Warfarin Causes Rapid Calcification of the Elastic Lamellae in Rat Arteries and Heart Valves

Price, Paul A.; Faus, Samuel A.; Williamson, Matthew K.

doi:10.1161/01.atv.18.9.1400

Cited by 497 publications

(492 citation statements)

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“…MGP‐knockout mice developed soft‐tissue calcification resulting in vascular stiffening and died of vascular rupture 8 weeks after birth 16. Furthermore, both valvular and arterial calcification have been reported in animals on warfarin treatment 17. By contrast, limited data from experimental animal studies have indicated a potentially beneficial effect of novel, direct‐acting anticoagulants on the development and progression of atherosclerosis 18, 19, 20…”

Section: Discussionmentioning

confidence: 99%

Intake of Vitamin K Antagonists and Worsening of Cardiac and Vascular Disease: Results From the Population‐Based Gutenberg Health Study

Eggebrecht

Prochaska

Schulz

et al. 2018

JAHA

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BackgroundPreclinical data have indicated a link between use of vitamin K antagonists (VKA) and detrimental effects on vascular structure and function. The objective of the present study was to determine the relationship between VKA intake and different phenotypes of subclinical cardiovascular disease in the population.Methods and ResultsClinical and laboratory data, as well as medical–technical examinations were assessed from 15 010 individuals aged 35 to 74 years during a highly standardized 5‐hour visit at the study center of the population‐based Gutenberg Health Study. In total, the study sample comprised 287 VKA users and 14 564 VKA nonusers. Multivariable analysis revealed an independent association between VKA intake and stiffness index (β=+2.54 m/s; [0.41/4.66]; P=0.019), ankle‐brachial index (β=−0.03; [−0.04/−0.01]; P<0.0001), intima‐media thickness (β=+0.03 mm [0.01/0.05]; P=0.0098), left ventricular ejection fraction (β=−4.02% [−4.70/−3.33]; P<0.0001), E/E′ (β=+0.04 [0.01/0.08]; P=0.014) left ventricular mass (β=+5.34 g/m2.7 [4.26/6.44]; P<0.0001), and humoral markers of cardiac function and inflammation (midregional pro‐atrial natriuretic peptide: β=+0.58 pmol/L [0.50/0.65]; P<0.0001; midregional pro‐adrenomedullin: β=+0.18 nmol/L [0.14/0.22]; P<0.0001; N‐terminal pro B‐type natriuretic peptide: β=+1.90 pg/mL [1.63/2.17]; P<0.0001; fibrinogen: β=+143 mg/dL [132/153]; P<0.0001; C‐reactive protein: β=+0.31 mg/L [0.20/0.43]; P<0.0001). Sensitivity analysis in the subsample of participants with atrial fibrillation stratified by intake of VKA demonstrated consistent and robust results. Genetic variants in CYP2C9,CYP4F2, and VKORC1 were modulating effects of VKA on subclinical markers of cardiovascular disease.ConclusionsThese data demonstrate negative effects of VKA on vascular and cardiac phenotypes of subclinical cardiovascular disease, indicating a possible influence on long‐term disease development. These findings may be clinically relevant for the provision of individually tailored antithrombotic therapy.

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Section: Discussionmentioning

confidence: 99%

Intake of Vitamin K Antagonists and Worsening of Cardiac and Vascular Disease: Results From the Population‐Based Gutenberg Health Study

Eggebrecht

Prochaska

Schulz

et al. 2018

JAHA

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“…We speculate that the failure of some type I collagen structures to mineralize in vivo is due to the presence of powerful inhibitors of mineralization. Previous studies have shown that serum itself contains high levels of one potent inhibitor of hydroxyapatite formation, fetuin (a2-HS-glycoprotein) [28][29][30], and that the calcification of cartilage in vivo is normally prevented by the calcification inhibitory activity of the vitamin K-dependent matrix Gla protein [31,32]. It seems likely that type I collagen matrices that do not ordinarily calcify, such as tendon, contain other potent inhibitors of mineralization in vivo.…”

Section: Discussionmentioning

confidence: 99%

Mineralization of Decalcified Bone Occurs Under Cell Culture Conditions and Requires Bovine Serum But Not Cells

