title: Increased macrophage infiltration and neovascularization in congenital bicuspid aortic valve stenosis.
abstract: OBJECTIVE
  Patients with congenital bicuspid aortic valves have aortic valve stenosis at a relatively young age compared with patients with tricuspid aortic valves. We hypothesize that aortic valve stenosis evolves from a more aggressive inflammatory process, with increased macrophage/T-cell and neovessel content in congenital bicuspid aortic valveswhen compared with that seen in tricuspid valves.
  
  
  METHODS
  Fifty-one severely stenotic aortic valves were obtained at the time of aortic valve replacement. A total of 17 bicuspid and 34 tricuspid aortic valves were evaluated. Macrophage/T-cell infiltration (CD68 plus CD3) and neovessel density (CD34) were evaluated with immunohistochemical staining. Leaflet calcification and ossification were also quantified. Real-time polymerase chain reaction was used to assess expression of chondromodulin 1 and vascular endothelial growth factor.
  
  
  RESULTS
  The density of macrophages/T cells was greater in congenital bicuspid aortic valves than in tricuspid valves (51 ± 31 vs 23 ± 13 cells/mm(2), P = .002). Neovascularization was more frequently noted in congenital bicuspid aortic valves when compared with tricuspid valves (31 ± 10 vs 21 ± 9 vessels/mm(2), P = .0005), and calcification was more severe (P = .03). Expression of chondromodulin 1 demonstrated a 6-fold downregulation (P = .0003) and expression of vascular endothelial growth factor demonstrated a 2-fold increase (P = .02) in congenital bicuspid aortic valves compared with that seen in tricuspid valves. Multivariable analyses demonstrated significant associations between bicuspid aortic valve anatomy and increased inflammatory cell infiltration (β = 25.8, P = .0007) and neovascularization (β = 9.4, P = .001), despite adjusting for measured covariates.
  
  
  CONCLUSIONS
  The pathogenesis of aortic valve stenosis in bicuspid aortic valves is associated with a more aggressive inflammatory process with increased macrophage infiltration and neovascularization when compared with that seen in tricuspid valves.
authors.affiliation: Zena and Michael A. Weiner Cardiovascular Institute, Mount Sinai School of Medicine, New York, NY 10029, USA. pedro.moreno@msnyuhealth.org
authors.forename: Pedro R
authors.initials: PR
authors.lastname: Moreno
authors.forename: Luis
authors.initials: L
authors.lastname: Astudillo
authors.forename: Sammy
authors.initials: S
authors.lastname: Elmariah
authors.forename: K Raman
authors.initials: KR
authors.lastname: Purushothaman
authors.forename: Meeranani
authors.initials: M
authors.lastname: Purushothaman
authors.forename: Patrick A
authors.initials: PA
authors.lastname: Lento
authors.forename: Samin K
authors.initials: SK
authors.lastname: Sharma
authors.forename: Valentin
authors.initials: V
authors.lastname: Fuster
authors.forename: David H
authors.initials: DH
authors.lastname: Adams
mesh_terms: D000368:Aged; D015703:Antigens, CD / Q000032:analysis; D018952:Antigens, CD34 / Q000032:analysis; D015214:Antigens, Differentiation, Myelomonocytic / Q000032:analysis; D001021:Aortic Valve / Q000002:abnormalities / Q000276:immunology* / Q000473:pathology / Q000601:surgery; D001024:Aortic Valve Stenosis / Q000235:genetics / Q000276:immunology* / Q000473:pathology / Q000601:surgery; D017252:CD3 Complex / Q000032:analysis; D002114:Calcinosis / Q000276:immunology; D005260:Female; D006330:Heart Defects, Congenital / Q000150:complications* / Q000276:immunology / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D007249:Inflammation / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics; D016014:Linear Models; D008264:Macrophages / Q000276:immunology*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D008875:Middle Aged; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D009519:New York City; D012333:RNA, Messenger / Q000032:analysis; D012189:Retrospective Studies; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012720:Severity of Illness Index; D013601:T-Lymphocytes / Q000276:immunology; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics; D000097382:CD68 Molecule
chemical_list: D015703:Antigens, CD; D018952:Antigens, CD34; D015214:Antigens, Differentiation, Myelomonocytic; D017252:CD3 Complex; D036341:Intercellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A; C067980:CD68 antigen, human; D000097382:CD68 Molecule; C467484:VEGFA protein, human; C068675:CNMD protein, human