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Semin Vasc Med 2004; 4(4): 357-366
DOI: 10.1055/s-2004-869592
Copyright © 2004 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA.

Lipid Lowering Therapy in Atherosclerosis

Masanori Aikawa1 , Peter Libby1
  • 1Donald W. Reynolds Cardiovascular Clinical Research Center, Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts
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Publication History

Publication Date:
29 April 2005 (online)

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ABSTRACT

Dyslipidemia plays critical roles in the pathogenesis of coronary atherosclerosis, a chronic inflammatory disease. Vascular inflammation also triggers the onset of acute complications of atherosclerosis, such as myocardial infarction. Advances in cardiovascular medicine demonstrate that lipid-lowering therapy by 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) likely prevents acute coronary complications by limiting vascular inflammation. In particular, recent clinical evidence indicates aggressive lipid-lowering treatment for patients at risk. Preclinical studies also support the concept of anti-inflammatory properties of lipid lowering by either diet or statins. Therefore, dyslipidemia is the primary target of therapy for the prevention of coronary atherosclerosis and its acute thrombotic complications. Nevertheless, even aggressive statin therapy does not forestall many adverse events. Thus, current cardiovascular medicine also seeks mechanisms to mitigate vascular inflammation and atherosclerosis other than addressing low-density lipoprotein, and new therapeutic strategies beyond lipid lowering.

KEYWORDS

Atherosclerosis - inflammation - macrophages - HMG-CoA reductase inhibitors - plaque stabilization

REFERENCES

  • 1 Grundy S M, Cleeman J I, Merz C N et al.. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines.  Circulation. 2004;  110 227-239
    CrossrefPubMedGoogle Scholar
  • 2 Aikawa M, Libby P. The vulnerable atherosclerotic plaque; pathogenesis and therapeutic approach.  Cardiovasc Pathol. 2004;  13 125-138
    PubMedGoogle Scholar
  • 3 Anitschkow N, Chalatow S. On experimental cholesterin steatosis and its significance in the origin of some pathological processes (1913).  Arteriosclerosis. 1983;  3 178-182
    PubMedGoogle Scholar
  • 4 Vesselinovitch D. Animal models and the study of atherosclerosis.  Arch Pathol Lab Med. 1988;  112 1011-1017
    PubMedGoogle Scholar
  • 5 Aikawa M, Fukumoto Y, Rabkin E, Libby P. Rabbit models of atherosclerosis. In: Daniel I. Simon, Rogers C Vascular Disease and Injury: Preclinical Research Totowa, NJ; Humana Press 2000: 175-191
    Google Scholar
  • 6 LaRosa J C, Hunninghake D, Bush D et al.. The cholesterol facts. A summary of the evidence relating dietary fats, serum cholesterol, and coronary heart disease. A joint statement by the American Heart Association and the National Heart, Lung, and Blood Institute. The Task Force on Cholesterol Issues, American Heart Association.  Circulation. 1990;  81 1721-1733
    PubMedGoogle Scholar
  • 7 Libby P, Aikawa M, Schonbeck U. Cholesterol and atherosclerosis.  Biochim Biophys Acta. 2000;  1529 299-309
    PubMedGoogle Scholar
  • 8 Steinberg D, Parthasarathy S, Carew T E, Khoo J C, Witztum J L. Beyond cholesterol. Modifications of low-density lipoprotein that increase its atherogenicity.  N Engl J Med. 1989;  320 915-924
