Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Current Nutrition Reports
Published in: Current Nutrition Reports 3/2017

Open Access 01-09-2017 | Cardiovascular Disease (JHY Wu, Section Editor)

The Role of Vitamin K Status in Cardiovascular Health: Evidence from Observational and Clinical Studies

Authors: A. J. van Ballegooijen, J. W. Beulens

Published in: Current Nutrition Reports | Issue 3/2017

Login to get access

Abstract

Purpose of Review

Vitamin K is a fat-soluble vitamin required for the activation of several vitamin K-dependent proteins to confer functioning. A growing body of evidence supports that vitamin K has beneficial effects on bone and cardiovascular health. This review summarizes key evidence on vitamin K status as measured by circulating measures and cardiovascular outcomes.

Recent Findings

Overall, observational studies indicate that low vitamin K status as measured by high dephosphorylated uncarboxylated matrix gla protein concentrations plays a potential role in cardiovascular disease development, particularly in high-risk and chronic kidney disease populations. Very few vitamin K intervention trials have been conducted with cardiovascular-related outcomes. A couple of intervention trials studied the effect of the combination of vitamin D + K supplementation, which might have synergistic effects compared to vitamin K supplementation alone.

Summary

Assessing vitamin K status in prospective studies and well-designed randomized trials would provide important insight whether vitamin K is causally related to vascular calcification and cardiovascular disease.
Literature
1.
2.
Luo G, Ducy P, McKee MD, Pinero GJ, Loyer E, Behringer RR, et al. Spontaneous calcification of arteries and cartilage in mice lacking matrix GLA protein. Nature. 1997;386(6620):78–81.CrossRefPubMed
3.
4.
Braam LA, Dissel P, Gijsbers BL, Spronk HM, Hamulyak K, Soute BA, et al. Assay for human matrix gla protein in serum: potential applications in the cardiovascular field. Arterioscler Thromb Vasc Biol. 2000;20(5):1257–61.CrossRefPubMed
5.
Schurgers LJ, Cranenburg EC, Vermeer C. Matrix Gla-protein: the calcification inhibitor in need of vitamin K. Thromb Haemost. 2008;100(4):593–603.PubMed
6.
Cranenburg EC, Koos R, Schurgers LJ, Magdeleyns EJ, Schoonbrood TH, Landewe RB, et al. Characterisation and potential diagnostic value of circulating matrix Gla protein (MGP) species. Thromb Haemost. 2010;104(4):811–22.CrossRefPubMed
7.
Harshman SG, Shea MK. The role of vitamin K in chronic aging diseases: inflammation, cardiovascular disease, and osteoarthritis. Curr Nutr Rep. 2016;5(2):90–8.CrossRefPubMedPubMedCentral
8.
Nagata C, Wada K, Tamura T, Konishi K, Goto Y, Koda S, et al. Dietary soy and natto intake and cardiovascular disease mortality in Japanese adults: the Takayama study. Am J Clin Nutr. 2016;105(2):426–31.CrossRefPubMed
9.
Allen LH. Limitations of current indicators of micronutrient status. Nutr Rev. 2009;67(Suppl 1):S21–3.CrossRefPubMed
10.
Westerterp KR, Goris AH. Validity of the assessment of dietary intake: problems of misreporting. Curr Opin Clin Nutr Metab Care. 2002;5(5):489–93.CrossRefPubMed
11.
Riphagen IJ, van der Molen JC, van Faassen M, Navis G, de Borst MH, Muskiet FA, et al. Measurement of plasma vitamin K1 (phylloquinone) and K2 (menaquinones-4 and -7) using HPLC-tandem mass spectrometry. Clin Chem Lab Med. 2016;54(7):1201–10.CrossRefPubMed
12.
Shea MK, Booth SL. Concepts and controversies in evaluating vitamin K status in population-based studies. Nutrients. 2016;8(1):E8.CrossRefPubMed
13.
Udall JA. Human sources and absorption of vitamin K in relation to anticoagulation stability. JAMA. 1965;194(2):127–9.CrossRefPubMed
14.
15.
16.
Danziger J, Young RL, Shea MK, Tracy RP, Ix JH, Jenny NS, et al. Vitamin K-dependent protein activity and incident ischemic cardiovascular disease: the multi-ethnic study of atherosclerosis. Arterioscler Thromb Vasc Biol. 2016;36(5):1037–42.CrossRefPubMed
17.
Danziger J, Young RL, Shea KM, Duprez DA, Jacobs DR, Tracy RP, et al. Circulating Des-gamma-carboxy prothrombin is not associated with cardiovascular calcification or stiffness: The Multi-ethnic Study of Atherosclerosis (MESA). Atherosclerosis. 2016;252:68–74.CrossRefPubMed
18.
Kalra SS, Shanahan CM. Vascular calcification and hypertension: cause and effect. Ann Med. 2012;44(Suppl 1):S85–92.CrossRefPubMed
19.
