(Circulation. 1995;92:3172-3177.)
© 1995 American Heart Association, Inc.
Articles |
Hyperlipidemia and Coronary Disease
Correction of the Increased Thrombogenic Potential With Cholesterol Reduction
From the Laboratory of Thrombosis and Atherosclerosis, Department of Medicine, Montreal Heart Institute and University of Montreal, Canada (L.L., J.Y.T.L., G.L., C.B.S., D.W.) and the University of Western Australia, Queen Elizabeth II Medical Center, Nedlands, Perth, Australia (J.H.).
Correspondence to Jules Y.T. Lam, MD, Montreal Heart Institute, 5000 Belanger St, Montreal, Quebec, Canada, H1T 1C8.
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Abstract |
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Background Hypercholesterolemia is a risk factor for coronary disease, and platelet reactivity is increased with hypercholesterolemia, suggesting a prethrombotic risk. The aim of this study was to measure mural platelet thrombus formation on an injured arterial wall in a model simulating vessel stenosis and plaque rupture in hypercholesterolemic coronary disease patients before and after cholesterol reduction.
Methods and Results Thirty-two patients with stable coronary disease were studied. Platelet thrombus formation and serum lipids were measured in 16 hypercholesterolemic patients (cholesterol >5.2 mmol/L) before and after a mean of 2.5 months of pravastatin therapy (40 mg/d) and in 16 normocholesterolemic control patients. Thrombus formation was assessed by exposing porcine aortic media to the patient's flowing venous blood for 3 minutes at a shear rate of 754 or 2546 s-1 at 37°C in an ex vivo superfusion chamber. Quantitative morphometric platelet thrombus formation at baseline was higher in the hypercholesterolemic patients at both the high and low shear rates: 4.8±1.0 and 3.3±0.7 µm2/mm, respectively, compared with normocholesterolemic patients: 2.1±0.5 and 1.6±0.4 µm2/mm (both P<.05). In the hypercholesterolemic patients, pravastatin decreased total cholesterol from 6.5±0.2 to 4.5±0.2 mmol/L and LDL cholesterol from 4.5±0.2 to 2.8±0.1 mmol/L (both P<.05). Platelet thrombus formation at high and low shear rates decreased to 2.0±0.3 and 1.3±0.3 µm2/mm, respectively (both P<.05).
Conclusions Thus, hypercholesterolemia is associated with an enhanced platelet thrombus formation on an injured artery, increasing the propensity for acute thrombosis. Platelet thrombus formation at both high and low shear rates decreased as total and LDL cholesterol levels were reduced with pravastatin. Cholesterol lowering may therefore reduce the risk of acute coronary events in part by reducing the thrombogenic risk.
Key Words: cholesterol • pravastatin • platelets • thrombosis • coronary disease
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Introduction |
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TopAbstractIntroductionMethods Results Discussion References |
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Hypercholesterolemia is recognized as a risk factor for ischemic heart disease and coronary mortality.1 2 3 4 Lowering blood cholesterol levels reduces coronary events in subjects both without5 6 7 and with8 9 10 11 12 13 14 known coronary disease. Coronary angiographic trials have demonstrated that cholesterol lowering slows the progression of coronary atherosclerosis and may even induce regression.9 10 11 12 13 14 15 16 17 18 19 20 The number of patients enrolled in most of these studies was too small and the length of follow-up too short for a statistically significant difference in the rate of coronary events to be expected. Nevertheless, cholesterol lowering was associated with significantly fewer cardiovascular events in five of these trials.9 10 11 12 13
It has been suggested that the reduction in coronary events seen in the angiographic trials is greater than would be anticipated for the degree of angiographic improvement induced by cholesterol lowering.21 Plaque stabilization due to a decrease in the lipid content of the lesions most likely to rupture21 and improved endothelial function22 23 24 are two mechanisms that could partly account for the reduction in coronary events with cholesterol lowering. Another mechanism is a decrease in the tendency toward platelet thrombus formation with cholesterol lowering.
Circulating platelets are implicated in mural thrombus formation at the site of a plaque rupture,25 26 and platelets become hyperreactive in the presence of hypercholesterolemia.27 28 29 LDL cholesterol has been shown to activate human platelets and to increase the production of thromboxane B2 in vitro.29 However, in vitro platelet aggregation or thromboxane production may not accurately reflect the clinical situation, in vivo mural thrombosis. In this study, rheological conditions characteristic of a stenotic artery were simulated in an ex vivo flow chamber system that allowed exposure of flowing blood from coronary patients to an injured arterial wall. The purpose was to assess the influence of hypercholesterolemia and lowering cholesterol with a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor on platelet thrombus formation.
