Skip to main content
The American Journal of Pathology logoLink to The American Journal of Pathology
. 1986 Apr;123(1):134–145.

Calcification of bovine pericardium used in cardiac valve bioprostheses. Implications for the mechanisms of bioprosthetic tissue mineralization.

F J Schoen, J W Tsao, R J Levy
PMCID: PMC1888152  PMID: 2421577

Abstract

Calcification of bioprosthetic heart valves fabricated from glutaraldehyde-pretreated bovine pericardium has not been investigated. The objectives of this study were to characterize pericardium before and after glutaraldehyde pretreatment and to study the pathophysiology of mineralization of glutaraldehyde-preserved pericardium. Pericardial protein was approximately 90% collagen, predominantly Type I. Glutaraldehyde incorporation was complete following 24 hours' incubation (151 X 10(-9) mol/mg). Bovine pericardium pretreated in buffered 0.6% glutaraldehyde, implanted subcutaneously in young rats for 24 hours to 112 days, was analyzed chemically (calcium and phosphorus) and morphologically. Mineralization, detected at 48 hours' implantation, was initially associated with pericardial connective tissue cells and later also collagen. Mean calcium content was 114 micrograms/mg at 21 days and 199 micrograms/mg at 112 days. The morphologic features and the kinetics and degree of mineral accumulation in glutaraldehyde-pretreated bovine pericardium were strikingly similar to those previously determined for porcine aortic valve. These results predict that calcification will critically limit the late durability of clinical pericardial bioprostheses and suggest generalized mechanisms of bioprosthetic tissue mineralization which are probably dependent on modification of implant microstructure by glutaraldehyde pretreatment.