    CrossrefPubMedGoogle Scholar
  • 9 Tshimikas S, Glass C K, Steinberg D, Witztum J L. Lipoprotein oxidation, macrophages, immunity, and atherogenesis. In: Chein KR Molecular Basis of Cardiovascular Disease Philadelphia; Saunders 2004: 385-413
    Google Scholar
  • 10 Kodama T, Freeman M, Rohrer L, Zabrecky J, Matsudaira P, Krieger M. Type I macrophage scavenger receptor contains alphaα-helical and collagen-like coiled coils.  Nature. 1990;  343 531-535
    CrossrefPubMedGoogle Scholar
  • 11 Gotto A M, Farmer J A. Lipid-lowering trials. In: Braunwald E, Zipes DP, Libby P Heart Disease: A Text Book of Cardiovascular Medicine Philadelphia; WB Saunders 2001: 126-146
    Google Scholar
  • 12 Libby P, Aikawa M. Stabilization of atherosclerotic plaques: new mechanisms and clinical targets.  Nat Med. 2002;  8 1257-1262
    CrossrefPubMedGoogle Scholar
  • 13 Kinlay S, Timms T, Clark M et al.. Comparison of effect of intensive lipid lowering with atorvastatin to less intensive lowering with lovastatin on C-reactive protein in patients with stable angina pectoris and inducible myocardial ischemia.  Am J Cardiol. 2002;  89 1205-1207
    CrossrefPubMedGoogle Scholar
  • 14 van Wissen S, Trip M D, Smilde T J, de Graaf J, Stalenhoef A F, Kastelein J J. Differential hs-CRP reduction in patients with familial hypercholesterolemia treated with aggressive or conventional statin therapy.  Atherosclerosis. 2002;  165 361-366
    CrossrefPubMedGoogle Scholar
  • 15 Taylor A J, Kent S M, Flaherty P J, Coyle L C, Markwood T T, Vernalis M N. ARBITER: Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol: a randomized trial comparing the effects of atorvastatin and pravastatin on carotid intima medial thickness.  Circulation. 2002;  106 2055-2060
    CrossrefPubMedGoogle Scholar
  • 16 Cannon C P, Braunwald E, McCabe C H et al.. Intensive versus moderate lipid lowering with statins after acute coronary syndromes.  N Engl J Med. 2004;  350 1495-1504
    CrossrefPubMedGoogle Scholar
  • 17 Nissen S E, Tuzcu E M, Schoenhagen P et al.. Effect of intensive compared with moderate lipid-lowering therapy on progression of coronary atherosclerosis: a randomized controlled trial.  JAMA. 2004;  291 1071-1080
    CrossrefPubMedGoogle Scholar
  • 18 Fuster V, Badimon L, Badimon J J, Chesebro J H. The pathogenesis of coronary artery disease and the acute coronary syndromes.  N Engl J Med. 1992;  326 242-250 310-318
    CrossrefPubMedGoogle Scholar
  • 19 Libby P. Molecular bases of the acute coronary syndromes.  Circulation. 1995;  91 2844-2850
    CrossrefPubMedGoogle Scholar
  • 20 Moreno P R, Falk E, Palacios I F, Newell J B, Fuster V, Fallon J T. Macrophage infiltration in acute coronary syndromes. Implications for plaque rupture.  Circulation. 1994;  90 775-778
    PubMedGoogle Scholar
  • 21 van der Wal A C, Becker A E, van der Loos C M, Das P K. Site of intimal rupture or erosion of thrombosed coronary atherosclerotic plaques is characterized by an inflammatory process irrespective of the dominant plaque morphology.  Circulation. 1994;  89 36-44
    PubMedGoogle Scholar
  • 22 Galis Z S, Sukhova G K, Lark M W, Libby P. Increased expression of matrix metalloproteinases and matrix degrading activity in vulnerable regions of human atherosclerotic plaques.  J Clin Invest. 1994;  94 2493-2503
    CrossrefPubMedGoogle Scholar
