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      Vitamin K-Antagonists Accelerate Atherosclerotic Calcification and Induce a Vulnerable Plaque Phenotype

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          Abstract

          Background

          Vitamin K-antagonists (VKA) are treatment of choice and standard care for patients with venous thrombosis and thromboembolic risk. In experimental animal models as well as humans, VKA have been shown to promote medial elastocalcinosis. As vascular calcification is considered an independent risk factor for plaque instability, we here investigated the effect of VKA on coronary calcification in patients and on calcification of atherosclerotic plaques in the ApoE −/− model of atherosclerosis.

          Methodology/Principal Findings

          A total of 266 patients (133 VKA users and 133 gender and Framingham Risk Score matched non-VKA users) underwent 64-slice MDCT to assess the degree of coronary artery disease (CAD). VKA-users developed significantly more calcified coronary plaques as compared to non-VKA users. ApoE −/− mice (10 weeks) received a Western type diet (WTD) for 12 weeks, after which mice were fed a WTD supplemented with vitamin K 1 (VK 1, 1.5 mg/g) or vitamin K 1 and warfarin (VK 1&W; 1.5 mg/g & 3.0 mg/g) for 1 or 4 weeks, after which mice were sacrificed. Warfarin significantly increased frequency and extent of vascular calcification. Also, plaque calcification comprised microcalcification of the intimal layer. Furthermore, warfarin treatment decreased plaque expression of calcification regulatory protein carboxylated matrix Gla-protein, increased apoptosis and, surprisingly outward plaque remodeling, without affecting overall plaque burden.

          Conclusions/Significance

          VKA use is associated with coronary artery plaque calcification in patients with suspected CAD and causes changes in plaque morphology with features of plaque vulnerability in ApoE −/− mice. Our findings underscore the need for alternative anticoagulants that do not interfere with the vitamin K cycle.

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          Most cited references39

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          Coronary calcium as a predictor of coronary events in four racial or ethnic groups.

          In white populations, computed tomographic measurements of coronary-artery calcium predict coronary heart disease independently of traditional coronary risk factors. However, it is not known whether coronary-artery calcium predicts coronary heart disease in other racial or ethnic groups. We collected data on risk factors and performed scanning for coronary calcium in a population-based sample of 6722 men and women, of whom 38.6% were white, 27.6% were black, 21.9% were Hispanic, and 11.9% were Chinese. The study subjects had no clinical cardiovascular disease at entry and were followed for a median of 3.8 years. There were 162 coronary events, of which 89 were major events (myocardial infarction or death from coronary heart disease). In comparison with participants with no coronary calcium, the adjusted risk of a coronary event was increased by a factor of 7.73 among participants with coronary calcium scores between 101 and 300 and by a factor of 9.67 among participants with scores above 300 (P<0.001 for both comparisons). Among the four racial and ethnic groups, a doubling of the calcium score increased the risk of a major coronary event by 15 to 35% and the risk of any coronary event by 18 to 39%. The areas under the receiver-operating-characteristic curves for the prediction of both major coronary events and any coronary event were higher when the calcium score was added to the standard risk factors. The coronary calcium score is a strong predictor of incident coronary heart disease and provides predictive information beyond that provided by standard risk factors in four major racial and ethnic groups in the United States. No major differences among racial and ethnic groups in the predictive value of calcium scores were detected. Copyright 2008 Massachusetts Medical Society.
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            Apoptosis regulates human vascular calcification in vitro: evidence for initiation of vascular calcification by apoptotic bodies.

            The mechanisms involved in the initiation of vascular calcification are not known, but matrix vesicles, the nucleation sites for calcium crystal formation in bone, are likely candidates, because similar structures have been found in calcified arteries. The regulation of matrix vesicle production is poorly understood but is thought to be associated with apoptotic cell death. In the present study, we investigated the role of apoptosis in vascular calcification. We report that apoptosis occurs in a human vascular calcification model in which postconfluent vascular smooth muscle cell (VSMC) cultures form nodules spontaneously and calcify after approximately 28 days. Apoptosis occurred before the onset of calcification in VSMC nodules and was detected by several methods, including nuclear morphology, the TUNEL technique, and external display of phosphatidyl serine. Inhibition of apoptosis with the caspase inhibitor ZVAD.fmk reduced calcification in nodules by approximately 40%, as measured by the cresolphthalein method and alizarin red staining. In addition, when apoptosis was stimulated in nodular cultures with anti-Fas IgM, there was a 10-fold increase in calcification. Furthermore, incubation of VSMC-derived apoptotic bodies with (45)Ca demonstrated that, like matrix vesicles, they can concentrate calcium. These observations provide evidence that apoptosis precedes VSMC calcification and that apoptotic bodies derived from VSMCs may act as nucleating structures for calcium crystal formation.
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              Multislice computed tomographic characteristics of coronary lesions in acute coronary syndromes.

