group.  The influence of pretreatment low density lipoprotein cholesterol concentrations on the effect of hypercholesterolemic therapy on coronary atherosclerosis in angiographic trials.  Am J Cardiol.1995;76:78C-85C.
Jukema JW, Bruschke AVG, van Boven AJ.  et al.  Effects of lipid lowering by pravastatin on progression and regression of coronary artery disease in symptomatic men with normal to moderately elevated serum cholesterol levels: the Regression Growth Evaluation Statin Study (REGRESS).  Circulation.1995;91:2528-2540.
Scandinavian Simvastatin Survival Study Group.  Baseline serum cholesterol and treatment effect in the Scandinavian Simvastatin Survival Study (4S).  Lancet.1995;345:1274-1275.
West of Scotland Coronary Prevention Study Group.  Influence of pravastatin and plasma lipids on clinical events in the West of Scotland Coronary Prevention Study (WOSCOPS).  Circulation.1998;97:1440-1445.
The Expert Panel on Detection Evaluation, and Treatment of High Blood Cholesterol in Adults.  Expert Panel Report of the National Cholesterol Education Program.  Arch Intern Med.1986;148:36-69.
The Expert Panel on Detection Evaluation, and Treatment of High Blood Cholesterol in Adults.  Summary of the second report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel II).  JAMA.1993;269:3015-3023.
Study Group of the European Atherosclerosis Society.  The recognition and management of hyperlipidemia in adults: a policy statement of the European Atherosclerosis Society.  Eur Heart J.1988;9:571-600.
The Canadian Consensus Conference on Cholesterol.  Final report.  Can Med Assoc J.1988;26:369-388.
Pekkannen J, Linn S, Heiss G.  et al.  Ten-year mortality from cardiovascular disease in relaxation to cholesterol level among men with and without preexisting cardiovascular disease.  N Engl J Med.1990;322:1700-1707.
Pekkannen J, Tervahuata M, Nissinen A, Karvonen MJ. Does the predictive value of baseline coronary risk factors change over a 30-year follow-up?  Cardiology.1993;82:181-190.
Grover SA, Coupal L, Hu XP. Identifying adults at increased risk of coronary disease: how well do the current cholesterol guidelines work?  JAMA.1995;274:801-806.
Castelli WP, Garrison RJ, Wilson PWF, Abbott RD, Kalousdian S, Kannel WB. Incidence of coronary heart disease and lipoprotein cholesterol levels: the Framingham Study.  JAMA.1986;256:2835-2838.
Heinrich J, Ballaisen L, Schulte H, Assmann G, van de Loo J. Fibrinogen and factor VII in the prediction of coronary risk: results from the PROCAM Study in healthy men.  Arterioscler Thromb.1994;14:54-59.
Thompson SG, Kienast J, Pyke SDM, Haverkate F, van de Loo JCW.for the European Concerted Action on Thrombosis and Disabilities Angina Pectoris Study Group.  Hemostatic factors and the risk of myocardial infarction or sudden death in patients with angina pectoris.  N Engl J Med.1995;332:635-641.
Sweetnam PM, Thomas HF, Yarnell JWG, Beswick AD, Baker IA, Elwood PC. Fibrinogen, viscosity, and the 10-year incidence of ischaemic heart disease.  Eur Heart J.1996;17:1814-1820.
Tonkin A.for the Long-term Intervention With Pravastatin in Ischemic Disease (LIPID).  Not Available. Paper presented at: 70th Scientific Sessions of the American Heart Association; November 12, 1997. Orlando, Fla.
Downs JR, Clearfield M, Weis S.  et al.  Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS.  JAMA.1998;279:1615-1622.
Pitt B, Mancini GBJ, Ellis SG, Rosman HS, Park JS, McGovern ME. Pravastatin Limitation of Atherosclerosis in the Coronary Arteries (PLAC I): reduction in atherosclerosis progression and clinical events.  J Am Coll Cardiol.1995;26:1133-1139.
The Pravastatin Multinational Study Group for Cardiac Risk Patients.  Effects of pravastatin in patients with serum total cholesterol levels from 5.2 to 7.8 mmol/Liter (200 to 300 mg/dl) plus two additional atherosclerotic risk factors.  Am J Cardiol.1993;72:1031-1037.
Shepherd J, Cobb SM, Ford I.  et al.  Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia.  N Engl J Med.1995;333:1301-1307.
Crouse JR, Byington RP, Bond MG.  et al.  Pravastatin, Lipids, and Atherosclerosis in the Carotid Arteries (PLAC II).  Am J Cardiol.1995;75:455-459.
