title: Calcified rheumatic valve neoangiogenesis is associated with vascular endothelial growth factor expression and osteoblast-like bone formation.
abstract: BACKGROUND
  Rheumatic heart disease is the most common cause of valvular disease in developing countries. Despite the high prevalence of this disease, the cellular mechanisms are not well known. We hypothesized that rheumatic valve calcification is associated with an osteoblast bone formation and neoangiogenesis.
  
  
  RESULTS
  To test this hypothesis, we examined human rheumatic valves replaced at surgery (n=23), normal human valves (n=20) removed at cardiac transplantation, and degenerative mitral valve leaflets removed during surgical valve repair (n=15). Microcomputed tomography was used to assess mineralization fronts to reconstruct the extents of mineralization. Immunohistochemistry was used to localize osteopontin protein, alpha-actin, osteocalcin, vascular endothelial growth factor, von Willebrand factor, and CD68 (human macrophage). Microcomputed tomography demonstrated complex calcification developing within the heavily calcified rheumatic valves, not in the degenerative mitral valves and control valves. Immunohistochemistry localized osteopontin and osteocalcin to areas of smooth muscle cells within microvessels and proliferating myofibroblasts. Vascular endothelial growth factor was present in areas of inflammation and colocalized with the CD68 stain primarily in the calcified rheumatic valves. Alizarin red, osteopontin, and osteocalcin protein expression was upregulated in the calcified rheumatic valves and was present at low levels in the degenerative mitral valves.
  
  
  CONCLUSIONS
  These findings support the concept that rheumatic valve calcification is not a random passive process but a regulated, inflammatory cellular process associated with the expression of osteoblast markers and neoangiogenesis.
authors.affiliation: Division of Cardiology, Northwestern University, Feinberg School of Medicine, Chicago, Ill, Chicago, IL 60611, USA. n-rajamannan@northwestern.edu
authors.forename: Nalini M
authors.initials: NM
authors.lastname: Rajamannan
authors.forename: Thomas B
authors.initials: TB
authors.lastname: Nealis
authors.forename: Malayannan
authors.initials: M
authors.lastname: Subramaniam
authors.forename: Sanjay
authors.initials: S
authors.lastname: Pandya
authors.forename: Stuart R
authors.initials: SR
authors.lastname: Stock
authors.forename: Constatine I
authors.initials: CI
authors.lastname: Ignatiev
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Sebo
authors.forename: Todd K
authors.initials: TK
authors.lastname: Rosengart
authors.forename: William D
authors.initials: WD
authors.lastname: Edwards
authors.forename: Patrick M
authors.initials: PM
authors.lastname: McCarthy
authors.forename: Robert O
authors.initials: RO
authors.lastname: Bonow
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Spelsberg
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015415:Biomarkers / Q000032:analysis; D002114:Calcinosis / Q000473:pathology*; D005260:Female; D006349:Heart Valve Diseases / Q000209:etiology / Q000473:pathology*; D006351:Heart Valves / Q000737:chemistry / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D007249:Inflammation / Q000473:pathology; D008297:Male; D008875:Middle Aged; D018919:Neovascularization, Physiologic; D010006:Osteoblasts; D010012:Osteogenesis; D012214:Rheumatic Heart Disease / Q000150:complications*; D014054:Tomography; D042461:Vascular Endothelial Growth Factor A / Q000032:analysis*
chemical_list: D015415:Biomarkers; D042461:Vascular Endothelial Growth Factor A