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(Circulation. 2005;112:2875-2882.)
© 2005 American Heart Association, Inc.

Vascular Medicine

Sevelamer Prevents Uremia-Enhanced Atherosclerosis Progression in Apolipoprotein E–Deficient Mice

Olivier Phan, MD^*; Ognen Ivanovski, MD^*; Thao Nguyen-Khoa, PharmD, PhD; Nadya Mothu; Jesus Angulo, PhD; Ralf Westenfeld, MD; Markus Ketteler, MD; Natalie Meert, MSc; Julien Maizel, MD; Igor G. Nikolov, MD; Raymond Vanholder, MD, PhD; Bernard Lacour, PharmD, PhD; Tilman B. Drüeke, MD; Ziad A. Massy, MD, PhD

From the INSERM Unit 507 (O.P., O.I., T.N.-K., N.M., I.E.N., T.B.D.) and Laboratory of Biochemistry A (T.N.-K., B.L.), Necker Hospital, Paris, France; Centre de Morphologie Mathématique, Ecole des Mines de Paris, Fontainebleau, France (J.A.); Department of Nephrology and Immunology, University Hospital Aachen, Aachen, Germany (R.W., M.K.); Nephrology Section, Department of Internal Medicine, University Hospital, Gent, Belgium (N.M., R.V.); and INSERM ERI-12, Amiens, France, Sud University of Picardie and Amiens University Hospital, Amiens, France (J.M., Z.A.M.).

Correspondence to Ziad A. Massy, MD, PhD, Divisions of Clinical Pharmacology and Nephrology, INSERM ERI-12, University of Picardie and Amiens University Hospital, Avenue Rene Laennec, F-80054 Amiens, France. E-mail massy{at}u-picardie.fr

Received February 23, 2005; revision received July 28, 2005; accepted August 9, 2005.

Background— The novel phosphate binder sevelamer has been shown to prevent the progression of aortic and coronary calcification in uremic patients. Whether it also decreases the progression of atheromatous plaques is unknown. The aim of our study was to examine the effect of sevelamer administration on the development of atherosclerosis and aortic calcification in the uremic apolipoprotein E–deficient mouse as an established model of accelerated atherosclerosis.

Methods and Results— Female mice were randomly assigned to 4 groups: 2 groups of nonuremic mice (sevelamer versus control) and 2 groups of uremic mice (sevelamer versus control). Sevelamer was given at 3% with chow. The increases in serum phosphorus concentration and calcium-phosphorus product observed in uremic control mice were prevented by sevelamer. Serum total cholesterol was increased in the 2 uremic mouse groups and remained unchanged in response to sevelamer. After 8 weeks of sevelamer treatment, uremic mice exhibited a significantly lower degree of atherosclerosis (P<0.001) and vascular calcification than uremic control mice. Of interest, sevelamer exerted an effect on both intima and media calcification (P=0.005) in uremic mice. Among possible mechanisms involved, we found no evidence for the modulation by sevelamer of inflammation or selected uremic toxins. In contrast, nitrotyrosine staining as a measure of oxidative damage was significantly decreased in response to sevelamer treatment in control and uremic mice (P<0.005).

Conclusions— Sevelamer delays not only vascular calcification but also atherosclerotic lesion progression in uremic apolipoprotein E–deficient mice. It opens the possibility of a cholesterol-independent action of sevelamer on atheroma formation via effects on mineral metabolism, oxidative stress, or both.

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CLINICAL PERSPECTIVE