Association of Warfarin Use With Valvular and Vascular Calcification: A Review

Palaniswamy, Chandrasekar; Sekhri, Arunabh; Aronow, Wilbert S.; Kalra, Ankur; Peterson, Stephen J.

doi:10.1002/clc.20865

Cited by 52 publications

(29 citation statements)

References 36 publications

(34 reference statements)

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“…The functionality of MGP depends on correct gammacarboxylation of glutamate residues in the MGP protein (14), and non-gamma-carboxylated MGP has been observed in the vasculature after warfarin treatment (31). If there is sufficient inhibition of the gamma-carboxylation, it could increase the risk of AVM formation, although this has not been investigated.…”

Section: Discussionmentioning

confidence: 99%

Reducing Jagged 1 and 2 levels prevents cerebral arteriovenous malformations in matrix Gla protein deficiency

Yao¹,

Yao²,

Radparvar³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Significance Cerebral arteriovenous malformations (AVMs) are common vascular abnormalities that may lead to strokes. Signaling by bone morphogenetic proteins (BMPs) and Notch play important roles in the formation of cerebral AVMs, but the cross-talk between the pathways is poorly understood. We report that gene deletion of matrix Gla protein (MGP), a BMP inhibitor, causes cerebral AVMs in mice by activating activin receptor-like kinase 1, a BMP receptor. This activation enhances Notch activity and disrupts endothelial cell differentiation by inducing the Notch ligands Jagged 1 and 2. Reducing Jagged 1 and 2 expression prevents the disruption in differentiation and AVM formation. The findings suggest that MGP maintains the balance between BMP and Notch signaling and promotes a normal brain vasculature.

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Section: Discussionmentioning

confidence: 99%

Reducing Jagged 1 and 2 levels prevents cerebral arteriovenous malformations in matrix Gla protein deficiency

Yao¹,

Yao²,

Radparvar³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…Therefore, deficiency of vitamin K inhibits MGP activity, thus leading to vascular calcification enhancement. Warfarin, an antagonist to vitamin K, is a strong promoter of arterial calcification via blocking the activation of vitamin K-dependent MGP [30]. Many dialysis patients have cardiovascular complications, including artificial valve replacement, atrial fibrillation, and cardiogenic cerebral embolism, which might necessitate warfarin prescription.…”

Section: Inhibitory Factors (With Comment About the Risk Of Warfarin mentioning

confidence: 99%

Impact of vascular calcification on cardiovascular mortality in hemodialysis patients: clinical significance, mechanisms and possible strategies for treatment

Ohtake

Kobayashi

2017

Ren Replace Ther

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Vascular calcification has now been recognized as a major problem in dialysis patients because of its strong influence on the prognosis. Along with the regulatory failure of calcification-inhibitory system, active phenotypic change of vascular smooth muscle cells (VSMCs) to osteoblast-like cells is also involved in the progression of vascular calcification. Delaying or improving the vascular calcification is thought to be very important to improve the cardiovascular mortality in dialysis patients. Several interventional trials against vascular calcification using non-calcium-containing phosphate binders, low-dose active vitamin D plus cinacalcet, modification of dialysate calcium concentration, and sodium thiosulfate have been done, and some trials including non-calcium-containing phosphate binders showed beneficial effect on delaying vascular calcification in dialysis patients. However, delaying or improving vascular calcification has not been clearly proved to result in improved cardiovascular event and/or mortality rate by prospective interventional randomized controlled trials in dialysis patients. Whether the improvement of vascular calcification could directly lead to the improvement of survival is an urgent issue of clinical trials in dialysis patients.

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“…Recent data imply that the intake of VKA involves effects beyond the well‐known inhibition of the vitamin K–dependent coagulation factors (F) II, VII, IX, and X 2. Experimental data suggest that VKA may decrease the activity of the vitamin K–dependent proteins matrix GIa protein (MGP) and growth arrest–specific gene 6 (Gas‐6) by inhibiting the γ‐carboxylation process 3.…”

Section: Introductionmentioning

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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Association of Warfarin Use With Valvular and Vascular Calcification: A Review

Cited by 52 publications

References 36 publications

Reducing Jagged 1 and 2 levels prevents cerebral arteriovenous malformations in matrix Gla protein deficiency

Reducing Jagged 1 and 2 levels prevents cerebral arteriovenous malformations in matrix Gla protein deficiency

Impact of vascular calcification on cardiovascular mortality in hemodialysis patients: clinical significance, mechanisms and possible strategies for treatment

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

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