Thromb Haemost 2015; 113(05): 1135-1144
DOI: 10.1160/TH14-08-0675
New Technologies, Diagnostic Tools and Drugs
Schattauer GmbH

Menaquinone-7 supplementation improves arterial stiffness in healthy postmenopausal women

A double-blind randomised clinical trial
Marjo H. J. Knapen
1   VitaK & Cardiovascular Research Institute (CARIM), Maastricht University, The Netherlands
Lavienja A. J. L. M. Braam
1   VitaK & Cardiovascular Research Institute (CARIM), Maastricht University, The Netherlands
Nadja E. Drummen
1   VitaK & Cardiovascular Research Institute (CARIM), Maastricht University, The Netherlands
Otto Bekers
2   Central Diagnostic Laboratory, University Hospital Maastricht, The Netherlands
Arnold P. G. Hoeks
3   Biomedical Engineering, Maastricht University, The Netherlands
Cees Vermeer
1   VitaK & Cardiovascular Research Institute (CARIM), Maastricht University, The Netherlands
› Author Affiliations
Financial support: This work was supported by Nattopharma (Høvik, Norway). Any opinions, findings, conclusions, or recommendations expressed in this publication are those of the authors, and do not necessarily reflect the view of Nattopharma.
Further Information

Publication History

Received: 14 August 2014

Accepted after major revision: 31 February 2014

Publication Date:
24 November 2017 (online)


