Vitamin k2 References

In conclusion, long-term use of MK-7 supplements improves arterial stiffness in healthy postmenopausal women, especially in women having a high arterial stiffness.

Observational data suggest a link between menaquinone (MK, vitamin K2) intake and cardiovascular (CV) health. However, MK intervention trials with vascular endpoints are lacking. We investigated long-term effects of MK-7 (180 µg MenaQ7/day) supplementation on arterial stiffness in a double-blind, placebo-controlled trial. Healthy postmenopausal women (n=244) received either placebo (n=124) or MK-7 (n=120) for three years. Indices of local carotid stiffness (intima-media thickness IMT, Diameter end-diastole and Distension) were measured by echotracking. Regional aortic stiffness (carotid-femoral and carotid-radial Pulse Wave Velocity, cfPWV and crPWV, respectively) was measured using mechanotransducers. Circulating desphospho-uncarboxylated matrix Gla-protein (dp-ucMGP) as well as acute phase markers Interleukin-6 (IL-6), high-sensitive C-reactive protein (hsCRP), tumour necrosis factor-α (TNF-α) and markers for endothelial dysfunction Vascular Cell Adhesion Molecule (VCAM), E-selectin, and Advanced Glycation Endproducts (AGEs) were measured. At baseline dp-ucMGP was associated with IMT, Diameter, cfPWV and with the mean z-scores of acute phase markers (APMscore) and of markers for endothelial dysfunction (EDFscore). After three year MK-7 supplementation cfPWV and the Stiffness Index βsignificantly decreased in the total group, whereas distension, compliance, distensibility, Young’s Modulus, and the local carotid PWV (cPWV) improved in women having a baseline Stiffness Index β above the median of 10.8. MK-7 decreased dp-ucMGP by 50 % compared to placebo, but did not influence the markers for acute phase and endothelial dysfunction.

Knapen MH, Braam LA, Drummen NE, Bekers O, Hoeks AP, Vermeer C.
Thromb Haemost. 2015 Feb 19;113(5). [Epub ahead of print]

Associations have been found between various micronutrients and cardio-metabolic outcomes. Vitamin K deficiency has been associated with increased calcification of the main arteries and with insulin resistance. The present study aimed to examine the association between vitamin K intake and cardio-metabolic outcomes including cardiovascular disease, type 2 diabetes and the metabolic syndrome. A systematic review of the literature was performed in January 2010. Nine electronic databases, and trial registers, reference lists of retrieved articles and citations were searched. Intervention, cohort, case-control or cross-sectional studies in adults were included if they examined the association between vitamin K levels (dietary intake, biomarkers, supplements) on clinical outcomes relevant to cardio-metabolic disease. Five studies met the inclusion criteria (1 trial, 4 cohort studies). Heterogeneity of designs, exposures/interventions and outcomes meant that meta-analysis was not possible. No associations were found between vitamin K1 intake and coronary heart disease (CHD) (4 cohorts) or stroke (2 cohorts) in multivariate analyses. No differences were seen in the prevalence of diabetes in a trial of vitamin K1 supplementation. Two cohorts examined the effects of vitamin K2 intake on the incidence of CHD; both found significant associations where higher vitamin K2 intake was associated with fewer CHD events. Few studies have examined the effects of vitamin K intake on clinical outcomes relevant to cardio-metabolic disorders. None of the studies used biomarkers. Currently there is no evidence for an effect of vitamin K1, but results for vitamin K2 look promising. Further prospective studies are required to confirm these findings.

Rees K1, Guraewal S, Wong YL, Majanbu DL, Mavrodaris A, Stranges S, Kandala NB, Clarke A, Franco OH.
Maturitas. 2010 Oct;67(2):121-8. doi: 10.1016/j.maturitas.2010.05.006. Epub 2010 Jun 17.

Conclusions: This study shows that a high intake of menaquinones and high vitamin K status are associated with a lower occurrence of MetS.

