title: Statin therapy prevents expansive remodeling in venous bypass grafts.
abstract: BACKGROUND
  Venous grafts (VG) have high failure rates by 10 years in aortocoronary bypass surgery. We have previously shown that expansive remodeling followed by increased LDL retention are early atherosclerotic changes in experimental VG placed in the arterial circulation. The objective of this study was to determine whether statin therapy prevents these expansive remodeling changes.
  
  
  RESULTS
  Reversed jugular vein-to-common carotid artery interposition graft was constructed in 27 cholesterol-fed (0.5%) rabbits. Rabbits were randomized either to control or atorvastatin (5 mg/kg/day) groups, starting two weeks prior to vein graft implantation and continuing until sacrifice at 1 or 12 weeks post-surgery. Ultrasound measurements of arterial luminal cross-sectional area (CSA) were done at day 3 and at 4, 8 and 12 weeks post-surgery. Histomorphometric measurements were performed following sacrifice at 12 weeks. Atorvastatin treatment significantly decreased total plasma cholesterol levels at 4, 8 and 12 weeks (12 weeks: 6.7 ± 4.2 mmol/L versus control 38.7 ± 10.6 mmol/L, p<0.0002). Atorvastatin significantly reduced expansive remodeling at 4, 8 and 12 weeks (lumen CSA: 44.6 ± 6.6 mm(2) versus control 77.6 ± 10.7 mm(2), p<0.0001). Intimal CSA by histomorphometry was also significantly reduced by atorvastatin at 12 weeks (5.59 ± 2.19 mm(2) versus control 9.57 ± 2.43 mm(2), p<0.01). VG macrophage infiltration, MMP-2 activity and metalloelastase activity were reduced in the atorvastatin treated group.
  
  
  CONCLUSIONS
  Atorvastatin inhibits both expansive remodeling and intimal hyperplasia in arterialized VG, likely through inhibition of macrophage infiltration and reduction of tissue proteolytic activity. The mechanism proposed above may be important for preventing VG atherosclerosis and late VG failure.
authors.affiliation: Schulich Heart Centre, Sunnybrook Health Sciences Center, Toronto, Ontario, Canada.
authors.forename: Beiping
authors.initials: B
authors.lastname: Qiang
authors.forename: Jonathan
authors.initials: J
authors.lastname: Toma
authors.forename: Hiroko
authors.initials: H
authors.lastname: Fujii
authors.forename: Azriel B
authors.initials: AB
authors.lastname: Osherov
authors.forename: Nafiseh
authors.initials: N
authors.lastname: Nili
authors.forename: John D
authors.initials: JD
authors.lastname: Sparkes
authors.forename: Paul
authors.initials: P
authors.lastname: Fefer
authors.forename: Michelle
authors.initials: M
authors.lastname: Samuel
authors.forename: Jagdish
authors.initials: J
authors.lastname: Butany
authors.forename: Howard
authors.initials: H
authors.lastname: Leong-Poi
authors.forename: Bradley H
authors.initials: BH
authors.lastname: Strauss
mesh_terms: D000714:Anastomosis, Surgical; D000818:Animals; D000069059:Atorvastatin; D015415:Biomarkers / Q000097:blood; D017536:Carotid Artery, Common / Q000601:surgery; D049109:Cell Proliferation / Q000187:drug effects; D002791:Cholesterol, Dietary / Q000008:administration & dosage / Q000097:blood; D006538:Heptanoic Acids / Q000494:pharmacology*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D006965:Hyperplasia; D007150:Immunohistochemistry; D007601:Jugular Veins / Q000000981:diagnostic imaging / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000637:transplantation*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D053508:Matrix Metalloproteinase 12 / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D023421:Models, Animal; D058426:Neointima; D011758:Pyrroles / Q000494:pharmacology*; D011817:Rabbits; D013997:Time Factors; D014463:Ultrasonography; D058017:Vascular Grafting / Q000009:adverse effects*
chemical_list: D015415:Biomarkers; D002791:Cholesterol, Dietary; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011758:Pyrroles; D000069059:Atorvastatin; D020778:Matrix Metalloproteinase 2; D053508:Matrix Metalloproteinase 12