Relation of circulating Matrix Gla-Protein and anticoagulation status in patients with aortic valve calcification.
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.
Koos
Ralf
R
Department of Cardiology, Medical Faculty, RWTH Aachen University, Aachen, Germany. rkoos@ukaachen.de
Krueger
Thilo
T
Westenfeld
Ralf
R
Kühl
Harald Peter
HP
Brandenburg
Vincent
V
Mahnken
Andreas Horst
AH
Stanzel
Sven
S
Vermeer
Cees
C
Cranenburg
Ellen C M
EC
Floege
Jürgen
J
Kelm
Malte
M
Schurgers
Leon J
LJ
D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D000925:Anticoagulants / Q000008:administration & dosage / Q000009:adverse effects*; D001011:Aorta / Q000187:drug effects / Q000378:metabolism; D001021:Aortic Valve / Q000000981:diagnostic imaging / Q000187:drug effects*; D015415:Biomarkers / Q000097:blood; D002114:Calcinosis / Q000097:blood / Q000139:chemically induced* / Q000175:diagnosis; D002135:Calcium-Binding Proteins / Q000097:blood*; D016022:Case-Control Studies; D003430:Cross-Sectional Studies; D004195:Disease Models, Animal; D015536:Down-Regulation; D004452:Echocardiography; D016326:Extracellular Matrix Proteins / Q000097:blood*; D005260:Female; D005919:Glomerular Filtration Rate; D006349:Heart Valve Diseases / Q000097:blood / Q000139:chemically induced* / Q000175:diagnosis; D006801:Humans; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D008875:Middle Aged; D053495:Osteopontin / Q000235:genetics; D011379:Prognosis; D012333:RNA, Messenger / Q000378:metabolism; D018570:Risk Assessment; D012307:Risk Factors; D012720:Severity of Illness Index; D013997:Time Factors; D036542:Tomography, Spiral Computed; D014812:Vitamin K / Q000037:antagonists & inhibitors / Q000097:blood; D014859:Warfarin / Q000008:administration & dosage / Q000009:adverse effects*; D000097568:Matrix Gla Protein
D000925:Anticoagulants; D015415:Biomarkers; D002135:Calcium-Binding Proteins; D016326:Extracellular Matrix Proteins; D053495:Osteopontin; D012333:RNA, Messenger; D014812:Vitamin K; D014859:Warfarin; D000097568:Matrix Gla Protein; C506896:Spp1 protein, mouse