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Methods |
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TopAbstractIntroductionMethods Results Discussion References |
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Patient Population
The study population comprised 32 stable coronary patients, 26 men and 6 women, with a mean age of 62 years (range, 31 to 73 years); 16 had a total serum cholesterol >5.2 mmol/L, and the other 16, who served as control subjects, did not. All patients had stable coronary artery disease as evidenced by a previously well-documented myocardial infarction, typical stable angina, and a positive exercise test or coronary disease at angiography. Written informed consent was obtained from all patients.
Platelet thrombus deposition, serum lipids, platelet count, and plasma fibrinogen level were measured at baseline in all patients and after pravastatin treatment in the hypercholesterolemic patients. Thus, comparisons were obtained between normal and hypercholesterolemic patients and before and after cholesterol lowering in the hypercholesterolemic patients. No patient was taking aspirin or other platelet-inhibitor drug at the time of the study; other cardiac medication was maintained unchanged, except that all drugs were withdrawn for the 24 hours before the study. The patients were studied in the morning, having fasted and abstained from smoking for at least 12 hours. The tests were repeated in an identical fashion at the same time of day after 2 to 3 months of therapy with pravastatin 40 mg/d.
Study Protocol
A 19-gauge butterfly cannula was inserted
atraumatically without
a tourniquet into an antecubital vein, and the flowing venous blood
from the patient was drawn over porcine aortic media held in Plexiglas
superfusion flow chambers30 31 32 with a
peristaltic pump
(model 7014, Masterflex, Cole-Parmer Instruments Co) placed distal to
the chambers. The chambers were designed to mimic the tubelike shape of
the vascular system30 31 32 and contained
a window that
permitted direct exposure of an aortic media to the flowing venous
blood, which was discarded after its passage through the chambers. A
3-minute superfusion of the aortic media was performed at shear rates
of 754 and 2546 s-1, with the flow
chambers maintained at 37°C in a water bath.32 These
shear rates correspond to values of normal unobstructed arteries (106
to 500 s-1) and to values typical of
stenotic arteries (1680 to 3380
s-1). The aortic media used in the
superfusion chambers was obtained from normal pigs by opening the aorta
longitudinally and peeling off and discarding the intima and a thin
portion of the subjacent media. The remaining aortic media was then
divided into 35x15-mm segments to be placed inside the superfusion
flow chambers to be exposed to flowing blood in the
chamber.30 31 32 Exposure of the arterial
media
simulates a deep arterial wall injury with a thrombogenic
response similar to that of a plaque rupture.
After the perfusion, the aortic media strips were removed from the chambers, fixed in 10% formalin, and processed for histological analysis. Two vertical cross sections were made in the proximal, mid, and distal thirds of each vessel segment for a total of six histological sections for each shear rate. The tissues were stained with hematoxylin-phloxine-safranin. The stained histological tissue was then analyzed under a light microscope (model Diaplan, Leitz Co), and platelet thrombus formation on the aortic media was quantified morphometrically in square micrometers per millimeter by viewing the thrombus mass through the microscope at x100 magnification and tracing the outline using a side-tube attachment to the microscope. The traced outline was then planimetered with a digitizing tablet and an IBM-AT–compatible computer.
All measurements were made in a blinded fashion by one of the authors. Thrombus size measurements were expressed as the average of six analyzed sections per tissue (two in the proximal, two in the mid, and two in the distal section), expressed as the surface area in square micrometers and normalized to the cross-sectional diameter of the exposed media (in millimeters). This morphometric method has been previously validated and shows a strong correlation (r=.84, P=.0001) between the amount of 111In-labeled platelets deposited on the media and the morphometrically assessed thrombus size.32 There is also excellent reproducibility (r=.95, P=.0001) between measurements performed 1 week apart.32 Repeat studies on the same morning in 11 patients taking a placebo agent showed no serial change in platelet thrombus size as assessed by this technique.33 Repeat studies in 17 stable patients at a mean of 2.1 months and 7.6 months also showed no significant serial changes in platelet thrombus size.
Data Analysis
Data are expressed as mean±SEM.