  • 23 Sukhova G, Schoenbeck U, Rabkin E et al.. Evidence of increased collagenolysis by interstitial collagenases-1 and -3 in vulnerable human atheromatous plaques.  Circulation. 1999;  99 2503-2509
    PubMedGoogle Scholar
  • 24 Herman M P, Sukhova G K, Libby P et al.. Expression of neutrophil collagenase (matrix metalloproteinase-8) in human atheroma: a novel collagenolytic pathway suggested by transcriptional profiling.  Circulation. 2001;  104 1899-1904
    CrossrefPubMedGoogle Scholar
  • 25 Brinckerhoff C E, Matrisian L M. Matrix metalloproteinases: a tail of a frog that became a prince.  Nat Rev Mol Cell Biol. 2002;  3 207-214
    CrossrefPubMedGoogle Scholar
  • 26 Fukumoto Y, Deguchi J, Libby P et al.. Genetically-determined resistance to collagenase action augments interstitial collagen accumulation in atherosclerotic plaques.  Circulation. 2004;  , In press
    PubMedGoogle Scholar
  • 27 Libby P, Mach F, Schoenbeck U, Bourcier T, Aikawa M. Regulation of the thrombotic potential of atheroma.  Thromb Haemost. 1999;  82 736-741
    PubMedGoogle Scholar
  • 28 Farb A, Burke A P, Tang A L et al.. Coronary plaque erosion without rupture into a lipid core. A frequent cause of coronary thrombosis in sudden coronary death.  Circulation. 1996;  93 1354-1363
    CrossrefPubMedGoogle Scholar
  • 29 Bombeli T, Karsan A, Tait J F, Harlan J M. Apoptotic vascular endothelial cells become procoagulant.  Blood. 1997;  89 2429-2442
    PubMedGoogle Scholar
  • 30 Rajavashisth T B, Liao J K, Galis Z S et al.. Inflammatory cytokines and oxidized low density lipoproteins increase endothelial cell expression of membrane type 1-matrix metalloproteinase.  J Biol Chem. 1999;  274 11924-11929
    CrossrefPubMedGoogle Scholar
  • 31 Sugiyama S, Kugiyama K, Aikawa M, Nakamura S, Ogawa H, Libby P. Hypochlorous acid, a macrophage product, induces endothelial apoptosis and tissue factor expression. Involvement of myeloperoxidase-mediated oxidant in plaque erosion and thrombogenesis.  Arterioscler Thromb Vasc Biol. 2004;  24 1309-1314
    PubMedGoogle Scholar
  • 32 Lindstedt K A, Leskinen M J, Kovanen P T. Proteolysis of the pericellular matrix: a novel element determining cell survival and death in the pathogenesis of plaque erosion and rupture.  Arterioscler Thromb Vasc Biol. 2004;  24 1350-1358
    PubMedGoogle Scholar
  • 33 Griendling K K, FitzGerald G A. Oxidative stress and cardiovascular injury.  Circulation. 2003;  108 1912-1916 2034-2040
    CrossrefPubMedGoogle Scholar
  • 34 Kume N, Cybulsky M I, Gimbrone Jr M A. Lysophosphatidylcholine, a component of atherogenic lipoproteins, induces mononuclear leukocyte adhesion molecules in cultured human and rabbit arterial endothelial cells.  J Clin Invest. 1992;  90 1138-1144
    CrossrefPubMedGoogle Scholar
  • 35 Khan B V, Parthasarathy S S, Alexander R W, Medford R M. Modified low density lipoprotein and its constituents augment cytokine- activated vascular cell adhesion molecule-1 gene expression in human vascular endothelial cells.  J Clin Invest. 1995;  95 1262-1270
    PubMedGoogle Scholar
  • 36 Cushing S D, Berliner J A, Valente A J et al.. Minimally modified low density lipoprotein induces monocyte chemotactic protein 1 in human endothelial cells and smooth muscle cells.  Proc Natl Acad Sci U S A. 1990;  87 5134-5138
    CrossrefPubMedGoogle Scholar
  • 37 Collins T, Cybulsky M I. NF-kappaB: pivotal mediator or innocent bystander in atherogenesis?.  J Clin Invest. 2001;  107 255-264
