Cardiac valvular calcification is the predominant pathology necessitating cardiac valve replacement. However, the molecular mechanisms that result in cuspal calcification are unknown. Prior theories of valve calcification have emphasized a degenerative process involving mineralization of valves. Recent findings, however, suggest that valve calcification is not passive degeneration, but an active ongoing process that involves not only mineralization, but ossification or formation of bone. Bone extracellular matrix proteins have been identified in calcified valves and are thought to provide the framework for the calcification process. Furthermore, inflammatory cells such as macrophages and lymphocytes have been identified in calcified cardiac valves. The hypothesis of this proposed research is that cardiac valve calcification occurs due to a change in the cellular phenotype of an osteoblast-like progenitor cell in cardiac valves. These osteoblast- like cells secrete proteins such as bone extracellular matrix proteins, alkaline phosphatase and Collagen resulting in ossification and mineralization of the valve. Bone forming proteins, inflammatory cells and growth factors are necessary pathologic components for the calcification process.
The aims of this study are: 1. To compare the phenotypic characteristics of cells and proteins associated with ossified and mineralized portions of calcified cardiac valves. 2. To investigate mechanisms of valve calcification using a cell culture model of calcification. 3. To examine therapeutic strategies to inhibit valve calcification with a bisphosphonate in cell culture.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
1K08HL003974-01
Application #
2765476
Study Section
Special Emphasis Panel (ZHL1-CSR-Y (O1))
Program Officer
Lymn, Richard W
Project Start
1999-02-01
Project End
2004-01-31
Budget Start
1999-02-01
Budget End
2000-01-31
Support Year
1
Fiscal Year
1999
Total Cost
Indirect Cost
Name
University of Pennsylvania
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Clark-Greuel, Jocelyn N; Connolly, Jeanne M; Sorichillo, Elizabeth et al. (2007) Transforming growth factor-beta1 mechanisms in aortic valve calcification: increased alkaline phosphatase and related events. Ann Thorac Surg 83:946-53
Wolf, Ronald L; Wehrli, Suzanne L; Popescu, Andra M et al. (2005) Mineral volume and morphology in carotid plaque specimens using high-resolution MRI and CT. Arterioscler Thromb Vasc Biol 25:1729-35
Wu, Bing; Elmariah, Sammy; Kaplan, Frederick S et al. (2005) Paradoxical effects of statins on aortic valve myofibroblasts and osteoblasts: implications for end-stage valvular heart disease. Arterioscler Thromb Vasc Biol 25:592-7
Mohler 3rd, Emile R; Treat-Jacobson, Diane; Reilly, Muredach P et al. (2004) Utility and barriers to performance of the ankle-brachial index in primary care practice. Vasc Med 9:253-60
Mohler 3rd, Emile R (2004) Mechanisms of aortic valve calcification. Am J Cardiol 94:1396-402, A6
Jian, Bo; Narula, Navneet; Li, Quan-yi et al. (2003) Progression of aortic valve stenosis: TGF-beta1 is present in calcified aortic valve cusps and promotes aortic valve interstitial cell calcification via apoptosis. Ann Thorac Surg 75:457-65; discussion 465-6
Pitsilos, Stephanie; Hunt, Jennifer; Mohler, Emile R et al. (2003) Platelet factor 4 localization in carotid atherosclerotic plaques: correlation with clinical parameters. Thromb Haemost 90:1112-20
Hunt, Jennifer L; Fairman, Ronald; Mitchell, Marc E et al. (2002) Bone formation in carotid plaques: a clinicopathological study. Stroke 33:1214-9
Mohler 3rd, E R; Gannon, F; Reynolds, C et al. (2001) Bone formation and inflammation in cardiac valves. Circulation 103:1522-8
Mohler 3rd, E R; Mitchell, M E; Carpenter, J P et al. (2001) Therapeutic thrombin injection of pseudoaneurysms: a multicenter experience. Vasc Med 6:241-4

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