Atorvastatin and Thrombogenicity of the Carotid Atherosclerotic Plaque: the ATROCAP Study

Summary

Statins appear to have beneficial effects on fibrous cap stabilisation but their effects on plaque thrombogenicity have not been reported. To evaluate the thrombogenicity of human carotid plaques before and after atorvastatin treatment, 59 patients with bilateral carotid stenosis eligible for two-step carotid endoarterectomy (CEA) were randomly assigned to atorvastatin, 20 mg/day, or placebo. Histological and immunohistochemical analyses, Tissue Factor (TF), Tissue Factor Pathway Inhibitor (TFPI) antigens (Ag) and TF activity were determined in endoarterectomy specimens obtained at baseline and after treatment. Mean TFAg and TFPIAg levels from plaques removed at the first CEA were 55 ± 56 and 32 ± 26 pg/mg. After placebo, TFAg and TFPIAg content was higher in the second than the first CEA. Plaques removed at the second CEA from atorvastatin-treated patients had a lower macrophage content than plaques at the first CEA. TFAg and TFPIAg levels, and TF activity in plaques after atorvastatin treatment were lower (respectively 29, 18% and 56%) than after placebo. These findings indicate that atorvastatin reduce the inflammatory/thrombotic phenotype of carotid plaque, suggesting that these drugs may indeed have a beneficial effect on cerebrovascular events.

We are indebted to Pfizer Italia for providing atorvastatin, 20 mg, and placebo.

