Background: Atherosclerosis is the leading cause of death in developed countries. Although the mechanisms that underlie this process are not well defined, it has been proposed that atherosclerosis is mainly an inflammatory disease. In this context, a number of inflammatory markers have been studied for their ability to predict future cardiovascular events in asymptomatic individuals or patients with established atherosclerotic disease.
Methods and Results: The aim of our study was to evaluate the effect of micronized fenofibrate on serum inflammatory markers, such as C-reactive protein, fibrinogen, and plasma platelet-activating factor acetylhydrolase (PAF-AH) in patients with high triglyceride values. An analysis of baseline values revealed that hypertriglyceridemic patients (n = 58) exhibit an atherogenic phenotype, characterized not only by elevated lipid values but also by high concentrations of serum inflammatory markers. Along with the improvement in serum lipid profile (reduction in triglycerides and total cholesterol, low-density lipoprotein, and nonhigh-density lipoprotein-cholesterol, with a concomitant increase in high-density lipoprotein-cholesterol levels), fenofibrate administration significantly reduced the values of serum inflammatory markers by 34%, 9.5%, and 24.8% for C-reactive protein, fibrinogen, and plasma PAF-AH, respectively. However, with the exception of PAF-AH, these reductions in inflammatory markers were not correlated with the changes in lipid values.
Conclusions: In addition to its well-known hypolipidemic effects, fenofibrate may also possess significant anti-inflammatory properties that can contribute its antiatherogenic effect.
1. Ross R. The pathogenesis of atherosclerosis: A perspective for the 1990s. Nature362:801-809, 1993
2.
2. Ross R. Atherosclerosis-an inflammatory disease. N Engl J Med340:115-126, 1999
3.
3. Heinrich PC, Castell JV, Andus T. Interleukin-6 and the acute phase response. Biochem J265:621-636, 1990
4.
4. Biasucci LM, Liuzzo G, Grillo RL, et al. Elevated levels of C-reactive protein at discharge in patients with unstable angina predict recurrent instability. Circulation99: 855-860, 1999
5.
5. Ridker PM, Cushman M, Stampfer MJ, et al. Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men. N Engl J Med336:973-979, 1997
6.
6. Kannel WB, Wolf PA, Castelli WP, et al. Fibrinogen and risk of cardiovascular disease: The Framingham Study. JAMA9:1183-1186, 1987
7.
7. Meade TW, Mellows S, Brozovic M, et al. Haemostatic function and ischaemic heart disease: Principal results of the Northwick Park Heart study. Lancet6:533-537, 1986
8.
8. Stafforini DM, McIntyre TM, Carter ME, et al. Human plasma platelet-activating factor acetylhydrolase: Association with lipoprotein particles and role in the degradation of platelet-activating factor. J Biol Chem262:4215-4222, 1987
9.
9. Tselepis AD, Dentan C, Karabina SA, et al. PAF-degrading acetylhydrolase is preferentially associated with dense LDL and VHDL- 1 in human plasma. Catalytic characteristics and relation to the monocyte-derived enzyme. Arterioscler Thromb Vasc Biol15:1764-1773, 1995
10.
10. Packard CJ, O'Reilly DS, Caslake MJ, et al. Lipoproteinassociated phospholipase A2 as an independent predictor of coronary heart disease. N Engl J Med343:1148-1155, 2000
11.
11. Seman LJ, DeLuca C, Jenner JL, et al. Lipoprotein(a)-cholesterol and coronary heart disease in the Framingham Heart Study. Clin Chem45:1039-1046, 1999
12.
12. Milionis HJ, Winder AF, Mikhailidis DP. Lipoprotein (a) and stroke. J Clin Pathol53:487-496, 2000
13.
13. Ridker PM, Rifai N, Pfeffer MA, et al, for the Cholesterol and Recurrent Events (CARE) investigators. Long-term effects of pravastatin on plasma concentration of C-reactive protein. Circulation100:230-235, 1999
14.
14. Ridker PM, Rifai N, Clearfield M, et al for the Air Force/Texas Coronary Atherosclerosis Prevention Study investigators. Measurement of C-reactive protein for the targeting of statin therapy in the primary prevention of acute coronary syndromes. N Engl J Med344:1959-1965, 2001
15.
15. Robins SJ, Collins D, Wittes JT, et al, VA-HIT Study Group. Veterans Affairs High-Density Lipoprotein Intervention Trial. Relation of gemfibrozil treatment and lipid levels with major coronary events: VA-HIT: A randomized controlled trial. JAMA285:1585-1591, 2001
16.
16. Tsimihodimos V, Karabina SA, Tambaki AP, et al. Atorvastatin preferentially reduces LDL-associated Platelet-Activating Factor acetylhydrolase activity in dyslipidemias of type IIA and Type IIB. Arterioscler Thromb Vasc Biol22:306-311, 2002
17.
17. Von Clauss A. Gerinnungsphysiologische schnellmethode zur bestimmung des fibrinogens. Acta Haematol17:237-237, 1957
18.
18. Imhof A, Frohlich M, Loewel H, et al. Distributions of Creactive protein measured by high-sensitivity assays in apparently healthy men and women from different populations in Europe. Clin Chem49:669-672, 2003
19.
19. Ridker PM, Buring JE, Cook NR, et al. C-reactive protein, the metabolic syndrome, and risk of incident cardiovascular events. An 8-year follow-up of 14719 initially healthy American women. Circulation107:391-397, 2003
20.