Furberg CD, Adams Jr HP, Applegate WB.  et al.  Effect of lovastatin on early carotid atherosclerosis and cardiovascular events.  Circulation.1994;90:1679-1687.
Sacks FM, Pfeffer MA, Moye LA.  et al.  The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels.  N Engl J Med.1996;335:1001-1009.
Waters D, Higginson L, Gladstone P.  et al.  Effects of monotherapy with an HMG-CoA reductase inhibitor on the progression of coronary atherosclerosis as assessed by serial quantitative arteriography: the Canadian Coronary Atherosclerosis Intervention Trial.  Circulation.1994;89:959-968.
Salonen R, Nyyssonen K, Porkkala E.  et al.  Kuopio Atherosclerosis Prevention Study (KAPS): a population based primary preventive trial of the effect of LDL lowering on atherosclerotic progression in carotid and femoral arteries.  Circulation.1995;92:1758-1764.
MAAS Investigators.  Effect of simvastatin on coronary atheroma: the Multicentre Anti-atheroma Study (MAAS).  Lancet.1994;344:633-638.
Scandinavian Simvastatin Survival Study Group.  Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S).  Lancet.1994;344:1383-1389.
Blankenhorn DH, Azen SP, Kramsch DM.  et al.  Coronary angiographic changes with lovastatin therapy: the Monitored Atherosclerosis Regression Study (MARS).  Ann Intern Med.1993;119:969-976.
The Post Coronary Artery Bypass Graft Trial Investigators.  The effect of aggressive lowering of low-density lipoprotein cholesterol levels and low-dose anticoagulation on obstructive changes in saphenous-vein coronary-artery bypass grafts.  N Engl J Med.1997;336:153-162.
Grover SA, Abrahamowicz M, Joseph L, Brewer C, Coupal L, Suissa S. The benefits of treating hyperlipidemia to prevent coronary heart disease: estimating changes in life expectancy and morbidity.  JAMA.1992;267:816-822.
Vaughan CJ, Murphy MB, Buckley BM. Statins do more than lower cholesterol.  Lancet.1996;348:1079-1082.
Kinlay S, Selwyn AP, Delagrange D, Creager MA, Libby P, Ganz P. Biological mechanisms for the clinical success of lipid-lowering in coronary artery disease and the use of surrogate end points.  Curr Opin Lipidol.1996;7:389-397.
Byington RP, Jukema JW, Salonen JT.  et al.  Reduction in cardiovascular events during pravastatin therapy: pooled analysis of clinical events of the Pravastatin Atherosclerosis Intervention Program.  Circulation.1995;92:2419-2425.
Davies MJ, Thomas A. Thrombosis and acute coronary-artery lesions in sudden cardiac ischemic death.  N Engl J Med.1984;310:1137-1140.
Davies MJ, Thomas AC. Plaque fissuring: the cause of acute myocardial infarction, sudden ischaemic death and crescendo angina.  Br Heart J.1985;53:363-373.
Libby P. Molecular basis of acute coronary syndromes.  Circulation.1995;91:2844-2850.
Falk E, Shah PK, Fuster V. Coronary plaque disruption.  Circulation.1995;92:657-671.
Davies MJ. Stability and instability: two faces of coronary atherosclerosis: the Paul Dudley White Lecture, 1995.  Circulation.1996;94:2013-2020.
Farb A, Burke AP, Tang AL.  et al.  Coronary plaque erosion without rupture into a lipid core: a frequent cause of coronary thrombosis in sudden coronary death.  Circulation.1996;93:1354-1363.
Hackett D, Davies G, Maseri A. Preexisting coronary stenoses in patients with first myocardial infarction are not necessarily severe.  Eur Heart J.1988;9:1317-1323.
Berliner JA, Navab M, Fogelman AM.  et al.  Atherosclerosis: basic mechanisms: oxidation, inflammation, and genetics.  Circulation.1995;91:2488-2496.
Hansson GK, Holm J, Jonasson L. Detection of activated T lymphocytes in the human atherosclerotic plaque.  Am J Pathol.1989;135:169-175.
van der Wal AC, Becker AE, van der Loos CM, Das PK. Site of intimal rupture or erosion of thrombosed coronary atherosclerotic plaques is characterized by an inflammatory process irrespective of the dominant plaque morphology.  Circulation.1994;89:36-44.
Rekhter M, Zhang K, Narayanan A, Phan S, Schork M, Gordon D. Type I collagen gene expression in human atherosclerosis: localization to specific plaque regions.  Am J Pathol.1993;143:1634-1648.