Keywords

Carotid arteries - atherosclerosis - thrombosis - drugs

• References

• 1 Maron DJ, Fazio S, Linton MF. Current perspectives on statins. Circulation 2000; 101: 207-13.
• 2 Anonymous. Effects of pravastatin in patients with serum total cholesterol levels from 5.2 to 7.8 mmol/liter (200 to 300 mg/dl) plus two additional atherosclerotic risk factors. The Pravastatin Multinational Study Group for Cardiac Risk Patients. Am J Cardiol 1993; 72: 1031-7.
• 3 MAAS and investigators. Effect of simvastatin on coronary atheroma: the Multicentre Anti-Atheroma Study (MAAS). Lancet 1994; 344: 633-8.
• 4 Ballantyne CM, Herd JA, Dunn JK, Jones PH, Farmer JA, Gotto Jr AM. Effects of lipid lowering therapy on progression of coronary and carotid artery disease. Curr Opin Lipidol 1997; 08: 354-61.
• 5 Williams JK, Sukhova GK, Herrington DM, Libby P. Pravastatin has cholesterol-lowering independent effects on the artery wall of atherosclerotic monkeys. J Amer Coll Cardiol 1998; 31: 684-91.
• 6 Bellosta S, Via D, Canavesi M, Pfister P, Fumagalli R, Paoletti R, Bernini F. HMG-CoA reductase inhibitors reduce MMP-9 secretion by macrophages. Arterioscler Thromb Vasc Biol 1998; 18: 1671-8.
• 7 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: 265-72.
• 8 Aikawa M, Rabkin E, Sugiyama S, Voglic SJ, Fukumoto Y, Furukawa Y, Shiomi M, Schoen FJ, Libby P. An HMG-CoA reductase Inhibitor, Cerivastatin, suppress growth of macrophages expressing matrix metalloproteinases and tissue factor in vivo and in vitro. Circulation 2001; 103: 276-83.
• 9 Anonymous. MRC European Carotid Surgery Trial: interim results for symptomatic patients with severe (70–99%) or with mild (0–29%) carotid stenosis. European Carotid Surgery Trialists’ Collaborative Group Lancet 1991; 337: 1235-43.
• 10 Arbustini E, De Servi S, Bramucci E, Porcu E, Costante AM, Grasso M, Diegoli M, Fasani R, Morbini P, Angoli L. Comparison of coronary lesions obtained by directional coronary atherectomy in unstable angina, stable angina, and restenosis after either atherectomy or angioplasty. Am J Cardiol 1995; 75: 675-82.
• 11 Arbustini E, Dal Bello B, Morbini P, Gavazzi A, Specchia G, Vigano M. Immunohistochemical characterization of coronary thrombi in allograft vascular disease. Transplantation 2000; 69: 1095-101.
• 12 Arbustini E, Grasso M, Diegoli M, Pucci A, Bramerio M, Ardissino D, Angoli L, de Servi S, Bramucci E, Mussini A. Coronary atherosclerotic plaques with and without thrombus in ischemic heart syndromes: a morphologic, immunohistochemical, and biochemical study. Am J Cardiol 1991; 68: 36B-50B.
• 13 Caplice NM, Mueske CS, Kleppe LS, Simari RD. Presence of tissue factor pathway inhibitor in human atherosclerotic plaques is associated with reduced tissue factor activity. Circulation 1998; 98: 1051-7.
• 14 Ollivier V, Houssaye S, Ternisien C, Leon A, de Verneuil H, Elbim C, Mackman N, Edgington TS, de Prost D. Endotoxin-induced tissue factor messenger RNA in human monocytes is negatively regulated by a cyclic AMP-dependent mechanism. Blood 1993; 81: 973-9.
• 15 Camera M, Giesen LA, Fallon J, Aufiero BM, Taubman M, Tremoli E, Nemerson Y. Cooperation between VEGF and TNF-α is necessary for exposure of active Tissue Factor on the surface of human endothelial cells. Arterioscl Thromb Vasc Biol 1999; 19: 531-7.
• 16 Bradford MM. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 1976; 72: 248-54.
• 17 Clauss A. Gerinnungsphysiologishe Schnellmethode zur Bestimmung des Fibrinogens. Acta Haematol 1957; 17: 237-46.
• 18 Bucolo G, David H. Quantitative determination of serum triglycerides by the use of enzymes. Clin Chem 1973; 19: 476-82.
• 19 Warnick GR, Benderson J, Albers JJ. Dextran sulfate-Mg2+ precipitation procedure for quantitation of high-density-lipoprotein cholesterol. Clin Chem 1982; 28: 1379-88.
• 20 Friedewald WT, Levy RI, Fredrickson DS. Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem 1972; 18: 499-502.
• 21 Toschi V, Gallo R, Lettino M, Fallon JT, Gertz SD, Fernandez-Ortiz A, Chesebro JH, Badimon L, Nemerson Y, Fuster V, Badimon JJ. Tissue factor modulates the thrombogenicity of human atherosclerotic plaques. Circulation 1997; 95: 594-9.
• 22 Ardissino D, Merlini PA, Ariens R, Coppola R, Bramucci E, Mannucci PM. Tissue-factor antigen and activity in human coronary atherosclerotic plaques. Lancet 1997; 349: 769-71.
• 23 Crawley J, Lupu F, Westmuckett AD, Severs NJ, Kakkar VV, Lupu C. Expression, localization, and activity of tissue factor pathway inhibitor in normal and atherosclerotic human vessels. Arterioscler Thromb Vasc Biol 2000; 20: 1362-73.
• 24 Kaikita K, Takeya M, Ogawa H, Suefuji H, Yasue H, Takahashi K. Colocalization of tissue factor and tissue factor pathway inhibitor in coronary atherosclerosis. J Pathol 1999; 188: 180-8.
• 25 Crawley J, Goulding DA, Ferreira V, Severs N, Lupu F. Expression and localization of tissue factor pathway inhibitor-2 in normal and atherosclerotic human vessels. Arterioscler Thromb Vasc Biol 2002; 22: 218-24.
• 26 Crisby M, Nordin-Fredriksson G, Shah P, Yano J, Zhu J, Nilsson J. Pravastatin treatment increases collage content, inflammation, metalloproteinases, and cell death in human carotid plaques. Circulation 2001; 103: 926-33.
• 27 Kim HK, Song KS, Park YS, Yun YS, Shim WH. Changes of plasma tissue factor and tissue factor pathway inhibitor antigen levels and induction of tissue factor expression on the monocytes in coronary artery disease. Cardiology 2000; 93: 31-6.
• 28 Caplice NM, Mueske CS, Kleppe LS, Peterson TE, Broze Jr GJ, Simari RD. Expression of tissue factor pathway inhibitor in vascular smooth muscle cells and its regulation by growth factors. Circ Res 1998; 83: 1264-70.
• 29 Pendurthi UR, Rao LV, Williams JT, Idell S. Regulation of tissue factor pathway inhibitor expression in smooth muscle cells. Blood 1999; 94: 579-86.
• 30 Libby P, Aikawa M. New insights into plaque stabilisation by lipid lowering. Drugs 1998; 56: 9-13.
• 31 Vaughan CJ, Gotto Jr AM, Basson CT. The evolving role of statins in the management of atherosclerosis. J Am Coll Cardiol 2000; 35: 1-10.
• 32 Corsini A, Mazzotti M, Raiteri M, Soma MR, Gabbiani G, Fumagalli R, Paoletti R. Relationship between mevalonate pathway and arterial myocyte proliferation: in vitro studies with inhibitors of HMG-CoA reductase. Atherosclerosis 1993; 101: 117-25.
• 33 Kempen HJ, Vermeer M, de Wit E, Havekes LM. Vastatins inhibit cholesterol ester accumulation in human monocyte-derived macrophages. Arterioscl Thromb 1991; 11: 146-53.
• 34 Bernini F, Scurati N, Bonfadini G, Fumagalli R. HMGCoA reductase inhibitors reduce acetyl LDL endocytosis in mouse peritoneal macrofages. Arterioscler Thromb Vasc Biol 1995; 15: 1352.
• 35 Tatsuno I, Tanaka T, Oeda T, Yasuda T, Kitagawa M, Saito Y, Hirai A. Geranylgeranylpyrophosphate, a metabolite of mevalonate, regulates the cell cycle progression and DNA synthesis in human lymphocytes. Biochem Bioph Res Comm 1997; 241: 376-82.
• 36 Camera M, Toschi V, Comparato C, Baetta R, Rossi F, Fuortes M, Ezekowitz MD, Paoletti R, Tremoli E. Cholesterol-induced thrombogenicity of the vessel wall: inhibitory effect of fluvastatin. Thromb Haemost. 2002 in press.
• 37 Bucher HC, Griffith LE, Guyatt GH. Effect of HMGcoA reductase inhibitors on stroke. A meta-analysis of randomized, controlled trials. Ann Inter Med 1998; 128: 89-95.
• 38 Byington RP, Davis BR, Plehn JF, White HD, Baker J, Cobbe SM, Shepherd J. Reduction of Stroke Events With Pravastatin: The Prospective Pravastatin Pooling (PPP) Project. Circulation 2001; 103: 387-92.
• 39 Schwartz GG, Olsson AG, Ezekowitz MD, Ganz P, Oliver MF, Waters D, Zeiher A, Chaitman BR, Leslie S, Stern T. Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering Study I. Effects of atorvastatin on early recurrent ischemic events in acute coronary syndromes: the MIRACL study: a randomized controlled trial. Jama 2001; 285: 1711-8.
• 40 Hebert PR, Gaziano JM, Hennekens CH. An overview of trials of cholesterol lowering and risk of stroke. Arch Intern Med 1995; 155: 50-5.