Lipid Lowering Therapy in Atherosclerosis

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
• 2 Aikawa M, Libby P. The vulnerable atherosclerotic plaque; pathogenesis and therapeutic approach.  Cardiovasc Pathol. 2004;  13 125-138
• 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
• 4 Vesselinovitch D. Animal models and the study of atherosclerosis.  Arch Pathol Lab Med. 1988;  112 1011-1017
• 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
• 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
• 7 Libby P, Aikawa M, Schonbeck U. Cholesterol and atherosclerosis.  Biochim Biophys Acta. 2000;  1529 299-309
• 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
• 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
• 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
• 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
• 12 Libby P, Aikawa M. Stabilization of atherosclerotic plaques: new mechanisms and clinical targets.  Nat Med. 2002;  8 1257-1262
• 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
• 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
• 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
• 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
• 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
• 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
• 19 Libby P. Molecular bases of the acute coronary syndromes.  Circulation. 1995;  91 2844-2850
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 27 Libby P, Mach F, Schoenbeck U, Bourcier T, Aikawa M. Regulation of the thrombotic potential of atheroma.  Thromb Haemost. 1999;  82 736-741
• 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
• 29 Bombeli T, Karsan A, Tait J F, Harlan J M. Apoptotic vascular endothelial cells become procoagulant.  Blood. 1997;  89 2429-2442
• 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
• 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
• 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
• 33 Griendling K K, FitzGerald G A. Oxidative stress and cardiovascular injury.  Circulation. 2003;  108 1912-1916 2034-2040
• 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
• 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
• 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
• 37 Collins T, Cybulsky M I. NF-kappaB: pivotal mediator or innocent bystander in atherogenesis?.  J Clin Invest. 2001;  107 255-264
• 38 Sakai M, Kobori S, Miyazaki A, Horiuchi S. Macrophage proliferation in atherosclerosis.  Curr Opin Lipidol. 2000;  11 503-509
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 46 Davignon J, Ganz P. Role of endothelial dysfunction in atherosclerosis.  Circulation. 2004;  109 III27-III32
• 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
• 48 Halcox J PJ, Schenke W H, Zalos G et al.. Prognostic value of coronary vascular endothelial dysfunction.  Circulation. 2002;  106 653-658
• 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
• 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
• 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
• 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
• 53 Heinecke J W. Oxidative stress: new approaches to diagnosis and prognosis in atherosclerosis.  Am J Cardiol. 2003;  91 12A-16A
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 62 Liao J K. Isoprenoids as mediators of the biological effects of statins.  J Clin Invest. 2002;  110 285-288
• 63 Davignon J. Beneficial cardiovascular pleiotropic effects of statins.  Circulation. 2004;  109 III39-III43
• 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
• 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
• 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
• 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
• 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
• 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
• 69 Kwak B, Mulhaupt F, Myit S, Mach F. Statins as a newly recognized type of immunomodulator.  Nat Med. 2000;  6 1399-1402
• 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
• 71 Mach F. Statins as novel immunomodulators: from cell to potential clinical benefit.  Thromb Haemost. 2003;  90 607-610
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 98 Velican C, Velican D. The precursors of coronary atherosclerotic plaques in subjects up to 40 years old.  Atherosclerosis. 1980;  37 33-46
• 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
• 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
• 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
• 101 Nickenig G. Should angiotensin II receptor blockers and statins be combined?.  Circulation. 2004;  110 1013-1020
• 102 Weiss D, Sorescu D, Taylor W R. Angiotensin II and atherosclerosis.  Am J Cardiol. 2001;  87 25C-32C
• 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
• 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
• 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
• 106 Ziouzenkova O, Perrey S, Marx N, Bacqueville D, Plutzky J. Peroxisome proliferator-activated receptors.  Curr Atheroscler Rep. 2002;  4 59-64
• 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
• 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
• 109 Kastelein J. What future for combination therapies?.  Int J Clin Pract Suppl. 2003;  134 45-50
• 110 Wald N J, Law M R. A strategy to reduce cardiovascular disease by more than 80%.  BMJ. 2003;  327 1419
• 111 Jaffer F A, Weissleder R. Seeing within: molecular imaging of the cardiovascular system.  Circ Res. 2004;  94 433-445