    CrossrefPubMedGoogle Scholar
  • 38 Sakai M, Kobori S, Miyazaki A, Horiuchi S. Macrophage proliferation in atherosclerosis.  Curr Opin Lipidol. 2000;  11 503-509
    PubMedGoogle Scholar
  • 39 Tsao P S, McEvoy L M, Drexler H, Butcher E C, Cooke J P. Enhanced endothelial adhesiveness in hypercholesterolemia is attenuated by L-arginine.  Circulation. 1994;  89 2176-2182
    PubMedGoogle Scholar
  • 40 De Caterina R, Libby P, Peng H B et al.. Nitric oxide decreases cytokine-induced endothelial activation. Nitric oxide selectively reduces endothelial expression of adhesion molecules and proinflammatory cytokines.  J Clin Invest. 1995;  96 60-68
    PubMedGoogle Scholar
  • 41 Khan B V, Harrison D G, Olbrych M T, Alexander R W, Medford R M. Nitric oxide regulates vascular cell adhesion molecule 1 gene expression and redox-sensitive transcriptional events in human vascular endothelial cells.  Proc Natl Acad Sci U S A. 1996;  93 9114-9119
    CrossrefPubMedGoogle Scholar
  • 42 Tsao P S, Wang B, Buitrago R, Shyy J Y, Cooke J P. Nitric oxide regulates monocyte chemotactic protein-1.  Circulation. 1997;  96 934-940
    PubMedGoogle Scholar
  • 43 Oemar B S, Tschudi M R, Godoy N, Brovkovich V, Malinski T, Luscher T F. Reduced endothelial nitric oxide synthase expression and production in human atherosclerosis.  Circulation. 1998;  97 2494-2498
    PubMedGoogle Scholar
  • 44 Aikawa M, Sugiyama S, Hill C et al.. Lipid lowering reduces oxidative stress and endothelial cell activation in rabbit atheroma.  Circulation. 2002;  106 1390-1396
    CrossrefPubMedGoogle Scholar
  • 45 Liao J K, Shin W S, Lee W Y, Clark S L. Oxidized low-density lipoprotein decreases the expression of endothelial nitric oxide synthase.  J Biol Chem. 1995;  270 319-324
    CrossrefPubMedGoogle Scholar
  • 46 Davignon J, Ganz P. Role of endothelial dysfunction in atherosclerosis.  Circulation. 2004;  109 III27-III32
    CrossrefPubMedGoogle Scholar
  • 47 Suwaidi J A, Hamasaki S, Higano S T, Nishimura R A, Holmes Jr D R, Lerman A. Long-term follow-up of patients with mild coronary artery disease and endothelial dysfunction.  Circulation. 2000;  101 948-954
    CrossrefPubMedGoogle Scholar
  • 48 Halcox J PJ, Schenke W H, Zalos G et al.. Prognostic value of coronary vascular endothelial dysfunction.  Circulation. 2002;  106 653-658
    CrossrefPubMedGoogle Scholar
  • 49 Yla-Herttuala S, Palinski W, Rosenfeld M E et al.. Evidence for the presence of oxidatively modified low density lipoprotein in atherosclerotic lesions of rabbit and man.  J Clin Invest. 1989;  84 1086-1095
    PubMedGoogle Scholar
  • 50 Ehara S, Ueda M, Naruko T et al.. Elevated levels of oxidized low density lipoprotein show a positive relationship with the severity of acute coronary syndromes.  Circulation. 2001;  103 1955-1960
    CrossrefPubMedGoogle Scholar
  • 51 Miller Y I, Chang M K, Binder C J, Shaw P X, Witztum J L. Oxidized low density lipoprotein and innate immune receptors.  Curr Opin Lipidol. 2003;  14 437-445
    PubMedGoogle Scholar
  • 52 Tsimikas S, Bergmark C, Beyer R W et al.. Temporal increases in plasma markers of oxidized low-density lipoprotein strongly reflect the presence of acute coronary syndromes.  J Am Coll Cardiol. 2003;  41 360-370
    PubMedGoogle Scholar
  • 53 Heinecke J W. Oxidative stress: new approaches to diagnosis and prognosis in atherosclerosis.  Am J Cardiol. 2003;  91 12A-16A
    PubMedGoogle Scholar