Context: The Metabolic Syndrome (MetS) is a cluster of metabolic abnormalities and is associated with increased risk of diabetes and cardiovascular diseases. Phylloquinone, menaquinones and vitamin K status are associated with several components of MetS, but the association with MetS has hardly been studied to date.
Objective: To examine whether the intake and/or status of vitamin K is associated with MetS and its components.
Design: This study comprised of two cohorts, one of 402 women and one of 400 men (40 – 80 years).
At follow-up 625 participants were still alive and willing to participate. Data were analyzed both cross-sectionally and longitudinally with Poisson and linear regression adjusted for multiple confounders. Baseline phylloquinone/menaquinone intakes were measured with a validated food frequency questionnaire and vitamin K status with serum desphospho-uncarborxylated matrix-Gla protein level.
Results: At baseline 270(34.5%) participants had MetS and 171(35.7%) at follow-up. Cross-sectionally, high menaquinones intakes were associated (Ptrend0.08) with a lower prevalence of MetS with a prevalence ratio (PR) of 0.74 (95%CI: 0.54;1.03) for the highest versus the lowest tertile. At follow-up, the highest tertiles of menaquinones intake (PR0.62, 95%CI: 0.40;0.95) and vitamin K status (PR0.57, 95%CI: 0.38;0.87) were associated (Ptrend0.01) with a lower occurrence of MetS. These associations were mainly driven by relations with lower triacylglycerol concentrations for menaquinones and lower waist circumference for vitamin K status. Phylloquinone intake was not associated with MetS prevalence.
Conclusions: This study shows that a high intake of menaquinones and high vitamin K status are associated with a lower occurrence of MetS.
Veerle Dam, MSc, Geertje W. Dalmeijer, Cees Vermeer,
Nadja E. Drummen, Marjo H. Knapen, Yvonne T. van der Schouw, Joline W. Beulens,
University Medical Center Utrecht, Netherlands; R&D Group VitaK, Maastricht University, the Netherlands
Revised manuscript:

This study from Korea found that Vitamin K2 supplementation in a group of healthy young men for 4 weeks increased their insulin sensitivity.

The improvement in insulin sensitivity could be due to an increase in carboxylated osteocalcin (cOC), unlike in rodents where it is purported to be the undercarboxylated osteocalcin (ucOC) that increases insulin sensitivity; it was concluded that further studies are needed to elucidate the exact mechanism of the increase in insulin sensitivity.

Hyung Jin Choi, MD, Juyoun Yu, BS, Hosanna Choi, BS, Jee Hyun An et al

doi: 10.2337/dc11-0551Diabetes Care September 2011vol. 34 no. 9 e147

The aim of this study was to investigate whether dietary phylloquinone and menaquinones intakes are related to the risk of type 2 diabetes.

Data from a prospective cohort study in 38,094 Dutch men and women, aged 20-70 years was used.

During 10.3 years of follow-up, 918 incident cases of diabetes were documented; phylloquinone intake tended to be associated with a reduced risk of type 2 diabetes and with the menaquinones intake, a linear, inverse association with risk of type 2 diabetes was observed.

This study showed that both phylloquinone and menaquinones intakes may be associated with a reduced risk of type 2 diabetes.

Beulens JW, van der A DL, Grobbee DE, Sluijs I, Spijkerman AM, van der Schouw YT.

Diabetes Care. 2010 Aug;33(8):1699-705. doi: 10.2337/dc09-2302. Epub 2010 Apr 27.

Effects of long-term vitamin K(1) (phylloquinone) or vitamin K(2) (menaquinone-4) supplementation on body composition and serum parameters in rats

Authors and Abstract

This study looking at the effects of vitamins K1 and K2 in rats found that the addition of K1 but not K2 increased the bone mineral density (BMD) of the femur; however the K2 group had a significant increase in two other parameters of bone strength – the minimum cross-sectional moment of inertia and the polar moment of inertia, compared to the control group.

