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(Circulation. 2009;119:306-313.)
© 2009 American Heart Association, Inc.

Vascular Medicine

Mechanisms of Aortic and Cardiac Dysfunction in Uremic Mice With Aortic Calcification

Julien Maizel, MD^*; Isabelle Six, PhD^*; Michel Slama, MD; Christophe Tribouilloy, MD, PhD; Henry Sevestre, MD; Sabrina Poirot, Tech; Philippe Giummelly, PhD; Jeffrey Atkinson, PhD; Gabriel Choukroun, MD, PhD; Michel Andrejak, MD; Said Kamel, Pharm D, PhD; Jean Claude Mazière, MD, PhD; Ziad A. Massy, MD, PhD

From INSERM, Unit ERI-12 (J.M., I.S., M.S., C.T., S.P., G.C., M.A., S.K., J.C.M., Z.A.M.), and Jules Verne University of Picardie and Amiens University Medical Center (J.M., I.S., M.S., C.T., H.S., G.C., M.A., S.K., J.C.M., Z.A.M.), Amiens, and Pharmacology Laboratory, Pharmacy Faculty, Henri Poincaré University, Nancy (P.G., J.A.), France.

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

Received September 18, 2007; accepted October 23, 2008.

Background— Chronic renal failure (CRF) is associated with cardiac dysfunction and increased aortic stiffness. The mechanisms involved are not clearly understood. We examined changes over time in cardiac and aortic function in a murine CRF model.

Methods and Results— Eight-week-old mice were randomly assigned to 1 of 4 groups: wild-type non-CRF, wild-type CRF, apolipoprotein E knockout non-CRF, and apolipoprotein E knockout CRF. Echocardiography was performed and blood samples were taken at baseline and after 6 and 10 weeks of CRF. Vascular reactivity and adhesion molecule expression were studied after 6 and 10 weeks of CRF. Left ventricular hypertrophy, altered left ventricular relaxation, and increased aortic stiffness were observed after 6 weeks of CRF and persisted after 10 weeks. The 4 groups of mice did not significantly differ in terms of arterial blood pressure and aortic structure. The degree of vascular calcification and serum total cholesterol concentration were higher in the CRF groups than in the non-CRF groups. These changes, however, could not explain the cardiac and vascular differences seen in the 2 CRF groups. In contrast, alterations in vascular reactivity, the upregulation of adhesion molecule expression, and CRF status were significantly associated with these changes.

Conclusions— In a mouse model of CRF, left ventricular hypertrophy, cardiac diastolic dysfunction, and increased aortic stiffness were not related to structural changes in the aorta (including aortic calcification) or high serum cholesterol levels. However, cardiac and aortic abnormalities were associated with the extent of subendothelial dysfunction and the severity of CRF.

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CLINICAL PERSPECTIVE

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