  • 54 Sugiyama S, Okada Y, Sukhova G K, Virmani R, Heinecke J W, Libby P. Macrophage myeloperoxidase regulation by granulocyte macrophage colony-stimulating factor in human atherosclerosis and implications in acute coronary syndromes.  Am J Pathol. 2001;  158 879-891
    PubMedGoogle Scholar
  • 55 Baldus S, Heeschen C, Meinertz T et al.. Myeloperoxidase serum levels predict risk in patients with acute coronary syndromes.  Circulation. 2003;  108 1440-1445
    CrossrefPubMedGoogle Scholar
  • 56 Aikawa M, Rabkin E, Okada Y et al.. Lipid lowering by diet reduces matrix metalloproteinase activity and increases collagen content of rabbit atheroma: a potential mechanism of lesion stabilization.  Circulation. 1998;  97 2433-2444
    PubMedGoogle Scholar
  • 57 Aikawa M, Rabkin E, Voglic S J et al.. Lipid lowering promotes accumulation of mature smooth muscle cells expressing smooth muscle myosin heavy chain isoforms in rabbit atheroma.  Circ Res. 1998;  83 1015-1026
    PubMedGoogle Scholar
  • 58 Aikawa M, Voglic S J, Sugiyama S et al.. Dietary lipid lowering reduces tissue factor expression in rabbit atheroma.  Circulation. 1999;  100 1215-1222
    PubMedGoogle Scholar
  • 59 Williams J K, Sukhova G K, Herrington D M, Libby P. Pravastatin has cholesterol-lowering independent effects on the artery wall of atherosclerotic monkeys.  J Am Coll Cardiol. 1998;  31 684-691
    CrossrefPubMedGoogle Scholar
  • 60 Aikawa M, Rabkin E, Sugiyama S et al.. An HMG-CoA reductase inhibitor, cerivastatin, suppresses growth of macrophages expressing matrix metalloproteinases and tissue factor in vivo and in vivo.  Circulation. 2001;  103 276-283
    PubMedGoogle Scholar
  • 61 Fukumoto Y, Libby P, Rabkin E et al.. Statins alter smooth muscle cell accumulation and collagen content in established atheroma of Watanabe heritable hyperlipidemic rabbits.  Circulation. 2001;  103 993-999
    PubMedGoogle Scholar
  • 62 Liao J K. Isoprenoids as mediators of the biological effects of statins.  J Clin Invest. 2002;  110 285-288
    PubMedGoogle Scholar
  • 63 Davignon J. Beneficial cardiovascular pleiotropic effects of statins.  Circulation. 2004;  109 III39-III43
    PubMedGoogle Scholar
  • 64 Crisby M, Nordin-Fredriksson G, Shah P K, Yano J, Zhu J, Nilsson J. Pravastatin treatment increases collagen content and decreases lipid content, inflammation, metalloproteinases, and cell death in human carotid plaques: implications for plaque stabilization.  Circulation. 2001;  103 926-933
    PubMedGoogle Scholar
  • 65 Blake G J, Ridker P M. C-reactive protein and other inflammatory risk markers in acute coronary syndromes.  J Am Coll Cardiol. 2003;  41 37S-42S
    CrossrefPubMedGoogle Scholar
  • 65a Ridker P M, Cannon C P, Morrow D et al.. Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis in Myocardial Infarction 22 (PROVE IT-TIMI 22) Investigators. C-reactive protein levels and outcomes after statin therapy.  N Engl J Med. 2005;  352 20-28
    CrossrefPubMedGoogle Scholar
  • 66 Colli S, Eligini S, Lalli M, Camera M, Paoletti R, Tremoli E. Vastatins inhibit tissue factor in cultured human macrophages. A novel mechanism of protection against atherothrombosis.  Arterioscler Thromb Vasc Biol. 1997;  17 265-272
    PubMedGoogle Scholar
  • 67 Laufs U, La Fata V, Plutzky J, Liao J K. Upregulation of endothelial nitric oxide synthase by HMG CoA reductase inhibitors.  Circulation. 1998;  97 1129-1135