Effects of vitamin K on fat metabolism

Interestingly, the addition of K1 or K2 significantly decreased the total fat accumulation; serum triglycerides were reduced by 48% in the K1 group; serum triglycerides were reduced by 29% in the K2 group compared with the control.

There were no significant differences in the levels of serum calcium, phosphorus, alkaline phosphatase, growth hormone, insulin-like growth hormone-1, insulin-like growth hormone binding protein-3, and cross-linked N-teleopeptide of type I collagen among the three groups.

Sogabe N, Maruyama R, Baba O, Hosoi T, Goseki-Sone M.

Department of Food and Nutrition, Japan Women’s University, Tokyo, Japan.

 Bone. 2011 May 1;48(5):1036-42. doi: 10.1016/j.bone.2011.01.020. Epub 2011 Feb 2.

Circulating matrix Gla protein is associated with coronary artery calcification and vitamin K status in healthy women

Authors and Summary

Matrix Gla protein (MGP) is a vitamin K-dependent protein and an inhibitor of vascular calcification. Vitamin K is required for the carboxylation of MGP and can thereby reduce calcification.

This study investigated the association of various types of MGP with coronary artery calcification (CAC) and vitamin K status in 200 healthy women.

Results and conclusion:

In high-risk populations, high total uncarboxylated MGP (t-ucMGP) was associated with decreased CAC, while high non-phosphorylated uncarboxylated MGP (dp-ucMGP) was associated with a poor vitamin K status.

These results show that dp-ucMGP may serve as a biomarker of vitamin K status, and circulating dp-ucMGP and t-ucMGP may serve as markers for the extent of CAC, but these findings need to be confirmed.

Dalmeijer GW¹, van der Schouw YT, Vermeer C, Magdeleyns EJ, Schurgers LJ, Beulens JW.

Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, 3508 GA Utrecht, The Netherlands. G.W.Dalmeijer@umcutrecht.nl

J Nutr Biochem. 2013 Apr;24(4):624-8. doi: 10.1016/j.jnutbio.2012.02.012. Epub 2012 Jul 20.

Something more to say about calcium homeostasis: the role of vitamin K2 in vascular calcification and osteoporosis

Authors and Abstract

Vitamin K2 deficiency is often present at subclinical levels in a large part of the healthy population, and is associated with vascular calcification and osteoporosis.

Further studies are necessary to confirm these findings.

Flore R, Ponziani FR, Di Rienzo TA, Zocco MA, Flex A, Gerardino L, Lupascu A, Santoro L, Santoliquido A, Di Stasio E, Chierici E, Lanti A, Tondi P, Gasbarrini A.

Eur Rev Med Pharmacol Sci. 2013 Sep;17(18):2433-40. Review.

High dietary menaquinone intake is associated with reduced coronary calcification 

Authors and Abstract

This study from Utrecht investigated the association of phylloquinone and menaquinone intake with coronary calcification in 564 post-menopausal women, and found that a high dietary menaquinone (vitamin K2) intake, but not phylloquinone (vitamin K1), is associated with reduced coronary calcification.

They concluded that an adequate menaquinone intake could be important in preventing cardiovascular disease.

 Beulens JW¹, Bots ML, Atsma F, Bartelink ML, Prokop M, Geleijnse JM, Witteman JC, Grobbee DE, van der Schouw YT.

Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, The Netherlands. J.Beulens@umcutrecht.nl

 2009 Apr;203(2):489-93. doi: 10.1016/j.atherosclerosis.2008.07.010. Epub 2008 Jul 19

A high menaquinone intake reduces the incidence of coronary heart disease

Authors and Summary

This study examined the relationship between dietary intake of vitamins K1 and K2 and the incidence of CHD.

 Data from the Prospect-EPIC cohort consisting of 16,057 women, enrolled between 1993 and 1997 and aged 49-70 years, who were free of cardiovascular diseases at baseline was used.

An inverse association between vitamin K₂ intake and risk of CHD was found.

The conclusions of this study were that a high intake of menaquinones (subtypes of vitamin K2), especially MK-7, MK-8 and MK-9, could protect against CHD.

