1061 Atorvastatin inhibits mitral regurgitation in an experimental hypercholesterolemia rabbit model

Abstract

Degenerative mitral regurgitation is the most common cause of mitral regurgitation in the United States. Recent epidemiologic studies have linked degenerative mitral valve disease and risk factors for atherosclerosis. In the current study, we studied a hypercholesterolemic rabbit model with and without atorvastatin to determine the cellular mechanisms of mitral leaflet abnormalities. Methods: 48 Watanabe rabbits were assigned to one of 3 groups: cholesterol (1%) diet, cholesterol (1%) plus atorvastatin (2.5 mg/kg), and normal diet for six months. The rabbits underwent transesophageal echocardiograms and then the mitral valves were harvested. Electron microscopy, immunohistologic staining, and Real-time PCR was performed. Immunohistologic staining of the mitral valves was performed using atherosclerotic markers macrophage (RAM11), alpha -actin smooth muscle, and Proliferating Cell Nuclear Antigen (PCNA). Bone matrix expression was determined by staining for osteopontin, osteocalcin, alizarin Red and measuring alkaline phosphatase gene expression. A 4-point grading system was used to visually describe the staining on each of the slides (0=no staining, 4=high staining). Real-time PCR was performed was performed to measure alkaline phosphatase gene expression. Results: Mitral regurgitation (3+), Macrophage (3.5+/-0.7), alpha-actin (4+/-0), osteopontin (4+/-0), osteocalcin (2.5+/-0.7), PCNA (4+/-0) and alkaline phosphatase (0.479+/-0.286) were increased the mitral valves from the cholesterol treated rabbits (p<0.05 as compared to control mitral valves). Alkaline phosphatase was unchanged in the control versus cholesterol treatment groups. Atorvastatin decreased the amount of mitral regurgitation (1+), atherosclerotic proliferative changesincluding macrophage (2.5+/-0.7), osteopontin (1.5+/-0.7), osteocalcin (2.5+/-0.7), PCNA (2+/-0) and alkaline phosphatase expression (0.479+/-0.286) in these treated valves. Conclusion: Experimental hypercholesterolemia induces proliferation and osteopontin expression in the mitral valve that may potentially be modified with the use of a lipid-lowering agent.