20. Jonkers IJ, Mohrschladt MF, Westendorp RG, et al. Severe hypertriglyceridemia with insulin resistance is associated with systemic inflammation: Reversal with bezafibrate therapy in a randomized controlled trial. Am J Med112:275-280, 2002
21.
21. Melenovsky V, Malik J, Wichterle D, et al. Comparison of the effects of atorvastatin or fenofibrate on nonlipid biochemical risk factors and the LDL particle size in subjects with combined hyperlipidemia. Am Heart J144:E6-E6, 2002
22.
22. Yudkin JS, Stehouwer CD, Emeis JJ, et al C-reactive protein in healthy subjects: Associations with obesity, insulin resistance, and endothelial dysfunction. A potential role for cytokines originating from adipose tissue?Arterioscler Thromb Vasc Biol19:972-978, 1999
23.
23. Mohamed-Ali V, Goodrick S, Rawesh A, et al. Human subcutaneous adipose tissue releases IL-6 but not TNF-oc in vivo. J Clin Endocrinol Metab82:4196-4200, 1997
24.
24. Tjoelker LW, Stafforini DM. Platelet-activating factor acetylhydrolases in health and disease. Biochim Biophys Acta1488:102-123, 2000
25.
25. Guerra R, Zhao B, Mooser V, et al. Determinants of plasma platelet-activating factor acetylhydrolase: Heritability and relationship to plasma lipoproteins. J Lipid Res38:2281-2288, 1997
26.
26. Mathur S, Barradas MA, Mikhailidis DP, et al. The effect of a slow release formulation of bezafibrate on lipids, glucose homeostasis, platelets and fibrinogen in type II diabetics: A pilot study. Diabetes Res14:133-138, 1990
27.
27. de Maat MP, Knipscheer HC, Kastelein JJ, et al. Modulation of plasma fibrinogen levels by ciprofibrate and gemfibrozil in primary hyperlipidaemia. Thromb Haemost77:75-79, 1997
28.
28. Malik J, Melenovsky V, Wichterle D, et al. Both fenofibrate and atorvastatin improve vascular reactivity in combined hyperlipidemia (fenofibrate versus atorvastatin trialFAT). Cardiovasc Res52:290-298, 2001
29.
29. Staels B, Koenig W, Habib A, et al. Activation of human aortic smooth-muscle cells is inhibited by PPARa but not by PPARy activators. Nature393:790-793, 1998
30.
30. Rizos E, Bairaktari E, Ganotakis E, et al. Effect of ciprofibrate on lipoproteins, fibrinogen, renal function, and hepatic enzymes. J Cardiovasc Pharmacol Ther7: 219-226, 2002
31.
31. Tsimihodimos V, Kakafika A, Tambaki AP, et al. Fenofibrate induces HDL-associated PAF-AH but attenuates enzyme activity associated with apo B-containing lipoproteins. J Lipid Res44:927-934, 2003
32.
32. Mikhailidis DP, Ganotakis ES, Spyropoulos KA, et al. Prothrombotic and lipoprotein variables in patients attending a cardiovascular risk management clinic: Response to ciprofibrate or lifestyle advice. Int Angiol17:225-233, 1998
33.
33. Genest J Jr, Nguyen NH, Theroux P, et al. Effect of micronized fenofibrate on plasma lipoprotein levels and hemostatic parameters of hypertriglyceridemic patients with low levels of high-density lipoprotein cholesterol in the fed and fasted state. J Cardiovasc Pharmacol35:164-172, 2000
34.
34. Elisaf M, Tsimichodimos V, Bairaktari E, et al. Effect of micronized fenofibrate and losartan combination on uric acid metabolism in hypertensive patients with hyperuricemia. J Cardiovasc Pharmacol34:60-63, 1999
35.
35. Idzior-Walus B, Sieradzki J, Rostworowski W, et al. Effects of comicronised fenofibrate on lipid and insulin sensitivity in patients with polymetabolic syndrome X. Eur J Clin Invest30:871-878, 2000
36.
36. Xu X, Otsuki M, Sumitani S, et al. RU486 antagonizes the inhibitory effect of peroxisome proliferator-activated receptor oc on interleukin-6 production in vascular endothelial cells. J Steroid Biochem Mol Biol81:141-146, 2002
37.
37. Quinn MT, Parthasarathy S, Steinberg D. Lysophosphatidylcholine: A chemotactic factor for human monocytes and its potential role in atherogenesis. Proc Natl Acad Sci USA85:2805-2809, 1988
38.
38. Gervois P, Vu-Dac N, Kleeman R, et al. Negative regulation of human fibrinogen gene expression by peroxisome proliferator-activated receptor ct agonists via inhibition of CCAAT box/enhancer-binding protein P. J Biol Chem276:33471-33477, 2001
39.
39. Kleeman R, Gervois PP, Verschuren L, et al. Fibrates down-regulate IL- 1 stimulated C-reactive protein gene expression in hepatocytes by reducing nuclear p5O-NFkBC/EBP-P complex formation. Blood101:545-551, 2003
40.
40. Chapman MJ, Guerin M, Bruckert E. Atherogenic, dense low-density lipoproteins. Pathophysiology and new therapeutic approaches. Eur Heart J19(Suppl A):A24-A30, 1998