    CrossrefPubMedGoogle Scholar
  • 68 Guijarro C, Blanco-Colio L M, Ortego M et al.. 3-Hydroxy-3-methylglutaryl coenzyme a reductase and isoprenylation inhibitors induce apoptosis of vascular smooth muscle cells in culture.  Circ Res. 1998;  83 490-500
    PubMedGoogle Scholar
  • 69 Kwak B, Mulhaupt F, Myit S, Mach F. Statins as a newly recognized type of immunomodulator.  Nat Med. 2000;  6 1399-1402
    CrossrefPubMedGoogle Scholar
  • 70 Mulhaupt F, Matter C M, Kwak B R et al.. Statins (HMG-CoA reductase inhibitors) reduce CD40 expression in human vascular cells.  Cardiovasc Res. 2003;  59 755-766
    CrossrefPubMedGoogle Scholar
  • 71 Mach F. Statins as novel immunomodulators: from cell to potential clinical benefit.  Thromb Haemost. 2003;  90 607-610
    PubMedGoogle Scholar
  • 72 Shimizu K, Aikawa M, Takayama K, Libby P, Mitchell R N. Direct anti-inflammatory mechanisms contribute to attenuation of experimental allograft arteriosclerosis by statins.  Circulation. 2003;  108 2113-2120
    CrossrefPubMedGoogle Scholar
  • 73 Sakai M, Kobori S, Matsumura T et al.. HMG-CoA reductase inhibitors suppress macrophage growth induced by oxidized low density lipoprotein.  Atherosclerosis. 1997;  133 51-59
    CrossrefPubMedGoogle Scholar
  • 74 Bellosta S, Via D, Canavesi M et al.. HMG-CoA reductase inhibitors reduce MMP-9 secretion by macrophages.  Arterioscler Thromb Vasc Biol. 1998;  18 1671-1678
    PubMedGoogle Scholar
  • 75 Bourcier T, Libby P. HMG CoA reductase inhibitors reduce plasminogen activator inhibitor-1 expression by human vascular smooth muscle and endothelial cells.  Arterioscler Thromb Vasc Biol. 2000;  20 556-562
    PubMedGoogle Scholar
  • 76 Masamura K, Oida K, Kanehara H et al.. Pitavastatin-induced thrombomodulin expression by endothelial cells acts via inhibition of small G proteins of the Rho family.  Arterioscler Thromb Vasc Biol. 2003;  23 512-517
    PubMedGoogle Scholar
  • 77 Egashira K, Hirooka Y, Kai H et al.. Reduction in serum cholesterol with pravastatin improves endothelium-dependent coronary vasomotion in patients with hypercholesterolemia.  Circulation. 1994;  89 2519-2524
    PubMedGoogle Scholar
  • 78 Treasure C B, Klein J L, Weintraub W S et al.. Beneficial effects of cholesterol-lowering therapy on the coronary endothelium in patients with coronary artery disease.  N Engl J Med. 1995;  332 481-487
    CrossrefPubMedGoogle Scholar
  • 79 Anderson T J, Meredith I T, Yeung A C, Frei B, Selwyn A P, Ganz P. The effect of cholesterol-lowering and antioxidant therapy on endothelium-dependent coronary vasomotion.  N Engl J Med. 1995;  332 488-493
    CrossrefPubMedGoogle Scholar
  • 80 Tamai O, Matsuoka H, Itabe H, Wada Y, Kohno K, Imaizumi T. Single LDL apheresis improves endothelium-dependent vasodilatation in hypercholesterolemic humans.  Circulation. 1997;  95 76-82
    PubMedGoogle Scholar
  • 81 Wilson S H, Simari R D, Best P J et al.. Simvastatin preserves coronary endothelial function in hypercholesterolemia in the absence of lipid lowering.  Arterioscler Thromb Vasc Biol. 2001;  21 122-128
    PubMedGoogle Scholar
  • 82 Laufs U, Wassmann S, Hilgers S, Ribaudo N, Bohm M, Nickenig G. Rapid effects on vascular function after initiation and withdrawal of atorvastatin in healthy, normocholesterolemic men.  Am J Cardiol. 2001;  88 1306-1307
    CrossrefPubMedGoogle Scholar