Hamlin

Price

2004

Calcif Tissue Int

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Abstract. The purpose of this study was to develop an in vitro model system for bone matrix mineralization in the absence of cells. For this model, we utilized EDTAdecalcified new-born rat tibias with the cartilaginous ends intact, allowing us to visually determine the specificity of mineralization within the bone. Our results show that supplementation of DMEM culture medium with 10mM b-glycerophosphate and 15% fetal bovine serum (FBS) results in non-physiological mineral percipitation in the tibia because of the generation of supraphysiological (5mM) levels of inorganic phosphate in the medium. The same medium supplemented only with inorganic phosphate to a final concentration of 2mM failed to mineralize a decalcified tibia matrix. However, additional supplementation of this medium with as little as 5% FBS resulted in mineralization of those regions of the type I collagen where mineral was found prior to decalcification, with no evidence for mineralization in the cartilage at the bone ends or in the periosteum. Analysis of the mineral by Fourier-transform infrared spectroscopy and powder X-ray diffraction shows that tibias that have been decalcified and then remineralized contain an apatitic mineral that is strikingly similar to the mineral in normal bone. Tendon, a type I collagen matrix not normally mineralized in vivo , also mineralizes when incubated in DMEM containing 2mM Pi and as little as 1.5% FBS, but not when incubated in DMEM without serum. These data indicate that serum contains a nucleator of type I collagen matrix mineralization, and that mineralization of type I collagen under cell culture conditions requires serum but not living cells.

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“…Hence, vitamin K is an important regulator of bone and cartilage mineralization. Vitamin K also regulates growth plate cartilage calcification, as revealed by effects of vitamin K antagonism by warfarin (6)(7)(8)(9)(10). Genetic deficiencies of MGP in humans and mice have been linked to skeletal abnormalities, including premature epiphyseal calcification and shortening of long limb bones, reflecting endochondral bone formation (11)(12)(13)(14).…”

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confidence: 99%

Low vitamin K status is associated with osteoarthritis in the hand and knee

Neogi

Booth

Zhang

et al. 2006

Arthritis & Rheumatism

146

101

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Objective. Poor intake of vitamin K is common. Insufficient vitamin K can result in abnormal cartilage and bone mineralization. Furthermore, osteophyte growth, seen in osteoarthritis (OA), may be a vitamin K-dependent process. We undertook this study to determine whether vitamin K deficiency is associated with radiographic features of OA.Methods. We conducted an analysis among 672 participants (mean age 65.6 years, 358 women) in the Framingham Offspring Study, a population-based prospective observational cohort. Levels of plasma phylloquinone (the primary form of vitamin K) had previously been measured in these participants, for whom we also had bilateral hand and knee radiographs. The main outcomes were 1) prevalence ratios (PRs) of OA, osteophytes, and joint space narrowing (JSN) per quartile of plasma phylloquinone level for each joint, adjusting for correlated joints using generalized estimating equations, and 2) adjusted mean number of joints with each feature per quartile of plasma phylloquinone level. Analyses were conducted in hands and knees separately and adjusted for age, sex, body mass index, total energy intake, plasma vitamin D, and femoral neck bone mineral density.Results. The PRs for OA, osteophytes, and JSN and adjusted mean number of joints with all 3 features in the hand decreased significantly with increasing plasma phylloquinone levels (P < 0.03 for all). For example, as plasma phylloquinone levels rose, the PR for hand OA decreased from 1.0 to 0.7 (P ‫؍‬ 0.005). For the knee, only the PR for osteophytes and the adjusted mean number of knee joints with osteophytes decreased significantly with increasing plasma phylloquinone levels (PR decreased from 1.0 to 0.6, P ‫؍‬ 0.01).Conclusion. These observational data support the hypothesis of an association between low plasma levels of vitamin K and increased prevalence of OA manifestations in the hand and knee.

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Warfarin Causes Rapid Calcification of the Elastic Lamellae in Rat Arteries and Heart Valves

Cited by 497 publications

References 45 publications

Intake of Vitamin K Antagonists and Worsening of Cardiac and Vascular Disease: Results From the Population‐Based Gutenberg Health Study

Intake of Vitamin K Antagonists and Worsening of Cardiac and Vascular Disease: Results From the Population‐Based Gutenberg Health Study

Mineralization of Decalcified Bone Occurs Under Cell Culture Conditions and Requires Bovine Serum But Not Cells

Low vitamin K status is associated with osteoarthritis in the hand and knee

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