Skip to main content
SpringerLink
Log in

Coronary arterial calcification as an active process: A new perspective on an old problem

  • Clinical Investigations
  • Published:
Calcified Tissue International Aims and scope Submit manuscript

Abstract

The mechanism and purpose of coronary atherosclerotic calcification remain unknown. However, evidence reviewed here suggests that calcification is not passive precipitation or adsorption, but instead is organized and regulated. Gla containing proteins and other proteins normally associated with bone metabolism appear to play an important role in this process. A variety of studies are currently in progress in our laboratory which we hope will provide a more comprehensive understanding of processes leading to coronary calcification as well as prognostic data useful in clinical cardiologic practice. A clearer understanding of the nature and significance of coronary calcification may well pave the way toward new interventions to protect myocardium and minimize the morbidity and mortality associated with coronary artery disease.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Blankenhorn DH (1961) Coronary arterial calcification, a review. Am J Med Sci 42:1–49

    Google Scholar 

  2. Morgan AD (1956) The pathogenesis of coronary occlusion. Charles C. Thomas, Springfield, IL

    Google Scholar 

  3. Virchow R (1863) Cellular pathology: as based upon physiological and pathological histology. Dover, New York (unabridged reprinting, 1971), pp 404–408

    Google Scholar 

  4. Hamby RI (1974) Coronary artery calcifications: clinical implications and angiographic correlates. Am Heart J 87:565–570

    Google Scholar 

  5. Bartel A (1974) The significance of coronary calcifications detected by fluoroscopy: a report of 360 patients. Circulation 49: 1247–1253

    Google Scholar 

  6. Agatston AS, Janowitz WR, Hildner FJ, Zusmer NR, Viamonte M, Detrano R (1990) Quantification of coronary artery calcium using ultrafast computed tomography. J Am Coll Cardiol 15: 827–832

    Google Scholar 

  7. Yu SY (1974) Calcification processes in atherosclerosis. In: WB Wagner, TB Clarkson (eds) Arterial mesenchyme and atherosclerosis. Plenum Press, New York, pp 403–425

    Google Scholar 

  8. Moon JY (1972) Factors affecting arterial calcification associated with atherosclerosis. Atherosclerosis 16:119–126

    Google Scholar 

  9. Blumenthal HT, Lansing AI, Wheeler PA (1944) Calcification of the media of the human aorta and its relation to intimal arteriosclerosis, aging and disease. Am J Pathol 20:665–687

    Google Scholar 

  10. Stary HC (1990) The sequence of cell and matrix changes in atherosclerotic lesions of coronary arteries in the first forty years of life. Eur Heart J 11(Suppl E):3–19

    Google Scholar 

  11. Schmid K, McSharry WO, Pameijer CH, Binette JP (1980) Chemical and physicochemical studies on the mineral deposits of the human atherosclerotic aorta. Atherosclerosis 37:199–210

    Google Scholar 

  12. Anderson HC (1989) Mechanism of mineral formation in bone. Lab Invest 60:320–330

    Google Scholar 

  13. Anderson HC (1988) Mechanisms of pathologic calcification. Rheum Dis Clin North Am 14:303–319

    Google Scholar 

  14. Anderson HC (1983) Calcific disease. A concept. Arch Pathol Lab Med 107:341–348

    Google Scholar 

  15. Tanimura A, McGregor DH, Anderson HC (1986) Calcification in atherosclerosis. I. Human studies. J Exp Pathol 2:261–272

    Google Scholar 

  16. Tanimura A, McGregor DH, Anderson HC (1986) Calcification in atherosclerosis. II. Animal studies. J Exp Pathol 2:275–297

    Google Scholar 

  17. Tanimura A, McGregor DH, Anderson HC (1983) Matrix vesicles in atherosclerotic calcification. Proc Soc for Exp Biol Med 172:173–177

    Google Scholar 

  18. Hirsch D, Azoury R, Sarig S, Kruth HS (1993) Colocalization of cholesterol and hydroxyapatite in human atherosclerotic lesions. Calcif Tissue Int 52:94–98

