Fluvastatin Decreases Soluble Thrombomodulin in Cardiac Transplant Recipients

Summary

We conducted a randomized, placebo controlled, double-blind, cross-over study, to assess the effects of a 4-week fluvastatin therapy on plasma markers of endothelial activation or injury in 20 transplanted heart recipients. The levels of thrombomodulin and von Willebrand factor antigen were higher at baseline in cardiac transplant recipients than in age and sex-matched healthy controls. Plasma total cholesterol showed a 21% reduction on fluvastatin therapy (p = 0.0001). Fluvastatin treatment had no significant effect on creatininemia, plasma cyclosporine, PAI-1 antigen, PAI-1 activity, tPA antigen, and Von Willebrand factor. However, fluvastatin produced a significant decrease of plasma thrombomodulin (66.7 ng/ml on placebo versus 58.8 ng/ml on fluvastatin, p <0.001), suggesting a rapid improvement of endothelial injury in these patients.

Keywords

Cardiac transplantation - cyclosporine - fluvastatin - endothelium - thrombomodulin

• References

• 1 The Pravastatin Multinational Study Group for cardiac risk patients. Effects of pravastatin in patients with serum cholesterol levels from 5.2 to 7.8 mmol/l (200 to 300 mg/dl) plus two additional atherosclerotic risk factors. Am J Cardiol 1993; 72: 1031-7.
• 2 Vaughan CJ, Murphy MB, Buckley BM. Statins do more than just lower cholesterol. Lancet 1996; 348: 1079-82.
• 3 John S, Schlaich M, Langenfeld M, Weihprecht H, Scmitz G, Weidinger G, Schmieder RE. Increased bioavailibility of nitric oxyde after lipid-lowering therapy in hypercholesterolemic patients. Circulation 1998; 98: 211-6.
• 4 O’Driscoll G, Green D, Taylor RR. Simvastatin, an HMG – Coenzyme A reductase inhibitor, improves endothelial function within 1 month. Circulation 1997; 95: 1126-31.
• 5 Weis M, Von Scheidt W. Cardiac allograft vasculopathy: a review. Circulation 1997; 96: 2069-77.
• 6 Davis SF, Yeung AC, Meredith I, Charbonneau F, Ganz P, Selwyn AP, Anderson TJ. Early endothelial dysfunction predicts the development of transplant coronary artery disease at 1 year post-transplant. Circulation 1996; 93: 457-62.
• 7 Griffiths MH, Crowe AV, Papadaki L, Banner NR, Yacoub MH, Thompson FD, Neild GH. Cyclosporin nephrotoxicity in heart and lung transplant patients. QJM 1996; 89: 751-63.
• 8 Evans SM, Giddings JC, Muraki T, Yamamoto J. Expression of von Willebrand factor, P-selectin (CD 62P) and thrombomodulin in human endothelial cells in culture modulated by cyclosporin A. Clin Lab Haematol 1997; 19: 115-22.
• 9 Duymelinck C, Dauwe SE, Nouwen EJ, De Broe ME, Verpooten GA. Cholesterol feeding accentuates the cyclosporine induced elevation of renal plasminogen activator inhibitor type 1. Kidney Int 1997; 51: 1818-30.
• 10 Hunt BJ, Segal H, Yacoub M. Hemostatic changes in heart transplant recipients and their relationship to accelerated coronary sclerosis. Transplantation 1993; 55: 309-15.
• 11 Blann AD, Taberner DA. A reliable marker of endothelial cell dysfunction: does it exist?. Brit J Haematol 1995; 90: 244-8.
• 12 Zambrana JL, Velasco F, Castro P, Concha M, Vallés F, Montilla P, Jimenéz-Perepérez JA, Lopez-Miranda J, Pérez-Jiménez F. Comparison of Bezafibrate versus lovastatin for lowering plasma insulin, fibrinogen, and plasminogen activator inhibitor-1 concentrations in hyperlipemic heart transplant patients. Am J Cardiol 1997; 80: 836-40.
• 13 Bevilacqua M, Bettica P, Milani M, Vago T, Rogolino A, Righini V, Santoli E, Norbiato G. Effect of fluvastatin on lipids and fibrinolysis in coronary artery disease. Am J Cardiol 1997; 79: 84-7.
• 14 Mitropoulos KA, Armitage JM, Meade TW, Reeves BE, Wallendszus SSWilson, Lawson A, Peto R. for the Oxford cholesterol study group Randomized placebo-controlled study of the effects of simvastatin on haemostatic variables, lipoproteins and free fatty acids. Eur Heart J 1997; 18: 235-41.
• 15 Jovin IS, Heidinger K, Taborski U, Muller-Berghaus G. Lipid-lowering with statins and fibrinolytic parameters. Eur Heart J 1997; 18: 1516.
• 16 Locsey L, Asztalos L, Kincses Z, Balazs G. Fluvastatin (Lescol) treatment of hyperlipidaemia in patients with renal transplants. Int Urol Nephrol 1997; 29: 95-106.
• 17 Tani N, Hada K, Kitami A, Nakano M, Tkahashi H, Ito I, Shibata A. Effects of acetyl salicylic acid and cilostazol administration on serum thrombomodulin concentration in diabetic patients. Thromb Res 1993; 69: 153-8.
• 18 Blann AD, Davis A, Miller JP, Mc CNCollum. Von Willebrand factor and soluble E-selectin in hyperlipidemia: relationship to lipids and vascular disease. Am J Hematol 1997; 55: 15-23.
• 19 Laufs U, La VFata, Plutzky J, Liao JK. Upregulation of endothelial nitric oxyde synthase by HMG-CoA reductase inhibitors. Circulation 1998; 97: 1129-35.
• 20 Thogersen AM, Jansson JH, Boman K, Nilsson TK, Weinehall L, Huhtasaari F, Hallmans G. High plasminogen activator inhibitor and tissue plasminogen activator levels in plasma precede a first acute myocardial infarction in both men and women: evidence for the fibrinolytic system as an independent primary risk factor. Circulation 1998; 98: 2241-7.
• 21 Salomaa V, Matei C, Aleksic N, Sansores-Garcia L, Folsom AR, Juneja H, Chambless LE, Wu KK. Soluble thrombomodulin as a predictor of incident coronary heart disease and symptomless carotid artery atherosclerosis in the Atherosclerosis Risk in Communities (ARIC) Study: a case-cohort study. Lancet 353 9166: 1729-34.