Abstract 1540: Regular Exercise Prevents Aortic Valve Disease in LDLR Deficient Mice
Background: Currently the optimum timing of novel therapy for the prevention of calcific aortic valve (AV) disease is an active area of investigation. Recent reports suggest that physical inactivity or severe AV calcification indicates poor outcome in patients with AV stenosis. Thus, regular exercise training (ET) may be reasonable for the prevention of AV stenosis especially at an earlier time point before progression of AV calcification (eg, AV sclerosis). This study was designed to examine if ET prevents AV sclerosis, and if so, what mechanism(s) is involved, using a well-established animal model revealing AV disease.
Methods and Results: Four-week-old LDL receptor deficient (LDLR−/−) mice (n=94) were randomly divided into four groups: Group 1 (N), normal diet plus sedentary; group 2 (Chol), cholesterol (chol)-diet plus sedentary; group 3 (Reg), chol-diet plus regular ET for 16 wks (Treadmil, 60min/d, 5d/wk); group 4 (Occa), chol-diet plus occasional ET for 16 wks (1d/wk). Histological analysis at 20-wk-old showed that AV thickness increased significantly in chol-group compared to N-group. Importantly, regular ET but not occasional ET significantly reduced AV thickness as compared to chol-group (N;31.3±3.0, Chol; 50.1±3.4, Reg;30.4±1.2, Occa; 48.9±3.2μm, P<0.001). Immunohistochemistory revealed that chol-diet disrupted and regular ET preserved endothelial integrity on the AV surface(N; 95.7±1.0, Chol; 73.7±2.2, Reg; 95.8±2.3%, P<0.001). Exercise did not affect cholesterol levels. However, plasma myeloperoxidase, accumulation of macrophages and oxidized-LDL, in-situ superoxide, differentiation to myofibroblasts or osteoblasts at the AVs were markedly increased in chol-group and significantly decreased by regular ET. PCR revealed mRNA for Runx2 (osteogenic transcription factor) was increased in chol-group and significantly diminished by regular ET (P<0.05).
Conclusions: In the LDLR−/− mice, regular ET prevents AV sclerosis by numerous mechanisms including preservation of endothelial integrity, reduced inflammation or oxidative stress and finally inhibition of osteogenic pathway. Based on our new insights, a novel strategy such as regular ET may be useful for preventing AV disease particularly at an early stage of disease.