Calcified Tissue International

, Volume 85, Issue 6, pp 494–500 | Cite as

Does Prolonged Warfarin Exposure Potentiate Coronary Calcification in Humans? Results of the Warfarin and Coronary Calcification Study

  • Todd C. VillinesEmail author
  • Patrick G. O’Malley
  • Irwin M. Feuerstein
  • Susan Thomas
  • Allen J. Taylor


Warfarin has been shown to accelerate vascular calcification in experimental animals, and possibly humans, through inhibition of the vitamin K–dependent protein matrix gla protein, a potent inhibitor of tissue calcification. We performed a cross-sectional analysis of the extent of coronary artery calcification (CAC) in patients without coronary heart disease, currently taking or referred for warfarin therapy. The primary end point was severity of CAC measured by electron beam computed tomography attributed to duration of warfarin use, after adjustment for cardiovascular risk factors. Seventy patients (46 men, mean age 68 ± 13 years) were enrolled from three groups of warfarin use duration: (1) <6 months (n = 31, mean duration 1 ± 1 months), (2) 6–24 months (n = 11), and (3) >24 months (n = 28, mean 67 ± 40 months). Overall, the mean total CAC score (Agatston) was 293 ± 560: group 1 (175 ± 285), group 2 (289 ± 382), and group 3 (426 ± 789). In univariate analysis, there was a nonsignificant trend to increased CAC with increasing warfarin exposure (P = 0.18). Bivariate analysis revealed no correlation between warfarin duration and CAC score (r = 0.075, P = 0.537). Linear regression for the independent variable coronary calcium score controlling for warfarin treatment duration and intensity (duration of warfarin use months × mean INR), Framingham risk score, and creatinine clearance showed that only the Framingham risk score was associated with CAC (P = 0.001). Among patients without known coronary heart disease, duration of warfarin exposure was not associated with extent of coronary calcification.


Warfarin Vascular calcification Coronary calcification Matrix Gla protein Vitamin K dependent protein 