              To evaluate the feasibility of noninvasive assessment of the characteristics of disrupted atherosclerotic plaques, the authors interrogated the culprit lesions in acute coronary syndromes (ACS) by multislice computed tomography (CT). Disrupted atherosclerotic plaques responsible for ACS histopathologically demonstrate large lipid cores and positive vascular remodeling. It is expected that plaques vulnerable to rupture should bear similar imaging signatures by CT. Either 0.5-mm x 16-slice or 64-slice CT was performed in 38 patients with ACS and compared with 33 patients with stable angina pectoris (SAP) before percutaneous coronary intervention. The coronary plaques in ACS and SAP were evaluated for the CT plaque characteristics, including vessel remodeling, consistency of noncalcified plaque (NCP <30 HU or 30 HU
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2012
                29 August 2012
                : 7
                : 8
                : e43229
                Affiliations
                [1 ]Department of Biochemistry, Cardiovascular Research Institute Maastricht, Maastricht University Medical Centre, Maastricht, The Netherlands
                [2 ]Department of Cardiology, Cardiovascular Research Institute Maastricht, Maastricht University Medical Centre, Maastricht, The Netherlands
                [3 ]VitaK, Maastricht University, Maastricht, The Netherlands
                [4 ]Department of Cardiology, Cardiovascular Research Institute Maastricht, Maastricht University Medical Centre, Maastricht, The Netherlands
                [5 ]Division of Cardiology, University Hospital Düsseldorf, Düsseldorf, Germany
                [6 ]Division of Nephrology and Clinical Immunology, RWTH Aachen University, Aachen, Germany
                [7 ]Cardiovascular Division, King's College London, London, United Kingdom
                [8 ]Department of Biomedical Engineering, RWTH Aachen University, Aachen, Germany
                [9 ]Department of Pathology, Maastricht University Medical Centre, Maastricht, The Netherlands
                [10 ]Department of Cardiology, Mount Sinai School of Medicine, New York, New York, United States of America
                [11 ]Cardiology Center Netherlands, Utrecht, The Netherlands
                Brigham and Women's Hospital, Harvard Medical School, United States of America
                Author notes

                Competing Interests: The authors have the following competing interest: Dr. Schurgers is CEO of Vascular Products BV, and Dr. Vermeer is CEO of VitaK BV. All other authors have declare that no competing interests exist. There are no patents, products in development or marketed products to declare. This does not alter the authors' adherence to all the PLOS ONE policies on sharing data and materials, as detailed online in the guide for authors.

                Analyzed the data: IJ EL MC MH MW VV. Designed the study: LJS JN LH CPR. Performed measurements and calculations: IJ EL MC MH MW RW VV TK CS WJ-D EB. Wrote the final manuscript: LS IJ CR. Drafted the manuscript: LS CS CV CR.

                Article
                PONE-D-12-09698
                10.1371/journal.pone.0043229
                3430691
                22952653
                7bf44347-4a8b-432b-a36d-84ed7ab54abc
                Copyright @ 2012

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 5 April 2012
                : 18 July 2012
                Page count
                Pages: 14
                Funding
                European research grant as principal investigator from the European Interreg program IVA-VLANED-2.1 was granted to Dr. C. Reutelingsperger. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Biology
                Biochemistry
                Metabolism
                Bone and Mineral Metabolism
                Proteins
                Coagulation Factors
                Extracellular Matrix Proteins
                Regulatory Proteins
                Tissue Proteins
                Immunochemistry
                Histology
                Model Organisms
                Animal Models
                Mouse
                Medicine
                Cardiovascular
                Atherosclerosis
                Coronary Artery Disease
                Vascular Biology

                Uncategorized
                Uncategorized

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