Comparisons between
normocholesterolemic and baseline
hypercholesterolemic groups were performed by an
unpaired t test. Comparisons before and after
pravastatin treatment in the
hypercholesterolemic group were assessed by a
Student's paired t test. Differences were considered
significant if the two-tailed probability value was
P
.05.
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Results |
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TopAbstractIntroductionMethods Results Discussion References |
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The baseline characteristics of the hypercholesterolemic and normocholesterolemic patients are shown in Table 1
. The two
groups are similar with respect to clinical
features, other risk factors, and the use of cardiac medications.
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As shown in Table 2, the serum total and LDL
cholesterol levels were significantly higher in the
hypercholesterolemic patients. Total and LDL
cholesterol levels were 6.5±0.2 and 4.5±0.2 mmol/L at
baseline, respectively, and decreased to 4.5±0.2 and 2.8±0.1
mmol/L
after a mean of 2.5 months of pravastatin treatment (both
P<.05 versus baseline). HDL cholesterol and
triglycerides did not change significantly during treatment
(Table 2).
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Platelet Thrombus Formation on Arterial
Media
Platelet thrombus formation on an injured arterial
wall exposing the media was significantly higher in
hypercholesterolemic patients at both shear rates
of 754 and 2546 s-1 compared with
normocholesterolemic control subjects (Figs 1 and
2). The decrease in serum total and LDL
cholesterol induced by pravastatin in
hypercholesterolemic patients was associated with a
significant decrease in platelet thrombus formation, from 4.8±1.0
to 2.0±0.3 µm2/mm at the high shear rate and from
3.3±0.7 to 1.3±0.3 µm2/mm at the low shear rate
(both P<.05). Figs 1 and 2
illustrate a
typical histological section of platelet thrombus
formation on the exposed arterial wall media before and
after pravastatin treatment. The decrease in platelet
thrombus formation observed after 2.5 months of treatment with
pravastatin was not associated with any significant change
in plasma fibrinogen level or platelet count.
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The results of linear
regression analysis relating serum
total, LDL, and HDL cholesterol and
triglycerides to thrombus formation are listed in Table 3. LDL
cholesterol, and to a lesser degree
total cholesterol, correlated significantly with thrombus
formation. To assess whether the decrease in thrombus formation was due
to a direct effect of pravastatin and not to
cholesterol lowering, mural thrombus formation was assessed
after 1 week of pravastatin treatment, before serum total
and LDL cholesterol levels were reduced. Mural thrombus
formation at this time was unchanged compared with pretreatment.
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Discussion |
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TopAbstractIntroductionMethods Results Discussion References |
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This study demonstrates that in coronary disease patients, hypercholesterolemia is associated with an increased thrombogenic potential compared with normocholesterolemia. Lowering total and LDL cholesterol with pravastatin corrected the abnormality. No effect of pravastatin was seen either on LDL cholesterol or on mural thrombus formation after just 1 week of therapy, and the reduction in thrombogenic potential was moderately correlated with the decrease in LDL cholesterol level.
Cholesterol and Platelet Thrombosis
Enhanced mural thrombus
formation was evident when blood from
hypercholesterolemic patients was circulated over
the exposed media of an injured arterial wall under shear
flow conditions characteristic of stenotic vessels. This model
simulates the in vivo conditions of vessel stenosis and plaque
rupture typical of unstable coronary syndromes and for which
hypercholesterolemia is a risk factor.