Full text

PDF
141

Images in this article

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Alam M., Lakier J. B., Pickard S. D., Goldstein S. Echocardiographic evaluation of porcine bioprosthetic valves: experience with 309 normal and 59 dysfunctioning valves. Am J Cardiol. 1983 Aug;52(3):309–315. doi: 10.1016/0002-9149(83)90129-7. [DOI] [PubMed] [Google Scholar]
  2. Allen D. J., DiDio L. J., Zacharias A., Fentie I., McGrath A. J., Puig L. B., Pomerantzeff P. N., Zerbini E. J. Microscopic study of normal parietal pericardium and unimplanted Puig-Zerbini pericardial valvular heterografts. J Thorac Cardiovasc Surg. 1984 Jun;87(6):845–855. [PubMed] [Google Scholar]
  3. Anderson H. C. Calcific diseases. A concept. Arch Pathol Lab Med. 1983 Jul;107(7):341–348. [PubMed] [Google Scholar]
  4. Arbustini E., Jones M., Moses R. D., Eidbo E. E., Carroll R. J., Ferrans V. J. Modification by the Hancock T6 process of calcification of bioprosthetic cardiac valves implanted in sheep. Am J Cardiol. 1984 May 1;53(9):1388–1396. doi: 10.1016/0002-9149(84)90099-7. [DOI] [PubMed] [Google Scholar]
  5. Boskey A. L. Current concepts of the physiology and biochemistry of calcification. Clin Orthop Relat Res. 1981 Jun;(157):225–257. [PubMed] [Google Scholar]
  6. Buch W. S., Kosek J. C., Angell W. W., Shumway S. E. Deterioration of formalin-treated aortic valve heterografts. J Thorac Cardiovasc Surg. 1970 Nov;60(5):673–682. [PubMed] [Google Scholar]
  7. Chandrakasan G., Torchia D. A., Piez K. A. Preparation of intact monomeric collagen from rat tail tendon and skin and the structure of the nonhelical ends in solution. J Biol Chem. 1976 Oct 10;251(19):6062–6067. [PubMed] [Google Scholar]
  8. Cheung D. T., Nimni M. E. Mechanism of crosslinking of proteins by glutaraldehyde I: reaction with model compounds. Connect Tissue Res. 1982;10(2):187–199. doi: 10.3109/03008208209034418. [DOI] [PubMed] [Google Scholar]
  9. Cheung D. T., Nimni M. E. Mechanism of crosslinking of proteins by glutaraldehyde II. Reaction with monomeric and polymeric collagen. Connect Tissue Res. 1982;10(2):201–216. doi: 10.3109/03008208209034419. [DOI] [PubMed] [Google Scholar]
  10. Cheung D. T., Perelman N., Ko E. C., Nimni M. E. Mechanism of crosslinking of proteins by glutaraldehyde III. Reaction with collagen in tissues. Connect Tissue Res. 1985;13(2):109–115. doi: 10.3109/03008208509152389. [DOI] [PubMed] [Google Scholar]
  11. Eyre D. R. Collagen: molecular diversity in the body's protein scaffold. Science. 1980 Mar 21;207(4437):1315–1322. doi: 10.1126/science.7355290. [DOI] [PubMed] [Google Scholar]
  12. Ferrans V. J., Boyce S. W., Billingham M. E., Jones M., Ishihara T., Roberts W. C. Calcific deposits in porcine bioprostheses: structure and pathogenesis. Am J Cardiol. 1980 Nov;46(5):721–734. doi: 10.1016/0002-9149(80)90421-x. [DOI] [PubMed] [Google Scholar]
  13. Fishbein M. C., Levy R. J., Ferrans V. J., Dearden L. C., Nashef A., Goodman A. P., Carpentier A. Calcifications of cardiac valve bioprostheses. Biochemical, histologic, and ultrastructural observations in a subcutaneous implantation model system. J Thorac Cardiovasc Surg. 1982 Apr;83(4):602–609. [PubMed] [Google Scholar]
  14. Gabbay S., Bortolotti U., Factor S., Shore D. F., Frater R. W. Calcification of implanted xenograft pericardium. Influence of site and function. J Thorac Cardiovasc Surg. 1984 May;87(5):782–787. [PubMed] [Google Scholar]
  15. Galioto F. m., Jr, Midgley F. M., Kapur S., Perry L. W., Watson D. C., Shapiro S. R., Ruckman R. N., Scott L. P., 3rd Early failures of Ionescu-Shiley bioprosthesis after mitral valve replacement in children. J Thorac Cardiovasc Surg. 1982 Feb;83(2):306–310. [PubMed] [Google Scholar]
  16. Gallo I., Nistal F., Revuelta J. M., Garcia-Satue E., Artiñano E., Duran C. G. Incidence of primary tissue valve failure with the Ionescu-Shiley pericardial valve. Preliminary results. J Thorac Cardiovasc Surg. 1985 Aug;90(2):278–280. [PubMed] [Google Scholar]
