Oral anticoagulant treatment: friend or foe in cardiovascular disease?

Schurgers, Leon J.; Aebert, Hermann; Vermeer, Cees; Bültmann, B.; Janzen, Jan

doi:10.1182/blood-2004-04-1277

Cited by 161 publications

(131 citation statements)

References 12 publications

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“…Vitamin K antagonists such as warfarin induce the incomplete g-carboxylation of matrix g-carboxyglutamic acid protein and attenuate the synthesis and function of matrix g-carboxyglutamic acid protein. 24 Previous observational studies in Western countries showed that aortic valve calcifications were significantly larger in patients treated with oral anticoagulants, 25,26 a finding that is compatible with our current data from Japanese patients. In a society with many elderly, such as in Western countries and Japan, the use of oral anticoagulants to prevent thromboembolic events has increased correspondingly with the rising prevalence of atrial fibrillation, but the effects of warfarin on the progression of CAVD were independent of the presence of atrial fibrillation in this study.…”

Section: Prognostic Factors For Progression Of Early-stage Cavdsupporting

confidence: 82%

Prognostic factors for progression of early- and late-stage calcific aortic valve disease in Japanese: The Japanese Aortic Stenosis Study (JASS) Retrospective Analysis

Yamamoto

Yoshida

et al. 2010

Hypertens Res

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Calcific aortic valve disease (CAVD) is the most common etiology of acquired valvular heart disease, and hypertension is a principal underlying disease. The Japanese Aortic Stenosis Study (JASS) Retrospective Analysis is a retrospective observational study to clarify the prognostic factors for progression of CAVD in Japanese. Data from 556 subjects who met the following criteria were analyzed: (1) X50 years old; (2) calcification in any aortic valve leaflet or peak aortic jet velocity X2 m s À1 on an echocardiographic study performed between July 2004 and June 2007; and (3) availability of earlier echocardiographic data from within the previous 2-5 years to assess the progression of CAVD. The subjects were divided into two groups according to CAVD severity on the preceding echocardiographic examination. In early-stage subjects with calcification in one or zero leaflets who were without aortic stenosis on the preceding echocardiographic study (n¼157), the prognostic factors for progression were the following: (1) no use of angiotensin receptor blockers (ARB) and (2) use of warfarin. In late-stage subjects with calcification in two or three leaflets and/or aortic stenosis on the preceding echocardiographic study (n¼399), progression was observed in females and in subjects with low hemoglobin and a concentric left ventricle. There was no relation between medications and changes in CAVD. Prognostic factors for the progression of CAVD were different between the early and late stages. Initiation of ARB treatment during the early stage may be effective, and we should be vigilant about progression of CAVD in patients treated with warfarin.

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Section: Prognostic Factors For Progression Of Early-stage Cavdsupporting

confidence: 82%

Prognostic factors for progression of early- and late-stage calcific aortic valve disease in Japanese: The Japanese Aortic Stenosis Study (JASS) Retrospective Analysis

Yamamoto

Yoshida

et al. 2010

Hypertens Res

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“…However, a small computed tomography study found that warfarin use was associated with both valvular and coronary calcification (41). Histopathologic examination of aortic valves replaced for aortic stenosis found that those patients treated with warfarin had a two-fold increase in valvular calcification (42). Warfarin initiation has also been associated with calcemic uremic arteriopathy (43), a systemic vascular calcification syndrome typically involving small capillaries.…”