Previous studies relating cholesterol levels to platelet reactivity and thromboxane production have usually shown some relationship. Enhanced platelet reactivity has been reported in the presence of high LDL cholesterol levels and low platelet reactivity with low LDL cholesterol levels,27 28 29 although other studies have yielded conflicting results.34 35 Studies that focus mainly on platelet aggregatory responses to selected agonists may not accurately reflect thrombotic conditions in the intact circulation. The time-consuming and extensive steps involved in preparing platelet-rich plasma may modify platelet function and deplete short half-life mediators such as endothelium-derived relaxing factor, prostacyclin, and thromboxane. Other blood components that affect platelet function, such as red blood cells and neutrophils, as well as blood flow and shear forces are also excluded from the testing milieu of the platelet-rich plasma. The in vivo situation of vessel stenosis and plaque disruption exposes platelets to multiple agonists simultaneously. Thus, in the absence of a vessel wall component and shear stresses, the assessment of platelet function by aggregometry may not provide an adequate evaluation of the presence or absence of an antithrombotic effect. It is interesting to note that dipyridamole significantly inhibits platelet aggregation responses and yet has few antithrombotic properties when tested clinically.36 Our present study differs from previous reports because mural thrombosis was assessed directly under different shear-rate conditions by flowing blood over an injured arterial wall by a method that has been previously validated and has shown a good correlation with 111In-labeled platelet deposition.32
Thrombosis and Coronary Events
The underlying mechanism
responsible for the unstable
coronary syndromes is usually the formation of an occlusive or
subocclusive mural thrombus overlying an injured vessel wall or a
ruptured atherosclerotic plaque.25 26 There is thus a
compelling rationale to consider prevention of thrombosis as an
effective approach to the prevention of unstable coronary
syndromes. Indeed, the significant reduction in coronary events
by antiplatelet or anticoagulant therapy provides convincing
evidence for the role of platelet thrombosis in ischemic
heart disease.37 38
Our findings suggest that hypercholesterolemia, in addition to its known effect of promoting atherogenesis, also increases the risk of a clinically significant coronary thrombosis developing at the site of plaque rupture. Autopsy studies have revealed that plaque rupture without clinical sequelae is a relatively common phenomenon.39 Thus, by increasing thrombogenic potential, hypercholesterolemia may increase cardiovascular risk in part by increasing the proportion of plaque ruptures that lead to a thrombotic coronary event. It is therefore likely that the cardiovascular risk associated with hypercholesterolemia may be due at least as much to effects on thrombogenesis as to long-term effects on atherogenesis.
Clinical Relevance
In this study, mural thrombus formation
returned to control values
within 2 to 3 months after cholesterol-lowering therapy
with an HMG-CoA reductase inhibitor was initiated.
Improvement in endothelial function in the epicardial
coronary arteries that has been reported with
lipid-lowering therapy is observed after 6 months of therapy or
more in humans.23 24 In addition, the effect of
cholesterol lowering on the angiographic evolution of
coronary atherosclerosis occurs over a much
longer
interval.9 10 11 12 13 14 15 16 17 18
How quickly cholesterol
lowering reduces the risk of coronary events is a controversial
question. Some studies5 9 40 suggest a
lag time of 3 years
before any benefit accrues. We have shown that lowering serum
cholesterol may be an important early mechanism to decrease
mural thrombus formation and may reveal itself as a powerful means of
achieving reduction of coronary events in
hypercholesterolemic patients in the short term.
This is supported by evidence from the Pravastatin
Multinational Study,41 which has shown a significant
reduction in coronary events after only 6 months of treatment,
with the survival curves in favor of pravastatin diverging
as early as 1 to 2 months after therapy. It is thus tempting to
postulate that the early benefit is more likely due to a decrease in
thrombogenic potential than to an angiographic effect or plaque
stabilization,21 and this effect on thrombogenesis may
even antedate beneficial changes in endothelial
function, which may require 6 months or more of therapy.42
This finding is exciting because it may also imply that the magnitude
and rate of recovery during regression of
atherosclerosis may be greater in relation to
platelet thrombosis than for endothelial function,
and both are far greater than for structural coronary lesions.
Interestingly, platelet inhibitors, which are not known
to stabilize plaques or ameliorate endothelial
function, have also been shown to decrease coronary
events.43
The demonstration of a correlation between LDL cholesterol and mural thrombus formation not only strengthens the association between hyperlipidemia and mural thrombosis but also supports the possibility that an appreciable part of the lipid effect was mediated through LDL cholesterol. The lack of an interaction of thrombus formation with HDL cholesterol or with triglycerides could indicate that these fractions do not play an important role in thrombogenesis, even if they are implicated in atherogenesis. Platelets have been shown to be hyperreactive in the presence of high LDL cholesterol levels,27 28 29 possibly in part because of an enhanced thromboxane biosynthesis.28 29 At high concentrations in vitro, LDL itself may trigger platelet aggregation.44 Other studies have shown an increased fibrinogen binding to platelets45 or even an increased cholesterol and phospholipid content of platelets from hypercholesterolemic subjects.46 All these mechanisms may contribute to the increased thrombogenic risk. Our study was not designed to assess mechanistic issues, and we cannot exclude the possibility that other properties of the drug might be responsible for the observed decrease in thrombus formation besides a potential effect at the various levels mentioned above.
