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      Menaquinone-7 Supplementation to Reduce Vascular Calcification in Patients with Coronary Artery Disease: Rationale and Study Protocol (VitaK-CAC Trial)

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          Abstract

          Coronary artery calcification (CAC) develops early in the pathogenesis of atherosclerosis and is a strong and independent predictor of cardiovascular disease (CVD). Arterial calcification is caused by an imbalance in calcification regulatory mechanisms. An important inhibitor of calcification is vitamin K-dependent matrix Gla protein (MGP). Both preclinical and clinical studies have shown that inhibition of the vitamin K-cycle by vitamin K antagonists (VKA) results in elevated uncarboxylated MGP (ucMGP) and subsequently in extensive arterial calcification. This led us to hypothesize that vitamin K supplementation may slow down the progression of calcification. To test this, we designed the VitaK-CAC trial which analyses effects of menaquinone-7 (MK-7) supplementation on progression of CAC. The trial is a double-blind, randomized, placebo-controlled trial including patients with coronary artery disease (CAD). Patients with a baseline Agatston CAC-score between 50 and 400 will be randomized to an intervention-group (360 microgram MK-7) or a placebo group. Treatment duration will be 24 months. The primary endpoint is the difference in CAC-score progression between both groups. Secondary endpoints include changes in arterial structure and function, and associations with biomarkers. We hypothesize that treatment with MK-7 will slow down or arrest the progression of CAC and that this trial may lead to a treatment option for vascular calcification and subsequent CVD.

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          Most cited references25

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          Long-term prognosis associated with coronary calcification: observations from a registry of 25,253 patients.

          The purpose of this study was to develop risk-adjusted multivariable models that include risk factors and coronary artery calcium (CAC) scores measured with electron-beam tomography in asymptomatic patients for the prediction of all-cause mortality. Several smaller studies have documented the efficacy of CAC testing for assessment of cardiovascular risk. Larger studies with longer follow-up will lend strength to the hypothesis that CAC testing will improve outcomes, cost-effectiveness, and safety of primary prevention efforts. We used an observational outcome study of a cohort of 25,253 consecutive, asymptomatic individuals referred by their primary physician for CAC scanning to assess cardiovascular risk. Multivariable Cox proportional hazards models were developed to predict all-cause mortality. Risk-adjusted models incorporated traditional risk factors for coronary disease and CAC scores. The frequency of CAC scores was 44%, 14%, 20%, 13%, 6%, and 4% for scores of 0, 1 to 10, 11 to 100, 101 to 400, 401 to 1,000, and >1,000, respectively. During a mean follow-up of 6.8 +/- 3 years, the death rate was 2% (510 deaths). The CAC was an independent predictor of mortality in a multivariable model controlling for age, gender, ethnicity, and cardiac risk factors (model chi-square = 2,017, p 1,000, respectively (p 1,000 (p < 0.0001). This large observational data series shows that CAC provides independent incremental information in addition to traditional risk factors in the prediction of all-cause mortality.
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            Coronary artery calcification: pathogenesis and prognostic implications.

            Coronary artery calcification (CAC) is a risk factor for adverse outcomes in the general population and in patients with coronary artery disease. The pathogenesis of CAC and bone formation share common pathways, and risk factors have been identified that contribute to the initiation and progression of CAC. Efforts to control CAC with medical therapy have not been successful. Event-free survival is also reduced in patients with coronary calcification after both percutaneous coronary intervention (PCI) and bypass graft surgery. Although drug-eluting stents and devices for plaque modification have modestly improved outcomes in calcified vessels, adverse event rates are still high. Innovative pharmacologic and device-based approaches are needed to improve the poor prognosis of patients with CAC.
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              Vitamin K-dependent carboxylation of matrix Gla-protein: a crucial switch to control ectopic mineralization.

              Vascular mineralization has recently emerged as a risk factor for cardiovascular morbidity and mortality. Previously regarded as a passive end-stage process, vascular mineralization is currently recognized as an actively regulated process with cellular and humoral contributions. The discovery that the vitamin K-dependent matrix Gla-protein (MGP) is a strong inhibitor of vascular calcification has propelled our mechanistic understanding of this process and opened novel avenues for diagnosis and treatment. This review focuses on molecular mechanisms of vascular mineralization involving MGP and discusses the potential for treatments and biomarkers to monitor patients at risk for vascular mineralization. Copyright © 2013 Elsevier Ltd. All rights reserved.
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                Author and article information

                Journal
                Nutrients
                Nutrients
                nutrients
                Nutrients
                MDPI
                2072-6643
                28 October 2015
                November 2015
                : 7
                : 11
                : 8905-8915
                Affiliations
                [1 ]Department of Internal Medicine, Maastricht University Medical Centre (MUMC+), Maastricht 6229HX, The Netherlands; b.vanvarik@ 123456maastrichtuniversity.nl (B.J.V.); r.rennenberg@ 123456mumc.nl (R.J.M.W.R.); p.deleeuw@ 123456maastrichtuniversity.nl (P.W.L.); aa.kroon@ 123456mumc.nl (A.A.K.)
                [2 ]Department of Internal Medicine, Zuyderland Medical Centre, Sittard 6162BG, The Netherlands
                [3 ]Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), University of Maastricht, Maastricht 6229ER, The Netherlands; l.schurgers@ 123456maastrichtuniversity.nl (L.J.S.); k.reesink@ 123456maastrichtuniversity.nl (K.D.R.)
                [4 ]Departments of Cardiology and Radiology, Maastricht University Medical Centre (MUMC+), Maastricht 6229HX, The Netherlands; b.kietselaer@ 123456mumc.nl
                [5 ]R&D Group VitaK, Maastricht University, Maastricht 6229EV, The Netherlands; c.vermeer@ 123456vitak.com
                [6 ]Department of Cardiology, VieCuri Medical Centre, Venlo 5912 BL, The Netherlands; jmeeder@ 123456viecuri.nl (J.G.M.); brahel@ 123456viecuri.nl (B.M.R.); yvonne.cauteren@ 123456mumc.nl (Y.J.M.C.)
                [7 ]Department of Radiology, VieCuri Medical Centre, Venlo 5912BL, The Netherlands; ghoffland@ 123456viecuri.nl
                Author notes
                [* ]Correspondence: liv.vossen@ 123456mumc.nl ; Tel.: +31-43-3877366; Fax: +31-43-3875642
                Article
                nutrients-07-05443
                10.3390/nu7115443
                4663571
                26516910
                20a3308c-80c9-4e05-9902-1a16ada4c55f
                © 2015 by the authors; licensee MDPI, Basel, Switzerland.

                This article is an open access article distributed under the terms and conditions of the Creative Commons by Attribution (CC-BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 05 August 2015
                : 10 October 2015
                Categories
                Article

                Nutrition & Dietetics
                vascular calcification,coronary artery calcification,matrix gla protein,vitamin k2,menaquinone-7

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