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(Circulation. 2001;103:926.)
© 2001 American Heart Association, Inc.
Clinical Investigation and Reports |
Pravastatin Treatment Increases Collagen Content and Decreases Lipid Content, Inflammation, Metalloproteinases, and Cell Death in Human Carotid Plaques
Implications for Plaque Stabilization
From the Department of Neurology, Huddinge University Hospital, Stockholm (M.C.), and Department of Medicine, Malmö University Hospital, Lund University, Malmö (G.N.-F., J.N.), Sweden; and the Atherosclerosis Research Center and the Division of Cardiology, Cedars Sinai Medical Center and UCLA School of Medicine, Los Angeles, Calif (P.K.S., J.Y., J.Z.).
Correspondence to P.K. Shah, MD, Cedars Sinai Medical Center, Room 5347, 8700 Beverly Blvd, Los Angeles, CA 90048. E-mail shahp{at}cshs.org; or Milita Crisby, MD, Department of Neurology, Huddinge University Hospital, 141 86 Huddinge, Sweden.
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Abstract |
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Background—The clinical benefits of lipid lowering with statins are attributed to changes in plaque composition leading to lesion stability, but supporting clinical data from human studies are lacking. Therefore, we investigated the effect of 3 months of pravastatin treatment on composition of human carotid plaques removed during carotid endarterectomy.
Methods and Results—Consecutive patients with symptomatic carotid artery stenosis received 40 mg/d pravastatin (n=11) or no lipid-lowering therapy (n=13; control subjects) for 3 months before scheduled carotid endarterectomy. Carotid plaque composition was assessed with special stains and immunocytochemistry with quantitative image analysis. Plaques from the pravastatin group had less lipid by oil red O staining (8.2±8.4% versus 23.9±21.1% of the plaque area, P<0.05), less oxidized LDL immunoreactivity (13.3±3.6% versus 22.0±6.5%, P<0.001), fewer macrophages (15.0±10.2% versus 25.3±12.5%, P<0.05), fewer T cells (11.2±9.3% versus 24.3±13.4%, P<0.05), less matrix metalloproteinase 2 (MMP-2) immunoreactivity (3.6±3.9% versus 8.4±5.3%, P<0.05), greater tissue inhibitor of metalloproteinase 1 (TIMP-1) immunoreactivity (9.0±6.2% versus 3.1±3.9%, P<0.05), and a higher collagen content by Sirius red staining (12.4±3.1% versus 7.5±3.5%, P<0.005). Cell death by TUNEL staining was reduced in the pravastatin group (17.7±7.8% versus 32.0±12.6%, P<0.05).
Conclusions—Pravastatin decreased lipids, lipid oxidation, inflammation, MMP-2, and cell death and increased TIMP-1 and collagen content in human carotid plaques, confirming its plaque-stabilizing effect in humans.
Key Words: pravastatin • plaque • inflammation
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Several trials have demonstrated reduced cardiovascular events and mortality with lipid-lowering therapy.1 2 3 4 5 Angiographic studies show less progression, more regression, and less new lesion development with lipid-lowering therapy.6 7 8 9 Greater clinical event reduction, however, compared with only modest changes in stenosis severity, suggests that lipid lowering may produce clinical benefit largely by "stabilizing" plaques against disruption.6 7 8 9 This concept of plaque stabilization is predicated on the principle that a reduction in lipid content and inflammatory activity, 2 of the major determinants of plaque instability, would reduce the risk of plaque disruption, thereby preventing adverse clinical events.9 10 11 12 Although animal studies have supported this hypothesis, data in humans are lacking.13 14 15 16 Therefore, in this study, we determined the effect of 3 months of lipid-lowering therapy with pravastatin on carotid plaque composition in patients undergoing carotid endarterectomy (CEA) for symptomatic severe internal carotid artery stenosis.