  1. 1.
    Berkner KL, Runge KW (2004) The physiology of vitamin K nutriture and vitamin K–dependent protein function in atherosclerosis. J Thromb Haemost 2:2118–2132CrossRefPubMedGoogle Scholar
  2. 2.
    Luo G, Ducy P, McKee MD, Pinero GJ, Loyer E, Behringer RR, Karsenty G (1997) Spontaneous calcification of arteries and cartilage in mice lacking matrix GLA protein. Nature 386:78–81CrossRefPubMedGoogle Scholar
  3. 3.
    Spronk HM, Soute BA, Schurgers LJ, Cleutjens JP, Thijssen HH, De Mey JG, Vermeer C (2001) Matrix Gla protein accumulates at the border of regions of calcification and normal tissue in the media of the arterial vessel wall. Biochem Biophys Res Commun 289:485–490CrossRefPubMedGoogle Scholar
  4. 4.
    Schurgers LJ, Teunissen KJ, Knapen MH, Kwaijtaal M, van DR, Appels A, Reutelingsperger CP, Cleutjens JP, Vermeer C (2005) Novel conformation-specific antibodies against matrix gamma-carboxyglutamic acid (Gla) protein: undercarboxylated matrix Gla protein as marker for vascular calcification. Arterioscler Thromb Vasc Biol 25:1629–1633Google Scholar
  5. 5.
    Howe AM, Webster WS (2000) Warfarin exposure and calcification of the arterial system in the rat. Int J Exp Pathol 81:51–56CrossRefPubMedGoogle Scholar
  6. 6.
    Price PA, Faus SA, Williamson MK (1998) Warfarin causes rapid calcification of the elastic lamellae in rat arteries and heart valves. Arterioscler Thromb Vasc Biol 18:1400–1407PubMedGoogle Scholar
  7. 7.
    Holden RM, Sanfilippo AS, Hopman WM, Zimmerman D, Garland JS, Morton AR (2007) Warfarin and aortic valve calcification in hemodialysis patients. J Nephrol 20:417–422PubMedGoogle Scholar
  8. 8.
    Koos R, Mahnken AH, Muhlenbruch G, Brandenburg V, Pflueger B, Wildberger JE, Kuhl HP (2005) Relation of oral anticoagulation to cardiac valvular and coronary calcium assessed by multislice spiral computed tomography. Am J Cardiol 96:747–749CrossRefPubMedGoogle Scholar
  9. 9.
    Schurgers LJ, Aebert H, Vermeer C, Bultmann B, Janzen J (2004) Oral anticoagulant treatment: friend or foe in cardiovascular disease? Blood 104:3231–3232CrossRefPubMedGoogle Scholar
  10. 10.
    Holden RM, Booth SL (2007) Vascular calcification in chronic kidney disease: the role of vitamin K. Nat Clin Pract Nephrol 3:522–523CrossRefPubMedGoogle Scholar
  11. 11.
    Vermeer C, Hamulyak K (2004) Vitamin K: lessons from the past. J Thromb Haemost 2:2115–2117CrossRefPubMedGoogle Scholar
  12. 12.
    Cockcroft DW, Gault MH (1976) Prediction of creatinine clearance from serum creatinine. Nephron 16:31–41CrossRefPubMedGoogle Scholar
  13. 13.
    Shoker A, Hossain MA, Koru-Sengul T, Raju DL, Cockcroft D (2006) Performance of creatinine clearance equations on the original Cockcroft-Gault population 29. Clin Nephrol 66:89–97PubMedGoogle Scholar
  14. 14.
    Agatston AS, Janowitz WR, Hildner FJ, Zusmer NR, Viamonte M Jr, Detrano R (1990) Quantification of coronary artery calcium using ultrafast computed tomography. J Am Coll Cardiol 15:827–832PubMedCrossRefGoogle Scholar
  15. 15.
    Sangiorgi G, Rumberger JA, Severson A, Edwards WD, Gregoire J, Fitzpatrick LA, Schwartz RS (1998) Arterial calcification and not lumen stenosis is highly correlated with atherosclerotic plaque burden in humans: a histologic study of 723 coronary artery segments using nondecalcifying methodology. J Am Coll Cardiol 31:126–133CrossRefPubMedGoogle Scholar
  16. 16.
    Taylor AJ, Feuerstein I, Wong H, Barko W, Brazaitis M, O’Malley PG (2001) Do conventional risk factors predict subclinical coronary artery disease? Results from the prospective army coronary calcium project. Am Heart J 141:463–468CrossRefPubMedGoogle Scholar
  17. 17.
    Wilson PW, D’Agostino RB, Levy D, Belanger AM, Silbershatz H, Kannel WB (1998) Prediction of coronary heart disease using risk factor categories. Circulation 97:1837–1847PubMedGoogle Scholar
  18. 18.
    McClelland RL, Chung H, Detrano R, Post W, Kronmal RA (2006) Distribution of coronary artery calcium by race, gender, and age: results from the multi-ethnic study of atherosclerosis (MESA). Circulation 113:30–37CrossRefPubMedGoogle Scholar
  19. 19.
    Dam H (1935) The antihaemorrhagic vitamin of the chick. Biochem J 29:1273–1285PubMedGoogle Scholar