In conclusion, this study has conceptual and practical implications. Hypercholesterolemia is associated with an enhanced thrombogenic risk, which can be significantly decreased with pravastatin. This benefit occurs early, as early as 2 to 3 months after onset of therapy, and may antedate beneficial changes in endothelial function or atherosclerotic plaque stabilization or regression.
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Acknowledgments |
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L. Lacoste was supported by a Faculté des Etudes Supérieures (FES) scholarship from the University of Montreal. J. Hung, MD, was supported by the University of Western Australia, Queen Elizabeth II Medical Center, Nedlands, Perth, Australia. J.Y.T. Lam was supported in part by the Medical Research Council of Canada, the Heart and Stroke Foundation of Canada, and the Fonds de la Recherche en Santé du Québec.
Received January 26, 1995; revision received July 17, 1995; accepted July 19, 1995.
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  F. Gao, L. Linhartova, A. McD. Johnston, and D. R. Thickett Statins and sepsis Br. J. Anaesth., March 1, 2008; 100(3): 288 - 298. [Abstract] [Full Text] [PDF]
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 M. E. Alnaeb, F. Youssef, D. P. Mikhailidis, and G. Hamilton Short-term Lipid-Lowering Treatment with Atorvastatin Improves Renal Function But Not Renal Blood Flow Indices in Patients with Peripheral Arterial Disease Angiology, January 1, 2006; 57(1): 65 - 71. [Abstract] [PDF]
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 M. Ii, H. Nishimura, K. F. Kusano, G. Qin, Y.-s. Yoon, A. Wecker, T. Asahara, and D. W. Losordo Neuronal Nitric Oxide Synthase Mediates Statin-Induced Restoration of Vasa Nervorum and Reversal of Diabetic Neuropathy Circulation, July 5, 2005; 112(1): 93 - 102. [Abstract] [Full Text] [PDF]
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 A. Undas, K. E. Brummel-Ziedins, and K. G. Mann Statins and Blood Coagulation Arterioscler. Thromb. Vasc. Biol., February 1, 2005; 25(2): 287 - 294. [Abstract] [Full Text] [PDF]
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M. P. McGowan and for the Treating to New Target Study Group There Is No Evidence for an Increase in Acute Coronary Syndromes After Short-Term Abrupt Discontinuation of Statins in Stable Cardiac Patients Circulation, October 19, 2004; 110(16): 2333 - 2335. [Abstract] [Full Text] [PDF]
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 C H Lee, P de Feyter, P W Serruys, F Saia, P A Lemos, D Goedhart, P R Soares, V A W M Umans, M Ciccone, and M Cortellaro Beneficial effects of fluvastatin following percutaneous coronary intervention in patients with unstable and stable angina: results from the Lescol intervention prevention study (LIPS) Heart, October 1, 2004; 90(10): 1156 - 1161. [Abstract] [Full Text] [PDF]
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J. P. Werba, E. Tremoli, P. Massironi, M. Camera, A. Cannata, F. Alamanni, P. Biglioli, and A. Parolari Statins in coronary bypass surgery: rationale and clinical use Ann. Thorac. Surg., December 1, 2003; 76(6): 2132 - 2140. [Abstract] [Full Text] [PDF]
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D Tousoulis, G Davies, C Stefanadis, P Toutouzas, and J A Ambrose Inflammatory and thrombotic mechanisms in coronary atherosclerosis Heart, September 1, 2003; 89(9): 993 - 997. [Abstract] [Full Text] [PDF]
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 T. Maeda, T. Kawane, and N. Horiuchi Statins Augment Vascular Endothelial Growth Factor Expression in Osteoblastic Cells via Inhibition of Protein Prenylation Endocrinology, February 1, 2003; 144(2): 681 - 692. [Abstract] [Full Text] [PDF]
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D. D. Waters, G. G. Schwartz, A. G. Olsson, A. Zeiher, M. F. Oliver, P. Ganz, M. Ezekowitz, B. R. Chaitman, S. J. Leslie, T. Stern, et al. Effects of Atorvastatin on Stroke in Patients With Unstable Angina or Non-Q-Wave Myocardial Infarction: A Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) Substudy Circulation, September 24, 2002; 106(13): 1690 - 1695. [Abstract] [Full Text] [PDF]