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Methods |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Consecutive patients with carotid artery stenosis (>70% diameter stenosis on angiography) according to the North American Symptomatic Carotid Endarterectomy Trial (NASCET) criteria and symptomatic with ipsilateral transient ischemic attack were included prospectively in this study at Huddinge University Hospital, Stockholm, Sweden, during a 9-month period.17 The institutional ethics committee approved the study, and informed consent was obtained before enrollment. Eleven patients received 40 mg/d pravastatin for an average of 3 months before CEA, whereas 13 patients did not receive any lipid-lowering therapy (control subjects). Patients in both groups received dietary counseling. Ongoing lipid-lowering medication was an exclusion criterion. Fasting plasma total cholesterol, LDL, HDL, and triglyceride levels were measured at baseline and during the follow-up postoperative period with commercially available assays.
Tissue Preparation
After surgery, the CEA specimens were cut
perpendicular to the long axis into 2 halves. The first half was
snap-frozen and stored at -70°C. The second half was fixed in 4%
formalin/50 mmol/L BHT/0.2% EDTA overnight at room temperature and cut
into 2 halves as above, 1 of which was used for oil red O staining and
the other embedded in paraffin for terminal deoxynucleotidyl
transferase (TdT)–mediated dUTP nick end-labeling (TUNEL) and
immunohistochemistry. Two parallel tissue sections were used from each
carotid plaque for immunohistochemical, TUNEL, and oil red O studies.
Tissue sections were deparaffinized before the TUNEL procedure and
immunostaining by subsequent washes (xylene; ethanol 100%, 95%, and
70% diluted in distilled H2O).
TUNEL Staining
The TUNEL procedure was performed with the In Situ
Apoptosis Kit (Apo-Tag, Oncor). Proteinase K (20 µg/mL) was applied
to tissue sections for 15 minutes at room temperature. Endogenous
peroxidase was blocked by incubation of sections with 2%
H2O2 for 5 minutes.
Sections were incubated with the TdT enzyme for 2 hours at 37°C.
Antidigoxin-peroxidase solution was applied for 30 minutes, followed by
exposure to diaminobenzidine (DAB) substrate for 3 to 5 minutes and
counterstaining with hematoxylin.
Immunohistohemistry
Mouse monoclonal antibodies were used for
immunostaining of macrophages (CD68 KP-1, DAKO, 1:200), smooth muscle
cells (SMCs; HHF-35, DAKO, 1:800), oxidized LDL (NA 59, a gift from
Joseph Witztum, MD, University of California San Diego, 1:600), nuclear
factor-
B (NF-B; p65 subunit, Boehringer Mannheim, 1:200), and
sheep anti–human apoB for LDL apolipoprotein B-100 (apoB, Boehringer
Mannheim, 1:6000). Rabbit polyclonal antibody (CD3, DAKO, 1:200) was
applied for detection of activated T cells. Matrix metalloproteinase
(MMP) and tissue inhibitor of metalloproteinases (TIMP)
immunoreactivity were determined by use of specific antibodies (Biotrak
Inc). Immunostaining for adhesion molecules was performed with
recombinant human vascular cell adhesion molecule-1 (rhVCAM-1) and goat
anti–human intercellular cell adhesion molecule-1 (ICAM-1; R&D
Systems, 1:200). For CD 3 and CD 68 antibody staining, enzymatic
digestion was performed by pretreatment of sections with pronase for 5
minutes. Before immunostaining for NF-B, sections were treated in a
microwave oven in 0.1 mol/L citrate buffer, pH 6.0. Endogenous
peroxidase was blocked by incubation with 0.3%
H2O2 in methanol for 30
minutes. Slides were incubated with normal horse serum or 5% BSA for
30 minutes and then primary antibody for 1 hour at room temperature at
the concentrations mentioned above. The apoB immunostaining was
performed overnight at +4°C. Control slides were incubated with a
mouse monoclonal IgG2b (Immunotech SA, 1:50) or PBS solution. The
sections were incubated with the complementary secondary antibody for
30 minutes and then with avidin-biotin for 30 minutes. Sections were
exposed to DAB for 3 to 5 minutes and counterstained with hematoxylin.
Double immunostaining for macrophages and SMCs was used to identify the
cellular source of MMP and TIMP.