  • 83 Tsunekawa T, Hayashi T, Kano H et al.. Cerivastatin, a hydroxymethylglutaryl coenzyme a reductase inhibitor, improves endothelial function in elderly diabetic patients within 3 days.  Circulation. 2001;  104 376-379
    PubMedGoogle Scholar
  • 84 Wassmann S, Faul A, Hennen B, Scheller B, Bohm M, Nickenig G. Rapid effect of 3-hydroxy-3-methylglutaryl coenzyme a reductase inhibition on coronary endothelial function.  Circ Res. 2003;  93 e98-103
    CrossrefPubMedGoogle Scholar
  • 85 Giroux L M, Davignon J, Naruszewicz M. Simvastatin inhibits the oxidation of low-density lipoproteins by activated human monocyte-derived macrophages.  Biochim Biophys Acta. 1993;  1165 335-338
    PubMedGoogle Scholar
  • 86 Leonhardt W, Kurktschiev T, Meissner D et al.. Effects of fluvastatin therapy on lipids, antioxidants, oxidation of low density lipoproteins and trace metals.  Eur J Clin Pharmacol. 1997;  53 65-69
    CrossrefPubMedGoogle Scholar
  • 87 Aviram M, Fuhrman B. LDL oxidation by arterial wall macrophages depends on the oxidative status in the lipoprotein and in the cells: role of prooxidants vs. antioxidants.  Mol Cell Biochem. 1998;  188 149-159
    CrossrefPubMedGoogle Scholar
  • 88 Franzoni F, Quinones-Galvan A, Regoli F, Ferrannini E, Galetta F. A comparative study of the in vitro antioxidant activity of statins.  Int J Cardiol. 2003;  90 317-321
    CrossrefPubMedGoogle Scholar
  • 89 Shishehbor M H, Brennan M L, Aviles R J et al.. Statins promote potent systemic antioxidant effects through specific inflammatory pathways.  Circulation. 2003;  108 426-431
    CrossrefPubMedGoogle Scholar
  • 90 Fuhrman B, Koren L, Volkova N, Keidar S, Hayek T, Aviram M. Atorvastatin therapy in hypercholesterolemic patients suppresses cellular uptake of oxidized-LDL by differentiating monocytes.  Atherosclerosis. 2002;  164 179-185
    CrossrefPubMedGoogle Scholar
  • 91 Law M R, Wald N J, Rudnicka A R. Quantifying effect of statins on low density lipoprotein cholesterol, ischaemic heart disease, and stroke: systematic review and meta-analysis.  BMJ. 2003;  326 1423
    CrossrefPubMedGoogle Scholar
  • 92 Lesaffre E, Kocmanova D, Lemos P A, Disco C M, Serruys P W. A retrospective analysis of the effect of noncompliance on time to first major adverse cardiac event in LIPS.  Clin Ther. 2003;  25 2431-2447
    CrossrefPubMedGoogle Scholar
  • 93 Expert N CEP. Panel on Detection E, and Treatment of High Blood Cholesterol in Adults. Executive Summary of the Third Report of The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III).  JAMA. 2001;  285 2486-2497
    CrossrefPubMedGoogle Scholar
  • 94 Group HPSC . MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial.  Lancet. 2002;  360 7-22
    CrossrefPubMedGoogle Scholar
  • 95 Kinlay S, Schwartz G G, Olsson A G et al.. Effect of atorvastatin on risk of recurrent cardiovascular events after an acute coronary syndrome associated with high soluble CD40 ligand in the Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) Study.  Circulation. 2004;  110 386-391
    CrossrefPubMedGoogle Scholar
  • 96 Shepherd J, Blauw G J, Murphy M B et al.. Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial.  Lancet. 2002;  360 1623-1630
    CrossrefPubMedGoogle Scholar
  • 97 O'Keefe Jr J H, Cordain L, Harris W H, Moe R M, Vogel R. Optimal low-density lipoprotein is 50 to 70 mg/dl: lower is better and physiologically normal.  J Am Coll Cardiol. 2004;  43 2142-2146
    CrossrefPubMedGoogle Scholar