  17. Hagler H. K., Lopez L. E., Murphy M. E., Greico C. A., Buja L. M. Quantitative x-ray microanalysis of mitochondrial calcification in damaged myocardium. Lab Invest. 1981 Sep;45(3):241–247. [PubMed] [Google Scholar]
  18. Hauschka P. V. Quantitative determination of gamma-carboxyglutamic acid in proteins. Anal Biochem. 1977 May 15;80(1):212–223. doi: 10.1016/0003-2697(77)90640-6. [DOI] [PubMed] [Google Scholar]
  19. Ionescu M. I., Smith D. R., Hasan S. S., Chidambaram M., Tandon A. P. Clinical durability of the pericardial xenograft valve: ten years experience with mitral replacement. Ann Thorac Surg. 1982 Sep;34(3):265–277. doi: 10.1016/s0003-4975(10)62496-4. [DOI] [PubMed] [Google Scholar]
  20. Ishihara T., Ferrans V. J., Jones M., Boyce S. W., Kawanami O., Roberts W. C. Histologic and ultrastructural features of normal human parietal pericardium. Am J Cardiol. 1980 Nov;46(5):744–753. doi: 10.1016/0002-9149(80)90424-5. [DOI] [PubMed] [Google Scholar]
  21. Ishihara T., Ferrans V. J., Jones M., Boyce S. W., Roberts W. C. Structure of bovine parietal pericardium and of unimplanted Ionescu-Shiley pericardial valvular bioprostheses. J Thorac Cardiovasc Surg. 1981 May;81(5):747–757. [PubMed] [Google Scholar]
  22. Kim K. M. Calcification of matrix vesicles in human aortic valve and aortic media. Fed Proc. 1976 Feb;35(2):156–162. [PubMed] [Google Scholar]
  23. Laemmli U. K., Favre M. Maturation of the head of bacteriophage T4. I. DNA packaging events. J Mol Biol. 1973 Nov 15;80(4):575–599. doi: 10.1016/0022-2836(73)90198-8. [DOI] [PubMed] [Google Scholar]
  24. Levy R. J., Hawley M. A., Schoen F. J., Lund S. A., Liu P. Y. Inhibition by diphosphonate compounds of calcification of porcine bioprosthetic heart valve cusps implanted subcutaneously in rats. Circulation. 1985 Feb;71(2):349–356. doi: 10.1161/01.cir.71.2.349. [DOI] [PubMed] [Google Scholar]
  25. Levy R. J., Lian J. B., Gallop P. Atherocalcin, a gamma-carboxyglutamic acid containing protein from atherosclerotic plaque. Biochem Biophys Res Commun. 1979 Nov 14;91(1):41–49. doi: 10.1016/0006-291x(79)90580-1. [DOI] [PubMed] [Google Scholar]
  26. Levy R. J., Schoen F. J., Howard S. L. Mechanism of calcification of porcine bioprosthetic aortic valve cusps: role of T-lymphocytes. Am J Cardiol. 1983 Sep 1;52(5):629–631. doi: 10.1016/0002-9149(83)90040-1. [DOI] [PubMed] [Google Scholar]
  27. Levy R. J., Schoen F. J., Levy J. T., Nelson A. C., Howard S. L., Oshry L. J. Biologic determinants of dystrophic calcification and osteocalcin deposition in glutaraldehyde-preserved porcine aortic valve leaflets implanted subcutaneously in rats. Am J Pathol. 1983 Nov;113(2):143–155. [PMC free article] [PubMed] [Google Scholar]
  28. Levy R. J., Schoen F. J., Sherman F. S., Nichols J., Hawley M. A., Lund S. A. Calcification of subcutaneously implanted type I collagen sponges. Effects of formaldehyde and glutaraldehyde pretreatments. Am J Pathol. 1986 Jan;122(1):71–82. [PMC free article] [PubMed] [Google Scholar]
  29. Levy R. J., Wolfrum J., Schoen F. J., Hawley M. A., Lund S. A., Langer R. Inhibition of calcification of bioprosthetic heart valves by local controlled-release diphosphonate. Science. 1985 Apr 12;228(4696):190–192. doi: 10.1126/science.3919445. [DOI] [PubMed] [Google Scholar]
  30. Levy R. J., Zenker J. A., Lian J. B. Vitamin K-dependent calcium binding proteins in aortic valve calcification. J Clin Invest. 1980 Feb;65(2):563–566. doi: 10.1172/JCI109700. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Lian J. B., Skinner M., Glimcher M. J., Gallop P. The presence of gamma-carboxyglutamic acid in the proteins associated with ectopic calcification. Biochem Biophys Res Commun. 1976 Nov 22;73(2):349–355. doi: 10.1016/0006-291x(76)90714-2. [DOI] [PubMed] [Google Scholar]