Specificity of the NA 59 antibody immunostaining was confirmed by elimination of staining with preincubation of antibody with 100 µg/mL of oxidized LDL for 2 hours at 37°C before application to the tissue. The LDL was prepared as described by Redgrave and Carlson18 with an EDTA concentration of 10 mmol/L. EDTA was removed before oxidation by filtration on an Econo-Pac 10 DG gel column (BioRad). Protein content was determined according to Lowry et al.19 LDL (300 µg/mL) was oxidized by incubation in 10 µmol/L CuSO4/RPMI 1640 at 37°C for 18 hours and confirmed by agarose gel electrophoresis.
Oil Red O Staining for Lipid Content
Two parallel carotid sections from each CEA specimen
were incubated in 60% isopropanol for 2 minutes and then in oil red O
solution for 20 minutes and rinsed in H2O. One
of the sections was counterstained with
hematoxylin.
Sirius Red Staining for Collagen
Content
Sirius red polarization microscopy was used to detect
interstitial collagen. Collagen types I and III are identified by
birefringence under polarized light illumination. Carotid plaque
sections were rinsed with distilled water and incubated with 0.1%
Sirius red in saturated picric acid for 90 minutes. Sections were
rinsed 2 times with 0.01N HCl for 1 minute and then immersed in
distilled water. After dehydration with 70% ethanol for 30 seconds,
the sections were observed under polarized light after coverslipping.
The sections were photographed with identical exposure settings for all
sections.
Image Analysis of Immunostaining and Oil Red O
Stains
All parameters of atherosclerotic lesions were
assessed by an observer blinded to treatment assignment using
microimage analysis software or image-Pro Plus software (Media
Cybernetics), a BX 60 Olympus or Nikon E600 microscope, and a Spot II
or Sony digital camera. Exposure times for each section were kept
constant. Color segmentation was used to separate staining area from
background on the basis of the color characteristics within the area of
interest. For oil red O, Sirius red, apoB, NA 59, MMPs, and TIMP, the
percentage of positively stained area as a function of the total plaque
area was determined by computer-assisted morphometry of the plaques,
and for cells expressing CD 3, CD 68, HHF-35, VCAM-1, ICAM-1, and
NF-B immunoreactivity, the percentages of positive-stained cells
were measured.
Statistical Analysis
Data are presented as mean±SD. Unpaired
t test was used to compare the
2 groups, and changes in lipid values in each group from baseline to
follow-up were tested with a paired
t test. A value of
P<0.05 was considered
statistically significant.
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Results |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Clinical characteristics and baseline lipoprotein levels were comparable in the 2 groups (Tables 1
and 2). In control subjects, lipoprotein
levels did not change significantly during follow-up, whereas total
cholesterol decreased by 27% and LDL cholesterol decreased by 34% in
the pravastatin group
(Table 2).
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Carotid plaques of both groups had the morphology of advanced lesions, with a lipid-rich acellular core and sites of rupture, superimposed thrombosis, and intraplaque hemorrhage.
Lipid Content, Oxidized LDL, and ApoB-100
Immunoreactivity
The lipid content by oil red O and the oxidized LDL
content were significantly lower in the plaques of the
pravastatin-treated group than in control subjects. ApoB-100 content,
however, was comparable between the groups
(Figure 1, Table 3).
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Cellular Composition, Adhesion Molecules,
NF-B, and Cell Death
Plaques from the pravastatin-treated group had reduced
immunoreactivity for macrophages (CD 68) and T cells (CD 3). Reduced
ICAM-1 and VCAM-1 in the pravastatin group was not statistically
different between the groups. The fraction of cells with positive
immunoreactivity for SMC 
-actin was slightly higher in the
pravastatin group than in control subjects. NF-B immunoreactivity
was similar between the 2 groups
(Figure 2, Tables 4 and 5).
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The TUNEL assay identifies cells with DNA fragmentation.
Compared with the control subjects, the fraction of TUNEL-positive
cells was reduced by 
50% in the pravastatin group. Most of the
apoptotic cells were identified as SMCs in serial
sections.
