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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

Milita Crisby, MD; Gunilla Nordin-Fredriksson, MD; Prediman K. Shah, MD; Juliana Yano, BS; Jenny Zhu, BS; Jan Nilsson, MD, PhD

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.

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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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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J Am Coll CardiolHome page
M. Kawasaki, K. Sano, M. Okubo, H. Yokoyama, Y. Ito, I. Murata, K. Tsuchiya, S. Minatoguchi, X. Zhou, H. Fujita, et al.
Volumetric Quantitative Analysis of Tissue Characteristics of Coronary Plaques After Statin Therapy Using Three-Dimensional Integrated Backscatter Intravascular Ultrasound
J. Am. Coll. Cardiol., June 21, 2005; 45(12): 1946 - 1953.
[Abstract] [Full Text] [PDF]


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Circ. Res.Home page
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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NEJMHome page
G. K. Hansson
Inflammation, Atherosclerosis, and Coronary Artery Disease
N. Engl. J. Med., April 21, 2005; 352(16): 1685 - 1695.
[Full Text] [PDF]


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CirculationHome page
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 Am Coll CardiolHome page
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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ANGIOLOGYHome page
N. P. Kadoglou, S. S. Daskalopoulou, D. Perrea, and C. D. Liapis
Matrix Metalloproteinases and Diabetic Vascular Complications
Angiology, March 1, 2005; 56(2): 173 - 189.
[Abstract] [PDF]


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J Am Coll CardiolHome page
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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Am. J. Roentgenol.Home page
K. R. Nandalur, E. Baskurt, K. D. Hagspiel, C. D. Phillips, and C. M. Kramer
Calcified Carotid Atherosclerotic Plaque Is Associated Less with Ischemic Symptoms Than Is Noncalcified Plaque on MDCT
Am. J. Roentgenol., January 1, 2005; 184(1): 295 - 298.
[Abstract] [Full Text] [PDF]


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Arterioscler. Thromb. Vasc. Bio.Home page
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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StrokeHome page
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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JNMHome page
P. L. Weissberg
Noninvasive Imaging of Atherosclerosis: The Biology Behind the Pictures
J. Nucl. Med., November 1, 2004; 45(11): 1794 - 1795.
[Full Text] [PDF]


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Nephrol Dial TransplantHome page
J. Tunon, L. M. Blanco-Colio, J. L. Martin-Ventura, and J. Egido
Intensive treatment with statins and the progression of cardiovascular diseases: the beginning of a new era?
Nephrol. Dial. Transplant., November 1, 2004; 19(11): 2696 - 2699.
[Full Text] [PDF]


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StrokeHome page
T. J. DeGraba
Immunogenetic Susceptibility of Atherosclerotic Stroke: Implications on Current and Future Treatment of Vascular Inflammation
Stroke, November 1, 2004; 35(11_suppl_1): 2712 - 2719.
[Abstract] [Full Text] [PDF]


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Arch Intern MedHome page
F. A. Spencer, G. C. Fonarow, P. D. Frederick, R. S. Wright, N. Every, R. J. Goldberg, J. M. Gore, W. Dong, R. C. Becker, W. French, et al.
Early Withdrawal of Statin Therapy in Patients With Non-ST-Segment Elevation Myocardial Infarction: National Registry of Myocardial Infarction
Arch Intern Med, October 25, 2004; 164(19): 2162 - 2168.
[Abstract] [Full Text] [PDF]


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CirculationHome page
J. A.C. Lima, M. Y. Desai, H. Steen, W. P. Warren, S. Gautam, and S. Lai
Statin-Induced Cholesterol Lowering and Plaque Regression After 6 Months of Magnetic Resonance Imaging-Monitored Therapy
Circulation, October 19, 2004; 110(16): 2336 - 2341.
[Abstract] [Full Text] [PDF]


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CirculationHome page
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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Ann Rheum DisHome page
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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CirculationHome page
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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CirculationHome page
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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CirculationHome page
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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ANN INTERN MEDHome page
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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StrokeHome page
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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CirculationHome page
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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NeurologyHome page
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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Clin. Chem.Home page
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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J. Immunol.Home page
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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Eur Heart J SupplHome page
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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Eur Heart J SupplHome page
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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J Am Coll CardiolHome page
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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CirculationHome page
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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Cardiovasc ResHome page
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]