    Google Scholar 

  19. Detrano R, Wong N, French WJ, Georgiou D, Young EK, Brezden O, Brundage B (1993) Prevalence of coronary calcific deposits in 1,000 high risk, asymptomatic individuals. Eur Heart J 13:P1065

    Google Scholar 

  20. Detrano R, Salcedo EE, Hobbs RE, Yiannikas J (1986) Cardiac cinefluoroscopy as an inexpensive aid in the diagnosis of coronary artery diease. Am J Cardiol 56:1041–1046

    Google Scholar 

  21. Detrano R, Markovic D, Simpfendorfer C, Franco I, Hollman J, Grigera F, Stewart W, Ratliff W (1985) Digital subtraction fluoroscopy: a new method of detecting coronary calcifications with improved sensitivity for the prediction of coronary disease. Circulation 71:725–732

    Google Scholar 

  22. Tanenbaum SR, Kondos GT, Veselik KE (1989) Detection of calcific deposits in coronary arteries by ultrafast computed tomography and correlation with angiography. Am J Cardiol 63: 870–872

    Google Scholar 

  23. Breen JF, Sheedy PF, Schwartz RS, Stanson AW, Kaufmann RB, Moll PP, Rumberger JA (1992) Coronary artery calcification detected with ultrafast CT as an indication of coronary artery disease. Radiology 185:435–439

    Google Scholar 

  24. Schwartz RS (1993) Fast CT scans. Data presented at The American College of Cardiology 42nd Annual Scientific Session, March 18, 1993

  25. Romeo R, Augustyn JM, Mandel G (1989) Isolation and characterization of human apatite-inducing aortic proteolipid. Exp Mol Pathol 51:149–158

    Google Scholar 

  26. Ennever J, Vogel JJ, Riggan LJ (1980) Calcification by proteolipid from atherosclerotic aorta. Atherosclerosis 35:209–213

    Google Scholar 

  27. Vogel JJ, Boyan-Salyers BD (1976) Acidic lipids associated with the local mechanism of calcification. Clin Orthop 118:230–241

    Google Scholar 

  28. Vermeer C (1990) Gamma-carboxyglutamate-containing proteins and the vitamin K-dependent carboxylase. Biochem J 266: 625–636

    Google Scholar 

  29. Gallop PM, Lian JB, Hauschka PV (1980) Carboxylated calcium-binding proteins and vitamin K. N Engl J Med 302:1460–1466

    Google Scholar 

  30. Price PA (1989) Gla-containing proteins of bone. Connect Tissue Res 21:51–60

    Google Scholar 

  31. van de Loo PG, Boute BA, van Haarlem LJ, Vermeer C (1987) The effect of Gla-containing proteins on the precipitation of insoluble salts. Biochem Biophys Res Commun 142:113–119

    Google Scholar 

  32. Romberg RW, Werness PG, Riggs BL, Mann KG (1986) Inhibition of hydroxyapatite crystal growth by bone-specific and other calcium-binding proteins. Biochemistry 25:1176–1180

    Google Scholar 

  33. Nishimoto SK, Price PA (1979) Proof that gamma carboxy glutamic acid containing bone protein is synthesized in calf bone. Comparative synthesis rate and effect of coumadin on synthesis. J Biol Chem 254:437–441

    Google Scholar 

  34. Price PA, Otsuka AS, Poser JW (1977) Comparison of gamma-carboxyglutamic acid containing proteins from bovine and swordfish bone: primary structure and Ca binding. In: Wasserman RH, Corradine RA, Carafoli E, Kretsinger RH, MacLennan DH, Siegel FL (eds) Calcium binding proteins and calcium function, Elsevier, Amsterdam, pp 333–337

    Google Scholar 

  35. Price PA, Epstein DJ, Lothringer JW, Nishimoto SK, Poser JW, Williamson MK (1979) Structure and function of the vitamin K-dependent protein of bone. In: Suttie JW (ed) Vitamin K metabolism and vitamin K-dependent proteins. University Park Press, Baltimore, pp 219–230

