Calcific aortic valve stenosis in old hypercholesterolemic mice

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) C57B1/6 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.