Warner SJC, Friedman GB, Libby P. Immune interferon inhibits proliferation and induces 2‘-5‘-oligoadenylate synthetase gene expression in human vascular smooth muscle cells.  J Clin Invest.1989;83:1174-1182.
Amento EP, Ehsani N, Palmer H, Libby P. Cytokines positively and negatively regulate interstitial collagen gene expression in human vascular smooth muscle cells.  Arterioscler Thromb.1991;11:1223-1230.
Shiomi M, Ito T, Tsukada T.  et al.  Reduction of serum cholesterol levels alters lesional composition of atherosclerotic plaques: effect of pravastatin sodium on atherosclerosis in mature WHHL rabbits.  Arterioscler Thromb Vasc Biol.1995;15:1938-1944.
Williams JK, Sukhova GK, Herrington DM, Libby P. Pravastatin has cholesterol-lowering independent effects on the artery wall of atherosclerotic monkeys.  J Am Coll Cardiol.1998;31:684-691.
Dimmeler S, Haendeler J, Galle J, Zeiher AM. Oxidized low-density lipoprotein induces apoptosis of human endothelial cells by activation of CPP32-like proteases: a mechanistic clue to the "response to injury" hypothesis.  Circulation.1997;95:1760-1763.
Nickenig G, Sachinidis A, Michaelsen F, Bohm M, Seewald S, Vetter H. Upregulation of vascular angiotensin II receptor gene expression by low-density lipoprotein in vascular smooth muscle cells.  Circulation.1997;95:473-478.
Pedreno J, de Castellarnau C, Cullare C.  et al.  LDL binding sites on platelets differ from the "classical" receptor of nucleated cells.  Arterioscler Thromb.1992;12:1353-1362.
Chen LY, Mehta P, Mehta JL. Oxidized LDL decreases L-arginine uptake and nitric oxide synthase protein expression in human platelets: relevance of the effect of oxidized LDL on platelet function.  Circulation.1996;93:1740-1746.
Hassall DG, Owens JS, Bruckdorfer KR. The aggregation of isolated human platelets in the presence of lipoproteins and prostacyclin.  Biochem J.1983;216:43-49.
Dentan C, Lesnik P, Chapman MJ, Ninio E. PAF-acether-degrading acetylhydrolase in plasma LDL is inactivated by copper- and cell-mediated oxidation.  Arterioscler Thromb.1994;14:353-360.
Broze Jr GJ. The role of tissue factor pathway inhibitor in a revised coagulation cascade.  Semin Hematol.1992;29:159-169.
Sanders NL, Bajaj SP, Zivelin A, Rapaport SI. Inhibition of tissue factor/factor VII activity in plasma requires factor X and an additional plasma component.  Blood.1985;66:204-212.
Woodward M, Lowe GDO, Rumley A.  et al.  Epidemiology of coagulation factors, inhibitors and activation markers, the Third Glasgow MONICA Survey II: relationships to cardiovascular risk factors and prevalent cardiovascular disease.  Br J Haematol.1997;97:785-797.
Rosenson RS, Lowe GDO. Effects of lipids and lipoproteins on thrombosis and rheology.  Atherosclerosis.1998;140:271-280.
Balleisen L, Assmann G, Bailey J, Epping P-H, Schulte H, van de Loo J. Epidemiological study on factor VII, factor VIII and fibrinogen in an industrial population, II: baseline data on the relation to blood pressure, blood glucose, uric acid, and lipid fractions.  Thromb Haemost.1985;54:721-723.
Leung WH, Lau CP, Wong CK. Beneficial effect of cholesterol-lowering therapy on coronary endothelium-dependent relaxation in hypercholesterolaemic patients.  Lancet.1993;341:1496-1500.
Anderson TJ, Gerhard MD, Meredith IT.  et al.  Systemic nature of endothelial dysfunction in atherosclerosis.  Am J Cardiol.1995;75:71B-74B.
Egashira K, Hirooka Y, Kai H.  et al.  Reduction in serum cholesterol with pravastatin improves endothelium-dependent coronary vasomotion in patients with hypercholesterolemia.  Circulation.1994;89:2519-2524.
Treasure CB, Klein JL, Weintraub WS.  et al.  Beneficial effects of cholesterol-lowering therapy on the coronary endothelium in patients with coronary artery disease.  N Engl J Med.1995;332:481-487.