  32. Mannschott P., Herbage D., Weiss M., Buffevant C. Collagen heterogeneity in pig heart valves. Biochim Biophys Acta. 1976 May 20;434(1):177–183. doi: 10.1016/0005-2795(76)90048-9. [DOI] [PubMed] [Google Scholar]
  33. Milano A., Bortolotti U., Talenti E., Valfrè C., Arbustini E., Valente M., Mazzucco A., Gallucci V., Thiene G. Calcific degeneration as the main cause of porcine bioprosthetic valve failure. Am J Cardiol. 1984 Apr 1;53(8):1066–1070. doi: 10.1016/0002-9149(84)90638-6. [DOI] [PubMed] [Google Scholar]
  34. Miller E. J., Rhodes R. K. Preparation and characterization of the different types of collagen. Methods Enzymol. 1982;82(Pt A):33–64. doi: 10.1016/0076-6879(82)82059-4. [DOI] [PubMed] [Google Scholar]
  35. Nimni M. E. Collagen: structure, function, and metabolism in normal and fibrotic tissues. Semin Arthritis Rheum. 1983 Aug;13(1):1–86. doi: 10.1016/0049-0172(83)90024-0. [DOI] [PubMed] [Google Scholar]
  36. Oyer P. E., Stinson E. B., Miller D. C., Jamieson S. W., Mitchell R. S., Shumway N. E. Thromboembolic risk and durability of the Hancock bioprosthetic cardiac valve. Eur Heart J. 1984 Oct;5 (Suppl 500):81–85. doi: 10.1093/eurheartj/5.suppl_d.81. [DOI] [PubMed] [Google Scholar]
  37. Reul G. J., Jr, Cooley D. A., Duncan J. M., Frazier O. H., Hallman G. L., Livesay J. J., Ott D. A., Walker W. E. Valve failure with the Ionescu-Shiley bovine pericardial bioprosthesis: analysis of 2680 patients. J Vasc Surg. 1985 Jan;2(1):192–204. [PubMed] [Google Scholar]
  38. Rose A. G. Pathology of the formalin-treated heterograft porcine aortic valve in the mitral position. Thorax. 1972 Jul;27(4):401–409. doi: 10.1136/thx.27.4.401. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Sanders S. P., Levy R. J., Freed M. D., Norwood W. I., Castaneda A. R. Use of Hancock porcine xenografts in children and adolescents. Am J Cardiol. 1980 Sep;46(3):429–438. doi: 10.1016/0002-9149(80)90012-0. [DOI] [PubMed] [Google Scholar]
  40. Schoen F. J., Hobson C. E. Anatomic analysis of removed prosthetic heart valves: causes of failure of 33 mechanical valves and 58 bioprostheses, 1980 to 1983. Hum Pathol. 1985 Jun;16(6):549–559. doi: 10.1016/s0046-8177(85)80103-9. [DOI] [PubMed] [Google Scholar]
  41. Schoen F. J., Levy R. J. Bioprosthetic heart valve failure: pathology and pathogenesis. Cardiol Clin. 1984 Nov;2(4):717–739. [PubMed] [Google Scholar]
  42. Schoen F. J., Levy R. J., Nelson A. C., Bernhard W. F., Nashef A., Hawley M. Onset and progression of experimental bioprosthetic heart valve calcification. Lab Invest. 1985 May;52(5):523–532. [PubMed] [Google Scholar]
  43. Silver M., Hudson R. E., Trimble A. S. Morphologic observations on heart valve prostheses made of fascia lata. J Thorac Cardiovasc Surg. 1975 Aug;70(2):360–366. [PubMed] [Google Scholar]
  44. Thubrikar M. J., Nolan S. P., Deck J. D., Aouad J., Levitt L. C. Intrinsic calcification of T6-processed and control porcine and bovine bioprostheses in calves. Trans Am Soc Artif Intern Organs. 1983;29:245–249. [PubMed] [Google Scholar]
  45. Valente M., Bortolotti U., Thiene G. Ultrastructural substrates of dystrophic calcification in porcine bioprosthetic valve failure. Am J Pathol. 1985 Apr;119(1):12–21. [PMC free article] [PubMed] [Google Scholar]
  46. Wuthier R. E. A review of the primary mechanism of endochondral calcification with special emphasis on the role of cells, mitochondria and matrix vesicles. Clin Orthop Relat Res. 1982 Sep;(169):219–242. [PubMed] [Google Scholar]
  47. Yarbrough J. W., Roberts W. C., Reis R. L. Structural alterations in tissue cardiac valves implanted in patients and in calves. J Thorac Cardiovasc Surg. 1973 Mar;65(3):364–375. [PubMed] [Google Scholar]

Articles from The American Journal of Pathology are provided here courtesy of American Society for Investigative Pathology

RESOURCES