  • 98 Velican C, Velican D. The precursors of coronary atherosclerotic plaques in subjects up to 40 years old.  Atherosclerosis. 1980;  37 33-46
    PubMedGoogle Scholar
  • 99 Aikawa M, Sivam P N, Kuro-o M et al.. Human smooth muscle myosin heavy chain isoforms as molecular markers for vascular development and atherosclerosis.  Circ Res. 1993;  73 1000-1012
    PubMedGoogle Scholar
  • 100 Glueck C J, Kelley W, Gupta A, Fontaine R N, Wang P, Gartside P S. Prospective 10-year evaluation of hypobetalipoproteinemia in a cohort of 772 firefighters and cross-sectional evaluation of hypocholesterolemia in 1,479 men in the National Health and Nutrition Examination Survey I.  Metabolism. 1997;  46 625-633
    CrossrefPubMedGoogle Scholar
  • 100a Nissen S E, Tuzcu E M, Schoenhagen P et al.. Reversal of Atherosclerosis with Aggressive Lipid Lowering (REVERSAL) Investigators. Statin therapy, LDL cholesterol, C-reactive protein, and coronary artery disease.  N Engl J Med. 2005;  352 29-38
    CrossrefPubMedGoogle Scholar
  • 101 Nickenig G. Should angiotensin II receptor blockers and statins be combined?.  Circulation. 2004;  110 1013-1020
    CrossrefPubMedGoogle Scholar
  • 102 Weiss D, Sorescu D, Taylor W R. Angiotensin II and atherosclerosis.  Am J Cardiol. 2001;  87 25C-32C
    CrossrefPubMedGoogle Scholar
  • 103 Cannon C P. Effectiveness of clopidogrel versus aspirin in preventing acute myocardial infarction in patients with symptomatic atherothrombosis (CAPRIE trial).  Am J Cardiol. 2002;  90 760-762
    CrossrefPubMedGoogle Scholar
  • 104 Bocan T M, Krause B R, Rosebury W S et al.. The ACAT inhibitor avasimibe reduces macrophages and matrix metalloproteinase expression in atherosclerotic lesions of hypercholesterolemic rabbits.  Arterioscler Thromb Vasc Biol. 2000;  20 70-79
    PubMedGoogle Scholar
  • 105 Perrey S, Legendre C, Matsuura A et al.. Preferential pharmacological inhibition of macrophage ACAT increases plaque formation in mouse and rabbit models of atherogenesis.  Atherosclerosis. 2001;  155 359-370
    CrossrefPubMedGoogle Scholar
  • 106 Ziouzenkova O, Perrey S, Marx N, Bacqueville D, Plutzky J. Peroxisome proliferator-activated receptors.  Curr Atheroscler Rep. 2002;  4 59-64
    PubMedGoogle Scholar
  • 107 Farnier M, Salko T, Isaacsohn J L, Troendle A J, Dejager S, Gonasun L. Effects of baseline level of triglycerides on changes in lipid levels from combined fluvastatin + fibrate (bezafibrate, fenofibrate, or gemfibrozil).  Am J Cardiol. 2003;  92 794-797
    CrossrefPubMedGoogle Scholar
  • 108 Ballantyne C M, Houri J, Notarbartolo A et al.. Effect of ezetimibe coadministered with atorvastatin in 628 patients with primary hypercholesterolemia: a prospective, randomized, double-blind trial.  Circulation. 2003;  107 2409-2415
    CrossrefPubMedGoogle Scholar
  • 109 Kastelein J. What future for combination therapies?.  Int J Clin Pract Suppl. 2003;  134 45-50
    PubMedGoogle Scholar
  • 110 Wald N J, Law M R. A strategy to reduce cardiovascular disease by more than 80%.  BMJ. 2003;  327 1419
    CrossrefPubMedGoogle Scholar
  • 111 Jaffer F A, Weissleder R. Seeing within: molecular imaging of the cardiovascular system.  Circ Res. 2004;  94 433-445
    CrossrefPubMedGoogle Scholar

Masanori AikawaM.D. Ph.D. 

Brigham and Women's Hospital, 77 Avenue Louis Pasteur

NRB 741, Boston, MA 02115

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