Relation of circulating matrix Gla-protein and anticoagulation status in patients with aortic valve calcification

Summary

Matrix-Gla Protein (MGP) is a vitamin K-dependent protein acting as a local inhibitor of vascular calcification. Vitamin K-antagonists (oral anticoagulant; OAC) inhibit the activation of MGP by blocking vitamin K-metabolism. The aim of this study was to investigate the effect of long-term OAC treatment on circulating MGP levels in humans and on MGP expression in mice. Additionally, we tested the association between circulating inactive MGP (ucMGP) levels and the presence and severity of AVC in patients with aortic valve disease (AVD). We analysed circulating ucMGP levels in 191 consecutive patients with echocardiographically proven calcific AVD and 35 control subjects. The extent of AVC in the patients was assessed by multislice spiral computed tomography. Circulating ucMGP levels were significantly lower in patients with AVD (348.6 ± 123.1 nM) compared to the control group (571.6 ± 153.9 nM, p < 0.001). Testing the effect of coumarin in mice revealed that also the mRNA expression of MGP in the aorta was downregulated. Multifactorial analysis revealed a significant effect of glomerular filtration rate and long-term OAC therapy on circulating ucMGP levels in the patient group. Subsequently, patients on long-term OAC had significantly increased AVC scores. In conclusion, patients with calcific AVD had significantly lower levels of circulating ucMGP as compared to a reference population, free of coronary and valvular calcifications. In addition, our data suggest that OAC treatment may decrease local expression of MGP, resulting in decreased circulating MGP levels and subsequently increased aortic valve calcifications as an adverse side effect.

Keywords

Oral anticoagulation - aortic valve calcification - protein function - imaging - matrix Gla protein