Anderson TJ, Meredith IT, Yeung AC, Frei B, Selwyn AP, Ganz P. The effect of cholesterol-lowering and antioxidant therapy on endothelium-dependent coronary vasomotion.  N Engl J Med.1995;332:488-493.
Winniford M, Hodgson J, Yeung A.  et al.  CARAT Study: the effect of cholesterol lowering on coronary blood flow. Study presented at: 66th Congress of the European Atherosclerosis Society; July 1996; Florence, Italy.
Stroes ESG, Koomans HA, deBruin TWA, Rabelink TJ. Vascular function in the forearm of hypercholesterolaemic patients off and on lipid-lowering medication.  Lancet.1995;346:467-471.
Vogel RA, Corretti MC, Plotnick GD. Changes in flow-mediated brachial artery vasoactivity with lowering of desirable cholesterol levels in healthy middle-aged men.  Am J Cardiol.1996;77:37-40.
Hayoz D, Weber R, Rutschmann B.  et al.  Postischemic blood flow response in hypercholesterolemic patients.  Hypertension.1995;26:497-502.
O'Driscoll G, Green D, Taylor RR. Simvastatin, an HMG-coenzyme A reductase inhibitor, improves endothelial function within 1 month.  Circulation.1997;95:1126-1131.
van Boven AJ, Jukema JW, Zwinderman AH, Crijns HJ, Lie KI, Bruschke AVG. Reduction of transient myocardial ischemia with pravastatin in addition to the conventional treatment in patients with angina pectoris.  Circulation.1996;94:1503-1505.
Andrews TC, Raby K, Barry J.  et al.  Effect of cholesterol reduction on myocardial ischemia in patients with coronary disease.  Circulation.1997;95:324-328.
Eichstadt HW, Eskotter H, Hoffmann I, Amthauer HW, Weidinger G. Improvement of myocardial perfusion by short-term fluvastatin therapy in coronary artery disease.  Am J Cardiol.1995;76:122A-125A.
Aengevaeren WRM, Uijen GJH, Jukema JW, Bruschke AVG, Werf T. Functional evaluation of lipid-lowering therapy by pravastatin in the Regression Growth Evaluation Statin Study.  Circulation.1997;96:429-435.
Straznicky NE, Howes LG, Lam W, Louis WJ. Effects of pravastatin on cardiovascular reactivity to norepinephrine and angiotensin II in patients with hypercholesterolemia and systemic hypertension.  Am J Cardiol.1995;75:582-586.
Vallance P, Collier J, Bhagat K. Infection, inflammation, and infarction: does acute endothelial dysfunction provide a link?  Lancet.1997;349:1391-1392.
Neumann FJ, Marx N, Gawaz M.  et al.  Induction of cytokine expression in leukocytes by binding of thrombin-stimulated platelets.  Circulation.1997;95:2387-2394.
Green F, Humphries S. Control of plasma fibrinogen levels.  Baillieres Clin Haematol.1989;2:945-959.
Padgett RC, Heistad DD, Mugge A, Armstrong ML, Piegors DJ, Lopez JAG. Vascular responses to activated leukocytes after regression of atherosclerosis.  Circ Res.1992;70:423-429.
Weber C, Erl W, Weber KSC, Weber PC. HMG-CoA reductase inhibitors decrease CD11b expression and CD11b-dependent adhesion of monocytes to endothelium and reduce increased adhesiveness of monocytes isolated from patients with hypercholesterolemia.  J Am Coll Cardiol.1997;30:1212-1217.
Kimura M, Kurose I, Russell J, Granger DN. Effects of fluvastatin on leukocyte-endothelial cell adhesion in hypercholesterolemic rats.  Arterioscler Thromb Vasc Biol.1997;17:1521-1526.
Kobashigawa JA, Katznelson S, Laks H.  et al.  Effect of pravastatin on outcomes after cardiac transplantation.  N Engl J Med.1995;333:621-627.
Richardson PD, Davies MJ, Born GVR. Influence of plaque configuration and stress distribution on fissuring of coronary atherosclerotic plaques.  Lancet.1989;2:941-944.
Cheng GC, Loree HM, Kamm RD, Fishbein MC, Lee RT. Distribution of circumferential stress in ruptured and stable atherosclerotic lesions: a structural analysis with histopathological correlation.  Circulation.1993;87:1179-1187.
Wilcox JN, Smith KM, Schwartz SM, Gordon D. Localization of tissue factor in the normal vessel wall and in the atherosclerotic plaque.  Proc Natl Acad Sci U S A.1989;86:2839-2843.
