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Characterization of Changes in Systolic and Diastolic Function in a Mouse Model of Hemodynamically-Significant Aortic Valve Stenosis
Grace C. Verzosa, Bin Zhang, Carolyn Roos, Jordan D. Miller.
Mayo Clinic, Rochester, MN, USA.

Objectives: While mouse models of fibro-calcific aortic valve (AV) disease have provided critical insights into mechanisms contributing to the development of aortic valve calcification and stenosis, there are limited data available examining changes in cardiac function over time in these models. Thus, the purpose of this study was to thoroughly characterize changes in cardiac function over time in a mouse model that develops hemodynamically significant aortic valve stenosis. Methods: Male and female “Reversa” mice (ldlr-deficient, apoB100-only mice in which cholesterol levels can be normalized with a genetic switch) were used in these studies. Normocholesterolemic mice were fed a chow diet and were “reversed” at 2 months of age. Hypercholesterolemic mice were placed on a Western diet at 2 months of age. Aortic valve function and ventricular function were examined 3 and 6 months after “Reversing” mice or starting Western diet. Two-dimensional and Doppler echocardiogram was performed at 3 and 6 months. Results: Aortic valve cusp separation distance was reduced in hypercholesterolemic mice compared to normocholesterolemic mice at both time points. At 3 months, there were no significant differences in left ventricular (LV) ejection fraction (EF) or fractional shortening (FS) between sexes or across treatment groups. LV mass was, however, significantly higher in male mice in both treatment groups. E/e' was higher in hypercholesterolemic female mice compared to other groups. AV cusp separation distance was not significantly reduced from 3 to 6 month time points, but LV mass was significantly increased in both groups over time. Furthermore, EF and FS decreased at 6 months in male mice but not in female mice. Interestingly, pulmonary artery acceleration time was shortened in both treatment groups. Conclusions: Male Reversa mice have worsened left ventricular systolic function in early stages of valve disease compared to their female counterparts. In contrast, female mice develop diastolic dysfunction earlier than male mice. Importantly, Doppler echocardiographic parameters such as E/e', and pulmonary artery acceleration time may be used in addition to conventional measures of ventricular function (e.g., EF, FS and LV mass) to better understand cardiac responses to chronic, progressive left ventricular overload.

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