Calcified rheumatic valve neoangiogenesis is associated with vascular endothelial growth factor expression and osteoblast-like bone formation.
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.
Rajamannan
Nalini M
NM
Division of Cardiology, Northwestern University, Feinberg School of Medicine, Chicago, Ill, Chicago, IL 60611, USA. n-rajamannan@northwestern.edu
Nealis
Thomas B
TB
Subramaniam
Malayannan
M
Pandya
Sanjay
S
Stock
Stuart R
SR
Ignatiev
Constatine I
CI
Sebo
Thomas J
TJ
Rosengart
Todd K
TK
Edwards
William D
WD
McCarthy
Patrick M
PM
Bonow
Robert O
RO
Spelsberg
Thomas C
TC
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*
D015415:Biomarkers; D042461:Vascular Endothelial Growth Factor A