Fernandez-Ortiz A, Badimon JJ, Falk E.  et al.  Characterization of the relative thrombogenicity of atherosclerotic plaque components: implications for consequences of plaque rupture.  J Am Coll Cardiol.1994;23:1562-1569.
Bernini F, Didoni G, Bonfadini G, Bellosta S, Fumagalli R. Requirement for mevalonate in acetylated LDL induction of cholesterol esterification in macrophages.  Atherosclerosis.1993;104:19-26.
Kempen HJM, Vermeer M, deWit E, Havekes LM. Vastatins inhibit cholesterol ester accumulation in human monocyte-derived macrophages.  Arterioscler Thromb.1991;11:146-153.
Armstrong ML, Warner E, Connor W. Regression of coronary atheromatosis in rhesus monkeys.  Circ Res.1970;27:59-67.
Clarkson TB, Bond MG, Bullock BC, Marzetta CA. A study of atherosclerosis regression in Macaca mulatta Exp Mol Pathol.1981;34:345-368.
Small DM, Bond MG, Waugh D, Prack M, Sawyer JK. Physiocochemical and histological changes in the arterial wall of nonhuman primates during progression and regression of atherosclerosis.  J Clin Invest.1984;73:1590-1605.
Small DM. Progression and regression of atherosclerotic lesions: insights from lipid physical biochemistry.  Arteriosclerosis.1988;8:103-129.
deGraaf J, Hak-Lemmers HLM, Hectors MPC, Demaker PCM, Hendriks JCM, Stalenhoef AFH. Enhanced susceptibility to in vitro oxidation of the dense low density lipoprotein subfraction in healthy subjects.  Arterioscler Thromb.1991;11:298-306.
Navab M, Berliner JA, Watson AD.  et al.  The yin and yang of oxidation in the development of the fatty streak: a review based on the 1994 George Lyman Duff Memorial Lecture.  Arterioscler Thromb Vasc Biol.1996;16:831-842.
Gardner CD, Fortmann SP, Krauss RM. Association of small low-density lipoprotein particles with the incidence of coronary artery disease in men and women.  JAMA.1996;276:875-881.
Stampfer MJ, Krauss RM, Ma J.  et al.  A prospective study of triglyceride level, low-density lipoprotein particle diameter, and risk of myocardial infarction.  JAMA.1996;276:882-888.
Miller BD, Alderman EL, Haskell WL, Fair JM, Krauss RM. Predominance of dense low-density lipoprotein particles predicts angiographic benefit of therapy in the Stanford Coronary Risk Intervention Project.  Circulation.1996;94:2146-2153.
Salonen R, Nyyssonen K, Porkkala-Sarataho E.  et al.  The Kuopio Atherosclerosis Prevention Study (KAPS): effect of pravastatin treatment on lipids, oxidation resistance of lipoproteins, and atherosclerotic progression.  Am J Cardiol.1995;76:34C-39C.
Hoffman R, Brook GJ, Aviram M. Hypolipidemic drugs reduce lipoprotein susceptibility to undergo lipid peroxidation: in vitro and ex vivo studies.  Atherosclerosis.1992;93:105-113.
Aviram M, Dankner G, Cogan U, Hochgraf E, Brook JG. Lovastatin inhibits low-density lipoprotein oxidation and alters its fluidity and uptake by macrophages: in vitro and in vivo studies.  Metabolism.1992;41:229-235.
Brosche T, Kral C, Summa JD, Platt D. Effective lovastatin therapy in elderly hypercholesterolemic patients—an antioxidative impact?  Arch Gerontol Geriatr.1996;22:207-221.
Ghirlanda G, Oradei A, Manto A.  et al.  Evidence of plasma CoQ10-lowering effect by HMG-CoA reductase inhibitors: a double-blind, placebo-controlled study.  J Clin Pharmacol.1993;33:226-229.
Watts GF, Castelluccio C, Rice-Evans C, Taub NA, Baurn H, Quinn PF. Plasma coenzyme Q (ubiquinone) concentrations in patients treated with simvastatin.  J Clin Pathol.1993;46:1055-1057.
Giroux LM, Davignon J, Naruszewicz M. Simvastatin inhibits the oxidation of low-density lipoproteins by activated human monocyte-derived macrophages.  Biochim Biophys Acta.1993;1165: 335-338.
Laaksonen R, Jokelainen K, Laakso J.  et al.  The effect of simvastatin treatment on natural antioxidants in low-density lipoproteins and high-energy phosphates and ubiquinone in skeletal muscle.  Am J Cardiol.1996;77:851-854.