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

  • References

  • 1 Laurent S. et al. Expert consensus document on arterial stiffness: methodological issues and clinical applications. Eur Heart J 2006; 27: 2588-2605.
  • 2 Mattace-Raso FU. et al. Arterial stiffness and risk of coronary heart disease and stroke: the Rotterdam Study. Circulation 2006; 113: 657-663.
  • 3 van Popele NM. et al. Aortic stiffness is associated with atherosclerosis of the coronary arteries in older adults: the Rotterdam Study. J Hypertension 2006; 24: 2371-2376.
  • 4 Safar H. et al. Aortic pulse wave velocity, an independent marker of cardiovascular risk. Arch Mal Coeur Vaiss 2002; 95: 1215-1218.
  • 5 Willum-Hansen T. et al. Prognostic value of aortic pulse wave velocity as index of arterial stiffness in the general population. Circulation 2006; 113: 664-670.
  • 6 Reference Values for Arterial Stiffness C. Determinants of pulse wave velocity in healthy people and in the presence of cardiovascular risk factors: ‘establishing normal and reference values’. Eur Heart J 2010; 31: 2338-2350.
  • 7 Bode AS. et al. Determination of brachial artery stiffness prior to vascular access creation: reproducibility of pulse wave velocity assessment. NDT 2012; 27: 2370-2376.
  • 8 Hayashi K. et al. Stiffness and elastic behavior of human intracranial and extracranial arteries. J Biomech 1980; 13: 175-184.
  • 9 Geleijnse JM. et al. Dietary intake of menaquinone is associated with a reduced risk of coronary heart disease: the Rotterdam Study. J Nutr 2004; 134: 3100-3105.
  • 10 Beulens JW. et al. High dietary menaquinone intake is associated with reduced coronary calcification. Atherosclerosis 2009; 203: 489-493.
  • 11 Gast GC. et al. A high menaquinone intake reduces the incidence of coronary heart disease. Nutr Metab Cardiovasc Dis 2009; 19: 504-510.
  • 12 Villines TC. et al. Vitamin K1 intake and coronary calcification. Coron Artery Dis 2005; 16: 199-203.
  • 13 Erkkila AT. et al. Phylloquinone intake as a marker for coronary heart disease risk but not stroke in women. Eur J Clin Nutr 2005; 59: 196-204.
  • 14 Erkkila AT. et al. Phylloquinone intake and risk of cardiovascular diseases in men. Nutr Metab Cardiovasc Dis 2007; 17: 58-62.
  • 15 Shearer MJ, Newman P. Metabolism and cell biology of vitamin K. Thromb Haemost 2008; 100: 530-547.
  • 16 Braam LA. et al. Beneficial effects of vitamins D and K on the elastic properties of the vessel wall in postmenopausal women: a follow-up study. Thromb Haemost 2004; 91: 373-380.
  • 17 Shea MK. et al. Vitamin K supplementation and progression of coronary artery calcium in older men and women. Am J Clin Nutr 2009; 89: 1799-1807.
  • 18 Schurgers LJ. et al. Vitamin K–containing dietary supplements: comparison of synthetic vitamin K1 and natto-derived menaquinone-7. Blood 2007; 109: 3279-3283.
  • 19 Cranenburg EC. et al. The Circulating Inactive Form of Matrix Gla Protein (ucMGP) as a Biomarker for Cardiovascular Calcification. J Vasc Res 2008; 45: 427-436.
  • 20 Rennenberg RJ. et al. Calcium scores and matrix Gla protein levels: association with vitamin K status. Eur J Clin Invest 2010; 40: 344-349.
  • 21 Schurgers LJ. et al. The circulating inactive form of matrix gla protein is a surrogate marker for vascular calcification in chronic kidney disease: a preliminary report. Clin J Am Soc Nephrol 2010; 05: 568-575.
  • 22 Mayer Jr. O. et al. Desphospho-uncarboxylated matrix Gla-protein is associated with mortality risk in patients with chronic stable vascular disease. Atherosclerosis 2014; 235: 162-168.
  • 23 Liabeuf S. et al. Vascular calcification in patients with type 2 diabetes: the involvement of matrix Gla protein. Cardiovasc Diabetol 2014; 13: 85.
  • 24 Dalmeijer GW. et al. Circulating matrix Gla protein is associated with coronary artery calcification and vitamin K status in healthy women. J Nutr Biochem 2013; 24: 624-628.
  • 25 Ueland T. et al. Circulating levels of non-phosphorylated undercarboxylated matrix Gla protein are associated with disease severity in patients with chronic heart failure. Clin Sci 2011; 121: 119-127.
  • 26 Shea MK. et al. Circulating uncarboxylated matrix gla protein is associated with vitamin k nutritional status, but not coronary artery calcium, in older adults. J Nutr 2011; 141: 1529-1534.
  • 27 Dalmeijer GW. et al. The effect of menaquinone-7 supplementation on circulating species of matrix Gla protein. Atherosclerosis 2012; 225: 397-402.
  • 28 Westenfeld R. et al. Effect of vitamin K2 supplementation on functional vitamin K deficiency in hemodialysis patients: a randomized trial. Am J Kidney Dis 2012; 59: 186-195.
  • 29 Theuwissen E. et al. Low-dose menaquinone-7 supplementation improved extra-hepatic vitamin K status, but had no effect on thrombin generation in healthy subjects. Br J Nutr 2012; 108: 1652-1657.
  • 30 van Bussel BC. et al. Endothelial dysfunction and low-grade inflammation are associated with greater arterial stiffness over a 6-year period. Hypertension 2011; 58: 588-595.
  • 31 Reddi K. et al. Interleukin 6 production by lipopolysaccharide-stimulated human fibroblasts is potently inhibited by naphthoquinone (vitamin K) compounds. Cytokine 1995; 07: 287-290.
  • 32 Shea MK. et al. Vitamin K, circulating cytokines, and bone mineral density in older men and women. Am J Clin Nutr 2008; 88: 356-363.
  • 33 Shea MK. et al. Vitamin K and vitamin D status: associations with inflammatory markers in the Framingham Offspring Study. Am J Epidemiol 2008; 167: 313-320.
  • 34 Juanola-Falgarona M. et al. Association between dietary phylloquinone intake and peripheral metabolic risk markers related to insulin resistance and diabetes in elderly subjects at high cardiovascular risk. Cardiovasc Diabetol 2013; 12: 7.
  • 35 Kristensen M. et al. Six weeks phylloquinone supplementation produces undesirable effects on blood lipids with no changes in inflammatory and fibrinolytic markers in postmenopausal women. Eur J Nutr 2008; 47: 375-379.
  • 36 Ebina K. et al. Vitamin K2 administration is associated with decreased disease activity in patients with rheumatoid arthritis. Mod Rheumatol 2013; 23: 1001-1007.
  • 37 Knapen MH. et al. Three-year low-dose menaquinone-7 supplementation helps decrease bone loss in healthy postmenopausal women. Osteoporos Int 2013; 24: 2499-2507.
  • 38 Shearer MJ. et al. Vitamin K nutrition, metabolism, and requirements: current concepts and future research. Adv Nutr 2012; 03: 182-195.
  • 39 Koivistoinen T. et al. Arterial pulse wave velocity in relation to carotid intimamedia thickness, brachial flow-mediated dilation and carotid artery distensibility: the Cardiovascular Risk in Young Finns Study and the Health 2000 Survey. Atherosclerosis 2012; 220: 387-393.
  • 40 Engelen L. et al. Reference intervals for common carotid intima-media thickness measured with echotracking: relation with risk factors. Eur Heart J 2013; 34: 2368-2380.
  • 41 Shea MK, Holden RM. Vitamin K status and vascular calcification: evidence from observational and clinical studies. Adv Nutr 2012; 03: 158-165.
  • 42 Luo G. et al. Spontaneous calcification of arteries and cartilage in mice lacking matrix GLA protein. Nature 1997; 385: 78-81.
  • 43 Price PA. et al. Warfarin causes rapid calcification of the elastic lamellae in rat arteries and heart valves. Arterioscler Thromb Vasc Biol 1998; 18: 1400-1407.
  • 44 Liu Y-P. et al. Inactive Matrix Gla Protein is causally related to health outcomes: a Mendelian randomization study in a Flemish population. Hypertension. 2014. in press.
  • 45 Cranenburg EC. et al. Characterisation and potential diagnostic value of circulating matrix Gla protein (MGP) species. Thromb Haemost 2010; 104: 811-822.
  • 46 Eastell R. et al. Cardiovascular disease and bone. Arch Biochem Biophys 2010; 503: 78-83.
  • 47 den Uyl D. et al. (Sub) clinical cardiovascular disease is associated with increased bone loss and fracture risk; a systematic review of the association between cardiovascular disease and osteoporosis. Arthritis Res Ther 2011; 13: R5.
  • 48 Katsuyama H. et al. Menaquinone-7 regulates gene expression in osteoblastic MC3T3E1 cells. Int J Mol Med 2007; 19: 279-284.
  • 49 Vermeersch SJ. et al. Age and gender related patterns in carotid-femoral PWV and carotid and femoral stiffness in a large healthy, middle-aged population. J Hypertension 2008; 26: 1411-1419.