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(Circulation. 2009;119:2693-2701.)
© 2009 American Heart Association, Inc.

Valvular Heart Disease

Lowering Plasma Cholesterol Levels Halts Progression of Aortic Valve Disease in Mice

Jordan D. Miller, PhD; Robert M. Weiss, MD; Kristine M. Serrano, BS; Robert M. Brooks, II, BS; Christopher J. Berry, MD; Kathy Zimmerman; Stephen G. Young, MD; Donald D. Heistad, MD

From the Departments of Internal Medicine (J.D.M., R.M.W., K.M.S., R.M.B., C.J.B., K.Z., D.D.H.) and Pharmacology (D.D.H.), University of Iowa Carver College of Medicine, and VA Medical Center (K.Z., D.D.H.), Iowa City, and David Geffen School of Medicine, University of California, Los Angeles (S.G.Y.).

Correspondence to Jordan D. Miller, PhD, or Donald D. Heistad, MD, University of Iowa, Department of Internal Medicine, 200 Hawkins Dr, Iowa City, IA 52242. E-mail jordan-miller{at}uiowa.edu or donald-heistad@uiowa.edu

Received November 13, 2008; accepted March 11, 2009.

Background— Treatment of hyperlipidemia produces functional and structural improvements in atherosclerotic vessels. However, the effects of treating hyperlipidemia on the structure and function of the aortic valve have been controversial, and any effects could be confounded by pleiotropic effects of hypolipidemic treatment. The goal of this study was to determine whether reducing elevated plasma lipid levels with a "genetic switch" in Reversa mice (Ldlr–/–/Apob^100/100/Mttp^fl/fl/Mx1-Cre^+/+) reduces oxidative stress, reduces pro-osteogenic signaling, and retards the progression of aortic valve disease.

Methods and Results— After 6 months of hypercholesterolemia, Reversa mice exhibited increases in superoxide, lipid deposition, myofibroblast activation, calcium deposition, and pro-osteogenic protein expression in the aortic valve. Maximum aortic valve cusp separation, as judged by echocardiography, was not altered. During an additional 6 months of hypercholesterolemia, superoxide levels, valvular lipid deposition, and myofibroblast activation remained elevated. Furthermore, calcium deposition and pro-osteogenic gene expression became more pronounced, and the aortic cusp separation decreased from 0.85±0.04 to 0.70±0.04 mm (mean±SE; P<0.05). Rapid normalization of cholesterol levels at 6 months of age (by inducing expression of Cre recombinase) normalized aortic valve superoxide levels, decreased myofibroblast activation, reduced valvular calcium burden, suppressed pro-osteogenic signaling cascades, and prevented reductions in aortic valve cusp separation.

Conclusions— Collectively, these data indicate that reducing plasma lipid levels by genetic inactivation of the mttp gene in hypercholesterolemic mice with early aortic valve disease normalizes oxidative stress, reduces pro-osteogenic signaling, and halts the progression of aortic valve stenosis.

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