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 L. K. Newby, A. Kristinsson, M. V. Bhapkar, P. E. Aylward, A. P. Dimas, W. W. Klein, D. K. McGuire, D. J. Moliterno, F. W. A. Verheugt, W. D. Weaver, et al. Early Statin Initiation and Outcomes in Patients With Acute Coronary Syndromes JAMA, June 19, 2002; 287(23): 3087 - 3095. [Abstract] [Full Text] [PDF]
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E. I. Lev, J. D. Marmur, M. Zdravkovic, J. I. Osende, J. Robbins, J. A. Delfin, M. Richard, E. Erhardtsen, M. S. Thomsen, A. M. Lincoff, et al. Antithrombotic Effect of Tissue Factor Inhibition by Inactivated Factor VIIa: An Ex Vivo Human Study Arterioscler. Thromb. Vasc. Biol., June 1, 2002; 22(6): 1036 - 1041. [Abstract] [Full Text] [PDF]
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C. Urbich, E. Dernbach, A. M. Zeiher, and S. Dimmeler Double-Edged Role of Statins in Angiogenesis Signaling Circ. Res., April 5, 2002; 90(6): 737 - 744. [Abstract] [Full Text] [PDF]
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S.M. Cobbe How best to combat the enemies? Lipid lowering Eur. Heart J. Suppl., February 1, 2002; 4(suppl_A): A48 - A52. [Abstract] [PDF]
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D. H. Walter, S. Fichtlscherer, M. B. Britten, P. Rosin, W. Auch-Schwelk, V. Schachinger, and A. M. Zeiher Statin therapy, inflammation and recurrent coronary events in patients following coronary stent implantation J. Am. Coll. Cardiol., December 1, 2001; 38(7): 2006 - 2012. [Abstract] [Full Text] [PDF]
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M. Takemoto and J. K. Liao Pleiotropic Effects of 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Inhibitors Arterioscler. Thromb. Vasc. Biol., November 1, 2001; 21(11): 1712 - 1719. [Abstract] [Full Text] [PDF]
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L. Badimon, G. Vilahur, S. Sanchez, and X. Duran Atheromatous plaque formation and thrombogenesis: formation, risk factors and therapeutic approaches Eur. Heart J. Suppl., August 1, 2001; 3(suppl_I): I16 - I22. [Abstract] [PDF]
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G. G. Schwartz, A. G. Olsson, M. D. Ezekowitz, P. Ganz, M. F. Oliver, D. Waters, A. Zeiher, B. R. Chaitman, S. Leslie, T. Stern, et al. Effects of Atorvastatin on Early Recurrent Ischemic Events in Acute Coronary Syndromes: The MIRACL Study: A Randomized Controlled Trial JAMA, April 4, 2001; 285(13): 1711 - 1718. [Abstract] [Full Text] [PDF]
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D.H Walter, V Schachinger, M Elsner, S Mach, S Dimmeler, W Auch-Schwelk, and A.M Zeiher Statin therapy is associated with reduced restenosis rates after coronary stent implantation in carriers of the PlA2allele of the platelet glycoprotein IIIa gene Eur. Heart J., April 1, 2001; 22(7): 587 - 595. [Abstract] [PDF]
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S. John, C. Delles, J. Jacobi, M. P. Schlaich, M. Schneider, G. Schmitz, and R. E. Schmieder Rapid improvement of nitric oxide bioavailability after lipid-lowering therapy with cerivastatin within two weeks J. Am. Coll. Cardiol., April 1, 2001; 37(5): 1351 - 1358. [Abstract] [Full Text] [PDF]
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B. D. Horne, J. B. Muhlestein, J. F. Carlquist, T. L. Bair, T. E. Madsen, N. I. Hart, and J. L. Anderson Statin therapy, lipid levels, C-reactive protein and the survival of patients with angiographically severe coronary artery disease J. Am. Coll. Cardiol., November 15, 2000; 36(6): 1774 - 1780. [Abstract] [Full Text] [PDF]
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J. S. Forrester, C. N. Bairey-Merz, and S. Kaul The aggressive low density lipoprotein lowering controversy J. Am. Coll. Cardiol., October 1, 2000; 36(4): 1419 - 1425. [Abstract] [Full Text] [PDF]
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J. De Sutter, R. Tavernier, M. De Buyzere, L. Jordaens, and G. De Backer Lipid lowering drugs and recurrences of life-threatening ventricular arrhythmias in high-risk patients J. Am. Coll. Cardiol., September 1, 2000; 36(3): 766 - 772. [Abstract] [Full Text] [PDF]