    Google Scholar 

  36. Hauschka PV (1982) Osteocalcin: the vitamin K-dependent calcium-binding protein of bone matrix. In: Akeson WH, Bornstein P, Glimcher MJ (eds) Heritable disorders of connective tissue. Mosby, St. Louis, pp 195–207

    Google Scholar 

  37. Poser JW, Price PA (1979) A method for decarboxylation of gamma-carboxyglutamic acid in proteins: properties of the decarboxylated gamma-carboxyglutamic acid from calf bone. J Biol Chem 254:431–436

    Google Scholar 

  38. Hogg PJ, Stenflo J (1991) Interaction of human protein Z with thrombin: evaluation of the species difference in the interaction between bovine and human protein Z and thrombin. Biochem Biophys Res Commun 178(3):801–807

    Google Scholar 

  39. Hogg PJ, Stenflo J (1991) Interaction of vitamin K-dependent protein z with thrombin. Consequences for the amidolytic activity of thrombin and the interaction of thrombin with phospholipid vesicles. J Biol Chem 266(17):10953–10958

    Google Scholar 

  40. Hauschka PV, Lian JB, Gallop PM (1975) Direct identification of the calcium-binding amino acid gamma carboxyglutamate in mineralized tissue. Proc Nat Acad Sci USA 72:3925–3929

    Google Scholar 

  41. Price PA, Otsuka AS, Poser JW, Kristaponis J, Raman N (1976) Characterization of a gamma-carboxyglutamic acid-containing protein from bone. Proc Nat Acad Sci USA 73:1447–1451

    Google Scholar 

  42. Hauschka PV (1985) Osteocalcin and its functional domains. In: Butler WT (ed) The chemistry and biology of mineralized tissue. Ebsco Media Birmingham, AL, pp 149–158

    Google Scholar 

  43. Hauschka PV, Lian JB, Cole DEC, Gundberg CM (1989) Osteocalcin and matrix gla protein: vitamin K-dependent proteins in bone. Physiol Rev 69:990–1047

    Google Scholar 

  44. Price PA (1985) Vitamin K-dependent formation of bone gla protein (osteocalcin) and its function. Vitam Horm 42:65–108

    Google Scholar 

  45. Price PA, Williamson MK (1985) Primary structure of bovine matrix gla protein, a new vitamin K-dependent bone protein. J Biol Chem 260:14971–14975

    Google Scholar 

  46. Gijsbers BLMG, van Haarlem LJM, Soute BAM, Ebberink RHM, Vermeer C (1990) Characterization of a gla-containing protein from calcified human atherosclerotic plaques. Arteriosclerosis 10:991–995

    Google Scholar 

  47. van Haarlem LJM, Soute BAM, Hemker HC, Vermeer C (1989) Characterization of gla-containing proteins from calcified human atherosclerotic plaques. Thesis, University of Limburg, Maastricht, The Netherlands

    Google Scholar 

  48. van Haarlem LJM, Soute BAM, Hemker HC, Vermeer C (1988) Characterization of gla-containing proteins from calcified human atherosclerotic plaques. In: Suttie JW (ed) Current advances in vitamin K research. Elsevier, New York, pp 287–292

    Google Scholar 

  49. Levy RJ, Lian JB, Gallop P (1979) Atherocalcin, a gamma-carboxyglutamic acid-containing protein from atherosclerotic plaque. Biochem Biophys Res Commun 91:41–49

    Google Scholar 

  50. Levy RJ, Howard SL, Oshry LJ (1986) Carboxyglutamic acid (Gla) containing proteins of human calcified atherosclerotic plaque solubilized by EDTA. Molecular weight distribution and relationship to osteocalcin. Atherosclerosis 59:155–160

