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(Circulation. 2006;114:2065-2069.)
© 2006 American Heart Association, Inc.

Valvular Heart Disease

Calcific Aortic Valve Stenosis in Old Hypercholesterolemic Mice

Robert M. Weiss, MD^*; Masuo Ohashi, MD^*; Jordan D. Miller, PhD; Stephen G. Young, MD; Donald D. Heistad, MD

From the Departments of Internal Medicine (R.M.W., M.O., J.D.M., D.D.H.) and Pharmacology (D.D.H.), the Roy J. and Lucille A. Carver College of Medicine, University of Iowa, and Veterans Affairs Medical Center (R.M.W., D.D.H.), Iowa City, Iowa; and the Division of Cardiology (S.G.Y.), Department of Internal Medicine, University of California, Los Angeles.

Correspondence to Robert M. Weiss, MD, Department of Internal Medicine, Room E317-A GH, University of Iowa College of Medicine, 200 Hawkins Dr, Iowa City, IA 52242. E-mail robert-weiss{at}uiowa.edu

Received April 14, 2006; revision received August 2, 2006; accepted August 7, 2006.

Background— Hypercholesterolemia and old age are clinical risk factors for development of aortic valve stenosis, and hypercholesterolemia is a putative therapeutic target. We tested the hypothesis that calcification and aortic valve stenosis would develop in genetically hypercholesterolemic old mice.

Methods and Results— Twenty-four low-density lipoprotein receptor–deficient apolipoprotein B-100–only (LDLr^–/–ApoB^100/100) mice were fed normal chow from weaning until age 20.1±0.5 months (mean±SE; range 17 to 22 months). Twenty-one age-matched (20.8±0.9 months, range 17 to 25 months) C57Bl/6 mice served as controls. Echocardiographic imaging was used to assess morphology and function of the aortic valve and left ventricle. A subset of 12 mice underwent invasive hemodynamic assessment of aortic valve function. Functionally significant aortic stenosis, with >75% reduction in valve area, occurred in 8 of 24 LDLr^–/–ApoB^100/100 mice and in 0 of 21 controls (P=0.01). In the subset that underwent catheterization, mice with echocardiographic evidence of aortic stenosis had a systolic transvalvular gradient of 57±6 mm Hg. In the group of all LDLr^–/–ApoB^100/100 mice with aortic stenosis, left ventricular mass was increased by 67% (P=0.001) and ejection fraction was decreased by 30% (P=0.004) compared with LDLr^–/–ApoB^100/100 without aortic stenosis. Von Kossa staining of the aortic valve demonstrated abundant mineralization in LDLr^–/–ApoB^100/100 mice but not in control mice. Superoxide (oxyethidium fluorescence) was present in valve tissue from all 3 groups of mice and was more abundant in mice with aortic stenosis.

Conclusions— Hypercholesterolemic LDLr^–/–ApoB^100/100 mice are prone to develop calcification and oxidative stress in the aortic valve, with functional valvular heart disease, mimicking the clinical syndrome. This discovery holds promise for elucidation of the pathophysiology of aortic valve disease mechanisms and for the design of effective nonsurgical treatment.

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