  20. 20.
    Vermeer C (1990) Gamma-carboxyglutamate-containing proteins and the vitamin K-dependent carboxylase. Biochem J 266:625–636PubMedGoogle Scholar
  21. 21.
    Berkner KL (2005) The vitamin K–dependent carboxylase. Annu Rev Nutr 25:127–149CrossRefPubMedGoogle Scholar
  22. 22.
    Schurgers LJ, Spronk HM, Skepper JN, Hackeng TM, Shanahan CM, Vermeer C, Weissberg PL, Proudfoot D (2007) Post-translational modifications regulate matrix Gla protein function: importance for inhibition of vascular smooth muscle cell calcification. J Thromb Haemost 5:2503–2511CrossRefPubMedGoogle Scholar
  23. 23.
    Meier M, Weng LP, Alexandrakis E, Ruschoff J, Goeckenjan G (2001) Tracheobronchial stenosis in Keutel syndrome. Eur Respir J 17:566–569CrossRefPubMedGoogle Scholar
  24. 24.
    Munroe PB, Olgunturk RO, Fryns JP, Van ML, Ziereisen F, Yuksel B, Gardiner RM, Chung E (1999) Mutations in the gene encoding the human matrix Gla protein cause Keutel syndrome. Nat Genet 21:142–144CrossRefPubMedGoogle Scholar
  25. 25.
    Herrmann SM, Whatling C, Brand E, Nicaud V, Gariepy J, Simon A, Evans A, Ruidavets JB, Arveiler D, Luc G, Tiret L, Henney A, Cambien F (2000) Polymorphisms of the human matrix gla protein (MGP) gene, vascular calcification, and myocardial infarction. Arterioscler Thromb Vasc Biol 20:2386–2393PubMedGoogle Scholar
  26. 26.
    O’Donnell CJ, Shea MK, Price PA, Gagnon DR, Wilson PW, Larson MG, Kiel DP, Hoffmann U, Ferencik M, Clouse ME, Williamson MK, Cupples LA, Hughes B, Booth SL (2006) Matrix Gla protein is associated with risk factors for atherosclerosis but not with coronary artery calcification. Arterioscler Thromb Vasc Biol 26:2769–2774CrossRefPubMedGoogle Scholar
  27. 27.
    D’Andrea G, D’Ambrosio RL, Di PP, Chetta M, Santacroce R, Brancaccio V, Grandone E, Margaglione M (2005) A polymorphism in the VKORC1 gene is associated with an interindividual variability in the dose-anticoagulant effect of warfarin. Blood 105:645–649CrossRefPubMedGoogle Scholar
  28. 28.
    Wang Y, Zhang W, Zhang Y, Yang Y, Sun L, Hu S, Chen J, Zhang C, Zheng Y, Zhen Y, Sun K, Fu C, Yang T, Wang J, Sun J, Wu H, Glasgow WC, Hui R (2006) VKORC1 haplotypes are associated with arterial vascular diseases (stroke, coronary heart disease, and aortic dissection). Circulation 113:1615–1621CrossRefPubMedGoogle Scholar
  29. 29.
    Lee TC, O’Malley PG, Feuerstein I, Taylor AJ (2003) The prevalence and severity of coronary artery calcification on coronary artery computed tomography in black and white subjects. J Am Coll Cardiol 41:39–44CrossRefPubMedGoogle Scholar
  30. 30.
    Zebboudj AF, Shin V, Bostrom K (2003) Matrix GLA protein and BMP-2 regulate osteoinduction in calcifying vascular cells. J Cell Biochem 90:756–765CrossRefPubMedGoogle Scholar
  31. 31.
    Yao Y, Zebboudj AF, Torres A, Shao E, Bostrom K (2007) Activin-like kinase receptor 1 (ALK1) in atherosclerotic lesions and vascular mesenchymal cells. Cardiovasc Res 74:279–289CrossRefPubMedGoogle Scholar
  32. 32.
    Proudfoot D, Skepper JN, Shanahan CM, Weissberg PL (1998) Calcification of human vascular cells in vitro is correlated with high levels of matrix Gla protein and low levels of osteopontin expression. Arterioscler Thromb Vasc Biol 18:379–388PubMedGoogle Scholar
  33. 33.
    Proudfoot D, Davies JD, Skepper JN, Weissberg PL, Shanahan CM (2002) Acetylated low-density lipoprotein stimulates human vascular smooth muscle cell calcification by promoting osteoblastic differentiation and inhibiting phagocytosis. Circulation 106:3044–3050CrossRefPubMedGoogle Scholar
  34. 34.
    Schinke T, McKee MD, Kiviranta R, Karsenty G (1998) Molecular determinants of arterial calcification. Ann Med 30:538–541CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  • Todd C. Villines
    • 1
    • 3
    Email author
  • Patrick G. O’Malley
    • 3
  • Irwin M. Feuerstein
    • 2
    • 3
  • Susan Thomas
    • 1
  • Allen J. Taylor
    • 1
    • 3
  1. 1.Cardiology Service, Department of MedicineWalter Reed Army Medical CenterWashingtonUSA
  2. 2.Department of RadiologyWalter Reed Army Medical CenterWashingtonUSA
  3. 3.Department of MedicineUniformed Services University of the Health ScienceBethesdaUSA

Personalised recommendations