MMP, TIMP, and Collagen Content
Plaques from the pravastatin group had less MMP-2 and
increased TIMP-1 immunoreactivity
(Figures 3 through 5 and
Table 6). The majority of the cells expressing MMP-2 were
macrophages with weak expression by SMCs, as identified by
morphological features, colocalization in contiguous sections
(Figure 4A), and double immunostaining
(Figure 4C). Macrophages but not -actin–reactive SMCs
were shown to express TIMP-1 on contiguous sections
(Figure 4B) and on double immunostaining. TIMP-1
immunoreactivity, however, exceeded macrophage immunoreactivity in the
pravastatin-treated group, suggesting that non–-actin–reactive
SMCs may have been an additional source of increased TIMP-1
immunoreactivity in the pravastatin group. There was no significant
difference in MMP-1, MMP-9, and TIMP-2 immunoreactivity between the 2
groups. Collagen content was significantly higher in the
pravastatin-treated group than in control subjects
(Figure 5).
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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This study shows that pravastatin treatment for 3 months is associated with reduced lipid content, oxidized LDL immunoreactivity, cell death, and inflammatory cell and MMP-2 immunoreactivity, along with an increase in TIMP-1 immunoreactivity and interstitial collagen content in human carotid plaques. We did not detect a significant change in MMP-1, MMP-9, and TIMP-2 expression, for reasons unclear to us, although more prolonged therapy may be necessary for these changes to occur, as suggested by experimental data.14 Despite the lack of a significant decrease in MMP-1 and MMP-9 immunoreactivity, increased collagen accumulation may nevertheless have resulted from an increase in TIMP-1, a potent inhibitor of both MMP-1 and MMP-9 activity, and reduced MMP-2 levels. Selective overexpression of MMP-2, capable of degrading basement membrane type IV collagen, has been shown in the proteoglycan-rich matrix underlying plaque erosion, where it has been implicated in loss of endothelial anchorage to the underlying matrix.20 21 Thus, a reduction in MMP-2 may also contribute to plaque stability by reducing plaque erosion, which has been shown to be a substrate for coronary thrombosis in
50% fatal
events.20 21
Reduction in MMP expression observed in this study may have resulted
from a decrease in the number of macrophages, as noted in this study,
and/or reduced gene transcription/activation of MMPs. Pravastatin
treatment resulted in substantially lower oxidized LDL
immunoreactivity, which may have resulted from either reduced vessel
wall lipid retention or direct antioxidant effects of
pravastatin.22 23
A reduced lipid content of plaques, along with a reduction in oxidized
LDL immunoreactivity, also suggests that decreased lipid accumulation
and reduced oxidative stress may have contributed to a reduction in
inflammation and TIMP-1 increase and MMP-2 reduction in the vessel
wall, because LDL oxidation is known to activate the inflammatory
cascade and regulate TIMP-1 and MMP
expression.24 25
The present findings indicate that pravastatin may affect plaque lipid
metabolism through inhibition of oxidative modification of LDL in the
vessel wall and favor removal by normal pathways. The observation that
pravastatin-treated lesions contained equal amounts of apoB-100 despite
decreased lipid content may thus be due to decreased
oxidation-dependent fragmentation of apoB-100. Clinical trials have shown that lipid-lowering therapy results in substantially greater reduction in cardiovascular events than would be expected from modest angiographic changes.1 2 3 4 8 9 The protective effect is also evident long before effects on lesion progression are detectable. These observations suggest the possibility that the beneficial effects of lipid lowering may result from mechanisms other than reduction of plaque size or stenosis severity.8 26 27 Because plaque disruption leading to thrombosis is a major cause of acute cardiovascular events, a reduced frequency of plaque disruption through increased stability represents one such possible mechanism.8 12 26 27 The vulnerability of plaques to disruption appears to be related to plaque composition as well as hemodynamic factors. Although advanced atherosclerotic lesions are heterogeneous in nature, the majority are characterized by a large lipid-rich core and a thin fibrous cap with increased numbers of inflammatory cells in the shoulder region of the plaque.27
