The overall objective is to develop sufficient information on the kinetic, thermodynamic, and structural properties of cardiovascular calcific deposits to make possible prevention and cure of this aspect of the pathology. There is strong evidence that the calcification occurs by way of acidic calcium phosphate (containing HPO4) precursors, the formation rates of which can be reduced by physiologically acceptable inhibitors.
Specific aims : I. Calcification modifiers, including Zn2+, Mg2+, Sr2+, and P2O74- ions, will be evaluated for their comparative abilities to alter rates of calcification. II. The applicability of the calcification mechanism will be tested by following the progression of bovine pericardium implant calcification in rats using a 32P-pyrolysis technique and Ca/P ratio measurements of the deposits. III. Deposits from different sites of the cardiovascular system will be analyzed to determine whether there are similarities that would indicate indirectly a common mechanism that controls their formation. IV. A comparison will be made of the products obtained by the direct versus the precursor calcification mechanism; one aspect of this is to determine conditions that lead to the formation of stoichiometric hydroxyapatite. V. The compositions and structures of the precursors of bioapatites found in cardiovascular deposits will be determined with the use of chemical analysis, IR, X-ray powder diffraction, and single-crystal analysis. VI. An alternative mechanism for the incorporation of carbonate found in cardiovascular deposits will be investigated. A hypothesis to be tested is that one of the precursors can incorporate carbonate into its structure to form a salt that will hydrolyze to carbonate apatite under physiological conditions. Elemental analyses, XRD, Raman and IR will be used to characterize the compounds. VII. A determination of the solubility of whitlockite, which is Ca18Mg2H2(PO4)14, occasionally found in other biological tissues, will help determine whether it could be a component of calcified cardiovascular deposits, which contain Mg ions. VIII. Mechanisms that cause intrinsic (subsurface) calcification of tissue-derived implants will be investigated. The results will characterize the permselective membrane properties of implant tissues and determine the diffusion features of physiological ions into the tissues. Contemporary experimental designs and statistical methods for analyzing data will be used.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Oral Biology and Medicine Subcommittee 1 (OBM)
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American Dental Association Foundation
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Tomazic, B B (2001) Physiochemical principles of cardiovascular calcification. Z Kardiol 90 Suppl 3:68-80
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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

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