title: Simvastatin preserves diastolic function in experimental hypercholesterolemia independently of its lipid lowering effect.
abstract: 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.
authors.affiliation: Division of Cardiovascular Diseases, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: Dallit
authors.initials: D
authors.lastname: Mannheim
authors.forename: Joerg
authors.initials: J
authors.lastname: Herrmann
authors.forename: Piero O
authors.initials: PO
authors.lastname: Bonetti
authors.forename: Ronit
authors.initials: R
authors.lastname: Lavi
authors.forename: Lilach O
authors.initials: LO
authors.lastname: Lerman
authors.forename: Amir
authors.initials: A
authors.lastname: Lerman
mesh_terms: D000818:Animals; D003971:Diastole / Q000187:drug effects*; D004195:Disease Models, Animal; D005260:Female; D006333:Heart Failure / Q000097:blood; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use; D006909:Hydroxyproline / Q000097:blood; D006937:Hypercholesterolemia / Q000188:drug therapy*; D008055:Lipids / Q000737:chemistry; D008833:Microcirculation; D055806:Microvessels; D009206:Myocardium / Q000473:pathology; D019821:Simvastatin / Q000627:therapeutic use*; D013552:Swine; D014057:Tomography, X-Ray Computed / Q000379:methods; D055114:X-Ray Microtomography / Q000379:methods
chemical_list: D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008055:Lipids; D019821:Simvastatin; D006909:Hydroxyproline