Willis RA, Folkers K, Tucker JL, Ye CQ, Xia LJ, Tamagawa H. Lovastatin decreases coenzyme Q levels in rats.  Proc Natl Acad Sci U S A.1990;87:8928-8930.
Marinari UM, Pronzato MA, Dapino D.  et al.  Effects of simvastatin on liver and plasma levels of cholesterol, dolichol and ubiquinol in hypercholesterolemic rats.  Ital J Biochem.1995;44:1-9.
Weissberg PL, Clesham GJ, Bennett MR. Is vascular smooth muscle cell proliferation beneficial?  Lancet.1996;347:305-307.
Cheng GC, Libby P, Grodzinsky AJ, Lee RT. Induction of DNA synthesis by a single transient mechanical stimulus of human vascular smooth muscle cells: role of fibroblast growth factor-2.  Circulation.1996;93:99-105.
Soma MR, Donetti E, Parolini C.  et al.  HMG CoA reductase inhibitors: in vivo effects on carotid intimal thickening in normocholesterolemic rabbits.  Arterioscler Thromb.1993;13:571-578.
Corsini A, Raiteri M, Soma M, Fumagalli R, Paoletti R. Simvastatin but not pravastatin inhibits the proliferation of rat aorta myocytes.  Pharmacol Res.1991;23:173-180.
Negre-Aminoux P, van Vliet AK, van Erck M.  et al.  Inhibition of proliferation of human smooth muscle cells by various HMG-CoA reductase inhibitors: comparison with other human cell types.  Biochim Biophys Acta.1997;1345:259-268.
Igarashi M, Takeda Y, Mori S.  et al.  Suppression of neointimal thickening by a newly developed HMG-CoA reductase inhibitor, BAYw6228, and its inhibitory effect on vascular smooth muscle cell growth.  Br J Pharmacol.1997;120:1172-1178.
Corsini A, Pazzucconi F, Pfister P, Paoletti R, Sirtori CR. Inhibitor of proliferation of arterial smooth-muscle cells by fluvastatin.  Lancet.1996;348:1584.
Nemerson Y. Tissue factor and haemostasis.  Blood.1988;71:1-8.
Colli S, Eligini S, Lalli M, Camera M, Paoletti R, Tremoli E. Vastatins inhibit tissue factor in cultured human macrophages.  Arterioscler Thromb Vasc Biol.1997;17:265-272.
Lesnik P, Vonica A, Guerin M, Moreau M, Chapman MJ. Anticoagulant activity of tissue factor pathway inhibitor in human plasma is preferentially associated with dense subspecies of LDL and HDL and with Lp(a).  Arterioscler Thromb.1993;13:1066-1075.
Sandset PM, Lund H, Norseth J, Abildgaard U, Ose L. Treatment with hydroxymethylglutaryl-coenzyme A reductase inhibitors in hypercholesterolemia induces changes in the components of the extrinsic coagulation system.  Arterioscler Thromb.1991;11:138-145.
Hansen JB, Huseby NE, Sandset PM, Svensson B, Lyngmo V, Nordoy A. Tissue factor pathway inhibitor and lipoproteins: evidence for association with and regulation by LDL in human plasma.  Arterioscler Thromb.1994;14:223-229.
Zitoun D, Bara L, Basdevant A, Samama MM. Levels of factor VIIc associated with decreased tissue factor pathway inhibitor and increased plasminogen activator inhibitor-1 in dyslipidemias.  Arterioscler Thromb Vasc Biol.1996;16:77-81.
Carvalho AC, Colman RW, Less RS. Platelet function in hyperlipoproteinemia.  N Engl J Med.1974;290:434-438.
Nofer JR, Tepel M, Kehrel B.  et al.  Low-density lipoproteins inhibit the Na+/H+ antiport in human platelets: a novel mechanism enhancing platelet activity in hypercholesterolemia.  Circulation.1997;95:1370-1377.
van Willigan G, Gorter G, Akkerman JWN. LDLs increase the exposure of fibrinogen binding sites on platelets and secretion of dense granules.  Arterioscler Thromb.1994;14:41-46.
Davi G, Averna M, Novo S.  et al.  Effects of synvinolin on platelet aggregation and thromboxane B2 synthesis in type IIa hypercholesterolemic patients.  Atherosclerosis.1989;79:79-83.
Notarbartolo A, Davi G, Averna M.  et al.  Inhibition of thromboxane biosynthesis and platelet function by simvastatin in type IIa hypercholesterolemia.  Arterioscler Thromb Vasc Biol.1995;15:247-251.