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S. Hamasaki, S. T. Higano, J. A. Suwaidi, R. A. Nishimura, K. Miyauchi, D. R. Holmes Jr, and A. Lerman Cholesterol-Lowering Treatment Is Associated With Improvement in Coronary Vascular Remodeling and Endothelial Function in Patients With Normal or Mildly Diseased Coronary Arteries Arterioscler. Thromb. Vasc. Biol., March 1, 2000; 20(3): 737 - 743. [Abstract] [Full Text] [PDF]
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M. Shechter, C. N. Bairey Merz, M. J. Paul-Labrador, and S. Kaul Blood glucose and platelet-dependent thrombosis in patients with coronary artery disease J. Am. Coll. Cardiol., February 1, 2000; 35(2): 300 - 307. [Abstract] [Full Text] [PDF]
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C. J. Vaughan, A. M. Gotto Jr., and C. T. Basson The evolving role of statins in the management of atherosclerosis J. Am. Coll. Cardiol., January 1, 2000; 35(1): 1 - 10. [Abstract] [Full Text] [PDF]
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S. Giri, P. D. Thompson, F. J. Kiernan, J. Clive, D. B. Fram, J. F. Mitchel, J. A. Hirst, R. G. McKay, and D. D. Waters Clinical and Angiographic Characteristics of Exertion-Related Acute Myocardial Infarction JAMA, November 10, 1999; 282(18): 1731 - 1736. [Abstract] [Full Text] [PDF]
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D. Waters Cholesterol Lowering : Should It Continue to Be the Last Thing We Do? Circulation, June 29, 1999; 99(25): 3215 - 3217. [Full Text] [PDF]
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J. Dupuis, J.-C. Tardif, P. Cernacek, and P. Theroux Cholesterol Reduction Rapidly Improves Endothelial Function After Acute Coronary Syndromes : The RECIFE (Reduction of Cholesterol in Ischemia and Function of the Endothelium) Trial Circulation, June 29, 1999; 99(25): 3227 - 3233. [Abstract] [Full Text] [PDF]
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A. Szczeklik, J. Musial, A. Undas, P. Gajewski, P. Gora, J. Swadzba, and M. Jankowski Inhibition of thrombin generation by simvastatin and lack of additive effects of aspirin in patients with marked hypercholesterolemia J. Am. Coll. Cardiol., April 1, 1999; 33(5): 1286 - 1293. [Abstract] [Full Text] [PDF]
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G. Dangas, J. J. Badimon, D. A. Smith, A. H. Unger, D. Levine, J. H. Shao, P. Meraj, C. Fier, J. T. Fallon, and J. A. Ambrose Pravastatin therapy in hyperlipidemia: effects on thrombus formation and the systemic hemostatic profile J. Am. Coll. Cardiol., April 1, 1999; 33(5): 1294 - 1304. [Abstract] [Full Text] [PDF]
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R A Archbold and A D Timmis Cholesterol lowering and coronary artery disease: mechanisms of risk reduction Heart, December 1, 1998; 80(6): 543 - 547. [Full Text]
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A. Geppert, S. Graf, R. Beckmann, S. Hornykewycz, E. Schuster, B. R. Binder, and K. Huber Concentration of Endogenous tPA Antigen in Coronary Artery Disease : Relation to Thrombotic Events, Aspirin Treatment, Hyperlipidemia, and Multivessel Disease Arterioscler. Thromb. Vasc. Biol., October 1, 1998; 18(10): 1634 - 1642. [Abstract] [Full Text] [PDF]
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P. M. Ridker, N. Rifai, M. A. Pfeffer, F. M. Sacks, L. A. Moye, S. Goldman, G. C. Flaker, and E. Braunwald Inflammation, Pravastatin, and the Risk of Coronary Events After Myocardial Infarction in Patients With Average Cholesterol Levels Circulation, September 1, 1998; 98(9): 839 - 844. [Abstract] [Full Text] [PDF]
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G. Dangas, J. J. Badimon, B. S. Coller, J. T. Fallon, S. K. Sharma, R. M. Hayes, P. Meraj, J. A. Ambrose, and J. D. Marmur Administration of Abciximab During Percutaneous Coronary Intervention Reduces Both Ex Vivo Platelet Thrombus Formation and Fibrin Deposition : Implications for a Potential Anticoagulant Effect of Abciximab Arterioscler. Thromb. Vasc. Biol., August 1, 1998; 18(8): 1342 - 1349. [Abstract] [Full Text] [PDF]
