Published Online
on June 13, 2005

A more recent version of this article appeared on June 21, 2005

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Submitted on May 5, 2004
Revised on February 9, 2005
Accepted on February 16, 2005

Calcified Rheumatic Valve Neoangiogenesis Is Associated With Vascular Endothelial Growth Factor Expression and Osteoblast-Like Bone Formation

Nalini M. Rajamannan MD^*, Thomas B. Nealis BSc, Malayannan Subramaniam PhD, Sanjay Pandya MD, Stuart R. Stock PhD, Constatine I. Ignatiev PhD, Thomas J. Sebo MD, PhD, Todd K. Rosengart MD, William D. Edwards MD, Patrick M. McCarthy MD, Robert O. Bonow MD, and Thomas C. Spelsberg PhD

From the Divisions of Cardiology and Cardiothoracic Surgery, Northwestern University, Feinberg School of Medicine, Chicago, Ill (N.M.R., T.B.N., S.P., P.M.M., R.O.B.); Departments of Molecular Biology and Biochemistry (M.S., T.C.S.) and Laboratory Medicine and Pathology (T.J.S., W.D.E.), Mayo Clinic, Rochester, Minn; Institute for Bioengineering and Nanoscience in Advanced Medicine, Northwestern University, Chicago, Ill (S.R.S., C.I.I.); Cardiology and Cardiothoracic Surgery, Northwestern Evanston Healthcare, Chicago, Ill (T.K.R.).

^* To whom correspondence should be addressed. E-mail: n-rajamannan{at}northwestern.edu.

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.

Methods and 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, -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.

Key words: angiogenesis • calcification • cardiovascular diseases • rheumatic heart disease • valves

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