Beigel Y, Fuchs J, Snir M, Green P, Lurie Y, Djaldetti M. Lovastatin therapy in hypercholesterolemia: effect on fibrinogen, hemorrheologic parameters, platelet activity, and red blood cell morphology.  J Clin Pharmacol.1991;31:512-517.
Mayer J, Eller T, Brauer P.  et al.  Effects of long-term treatment with lovastatin on the clotting system and blood platelets.  Ann Hematol.1992;64:196-201.
Aoki I, Aoki A, Kawano K.  et al.  Platelet-dependent thrombin generation in patients with hyperlipidemia.  J Am Coll Cardiol.1997;30:91-96.
Le Quan Sang KH, Levenson J, Megnien JL, Simon A, Devynck MA. Platelet cytosolic Ca2+ and membrane dynamics in patients with primary hypercholesterolemia: effects of pravastatin.  Arterioscler Thromb Vasc Biol.1995;15:759-764.
Lacoste L, Lam JYT, Hung J.  et al.  Hyperlipidemia and coronary disease: correction of the increased thrombogenic potential with cholesterol reduction.  Circulation.1995;92:3172-3177.
Lacoste L, Lam JYT. Comparative effect of pravastatin and simvastatin on platelet-thrombus formation in hypercholesterolemic coronary patients.  J Am Coll Cardiol.1996;27:413A.
Rosenson RS. Viscosity and ischemic heart disease.  J Vasc Med Biol.1993;4:206-212.
Rosenson RS, Tangney CC. Beneficial effects of statins.  Lancet.1996;348:1583.
Isaacsohn J, Setaro JF, Nicholas C.  et al.  Effects of lovastatin therapy on plasminogen activator inhibitor-1 antigen levels.  Am J Cardiol.1994;74:735-737.
Davidson M, McKenney J, Stein E.  et al.  Comparison of one-year efficacy and safety of atorvastatin versus lovastatin in primary hypercholesterolemia.  Am J Cardiol.1997;79:1475-1481.
Koenig W, Hehr R, Ditschuneit HH.  et al.  Lovastatin alters blood rheology in primary hyperlipoproteinemia: dependence on lipoprotein(a)?  J Clin Pharmacol.1992;32:539-545.
Koppensteiner R, Minar E, Ehringer H. Effect of lovastatin on hemorheology in type II hyperlipoproteinemia.  Atherosclerosis.1990;83:53-58.
Jay RH, Ramply MW, Betteridge DJ. Abnormalities of blood rheology in familial hypercholesterolemia: effects of treatment.  Am J Cardiol.1993;72:1031-1037.
Avellone G, Di Garbo V, Cordova R, Raneli G, De Simone R, Bompiani G. Changes induced by pravastatin treatment on hemostatic and fibrinolytic patterns in patients with type IIB hyperlipoproteinemia.  Curr Ther Res Clin Exp.1994;55:1335-1344.
Tsuda Y, Satoh K, Kitadai M.  et al.  Effects of pravastatin sodium and simvastatin on plasma fibrinogen level and blood rheology in type II hyperlipoproteinemia.  Atherosclerosis.1996;122:225-233.
Wada H, Mori Y, Kaneko T.  et al.  Hypercoagulable state in patients with hypercholesterolemia: effects of pravastatin.  Clin Ther.1992;14:829-834.
Branchi A, Rovellini A, Sommariva D, Gugliandolo AG, Fasoli A. Effect of three fibrate derivatives and of two HMG-CoA reductase inhibitors on plasma fibrinogen level in patients with primary hypercholesterolemia.  Thromb Haemost.1993;70:241-243.
The Writing Group for the PEPI Trial.  Effects of estrogen or estrogen/progestin regimens on heart disease risk factors in postmenopausal women: the Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial.  JAMA.1995;273:199-208.
Bo M, Bonino F, Neirotti M.  et al.  Hemorheologic and coagulative pattern in hypercholesterolemic subjects treated with lipid-lowering drugs.  Angiology.1991;42:106-113.
Mitropoulos KA, Armitage JM, Collins R.  et al.  Randomized placebo-controlled study of the effects of simvastatin on haemostatic variables, lipoproteins and free fatty acids.  Eur Heart J.1997;18:235-241.
Marais AD, Firth JC, Bateman ME, Byrnes P, Martens C, Mountney J. Atorvastatin: an effective lipid-modifying agent in familial hypercholesterolemia.  Arterioscler Thromb Vasc Biol.1997;17:1527-1531.