Several studies suggest that lipoproteins may contribute to the development of atherosclerosis by initiating and sustaining the inflammatory response in the vessel wall.24 Increased inflammation is also a feature of disrupted plaques. There is a strong positive correlation between concentration of macrophages localized at sites of intimal rupture and acute coronary syndromes.27 28 29 The secretion of matrix-degrading enzymes, ie, MMPs, largely by macrophages, may cause disruption of the plaque structure by depleting the fibrous cap of connective tissue matrix.30 31 32 Recent reports indicate that elevated levels of C-reactive protein (CRP), an acute-phase protein widely used as a marker of inflammation, is predictive of the risk of first myocardial infarction.33 The severity of the superficial inflammation seen in atherosclerotic lesions has been implicated as a statistically significant correlate of plaque rupture.29 34
It remains to be determined whether the decrease in inflammatory activity observed in plaques from the pravastatin group is due to a decreased presence of oxidized lipids. Recent data from subgroup analysis of the CARE study suggest that the beneficial clinical effects of pravastatin treatment in post–myocardial infarction patients with increased markers of inflammation may result in part from anti-inflammatory as well as lipid-lowering properties.35 36 These observations suggest that pravastatin may have anti-inflammatory effects that are independent of lipid-lowering effects.15 35 36 37
The vulnerable lesion characteristically has a thin fibrous
cap with few SMCs, many of which show signs of death by apoptosis or
oncosis (necrosis), which can be identified by TUNEL
staining.38 39
The lack of functional SMCs could lead to decreased collagen content,
thereby reducing fibrous cap tensile
strength.38 We found
reduced cell death (of mostly SMCs) in carotid plaques of
pravastatin-treated patients, which may either have resulted from a
direct effect of the drug or have been an indirect consequence of
reduced LDL oxidation in the
plaque.40 Because a change
in phenotype may change -actin expression by SMCs, -actin
staining may not have identified all SMCs, thereby accounting for the
lack of significant difference in SMC numbers between the 2 groups.
Further research is needed, however, to confirm this
observation.
Conclusions
This study demonstrates that pravastatin-induced
lipid-lowering therapy is associated with changes in human carotid
plaque composition that favor lesion stability, providing the first
strong evidence in support of plaque-stabilizing effects of statins in
humans.
Potential Limitations of the Study
The results of this study must be considered with the
following caveats: this was a nonrandomized study, and hidden biases
could explain the results. This is unlikely, however, because patients
were consecutive and well matched for various demographic features.
Although differences in composition were clearly demonstrated, the
possibility of sampling error should also be considered. We did not
measure the true mechanical properties of the plaques to ascertain
whether pravastatin-treated plaques were indeed more resistant to
rupture, although one could infer that from an increase in collagen
content and a reduction in lipid content and inflammation, all of which
appear to relate to the in vitro tensile strength of
plaques.41 42 43
Although favorable changes in lesion composition were observed within 3 months of pravastatin treatment, clinical trials suggest that event reduction takes 6 to 12 months after initiation of statins.1 2 3 4 5 This seeming discrepancy may result from the fact that a more complete lipid and inflammatory cell depletion is necessary to completely stabilize plaques, and such effects require more prolonged therapy. Nevertheless, our study shows that plaque composition is changing in the appropriate direction, and the findings do not conflict with the results of clinical trials.
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Acknowledgments |
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This study was supported by grants from the Swedish Medical Research Council, the Swedish Heart and Lung Foundation, Lars Hjertas Minne’s Foundation, and Bristol-Myers Squibb. The support of the Dora Herbert Family and Spaulding Family (to Dr Shah) is gratefully acknowledged. The authors express their sincere gratitude to Dr Björn Wiklund and Dr Rolf Pieper from the Department of Vascular Surgery, Huddinge University Hospital, for providing the carotid specimens.
Received November 6, 2000; revision received December 6, 2000; accepted December 14, 2000.
