Abstract 348: Effects of Normalizing Hyperlipidemia on Oxidative Stress and Disease Progression in a Mouse Model of Aortic Valve Stenosis
Treatment of hyperlipidemia produces functional and structural improvement in atherosclerotic vessels. Effects of treatment of hyperlipidemia on structure and function of the aortic valve, however, are controversial, and may be confounded by pleiotropic effects of drugs. We hypothesized treatment of hyperlipidemia using a “genetic switch” in Reversa mice (Ldlr−/ −/ Apob100/100/Mttpfl/fl/Mx1Cre+/+) would reduce oxidative stress and slow the progression of aortic valve disease. Following 6 months of hyperlipidemia (cholate-free Western diet = WD = 0.25% chol., 21% fat; total cholesterol levels >700 mg/dl), superoxide levels were significantly elevated in the aortic valve (dihydroethidium fluorescence: control = 5 ± 2 U/pixel, WD = 13 ± 3 U/pixel; p < 0.05) with very small reductions in maximum leaflet separation distance obtained from echocardiograms (control = 0.94 ± 0.07 mm, WD =0.89 ± 0.02 mm; p<0.05). In mice maintained on WD for an additional 6 months, leaflet separation decreased to 0.66 ± 0.06 mm (p < 0.05). Rapid normalization of cholesterol levels at 6 months (NC; total cholesterol <200 mg/dl) using a “genetic switch” normalized superoxide levels in the valve (NC = 4 ± 2 U/pixel, p = n.s. versus control animals) and prevented further reductions in leaflet separation distance (NC = 0.89 ± 0.05 mm; p = n.s.). Computerized planimetry of aortic valve area from high resolution cross-sectional magnetic resonance images through the aortic root (4.7 Tesla magnet, 0.04 mm2 in-plane pixel resolution) confirmed that normalization of cholesterol levels significantly slowed the rate of progression of valve stenosis (Δ valve area from 6–12 months: HC=−6.4 ± 4 %/month, NC = 0.6 ± 4%/month, p<0.05). Collectively, these data suggest that normalization of lipid levels in hypercholesterolemic mice with mild aortic valve disease normalizes oxidative stress and slows the progression of aortic valve stenosis.