Wierzbicki AS, Lumb PJ, Semra YK, Crook MA. Effect of atorvastatin on plasma fibrinogen.  Lancet.1998;351:569-570.
Behague I, Poirier O, Nicaud V.  et al.  β Fibrinogen gene polymorphisms are associated with plasma fibrinogen and coronary artery disease in patients with myocardial infarction: the ECTIM Study.  Circulation.1996;93:440-449.
Rosenson RS, Tangney CC, Hafner JM. Intraindividual variability of fibrinogen levels and cardiovascular risk profile.  Arterioscler Thromb.1994;14:1928-1932.
Meade TW, Ruddock V, Stirling Y, Chakrabarti R, Miller GJ. Fibrinolytic activity, clotting factors, and long-term incidence of ischaemic heart disease in the Northwick Park Heart Study.  Lancet.1993;342:1076-1079.
Hamsten A, Wiman B, De Faire U, Blomback M. Increased plasma levels of a rapid inhibitor of tissue plasminogen activator in young survivors of myocardial infarction.  N Engl J Med.1985;313:1557-1563.
Juhan-Vague I, Pyke SDM, Alessi MC, Jespersen J, Haverkate F, Thompson SG.for the ECAT Study Group.  Fibrinolytic factors and the risk of myocardial infarction or sudden death in patients with angina pectoris.  Circulation.1996;94:2057-2063.
Bevilacqua M, Bettica P, Milani M.  et al.  Effect of fluvastatin on lipids and fibrinolysis in coronary artery disease.  Am J Cardiol.1997;79:84-87.
Stein JH, Rosenson RS. Lipoprotein(a) and coronary heart disease.  Arch Intern Med.1997;157:1170-1176.
Harpel PC, Gordon BR, Parker TS. Plasmin catalyzes binding of lipoprotein(a) to immobilized fibrinogen and fibrin.  Proc Natl Acad Sci U S A.1989;86:3847-3851.
Leren TP, Hjermann I, Berg K, Leren P, Foss OP, Viksmoen L. Effects of lovastatin alone and in combination with cholestyramine on serum lipids and apolipoproteins in heterozygotes for familial hypercholesterolemia.  Atherosclerosis.1988;73: 135-141.
Kostner GM, Gavish D, Leopold B, Bolzano K, Weintraub MS, Breslow JL. HMG CoA reductase inhibitors lower LDL cholesterol without reducing Lp(a) levels.  Circulation.1989;80:1313-1319.
Slunga L, Johnson O, Dahlen GH. Changes in Lp(a) lipoprotein levels during the treatment of hypercholesterolemia with simvastatin.  Eur J Clin Pharmacol.1992;43:369-373.
Haffner S, Orchard T, Stein E, Schmidt D, LaBelle P. Effect of simvastatin on Lp(a) concentrations.  Clin Cardiol.1995;18:261-267.
Hunninghake DB, Stein EA, Mellies MJ. Effects of one year of treatment with pravastatin, an HMG-CoA reductase inhibitor, on lipoprotein(a).  J Clin Pharmacol.1993;33:574-580.
CME
Meets CME requirements for:
Browse CME for all U.S. States
Accreditation Information
The American Medical Association is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The AMA designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 CreditTM per course. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Physicians who complete the CME course and score at least 80% correct on the quiz are eligible for AMA PRA Category 1 CreditTM.
Note: You must get at least of the answers correct to pass this quiz.
You have not filled in all the answers to complete this quiz
The following questions were not answered:
Sorry, you have unsuccessfully completed this CME quiz with a score of
The following questions were not answered correctly:
Commitment to Change (optional):
Indicate what change(s) you will implement in your practice, if any, based on this CME course.
Your quiz results:
The filled radio buttons indicate your responses. The preferred responses are highlighted
For CME Course: A Proposed Model for Initial Assessment and Management of Acute Heart Failure Syndromes
Indicate what changes(s) you will implement in your practice, if any, based on this CME course.
NOTE:
Citing articles are presented as examples only. In non-demo SCM6 implementation, integration with CrossRef’s "Cited By" API will populate this tab (http://www.crossref.org/citedby.html).

Multimedia

Some tools below are only available to our subscribers or users with an online account.

Web of Science® Times Cited: 688

Related Content

Customize your page view by dragging & repositioning the boxes below.

Articles Related By Topic
Related Topics
PubMed Articles
JAMAevidence.com

Users' Guides to the Medical Literature
Statin Dosing and LDL Levels

Users' Guides to the Medical Literature
Using the Guide