Abstract

Heart diseases are a major cause of death, disability and economic los. Often, heart conditions coincide with blood vessel blockage by calcified plaques. The overall objective is to develop sufficient information on the kinetic and structural properties of cardiovascular deposits (CD) and on the inhibition mechanisms of agents that can prevent formation of CD. We propose to: I. Assess the therapeutic potential of various novel phosphonate drugs for control of formation and growth of calcified deposits by in vitro experiments of spontaneous precipitation and seeded growth of calcium phosphate. I. Study the inhibitory effects of drugs on dissolution and hydrolysis of OCP in order to investigate the potential of the drugs to stabilize cardiovascular calcification precursors and inhibit the transformation of the precursors to hydroxyapatite, the main constituent of CD. III. Follow the formation of precursors in vivo in the early stages of mineralization and study the inhibition effect of novel phosphonates on their formation and transformation by detection (32P- pyrolysis technique) of acidic phosphate ions (HPO4) in calcified deposits formed on subcutaneously implanted Bovine pericardium in rats. IV. Measure the dissolution and hydrolysis of OCP-carbonates under physiological conditions. Formation of OCP-CO3 and its transformation to carbonate apatite similar to CD has been proposed as an alternative mechanism for incorporation of carbonate into CD via OCP-CO3 intermediate. V. Investigate in vitro the mechanism of crystal growth on CD retrieved from patients by seeding supersaturated solutions of calcium phosphate with native and deproteinated CD powders. VI. Study the inhibition of calcium phosphate growth on CD in vitro in order to determine the effect of known bisphosphonates on crystal growth on mature CD. VII. Study the mechanism of incorporation of fluoride into CD by following the uptake of fluoride by CD and comparing with uptake by proposed precursors. The ultimate goal is to understand the process of cardiovascular calcification and to develop therapeutic treatments for atherosclerosis and prevention of the destruction of implanted bioprostheses.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL030035-10
Application #
2216547
Study Section
Oral Biology and Medicine Subcommittee 1 (OBM)
Project Start
1983-08-01
Project End
1998-02-28
Budget Start
1995-04-01
Budget End
1996-02-29
Support Year
10
Fiscal Year
1995
Total Cost
Indirect Cost

  Institution

Name
American Dental Association Foundation
Department
Type
DUNS #
789085941
City
Chicago
State
IL
Country
United States
Zip Code
60611

  Publications

Tomazic, B B (2001) Physiochemical principles of cardiovascular calcification. Z Kardiol 90 Suppl 3:68-80
Cohen, H; Solomon, V; Alferiev, I S et al. (1998) Bisphosphonates and tetracycline: experimental models for their evaluation in calcium-related disorders. Pharm Res 15:606-13
Tomazic, B B; Chow, L C; Carey, C M et al. (1997) An in vitro diffusion model for the study of calcification of bovine pericardium tissue. J Pharm Sci 86:1432-8
Skrtic, D; Eidelman, N; Golomb, G et al. (1996) In vitro inhibition of membrane-mediated calcification by novel phosphonates. Calcif Tissue Int 58:347-54
Tomazic, B B; Edwards, W D; Schoen, F J (1995) Physicochemical characterization of natural and bioprosthetic heart valve calcific deposits: implications for prevention. Ann Thorac Surg 60:S322-7
Van Gelder, J M; Breuer, E; Ornoy, A et al. (1995) Anticalcification and antiresorption effects of bisacylphosphonates. Bone 16:511-20
Tomazic, B B; Brown, W E; Schoen, F J (1994) Physicochemical properties of calcific deposits isolated from porcine bioprosthetic heart valves removed from patients following 2-13 years function. J Biomed Mater Res 28:35-47
Tomazic, B B; Brown, W E; Eanes, E D (1993) A critical evaluation of the purification of biominerals by hypochlorite treatment. J Biomed Mater Res 27:217-25
Tomazic, B B; Brown, W E; Queral, L A et al. (1988) Physiochemical characterization of cardiovascular calcified deposits. I. Isolation, purification and instrumental analysis. Atherosclerosis 69:5-19
Eidelman, N; Chow, L C; Brown, W E (1987) Calcium phosphate phase transformations in serum. Calcif Tissue Int 41:18-26

Showing the most recent 10 out of 12 publications