• References

• 1 Vermeer C. Gamma-carboxyglutamate-containing proteins and the vitamin K-dependent carboxylase. Biochem J 1990; 266: 625-636.
• 2 Luo GRDS, Hogue D, Karsenty G. The matrix Gla protein gene is a marker of the chondrogenesis cell lineage during mouse development. J Bone Miner Res 1995; 10: 325-334.
• 3 Wallin R, Cain D, Sane DC. Matrix Gla protein synthesis and gamma-carboxylation in the aortic vessel wall and proliferating vascular smooth muscle cells--a cell system which resembles the system in bone cells. Thromb Haemost 1999; 82: 1764-1767.
• 4 Berkner KL, Runge KW. The physiology of vitamin K nutriture and vitamin K-dependent protein function in atherosclerosis. J Thromb Haemost 2004; 2: 2118-2132.
• 5 Cranenburg EC, Schurgers LJ, Vermeer C. Vitamin K: the coagulation vitamin that became omnipotent. Thromb Haemost 2007; 98: 120-125.
• 6 Luo G, Ducy P, McKee MD. et al. Spontaneous calcification of arteries and cartilage in mice lacking matrix GLA protein. Nature 1997; 385: 78-81.
• 7 Price PA, Faus SA, Williamson MK. Warfarin causes rapid calcification of the elastic lamellae in rat arteries and heart valves. Arterioscler Thromb Vasc Biol 1998; 18: 1400-1407.
• 8 Schurgers LJ, Aebert H, Vermeer C. et al. Oral anticoagulant treatment: friend or foe in cardiovascular disease?. Blood 2004; 104: 3231-3232.
• 9 Koos R, Mahnken AH, Muhlenbruch G. et al. Relation of oral anticoagulation to cardiac valvular and coronary calcium assessed by multislice spiral computed tomography. Am J Cardiol 2005; 96: 747-749.
• 10 Rosenhek R, Binder T, Porenta G. et al. Predictors of outcome in severe, asymptomatic aortic stenosis. N Engl J Med 2000; 343: 611-617.
• 11 Raggi P, Shaw LJ, Berman DS. et al. Prognostic value of coronary artery calcium screening in subjects with and without diabetes. J Am Coll Cardiol 2004; 43: 1663-1669.
• 12 Cranenburg E, Vermeer C, Koos R. et al. The circulating inactive form of matrix gla protein (ucMGP) as a biomarker for cardiovascular disease. J Vasc Res 2008; 45: 427-436.
• 13 Schurgers LJ, Cranenburg ECM, Vermeer C. Matrix-Gla-protein: The calcification inhibitor in need of vitamin K. Thromb Haemost 2008; 100: 593-603.
• 14 Hermans MM, Vermeer C, Kooman JP. et al. Undercarboxylated matrix Gla protein levels are decreased in dialysis patients and related to parameters of calcium-phosphate metabolism and aortic augmentation index. Blood Purif 2007; 25: 395-401.
• 15 Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D. A more accurate method to estimate glomerular filtration rate from serum creatinine: A new prediction equation. Modification of Diet in Renal Disease Study Group. Ann Intern Med 1999; 130: 461-470.
• 16 Otto CM, Lind BK, Kitzman DW. et al. Association of aortic-valve sclerosis with cardiovascular mortality and morbidity in the elderly. N Engl J Med 1999; 341: 142-147.
• 17 Freeman RV, Otto CM. Spectrum of calcific aortic valve disease. Pathogenesis, disease progression and treatment strategies. Circulation 2005; 111: 3316-3326.
• 18 Bonow RO, Carabello BA, Chatterjee K. et al. ACC/AHA 2006 guidelines for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines developed in collaboration with the Society of Cardiovascular Anesthesiologists endorsed by the Society for Cardiovascular Angiography and Interventions and the Society of Thoracic Surgeons. J Am Coll Cardiol 2006; 48: e1-148.
• 19 Mahnken AH, Wildberger JE, Sinha AM. et al. Variation of the coronary calcium score depending on image reconstruction interval and scoring algorithm. Invest Radiol 2002; 37: 496-502.
• 20 Agatston AS, Janowitz WR, Hildner J. et al. Quantification of coronary artery calcium using ultrafast computed tomography. J Am Coll Cardiol 1990; 15: 827-832.
• 21 Koos R, Mahnken AH, Sinha AM. et al. Aortic valve calcification as a marker for aortic stenosis severity: Assessment on 16-MDCT. Am J Roentgenol 2004; 183: 1813-1818.
• 22 Schurgers LJ, Spronk HM, Soute BA. et al. Regression of warfarin-induced medial elastocalcinosis by high intake of vitamin K in rats. Blood 2007; 109: 2823-2831.
• 23 Westenfeld R, Schäfer C, Smeets R. et al. Fetuin-A (AHSG) prevents extraosseous calcification induced by uraemia and phosphate challenge in mice. Nephrol Dial Transplant 2007; 22: 1537-1546.
• 24 Price PA, Faus SA, Williamson MK. Warfarin-induced artery calcification is accelerated by growth and vitamin D. Arterioscler Thromb Vasc Biol 2000; 20: 317-327.
• 25 Osyczka AM, Leboy PS. Bone morphogenetic protein regulation of early osteoblast genes in human marrow stromal cells is mediated by extracellular signal-regulated kinase and phosphatidylinositol 3-kinase signaling. Endocrinology 2005; 146: 3428-3437.
• 26 Schurgers LJ, Teunissen KJ, Knapen MH. et al. Novel conformation-specific antibodies against matrix gamma-carboxyglutamic acid (Gla) protein: undercarboxylated matrix gla protein as marker for vascular calcification. Arterioscler Thromb Vasc Biol 2005; 25: 1629-1633.
• 27 Gage BF, Bisman-Deych E, Radford MJ. et al. Risk of osteoporotic fracture in elderly patients taking warfarin: results from the national registry of atrial fibrillation 2. Arch Intern Med 2006; 166: 241-246.
• 28 Helske S, Lindstedt KA, Laine M. et al. Induction of local angiotensin II-producing systems in stenotic aortic valves. J Am Coll Cardiol 2004; 44: 1859-1866.
• 29 Caulfield MT, Budoff MJ, Takasu J. et al. Angiotensin converting enzyme inhibitor use is associated with a decreased rate of aortic valve calcium accumulation. Circulation 2002 106. III-640. Abstract.
• 30 Rosenhek R, Rader F, Loho N. et al. Statins but not angiotensin-converting enzyme inhibitors delay progression of aortic stenosis. Circulation 2004; 110: 1291-1295.