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N. Nighoghossian, L. Derex, and P. Douek The Vulnerable Carotid Artery Plaque: Current Imaging Methods and New Perspectives Stroke, December 1, 2005; 36(12): 2764 - 2772. [Abstract] [Full Text] [PDF]
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R. Corti, V. Fuster, Z. A. Fayad, S. G. Worthley, G. Helft, W. F. Chaplin, J. Muntwyler, J. F. Viles-Gonzalez, J. Weinberger, D. A. Smith, et al. Effects of Aggressive Versus Conventional Lipid-Lowering Therapy by Simvastatin on Human Atherosclerotic Lesions: A Prospective, Randomized, Double-Blind Trial With High-Resolution Magnetic Resonance Imaging J. Am. Coll. Cardiol., July 5, 2005; 46(1): 106 - 112. [Abstract] [Full Text] [PDF]
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M. Yamakuchi, J. J.M. Greer, S. J. Cameron, K. Matsushita, C. N. Morrell, K. Talbot-Fox, W. M. Baldwin III, D. J. Lefer, and C. J. Lowenstein HMG-CoA Reductase Inhibitors Inhibit Endothelial Exocytosis and Decrease Myocardial Infarct Size Circ. Res., June 10, 2005; 96(11): 1185 - 1192. [Abstract] [Full Text] [PDF]
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J. Johnson, K. Carson, H. Williams, S. Karanam, A. Newby, G. Angelini, S. George, and C. Jackson Plaque Rupture After Short Periods of Fat Feeding in the Apolipoprotein E-Knockout Mouse: Model Characterization and Effects of Pravastatin Treatment Circulation, March 22, 2005; 111(11): 1422 - 1430. [Abstract] [Full Text] [PDF]
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J. J. Wentzel, R. Corti, Z. A. Fayad, P. Wisdom, F. Macaluso, M. O. Winkelman, V. Fuster, and J. J. Badimon Does shear stress modulate both plaque progression and regression in the thoracic aorta?: Human study using serial magnetic resonance imaging J. Am. Coll. Cardiol., March 15, 2005; 45(6): 846 - 854. [Abstract] [Full Text] [PDF]
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K. O'Neil-Callahan, G. Katsimaglis, M. R. Tepper, J. Ryan, C. Mosby, J. P.A. Ioannidis, and P. G. Danias Statins decrease perioperative cardiac complications in patients undergoing noncardiac vascular surgery: The Statins for Risk Reduction in Surgery (StaRRS) study J. Am. Coll. Cardiol., February 1, 2005; 45(3): 336 - 342. [Abstract] [Full Text] [PDF]
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M. Torzewski, P. X. Shaw, K.-R. Han, B. Shortal, K. J. Lackner, J. L. Witztum, W. Palinski, and S. Tsimikas Reduced In Vivo Aortic Uptake of Radiolabeled Oxidation-Specific Antibodies Reflects Changes in Plaque Composition Consistent With Plaque Stabilization Arterioscler Thromb Vasc Biol, December 1, 2004; 24(12): 2307 - 2312. [Abstract] [Full Text] [PDF]
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P. Amarenco, J. Labreuche, P. Lavallee, and P.-J. Touboul Statins in Stroke Prevention and Carotid Atherosclerosis: Systematic Review and Up-to-Date Meta-Analysis Stroke, December 1, 2004; 35(12): 2902 - 2909. [Abstract] [Full Text] [PDF]
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S. Tsimikas, J. L. Witztum, E. R. Miller, W. J. Sasiela, M. Szarek, A. G. Olsson, G. G. Schwartz, and for the Myocardial Ischemia Reduction with Aggress High-Dose Atorvastatin Reduces Total Plasma Levels of Oxidized Phospholipids and Immune Complexes Present on Apolipoprotein B-100 in Patients With Acute Coronary Syndromes in the MIRACL Trial Circulation, September 14, 2004; 110(11): 1406 - 1412. [Abstract] [Full Text] [PDF]
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P E Lazzerini, P L Capecchi, F Nerucci, A Fioravanti, F Chellini, M Piccini, S Bisogno, R Marcolongo, and F Laghi Pasini Simvastatin reduces MMP-3 level in interleukin 1{beta} stimulated human chondrocyte culture Ann Rheum Dis, July 1, 2004; 63(7): 867 - 869. [Abstract] [Full Text] [PDF]
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S. Tsimikas, H. K. Lau, K.-R. Han, B. Shortal, E. R. Miller, A. Segev, L. K. Curtiss, J. L. Witztum, and B. H. Strauss Percutaneous Coronary Intervention Results in Acute Increases in Oxidized Phospholipids and Lipoprotein(a): Short-Term and Long-Term Immunologic Responses to Oxidized Low-Density Lipoprotein Circulation, June 29, 2004; 109(25): 3164 - 3170. [Abstract] [Full Text] [PDF]
