Coumadin Increases Arterial Calcification 2010-01

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doi:10.1182/blood-2010-01-264598Prepublished online March 30, 2010;

Tim Leiner, Cees Vermeer, Peter W. de Leeuw and Abraham A. KroonRoger J.M.W. Rennenberg, Bernard J. van Varik, Leon J. Schurgers, Karly Hamulyak, Hugo ten Cate,arterial calcification in humansChronic coumarin treatment is associated with increased extra-coronary

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Chronic coumarin treatment is associated with increased

extra-coronary arterial calcification in humans

Short title: coumarins and arterial calcification

Roger J.M.W. Rennenberg1, Bernard J. van Varik

1, Leon J. Schurgers

2,3, Karly Hamulyak

1,

Hugo ten Cate1, Tim Leiner

4, Cees Vermeer

3, Peter W. de Leeuw

1, Abraham A. Kroon

1

1Department of Internal Medicine and Cardiovascular Research Institute Maastricht

(CARIM), Maastricht University Medical Centre (MUMC+), The Netherlands

2Department of Biochemistry and CARIM, MUMC+, Maastricht, The Netherlands

3VitaK BV, Maastricht, The Netherlands

4Department of Radiology and CARIM, MUMC+, The Netherlands

Corresponding author:

Roger J.M.W. Rennenberg

Department of Internal Medicine, Maastricht University Medical Centre

P. Debyelaan 25

PO Box 5800

6202 AZ Maastricht

Tel: +31 43 3877005, Fax: +31 43 3875006

E-mail: [email protected]

Blood First Edition Paper, prepublished online March 30, 2010; DOI 10.1182/blood-2010-01-264598

Copyright 2010 American Society of Hematology

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Abstract

Vascular calcification is a marker of increased cardiovascular risk. Vitamin K dependent

Matrix Gla protein (MGP) is important in inhibiting calcification. Since MGP activation is

vitamin K dependent, we performed a cross sectional study investigating the relationship

between the use of vitamin K antagonists and extra-coronary vascular calcification. From the

Dutch thrombosis services we selected 19 patients, aged < 55 years and without other

cardiovascular risk factors, who had used coumarins for more than 10 years, and compared

these to 18 matched healthy controls. MGP was measured and a plain X-ray of the thighs was

taken to assess femoral arterial calcifications. The odds ratio for calcification in patients

versus controls was 8.5 (95% CI 2.01-35.95). Coumarin use and MGP were associated with

calcification, even after adjusting for other risk factors. We conclude that long term use of

coumarins is associated with enhanced extra-coronary vascular calcification possibly through

the inhibition of MGP carboxylation.

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Introduction

Vascular calcification is a marker of increased cardiovascular morbidity and mortality.1

Matrix Gla Protein (MGP) is an important inhibitor of calcification.2-5

In animal studies, in

which carboxylation of MGP was blocked by vitamin K antagonists, excessive calcifications

of the arteries were found.6

In humans calcification of the coronary arteries (CaC) and heart

valves is increased in patients on vitamin K antagonists, whereas intake of vitamin K is

associated with less progression of CaC.7-10

Interestingly, the association between coumarin

use and CaC is absent in an older population, and there are no reports on extra-coronary

arterial calcification in coumarin users.11 Therefore, we performed a cross sectional study in

middle aged long term coumarin users and a matched control group to test the hypothesis that

chronic coumarin therapy is associated with femoral artery calcification as a proxy for

coronary calcification along with decreased carboxylation of MGP.



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Methods

We searched the database of the southern Dutch thrombosis services. For the present study we

selected patients younger than 55 years, who used coumarins for more than 10 years because

of a cardiac valve operation or recurrent venous thrombosis, and without previous

cardiovascular events. Spouses or close friends living in the same (social) environment were

invited as control subjects. The study was approved by the Maastricht University Medical

Centre ethics committee and all subjects gave informed consent in accordance with the

Declaration of Helsinki.

Clinical assessments included data on smoking behaviour, body mass index (kg/m2), and

blood pressure (average of three office measurements [Accutor Plus, Datascope corporation

Fairfield, NY, USA]). Fasting glucose levels, lipid profile, calcium, phosphate, and creatinine

were measured in serum with an automated analyzer (Beckmann Synchron CX 7-2, Fullerton

CA, USA). Endogenous creatinine clearance (ECC) was estimated using the Cockcroft and

Gault formula.12

Desphospho-uncarboxylated MGP (dp-ucMGP) was measured in plasma

using a sandwich ELISA (VitaK BV, Maastricht, The Netherlands) as has been described

previously.13

Femoral artery calcification was assessed by soft tissue 50 kV X-ray of the left

and right thigh (Siemens Aristos FX DR-Radiology-system, Siemens Erlangen Germany) in

supine position and slight endorotation of the foot. The images were digitally processed to

enhance soft tissue structures (Diamond View; Siemens, Erlangen, Germany) and evaluated

by an independent radiologist (TL), unaware of the clinical data. A subject was scored

positive for calcification when calcium deposits were visible along one or both femoral artery

regions.

Normally distributed variables are presented as mean with standard deviation, otherwise they

are presented as medians with minimum and maximum value. Differences between groups



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were assessed using Students t-test or Mann-Whitney-U test for continuous variables and

Chi-square test for ordinal and dichotomous variables. Calcification was correlated with age,

sex, smoking, coumarin use, BMI, systolic and diastolic blood pressure, fasting glucose, lipid

profile, serum creatinine, ECC, calcium, phosphate, calcium-phosphate product and dp-

ucMGP using Spearmans test for non-normally distributed variables, or Pearsons test for

normally distributed data. Multiple logistic regression analyses were done with several

models to evaluate the independent contribution of coumarins and dp-ucMGP to calcification.

Coumarin use and dp-ucMGP were analysed separately because of collinearity. The excess

risk for calcification has been expressed as odds ratio. We used SPSS 16.0.1 (SPSS inc.

Chicago, Illinois) for statistical calculations; a p-value


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Results and discussion

Of 21 identified patients, 2 refused to participate. Eighteen control subjects volunteered. The

characteristics of patients and controls are presented in Table 1. Median coumarin treatment

duration was 13 years (range 10-29 years). Target INR in all patients (3 with aortic valve

replacement) was 2,5 (range 2,0-3,0) Univariate analysis showed a correlation between

femoral artery calcification and coumarin use (r = 0.515, p < 0.001) and plasma dp-ucMGP

levels (r = 0.585, p < 0.001). Coumarin use and plasma dp-ucMGP levels showed a strong

correlation (r = 0.850, p < 0.001). Calcification was visible in 14 of 19 coumarin users

compared to 4 out of 18 controls (X2=9.8, p=0.002). The average dp-ucMGP level was 1439

( 481) pmol/l versus 299 ( 163) pmol/l in coumarin users and controls, respectively (p

Coumadin Increases Arterial Calcification 2010-01

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