However, more research is necessary to define optimal intake levels of vitamin K intake for the prevention of CHD.

Gast GC¹, de Roos NM, Sluijs I, Bots ML, Beulens JW, Geleijnse JM, Witteman JC, Grobbee DE, Peeters PH, van der Schouw YT.

Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, 3508 GA Utrecht, The Netherlands.

Nutr Metab Cardiovasc Dis. 2009 Sep;19(7):504-10. doi: 10.1016/j.numecd.2008.10.004. Epub 2009 Jan 28.

Matrix Gla-protein: the calcification inhibitor in need of vitamin K 

Authors and Summary

Vitamin K-dependent matrix Gla-protein (MGP) seems to be a potent inhibitor of arterial calcification, and currently appears to be the only mechanism for inhibiting arterial calcification. Vitamin K intake is therefore important to keep the risk and rate of calcification in blood vessels as low as possible.

Schurgers LJ¹, Cranenburg EC, Vermeer C.

VitaK, Maastricht University, Universiteitssingel 50, Maastricht, The Netherlands.

Thromb Haemost. 2008 Oct;100(4):593-603.

The physiology of vitamin K nutriture and vitamin K-dependent protein function in atherosclerosis

Authors and Summary

 Recent advances in the discovery of new functions for vitamin K-dependent (VKD) proteins have led to a substantial revision in our understanding of vitamin K physiology. VKD proteins are now known to be present in virtually every tissue and to be important to bone mineralization, arterial calcification, apoptosis, phagocytosis, growth control, chemotaxis, and signal transduction.

 The development of improved methods for analyzing vitamin K has shed considerable insight into the relative importance of different vitamin K forms in the diet.

New assays that measure the extent of carboxylation in VKD proteins have revealed that while the current recommended daily allowance for vitamin K is sufficient for maintaining functional haemostasis, the undercarboxylation of at least one non-haemostatic protein is frequently observed in the general population.

Many of the VKD proteins contribute to atherogenesis. Recent studies suggest involvement in arterial calcification, which may be influenced by dietary levels of vitamin K and also by anticoagulant drugs such as warfarin that antagonize vitamin K action.

Berkner KL, Runge KW.

Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic Lerner College of Medicine at Case Western Reserve University, Cleveland, OH 44195, USA

J Thromb Haemost. 2004 Dec;2(12):2118-32.

This study of 8000 men and women over the age of 55 showed that a high intake of K2 from dietary sources significantly reduced the incidence of arterial calcification and risk of death from cardiovascular disease by 50% compared to people with a low dietary K2 intake.

Vitamin K2 intake was also inversely related to severe arterial calcification, all-cause mortality or death from any cause.

Individuals with highest dietary K2 lived on average 7 years longer than K2 deficient people.

Geleijnse JM, Vermeer C, Grobbee DE, Schurgers LJ, Knapen MH, van der Meer IM, Hofman A, Witteman JC.

J Nutr. 2004 Nov;134(11):3100-5.

This study shows that extracellular matrix (ECM) calcification must be actively inhibited in soft tissues.

Matrix GLA protein (MGP), a mineral-binding protein, is the first inhibitor of calcification of arteries and cartilage to be characterized in vivo; it is synthesized by vascular smooth-muscle cells and chondrocytes – two cell types that produce an uncalcified extracellular matrix.

Mice that lack MGP develop to term but die within two months as a result of arterial calcification, and chondrocytes that elaborate a typical cartilage matrix can be seen in the affected arteries.

These MGP-deficient mice also exhibit inappropriate calcification of various cartilages, including the growth plate, which eventually leads to short stature, osteopaenia and fractures.

Luo G¹, Ducy P, McKee MD, Pinero GJ, Loyer E, Behringer RR, Karsenty G.

Department of Molecular Genetics, The University of Texas M.D. Anderson Cancer Center, Houston 77030, USA.

 1997 Mar 6;386(6620):78-81