Section: Warfarin's Effect On the Vasculaturementioning

confidence: 99%

Vitamin K-dependent Proteins, Warfarin, and Vascular Calcification

Danziger

2008

Clinical Journal of the American Society of Nephrology

216

149

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Vitamin K-dependent proteins (VKDPs) require carboxylation to become biologically active. Although the coagulant factors are the most well-known VKDPs, there are many others with important physiologic roles. Matrix Gla Protein (MGP) and Growth Arrest Specific Gene 6 (Gas-6) are two particularly important VKDPs, and their roles in vascular biology are just beginning to be understood. Both function to protect the vasculature; MGP prevents vascular calcification and Gas-6 affects vascular smooth muscle cell apoptosis and movement. Unlike the coagulant factors, which undergo hepatic carboxylation, MGP and Gas-6 are carboxylated within the vasculature. This peripheral carboxylation process is distinct from hepatic carboxylation, yet both are inhibited by warfarin administration. Warfarin prevents the activation of MGP and Gas-6, and in animals, induces vascular calcification. The relationship of warfarin to vascular calcification in humans is not fully known, yet observational data suggest an association. Given the high risk of vascular calcification in those patients with chronic kidney disease, the importance of understanding warfarin's effect on VKDPs is paramount. Furthermore, recognizing the importance of VKDPs in vascular biology will stimulate new areas of research and offer potential therapeutic interventions.

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“…The vitamin K antagonist war-farin may block vitamin K-dependent c-carboxylation within the liver and prevent hepatic formation of clotting factors. However, this process is not limited to the liver, and carboxylation of peripherally expressed vitamin K-dependent protein may be affected as well, thereby regulating calcium binding [8][9][10]. Thus, although the relationship between warfarin and vascular calcification in humans is not fully understood, observational studies suggest that inhibition of MGP carboxylation by the vitamin K antagonist warfarin results in extensive calcification of arteries in vitro and in vivo because of synthesis of the inactive undercarboxylated MGP (ucMGP) [10,11].…”

Section: Introductionmentioning

confidence: 99%

Undercarboxylated matrix Gla protein is associated with indices of heart failure and mortality in symptomatic aortic stenosis

Ueland¹,

Gullestad²,

Dahl³

et al. 2010

Journal of Internal Medicine

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Abstract. Ueland T, Gullestad L, Dahl CP, Aukrust P, Aakhus S, Solberg OG, Vermeer C, Schurgers LJ (Research Institute for Internal Medicine, University of Oslo, Oslo; University of Oslo, Oslo, Norway; and VitaK & Cardiovascular Research Institute CARIM (CV, LS), Maastricht University, Maastricht, The Netherlands) Undercarboxylated matrix Gla protein is associated with indices of heart failure and mortality in symptomatic aortic stenosis. J Intern Med 2010; 268: 483-492.Objective. Matrix Gla protein (MGP) is a calcification inhibitor and alterations in circulating MGP have been observed in different populations characterized by vascular calcification. We hypothesized that patients with calcific valvular aortic stenosis (AS) would have dysregulated circulating MGP levels.Design and subjects. We examined plasma levels of nonphosphorylated carboxylated and undercarboxylated MGP (dp-cMGP and dp-ucMGP, respectively) in 147 patients with symptomatic severe AS and in matched healthy controls. Main outcome measures.We further investigated the relationship between MGP levels and aortic pressure gradients and valve area by echocardiography and measures of heart failure. Finally, we assessed the prognostic value of elevated plasma dp-ucMGP level in relation to all-cause mortality in patients with AS.Results. We found markedly enhanced plasma levels of dp-cMGP and in particular of dp-ucMGP in patients with symptomatic AS. Although only weak correlations were found with the degree of AS, circulating dp-ucMGP was associated with cardiac function and long-term mortality in multivariate analysis. Conclusions.A dysregulated MGP system may have a role in the development of left ventricular dysfunction in patients with symptomatic AS.

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Oral anticoagulant treatment: friend or foe in cardiovascular disease?

Abstract: Calcification is a common complication in cardiovascular disease and may affect both arteries and heart valves. Matrix ␥-carboxyglutamic acid (Gla) protein (MGP) is a potent inhibitor of vascular calcification, the activity of which is regulated by vitamin K.

Cited by 161 publications

References 12 publications

Prognostic factors for progression of early- and late-stage calcific aortic valve disease in Japanese: The Japanese Aortic Stenosis Study (JASS) Retrospective Analysis

Prognostic factors for progression of early- and late-stage calcific aortic valve disease in Japanese: The Japanese Aortic Stenosis Study (JASS) Retrospective Analysis

Vitamin K-dependent Proteins, Warfarin, and Vascular Calcification

Undercarboxylated matrix Gla protein is associated with indices of heart failure and mortality in symptomatic aortic stenosis

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