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R. S. Rosenson and C. C. Tangney Antiatherothrombotic Properties of Statins: Implications for Cardiovascular Event Reduction JAMA, May 27, 1998; 279(20): 1643 - 1650. [Abstract] [Full Text] [PDF]
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F.-C. Schoebel, T. W. Jax, B.-E. Strauer, M. Leschke, and W. R. M. A. A. J. v. B. A. H. Z. J. W. J. A. V. G. van der Werf Functional Evaluation of Lipid-Lowering Therapy by Pravastatin • Response Circulation, May 12, 1998; 97(18): 1874 - 1875. [Full Text]
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Influence of Pravastatin and Plasma Lipids on Clinical Events in the West of Scotland Coronary Prevention Study (WOSCOPS) Circulation, April 21, 1998; 97(15): 1440 - 1445. [Abstract] [Full Text] [PDF]
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B. J. Meyer, J. J. Badimon, J. H. Chesebro, J. T. Fallon, V. Fuster, and L. Badimon Dissolution of Mural Thrombus by Specific Thrombin Inhibition With r-Hirudin : Comparison With Heparin and Aspirin Circulation, February 24, 1998; 97(7): 681 - 685. [Abstract] [Full Text] [PDF]
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M. P. M. de Maat, J. J. P. Kastelein, J. W. Jukema, A. H. Zwinderman, H. Jansen, B. Groenemeier, A. V. G. Bruschke, and C. Kluft -455G/A Polymorphism of the ß-Fibrinogen Gene is Associated With the Progression of Coronary Atherosclerosis in Symptomatic Men : Proposed Role for an Acute-Phase Reaction Pattern of Fibrinogen Arterioscler. Thromb. Vasc. Biol., February 1, 1998; 18(2): 265 - 271. [Abstract] [Full Text] [PDF]
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N. Delanty and C. J. Vaughan Vascular Effects of Statins in Stroke Stroke, November 1, 1997; 28(11): 2315 - 2320. [Abstract] [Full Text]
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O. Nygard, J. E. Nordrehaug, H. Refsum, P. M. Ueland, M. Farstad, and S. E. Vollset Plasma Homocysteine Levels and Mortality in Patients with Coronary Artery Disease N. Engl. J. Med., July 24, 1997; 337(4): 230 - 237. [Abstract] [Full Text] [PDF]
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A. P. Burke, A. Farb, G. T. Malcom, Y.-h. Liang, J. Smialek, and R. Virmani Coronary Risk Factors and Plaque Morphology in Men with Coronary Disease Who Died Suddenly N. Engl. J. Med., May 1, 1997; 336(18): 1276 - 1282. [Abstract] [Full Text] [PDF]
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G. O'Driscoll, D. Green, and R. R. Taylor Simvastatin, an HMG–Coenzyme A Reductase Inhibitor, Improves Endothelial Function Within 1 Month Circulation, March 4, 1997; 95(5): 1126 - 1131. [Abstract] [Full Text]
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S. Kaul, R. R. Makkar, M. Nakamura, F. I. Litvack, P. K. Shah, J. S. Forrester, T. C. Hutsell, and N. L. Eigler Inhibition of Acute Stent Thrombosis Under High-Shear Flow Conditions by a Nitric Oxide Donor, DMHD/NO: An Ex Vivo Porcine Arteriovenous Shunt Study Circulation, November 1, 1996; 94(9): 2228 - 2234. [Abstract] [Full Text]
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A. W. Chan, D. L. Bhatt, D. P. Chew, M. J. Quinn, D. J. Moliterno, E. J. Topol, and S. G. Ellis Early and Sustained Survival Benefit Associated With Statin Therapy at the Time of Percutaneous Coronary Intervention Circulation, February 12, 2002; 105(6): 691 - 696. [Abstract] [Full Text] [PDF]
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M. Vasa, S. Fichtlscherer, K. Adler, A. Aicher, H. Martin, A. M. Zeiher, and S. Dimmeler Increase in Circulating Endothelial Progenitor Cells by Statin Therapy in Patients With Stable Coronary Artery Disease Circulation, June 19, 2001; 103(24): 2885 - 2890. [Abstract] [Full Text] [PDF]
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C. Urbich, E. Dernbach, A. M. Zeiher, and S. Dimmeler Double-Edged Role of Statins in Angiogenesis Signaling Circ. Res., April 5, 2002; 90(6): 737 - 744. [Abstract] [Full Text] [PDF]
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