    Google Scholar 

  51. Suttie JW (1985) Vitamin K-dependent carboxylase. Ann Rev Biochem 54:459–477

    Google Scholar 

  52. Olson RE (1984) The function and metabolism of vitamin K. Ann Rev Nutr 4:281–337

    Google Scholar 

  53. Hubbard BR, Ulrich MMW, Jacobs M, Vermeer C, Walsh C, Furie B, Furie BC (1989) Vitamin K-dependent carboxylase: affinity purification from bovine liver B4 using a synthetic propeptide containing the gamma-carboxylation recognition site. Proc Nat Acad Sci USA 86:6893–6897

    Google Scholar 

  54. Lindhout MJ, Kop-Klaasen BH, Kop JM, Hemker HC (1978) Purification and properties of the phenprocoumon-induced decarboxyfactor x from bovine plasma: a comparison to normal factor x. Biochim Biophys Acta 533:302–317

    Google Scholar 

  55. Wallin R, Hutson S (1982) Vitamin K-dependent carboxylation. Evidence that at least two microsomal dehydrogenases reduce vitamin K1 to support carboxylation. J Biol Chem 257:1583–1586

    Google Scholar 

  56. Price PA, Kaneda Y (1987) Vitamin K counteracts the effect of warfarin in liver but not in bone. Thromb Res 46:121–131

    Google Scholar 

  57. van Haarlem LJM, Knapen MHJ, Hamulyak K, Vermeer C (1988) Circulating osteocalcin during oral anticoagulant therapy. Thromb Haemost 60:79–82

    Google Scholar 

  58. Price PA, Williamson MK, Lothringer JW (1981) Origin of the vitamin K-dependent bone protein found in plasma and its clearance by kidney and bone. J Biol Chem 256:12760–12766

    Google Scholar 

  59. Price PA, Williamson MK (1981) Effects of warfarin on bone. Studies on the vitamin K-dependent protein of rat bone. J Biol Chem 256:12754–12759

    Google Scholar 

  60. Fraser JD, Price PA (1988) Lung, heart, and kidney express high levels of mRNA for the vitamin K-dependent matrix gla protein. J Biol Chem 263:11033–11036

    Google Scholar 

  61. van Haarlem LJM, Ulrich MMW, Hemker HC, Soute BAM, Vermeer C (1987) Isolation and partial characterization of a vitamin K-dependent carboxylase from bovine aortae. Biochem J 245:251–255

    Google Scholar 

  62. de Boer-van den Berg MAG, van Haarlem LJM, Vermeer C (1986) Vitamin K-dependent carboxylase in human vessel wall (abstract). Thromb Res (suppl) 6:134

    Google Scholar 

  63. van Haarlem LJM, De Baets MH, Knapen MHJ, Hamulyak K, Vermeer C (1989) An ELISA assay for plaque Gla-protein (PGP) and its detection in plasma. Thesis, University of Limburg, Maastricht, The Netherlands

    Google Scholar 

  64. Simons DB, Schwartz RS, Edwards WD, Sheedy PF, Breen JF, Rumberger JA (1992) Noninvasive definition of anatomic coronary artery disease by ultrafast computed tomographic scanning: a quantitative pathologic comparison study. J Am Coll Card 20:1118–1126

    Google Scholar 

  65. McCarthy JH, Palmer FJ (1974) The incidence and significance of coronary artery calcification. Br Heart J 36:499–506

    Google Scholar 

  66. Warburton K, Tampas JP, Soule AB, Taylor HC (1968) Coronary artery calcification: its relationship to coronary artery stenosis and myocardial infarction. Radiology 91:109–115

    Google Scholar 

  67. Frink RJ, Achar RW, Brown AL, Kin Bcaide AW, Brandenburg RO (1970) Significance of calcification of the coronary arteries. Am J Cardiol 26:241–247

    Google Scholar 

  68. Ingram RT, Fitzpatrick LA, Edwards WD, Frye RL, Fisher LW, Schwartz RS (1993) Calcification in human coronary atherosclerosis is specifically associated with osteopontin, a bone matrix protein (abstract). J Am Coll Cardiol 21:363A

