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(Circulation. 1995;92:3172-3177.)
© 1995 American Heart Association, Inc.

Articles

Hyperlipidemia and Coronary Disease

Correction of the Increased Thrombogenic Potential With Cholesterol Reduction

Lucie Lacoste, PhD; Jules Y.T. Lam, MD; Joseph Hung, MD; Glaci Letchacovski, MD; Charles B. Solymoss, MD; David Waters, MD

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.

	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

	Introduction

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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 without^{5 6 7} and with^{8 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 function^{22 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.

	Methods

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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 chambers^{30 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 system^{30 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.

	Results

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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.

View this table: [in this window] [in a new window]   Table 1. Characteristics of Patients at Entry

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).

View this table: [in this window] [in a new window]   Table 2. Results of Lipids and Platelets Studies

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.

View larger version (71K): [in this window] [in a new window]   Figure 1. A representative histological section (hematoxylin-phloxine-safranin stain) showing the platelet thrombus formation (T) onto aortic media before (baseline) at a shear rate of 2546 s-1 and after pravastatin (Pravachol) therapy. M indicates aortic media with elastic lamina and smooth muscle cells.

View larger version (31K): [in this window] [in a new window]   Figure 2. Bar graphs showing platelet deposition at the high shear rate of 2546 s-1 (left) and at the low shear rate of 754 s-1 (right) in normocholesterolemic (Normochol) and hypercholesterolemic patients at baseline (basal) and after treatment with pravastatin (After Prava).

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.

View this table: [in this window] [in a new window]   Table 3. Correlation Between Cholesterol Subfractions and Mural Thrombosis at a Shear Rate of 2546 s-1

	Discussion

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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 studies^{5 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.

	Acknowledgments

 
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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