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

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Abstract

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.

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References

  1. Berkner KL, Runge KW (2004) The physiology of vitamin K nutriture and vitamin K–dependent protein function in atherosclerosis. J Thromb Haemost 2:2118–2132

    Article  PubMed  CAS  Google Scholar 

  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 386:78–81

    Article  PubMed  CAS  Google Scholar 

  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 289:485–490

    Article  PubMed  CAS  Google Scholar 

  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 25:1629–1633

  5. Howe AM, Webster WS (2000) Warfarin exposure and calcification of the arterial system in the rat. Int J Exp Pathol 81:51–56

    Article  PubMed  CAS  Google Scholar 

  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 18:1400–1407

    PubMed  CAS  Google Scholar 

  7. Holden RM, Sanfilippo AS, Hopman WM, Zimmerman D, Garland JS, Morton AR (2007) Warfarin and aortic valve calcification in hemodialysis patients. J Nephrol 20:417–422

    PubMed  CAS  Google Scholar 

  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 96:747–749

    Article  PubMed  CAS  Google Scholar 

  9. Schurgers LJ, Aebert H, Vermeer C, Bultmann B, Janzen J (2004) Oral anticoagulant treatment: friend or foe in cardiovascular disease? Blood 104:3231–3232

    Article  PubMed  CAS  Google Scholar 

  10. Holden RM, Booth SL (2007) Vascular calcification in chronic kidney disease: the role of vitamin K. Nat Clin Pract Nephrol 3:522–523

    Article  PubMed  Google Scholar 

  11. Vermeer C, Hamulyak K (2004) Vitamin K: lessons from the past. J Thromb Haemost 2:2115–2117

    Article  PubMed  CAS  Google Scholar 

  12. Cockcroft DW, Gault MH (1976) Prediction of creatinine clearance from serum creatinine. Nephron 16:31–41

    Article  PubMed  CAS  Google Scholar 

  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 66:89–97

    PubMed  CAS  Google Scholar 

  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 15:827–832

    Article  PubMed  CAS  Google Scholar 

  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 31:126–133

    Article  PubMed  CAS  Google Scholar 

  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 141:463–468

    Article  PubMed  CAS  Google Scholar 

  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 97:1837–1847

    PubMed  CAS  Google Scholar 

  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 113:30–37

    Article  PubMed  Google Scholar 

  19. Dam H (1935) The antihaemorrhagic vitamin of the chick. Biochem J 29:1273–1285

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  21. Berkner KL (2005) The vitamin K–dependent carboxylase. Annu Rev Nutr 25:127–149

    Article  PubMed  CAS  Google Scholar 

  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 5:2503–2511

    Article  PubMed  CAS  Google Scholar 

  23. Meier M, Weng LP, Alexandrakis E, Ruschoff J, Goeckenjan G (2001) Tracheobronchial stenosis in Keutel syndrome. Eur Respir J 17:566–569

    Article  PubMed  CAS  Google Scholar 

  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 21:142–144

    Article  PubMed  CAS  Google Scholar 

  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 20:2386–2393

    PubMed  CAS  Google Scholar 

  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 26:2769–2774

    Article  PubMed  CAS  Google Scholar 

  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 105:645–649

    Article  PubMed  CAS  Google Scholar 

  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 113:1615–1621

    Article  PubMed  Google Scholar 

  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 41:39–44

    Article  PubMed  Google Scholar 

  30. Zebboudj AF, Shin V, Bostrom K (2003) Matrix GLA protein and BMP-2 regulate osteoinduction in calcifying vascular cells. J Cell Biochem 90:756–765

    Article  PubMed  CAS  Google Scholar 

  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 74:279–289

    Article  PubMed  CAS  Google Scholar 

  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 18:379–388

    PubMed  CAS  Google Scholar 

  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 106:3044–3050

    Article  PubMed  CAS  Google Scholar 

  34. Schinke T, McKee MD, Kiviranta R, Karsenty G (1998) Molecular determinants of arterial calcification. Ann Med 30:538–541

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Cardiology Service, Department of Medicine, Walter Reed Army Medical Center, Building 2, Room 4A, 6900 Georgia Avenue, NW, Washington, DC, 20307, USA

    Todd C. Villines, Susan Thomas & Allen J. Taylor

  2. Department of Radiology, Walter Reed Army Medical Center, Washington, DC, USA

    Irwin M. Feuerstein

  3. Department of Medicine, Uniformed Services University of the Health Science, Bethesda, MD, USA

    Todd C. Villines, Patrick G. O’Malley, Irwin M. Feuerstein & Allen J. Taylor

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  1. Todd C. Villines
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  2. Patrick G. O’Malley
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  4. Susan Thomas
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  5. Allen J. Taylor
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Correspondence to Todd C. Villines.

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The opinions or assertions herein are the private views of the authors and are not to be construed as reflecting the views of the Department of the Army or the Department of Defense.

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Villines, T.C., O’Malley, P.G., Feuerstein, I.M. et al. Does Prolonged Warfarin Exposure Potentiate Coronary Calcification in Humans? Results of the Warfarin and Coronary Calcification Study. Calcif Tissue Int 85, 494–500 (2009). https://doi.org/10.1007/s00223-009-9300-4

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  • DOI: https://doi.org/10.1007/s00223-009-9300-4

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