  69. Young MF, Kerr JM, Ibaraki K, Heegaard A-M, Robey PG (1992) Structure, expression, and regulation of the major noncollagenous matrix proteins of bone. Clin Orthop Rel Res 281:275–294

    Google Scholar 

  70. Butler WT (1989) The nature and significance of osteopontin. Connect Tissue Res 23:123–136

    Google Scholar 

  71. Schwartz RS (1993) Data presented at the American College of Cardiology Scientific Session, March 18

  72. Severson AR, Ingram RT, Schwartz RS, Fitzpatrick LA (1993) Immunohistochemical staining of porcine vascular smooth muscle cells grown in vitro for bone sialoprotein, osteocalcin, osteopontin, osteonectin and procollagen type I (abstract). Anat Rec (suppl) 1:103

    Google Scholar 

  73. Severson AR, Ingram RT, Schwartz RS, Fitzpatrick LA (1993) Matrix proteins associated with bone calcification are present in human aortic vascular smooth muscle cells (abstract). Circulation 88:I-367

    Google Scholar 

  74. Giachelli C, Bae N, Lombardi D, Majesky M, Schwarts S (1991) Molecular cloning and characterization of 2B7, a rat mRNA which distinguishes smooth muscle cell phenotypes in vitro and is identical to osteopontin (secreted phosphoprotein I, 2aR). Biochem Biophys Res Commun 177:867–873

    Google Scholar 

  75. Gadeau A-P, Campan M, Millet D, Candresse T, Desgranges C (1993) Osteopontin overexpression is associated with arterial smooth muscle cell proliferation in vitro. Arteriosclerosis Thrombosis 13:120–125

    Google Scholar 

  76. Giachelli CM, Bae N, Almeida M, Denhardt DT, Alpers CE, Schwartz SM (1993) Osteopontin is elevated during neointima formation in rat arteries and is a novel component of human artherosclerotic plaques. J Clin Invest 92:1686–1696

    Google Scholar 

  77. Bostrom K, Watson KE, Horn S, Wortham C, Herman IM, Demer LL (1993) Bone morphogenetic protein expression in human atherosclerotic lesions. J Clin Invest 91:1800–1809

    Google Scholar 

  78. Watson KE, Bostrom K, Horn S, Wortham C, Lam T, Demer LL (1993) A subpopulation of intimal cells with osteoblast-like characteristics. Data presented at the American Heart Association Young Investigators Forum, California Institute of Technology, Pasadena, California, May 14

    Google Scholar 

  79. Fuster V, Badimon L, Badimon JJ, Cheseboro JH (1992) The pathogenesis of coronary artery disease and the acute coronary syndromes. N Engl J Med 326:242–250

    Google Scholar 

  80. Falk E (1991) Coronary thrombosis: pathogenesis and clinical manifestations. Am J Cardiol 68:28B-35B

    Google Scholar 

  81. Davies MJ, Thomas AC (1985) Plaque fissuring—the cause of acute myocardial infarction, sudden ischemic death, and crescendo angina. Br Heart J 53:363–373

    Google Scholar 

  82. Cheng GC, Loree HM, Kamm RD, Fishbein MC, Lee RT (1993) Distribution of circumferential stress in ruptured and stable atherosclerotic lesions. A structural analysis with histopathological correlation. Circulation 87:1179–1187

    Google Scholar 

  83. Gertz SD, Roberts WC (1990) Hemodynamic shear force in rupture of coronary arterial atherosclerotic plaques. Am J Cardiol 66:1368–1372

    Google Scholar 

  84. Richardson PD, Davies MJ, Born GVR (1989) Influence of plaque configuration and stress distribution on fissuring of coronary atherosclerotic plaques. Lancet 2:941–944

    Google Scholar 

  85. Muller JE, Tofler GH, Stone PH (1989) Circadian variation and triggers of onset of acute cardiovascular disease. Circulation 79:733–743