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J. Davignon Beneficial Cardiovascular Pleiotropic Effects of Statins Circulation, June 15, 2004; 109(23_suppl_1): III-39 - III-43. [Abstract] [Full Text]
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P. Amarenco and A. M. Tonkin Statins for Stroke Prevention: Disappointment and Hope Circulation, June 15, 2004; 109(23_suppl_1): III-44 - III-49. [Abstract] [Full Text] [PDF]
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 F. A. Spencer, J. Allegrone, R. J. Goldberg, J. M. Gore, K. A.A. Fox, C. B. Granger, R. H. Mehta, D. Brieger, and the GRACE Investigators* Association of Statin Therapy with Outcomes of Acute Coronary Syndromes: The GRACE Study Ann Intern Med, June 1, 2004; 140(11): 857 - 866. [Abstract] [Full Text] [PDF]
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G. A. Donnan and S. M. Davis Stroke and Cholesterol: Weakness of Risk Versus Strength of Therapy Stroke, June 1, 2004; 35(6): 1526 - 1526. [Full Text] [PDF]
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U. Schonbeck and P. Libby Inflammation, Immunity, and HMG-CoA Reductase Inhibitors: Statins as Antiinflammatory Agents? Circulation, June 1, 2004; 109(21_suppl_1): II-18 - II-26. [Abstract] [Full Text] [PDF]
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P. H. Lee, S. -H. Oh, O. Y. Bang, S. -Y. Joo, I. S. Joo, and K. Huh Infarct patterns in atherosclerotic middle cerebral artery versus internal carotid artery disease Neurology, April 27, 2004; 62(8): 1291 - 1296. [Abstract] [Full Text] [PDF]
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 Z. Xu, S. Zhao, H. Zhou, H. Ye, and J. Li Atorvastatin Lowers Plasma Matrix Metalloproteinase-9 in Patients with Acute Coronary Syndrome Clin. Chem., April 1, 2004; 50(4): 750 - 753. [Full Text] [PDF]
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A. McKay, B. P. Leung, I. B. McInnes, N. C. Thomson, and F. Y. Liew A Novel Anti-Inflammatory Role of Simvastatin in a Murine Model of Allergic Asthma J. Immunol., March 1, 2004; 172(5): 2903 - 2908. [Abstract] [Full Text] [PDF]
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 F.M Sacks Do statins play a role in the early management of the acute coronary syndrome? Eur. Heart J. Suppl., March 1, 2004; 6(suppl_A): A32 - A36. [Abstract] [Full Text] [PDF]
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M.J Chapman and M Caslake Non-high-density lipoprotein cholesterol as a risk factor: addressing risk associated with apolipoprotein B-containing lipoproteins Eur. Heart J. Suppl., March 1, 2004; 6(suppl_A): A43 - A48. [Abstract] [Full Text] [PDF]
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R. Corti, J. I. Osende, J. T. Fallon, V. Fuster, G. Mizsei, H. Jneid, S. D. Wright, W. F. Chaplin, and J. J. Badimon The selective peroxisomal proliferator-activated receptor-gamma agonist has an additive effect on plaque regression in combination with simvastatin in experimental atherosclerosis: in vivo study by high-resolution magnetic resonance imaging J. Am. Coll. Cardiol., February 4, 2004; 43(3): 464 - 473. [Abstract] [Full Text] [PDF]
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P. M Ridker and on behalf of the JUPITER Study Group Rosuvastatin in the Primary Prevention of Cardiovascular Disease Among Patients With Low Levels of Low-Density Lipoprotein Cholesterol and Elevated High-Sensitivity C-Reactive Protein: Rationale and Design of the JUPITER Trial* Circulation, November 11, 2003; 108(19): 2292 - 2297. [Full Text] [PDF]
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C. B Jones, D. C Sane, and D. M Herrington Matrix metalloproteinases: A review of their structure and role in acute coronary syndrome Cardiovasc Res, October 1, 2003; 59(4): 812 - 823. [Abstract] [Full Text] [PDF]
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