Vitamin K supplementation and progression of coronary artery calcium in older men and women

Shea, M. Kyla; O’Donnell, Christopher J; Hoffmann, Udo; Dallal, Gerard E.; Dawson‐Hughes, Bess; Ordovas, José M.; Price, Paul A.; Williamson, Matthew K.; Booth, Sarah L.

doi:10.3945/ajcn.2008.27338

Cited by 221 publications

(210 citation statements)

References 39 publications

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“…In line with this, supplementing elderly subjects for 3 years with vitamin K1 significantly halted the progression of coronary artery calcification in the group of participants adherent to treatment, supporting our view that improving the vascular vitamin K status positively affects vascular health. 24 Moreover, in subjects with normal renal function, the intake of dietary vitamin K2 was inversely correlated with the Figure 5. Vitamin K2 supplementation reduces dp-ucMGP but not dp-cMGP levels in dialysis patients.…”

Section: Discussionmentioning

confidence: 99%

Circulating Nonphosphorylated Carboxylated Matrix Gla Protein Predicts Survival in ESRD

Schlieper¹,

Westenfeld²,

Krüger³

et al. 2011

Journal of the American Society of Nephrology

210

181

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The mechanisms for vascular calcification and its associated cardiovascular mortality in patients with ESRD are not completely understood. Dialysis patients exhibit profound vitamin K deficiency, which may impair carboxylation of the calcification inhibitor matrix gla protein (MGP). Here, we tested whether distinct circulating inactive vitamin K-dependent proteins associate with all-cause or cardiovascular mortality. We observed higher levels of both desphospho-uncarboxylated MGP (dp-ucMGP) and desphospho-carboxylated MGP (dp-cMGP) among 188 hemodialysis patients compared with 98 agematched subjects with normal renal function. Levels of dp-ucMGP correlated with those of protein induced by vitamin K absence II (PIVKA-II; r ϭ 0.62, P Ͻ 0.0001). We found increased PIVKA-II levels in 121 (64%) dialysis patients, indicating pronounced vitamin K deficiency. Kaplan-Meier analysis showed that patients with low levels of dp-cMGP had an increased risk for all-cause and cardiovascular mortality. Multivariable Cox regression confirmed that low levels of dp-cMGP increase mortality risk (all-cause: HR, 2.2; 95% CI, 1.1 to 4.3; cardiovascular: HR, 2.7; 95% CI, 1.2 to 6.2). Furthermore, patients with higher vascular calcification scores showed lower levels of dp-cMGP. In 17 hemodialysis patients, daily supplementation with vitamin K2 for 6 weeks reduced dp-ucMGP levels by 27% (P ϭ 0.003) but did not affect dp-cMGP levels. In conclusion, the majority of dialysis patients exhibit pronounced vitamin K deficiency. Lower levels of circulating dp-cMGP may serve as a predictor of mortality in dialysis patients. Whether vitamin K supplementation improves outcomes requires further study. 22: 387-395, 201122: 387-395, . doi: 10.1681 Dialysis patients show an increased total and cardiovascular mortality. 1 Cardiovascular calcifications are well-established mortality predictors in ESRD patients. 2 Calcification is not only a passive but an actively regulated process dependent on calcification inhibitors. 3 Fetuin-A, a liver-derived protein, acts as a systemic calcification inhibitor, 4 and low serum levels have been shown to predict mortality in dialysis patients. 5 Matrix gla protein (MGP) is produced by vascular smooth muscle cells and acts locally in the vascular wall. 6 MGP can be modified by ␥-glutamate carboxylation and serine phosphorylation. The function of phosphorylation is not yet known, but recent data suggest that it plays a role in regulating the secretion of proteins into the extracellular environ- J Am Soc Nephrol

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Section: Discussionmentioning

confidence: 99%

Circulating Nonphosphorylated Carboxylated Matrix Gla Protein Predicts Survival in ESRD

Schlieper¹,

Westenfeld²,

Krüger³

et al. 2011

Journal of the American Society of Nephrology

210

181

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“…Besides blood coagulation, osteoporosis, and osteoarthritis, it became gradually aware that many physiological and pathological phenomena, such as fertility [36], atherosclerosis [37][38][39], brain development [40], dementia [41], and glucose metabolism [42][43][44], are related to the status of vitamin K sufficiency. We sincerely hope that vitamin K study leads to discoveries of new biological mechanisms and targets for disease prevention and treatment and eventually contributes to human culture and welfare.…”

Section: Resultsmentioning

confidence: 99%

Vitamin K, SXR, and GGCX

Azuma¹,

Inoue²

2017

Vitamin K2 - Vital for Health and Wellbeing

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Vitamin K was discovered in 1929 as a substance essential for blood coagulation and had been clinically utilized before the precise mechanism of action became aware in 1970s. The function as a cofactor of γ-glutamyl carboxylase (GGCX) was the mechanism firstly discovered with the identification of several substrate proteins including blood coagulation factors and osteocalcin. Recently, we and others have shown that vitamin K has other modes of function, such as ligand of nuclear receptor SXR (steroid and xenobiotic receptor) and its murine ortholog PXR (pregnane X receptor) and modulator of protein kinase A (PKA) activity. Besides its importance in blood coagulation, involvement of vitamin K has been shown in two major aging-related diseases, osteoporosis and osteoarthritis. Based on clinical and epidemiological studies, vitamin K is shown to have protective roles for both of them. Interestingly, clinical studies concerning single nucleotide polymorphisms (SNPs) of GGCX and γ-carboxylated status of osteocalcin suggested relationship between GGCX activity and bone-protective effect, while recent findings from basic research indicated that vitamin K functions mediated by SXR/PXR as well as GGCX are important in the bone metabolism. We also suggested that cartilage-protective effect is mediated by SXR/PXR signaling by animal experiments using Pxr knockout mice.

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“…This imprecision may have affected the association between lower calcification scores in the presence of higher levels of vitamin K and thus higher levels of cMGP. As far as this is concerned, it is important to realize that it has recently been shown that vitamin K supplementation was associated with slower progression of coronary calcium scores [12].…”

Section: Discussionmentioning

confidence: 99%

“…Several studies have reported on an association between high vitamin K intake and reduced cardiovascular risk or less arterial calcification [12][13][14]. On the contrary, the use of vitamin K antagonists is associated with increased coronary and cardiac valve calcification [15,16].…”

Section: Introductionmentioning

confidence: 99%

Calcium scores and matrix Gla protein levels: association with vitamin K status

Rennenberg

Leeuw

Kessels

et al. 2010

Eur J Clin Investigation

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Background Vascular calcification in humans is associated with an increased cardiovascular risk. Carboxylated matrix Gla protein (cMGP) inhibits vascular calcification. Vitamin K is an essential cofactor for the activation of uncarboxylated matrix Gla protein (ucMGP). It has been suggested that patients on long-term treatment with vitamin K antagonists develop aortic valve calcifications because of lower levels of circulating MGP. We therefore hypothesized that arterial calcification and a low vitamin K status are associated with ucMGP. To that aim, we measured arterial calcium scores, the osteocalcin ratio (OCR), as a proxy for vitamin K status, and ucMGP.

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Vitamin K supplementation and progression of coronary artery calcium in older men and women

Cited by 221 publications

References 39 publications

Circulating Nonphosphorylated Carboxylated Matrix Gla Protein Predicts Survival in ESRD

Circulating Nonphosphorylated Carboxylated Matrix Gla Protein Predicts Survival in ESRD

Vitamin K, SXR, and GGCX

Calcium scores and matrix Gla protein levels: association with vitamin K status

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