    Google Scholar 

  86. Barger AC, Beeuwkes R, Lainey LL, Silverman KJ (1991) Hypothesis: vasa vasorum and neovascularization of human coronary arteries. A possible role in the pathophysiology of atherosclerosis. N Engl J Med 88:8154–8158

    Google Scholar 

  87. Loree HM, Kamm RD, Atkinson CM, Lee RT (1991) Turbulent pressure fluctuations on surface of model vascular stenoses. Am J Physiol 261:H644-H650

    Google Scholar 

  88. Binns RL, Ku DN (1989) Effect of stenosis on wall motion: a possible mechanism of stroke and transient ischemic attack. Arteriosclerosis 9:842–847

    Google Scholar 

  89. Vito RP, Whang MC, Giddens DP, Zarins CK, Glagov S (1990) Stress analysis of the diseased arterial cross-section. In: Goldstein SA (ed) Advances in Bioengineering Proceedings ASME BED, New York, pp 273–276

    Google Scholar 

  90. Lee RT, Grodzinsky AJ, Frank EH, Kamm RD, Schoen FJ (1991) Structure-dependent dynamic mechanical behavior of fibrous caps from human atherosclerotic plaques. Circulation 83: 1764–1770

    Google Scholar 

  91. Little WC, Constantinescu M, Applegate RJ, Kutcher MA, Burrows MT, Kahl FR, Satamore WP (1988) Can coronary angiography predict the site of subsequent myocardial infarction in patients with mild-to-moderate coronary disease? Circulation 78:1157–1166

    Google Scholar 

  92. Ambrose JA, Tannenbaum MA, Alexopoulos D, Hjemdahl-Monsen H, Leavy J, Weiss M, Borrico S, Gorlin R, Fuster V (1988) Angiographic progression of coronary artery disease and the development of myocardial infarction. J Am Coll Cardiol 12:56–62

    Google Scholar 

  93. Loree HM, Kamm RD, Stringfellow RG, Lee RT (1992) Effects of fibrous cap thickness on peak circumferential stress in model atherosclerotic vessels. Circ Res 71:850–858

    Google Scholar 

  94. Sasayama S, Fujita M (1992) Recent insights into coronary collateral circulation. Circulation 85:1197–1204

    Google Scholar 

  95. Kass RW, Kotler MN, Yazdanfar S (1992) Stimulation of coronary collateral growth: current developments in angiogenesis and future clinical applications. Am Heart J 123:486–496

    Google Scholar 

  96. Schaper W, Gorge G, Winkler B, Schaper J (1988) The collateral circulation of the heart. Prog Cardiovas Dis 31:57–77

    Google Scholar 

  97. Torre, SR, Sharma SK, Israel DH, Almeida O, Goldman ME, Ambrose JA, Teichholz LE (1993) Plaque morphology in acute coronary syndromes: new insights from intravascular ultrasound (abstract). J Am Coll Cardiol 21:194A

  98. Lie JT, Hammond PI (1988) Pathology of the senescent heart: anatomic observations of 237 autopsy studies of patients 90 to 105 years old. Mayo Clin Proc 63:552–564

    Google Scholar 

  99. Detrano RC, Wong ND, French WJ, Tang W, Georgiou D, Young E, Brezden OS, Doherty TM, Brundage BH (1994) Prevalence of fluoroscopic coronary calcific deposits in 1,461 high-risk asymptomatic individuals. Am Heart J (in press)

Download references

Author information

Authors and Affiliations

  1. Division of Cardiology, Harbor-UCLA Medical Center, Torrance, California, USA

    T. M. Doherty & R. C. Detrano

  2. Saint John's Cardiovascular Research Center, Torrance, California, USA

    T. M. Doherty & R. C. Detrano

Authors
  1. T. M. Doherty
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. R. C. Detrano
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Doherty, T.M., Detrano, R.C. Coronary arterial calcification as an active process: A new perspective on an old problem. Calcif Tissue Int 54, 224–230 (1994). https://doi.org/10.1007/BF00301683

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF00301683

Key words

Search

Navigation