(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.
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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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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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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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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 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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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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 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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 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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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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 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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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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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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