title: Everolimus attenuates neointimal hyperplasia in cultured human saphenous vein grafts.
abstract: OBJECTIVE
  Neointimal hyperplasia is the first step in a cascade leading to a reduced patency rate of saphenous vein grafts in comparison to arterial grafts in coronary artery bypass grafting. Using cultured human saphenous vein grafts as a model for coronary artery bypass grafting, we investigated if the mammalian target of rapamycin inhibitor everolimus attenuates neointimal hyperplasia.
  
  
  METHODS
  Saphenous vein grafts from 10 patients undergoing coronary artery bypass grafting were processed as follows: from each patient, one segment served as baseline control at day 0. Two segments were cultured in a neointimal hyperplasia model separately. One received no treatment and the other everolimus (1 microM). All vein grafts underwent histomorphometric analysis, assessment of proliferation by Ki-67 immunostaining and quantification of phospho-S6 ribosomal protein using western blot analysis.
  
  
  RESULTS
  Everolimus treatment resulted in reduced neointimal hyperplasia (thickness 3.7+/-1.2 microm) compared to untreated controls (10.1+/-2.5 microm, p=0.008). The intima/intima+media-ratio was reduced in the everolimus group (0.10+/-0.02) compared to untreated controls (0.24+/-0.07, p=0.008). The number of Ki-67 positive proliferating cells in everolimus treated vein grafts (15+/-7 cells/high power field) showed a tendency of reduction compared to untreated controls (36+/-20 cells/high power field, p=0.036). Finally, everolimus treatment resulted in downregulation of S6 ribosomal protein phosphorylation in comparison to untreated controls.
  
  
  CONCLUSIONS
  Everolimus is able to reduce neointimal proliferation in cultured human saphenous vein grafts by inhibition of the mammalian target of rapamycin, even though different transfection methods are to be evaluated for a clinical application in coronary artery bypass grafting.
authors.affiliation: Department of Cardiac Surgery, Innsbruck Medical University, Innsbruck, Austria. severin.semsroth@i-med.ac.at
authors.forename: Severin
authors.initials: S
authors.lastname: Semsroth
authors.forename: Robert G
authors.initials: RG
authors.lastname: Stigler
authors.forename: Oliver Y
authors.initials: OY
authors.lastname: Bernecker
authors.forename: Elfriede
authors.initials: E
authors.lastname: Ruttmann-Ulmer
authors.forename: Jakob
authors.initials: J
authors.lastname: Troppmair
authors.forename: Karin
authors.initials: K
authors.lastname: Macfelda
authors.forename: Johannes O
authors.initials: JO
authors.lastname: Bonatti
authors.forename: Guenther
authors.initials: G
authors.lastname: Laufer
mesh_terms: D015153:Blotting, Western; D001026:Coronary Artery Bypass / Q000379:methods*; D000068338:Everolimus; D006801:Humans; D006965:Hyperplasia / Q000473:pathology / Q000517:prevention & control; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D019394:Ki-67 Antigen / Q000032:analysis; D009924:Organ Culture Techniques; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism; D012501:Saphenous Vein / Q000187:drug effects / Q000473:pathology* / Q000637:transplantation; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000627:therapeutic use; D017539:Tunica Intima / Q000187:drug effects / Q000473:pathology*; D014654:Vascular Patency / Q000187:drug effects
chemical_list: D007166:Immunosuppressive Agents; D019394:Ki-67 Antigen; D000068338:Everolimus; D019893:Ribosomal Protein S6 Kinases; D020123:Sirolimus