Simvastatin preserves diastolic function in experimental hypercholesterolemia independently of its lipid lowering effect

Objective: Isolated diastolic dysfunction is present in 40% of heart failure patients. It has been attributed to myocardial fibrosis and related to cardiovascular risk factor exposure. We hypothesized that simvastatin will improve these dynamics in experimental hypercholesterolemia (HC). Methods: Three groups of pigs were studied after 12 weeks of normal (N) diet, HC diet, or HC diet with simvastatin (80. mg/day) treatment. Cardiac function was assessed by electron beam computed tomography (EBCT) and percentage of myocardium occupied by microvessels (myocardial vascular fraction) was calculated by micro-CT. Collagen content was determined by Sirius red staining and confirmed by a quantitative, hydroxyoproline-based assay. Results: Compared with N, LDL serum concentration was higher in HC and HC. +. simvastatin (1.0 ± 0.1 vs. 7.9 ± 1.7 and 9.6 ± 1.2. mmol/L, p< 0.05 for both). Cardiac early diastolic filling was reduced in HC compared with N (102.4 ± 11.3 vs. 151.1 ± 12.1. mL/s; p< 0.05) but restored in HC. +. simvastatin (176.8 ± 21.3. mL/s, p< 0.05 vs. HC). Compared with N, myocardial vascular fraction was higher in HC but not in HC. +. simvastatin (1.98 ± 0.84 vs. 4.48 ± 0.31 and 2.95 ± 0.95%; p< 0.05 for HC vs. N). Myocardial collagen content was higher in HC than in HC. +. simvastatin and N (4.72 ± 1.03 vs. 1.62 ± 0.12 and 1.21 ± 0.24% area staining; p< 0.05 for HC vs. N), which was attributable mainly to an increase in collagen III (2.90 ± 0.48 vs. 1.62 ± 0.12 and 1.21 ± 0.24% area staining; p< 0.05 for HC vs. N). Conclusions: Simvastatin is able to prevent diastolic dysfunction in experimental HC independent of its lipid lowering effect. This beneficial effect is, at least partially, due to a decrease in myocardial fibrosis and angiogenesis.