Steppan J, Barodka V, Berkowitz DE, Nyhan D. Vascular stiffness and increased pulse pressure in the aging cardiovascular system. Cardiol Res Pract. 2011;2011:263585.CrossRefPubMedPubMedCentral
20.
Sweatt A, Sane DC, Hutson SM, Wallin R. Matrix Gla protein (MGP) and bone morphogenetic protein-2 in aortic calcified lesions of aging rats. J Thromb Haemost. 2003;1(1):178–85.CrossRefPubMed
21.
Price PA, Faus SA, Williamson MK. Warfarin causes rapid calcification of the elastic lamellae in rat arteries and heart valves. Arterioscler Thromb Vasc Biol. 1998;18(9):1400–7.CrossRefPubMed
22.
Schurgers LJ, Spronk HM, Soute BA, Schiffers PM, DeMey JG, Vermeer C. Regression of warfarin-induced medial elastocalcinosis by high intake of vitamin K in rats. Blood. 2007;109(7):2823–31.PubMed
23.
Dalmeijer GW, van der Schouw YT, Vermeer C, Magdeleyns EJ, Schurgers LJ, Beulens JW. Circulating matrix Gla protein is associated with coronary artery calcification and vitamin K status in healthy women. J Nutr Biochem. 2013;24(4):624–8.CrossRefPubMed
24.
Liabeuf S, Bourron O, Vemeer C, Theuwissen E, Magdeleyns E, Aubert CE, et al. Vascular calcification in patients with type 2 diabetes: the involvement of matrix Gla protein. Cardiovasc Diabetol. 2014;13:85.CrossRefPubMedPubMedCentral
25.
Pivin E, Ponte B, Pruijm M, Ackermann D, Guessous I, Ehret G, et al. Inactive matrix Gla-protein is associated with arterial stiffness in an adult population-based study. Hypertension. 2015;66(1):85–92.CrossRefPubMed
26.
Mayer O Jr, Seidlerova J, Wohlfahrt P, Filipovsky J, Vanek J, Cifkova R, et al. Desphospho-uncarboxylated matrix Gla protein is associated with increased aortic stiffness in a general population. J Hum Hypertens. 2016;30(7):418–23.CrossRefPubMed
27.
Sardana M, Vasim I, Varakantam S, Kewan U, Tariq A, Koppula MR, et al. Inactive matrix Gla-protein and arterial stiffness in type 2 diabetes mellitus. Am J Hypertens. 2017;30(2):196–201.CrossRefPubMed
28.
Ueland T, Gullestad L, Dahl CP, Aukrust P, Aakhus S, Solberg OG, et al. Undercarboxylated matrix Gla protein is associated with indices of heart failure and mortality in symptomatic aortic stenosis. J Intern Med. 2010;268(5):483–92.CrossRef
29.
Ueland T, Dahl CP, Gullestad L, Aakhus S, Broch K, Skardal R, et al. Circulating levels of non-phosphorylated undercarboxylated matrix Gla protein are associated with disease severity in patients with chronic heart failure. Clin Sci (Lond). 2011;121(3):119–27.CrossRef
30.
•• Shea MK, Booth SL, Miller ME, Burke GL, Chen H, Cushman M, et al. Association between circulating vitamin K1 and coronary calcium progression in community-dwelling adults: the Multi-Ethnic Study of Atherosclerosis. Am J Clin Nutr. 2013;98(1):197–208. This study is a randomized controlled trial, with vitamin K amounts that are feasible through diet. The study shows that vitamin D combined with vitamin K resulted in less progression of CAC in participants adherent to their supplements. CrossRefPubMedPubMedCentral
31.
• Dalmeijer GW, van der Schouw YT, Magdeleyns EJ, Vermeer C, Verschuren WM, Boer JM, et al. Matrix Gla protein species and risk of cardiovascular events in type 2 diabetic patients. Diabetes Care. 2013;36(11):3766–71. This is one of the first studies that estimated associations between circulating vitamin K status and CVD risk, showing that low vitamin K status is strongly associated with incident CVD. CrossRefPubMedPubMedCentral
32.
Dalmeijer GW, van der Schouw YT, Magdeleyns EJ, Vermeer C, Elias SG, Velthuis BK, et al. Circulating species of matrix Gla protein and the risk of vascular calcification in healthy women. Int J Cardiol. 2013;168(6):e168–70.CrossRef
33.
Dalmeijer GW, van der Schouw YT, Booth SL, de Jong PA, Beulens JW. Phylloquinone concentrations and the risk of vascular calcification in healthy women. Arterioscler Thromb Vasc Biol. 2014;34(7):1587–90.CrossRefPubMed
34.
van den Heuvel EG, van Schoor NM, Lips P, Magdeleyns EJ, Deeg DJ, Vermeer C, et al. Circulating uncarboxylated matrix Gla protein, a marker of vitamin K status, as a risk factor of cardiovascular disease. Maturitas. 2014;77(2):137–41.CrossRefPubMed
35.
Dalmeijer GW, van der Schouw YT, Magdeleyns EJ, Vermeer C, Verschuren WM, Boer JM, et al. Circulating desphospho-uncarboxylated matrix gamma-carboxyglutamate protein and the risk of coronary heart disease and stroke. J Thromb Haemost. 2014;12(7):1028–34.CrossRefPubMed
36.
Liu YP, Gu YM, Thijs L, Knapen MH, Salvi E, Citterio L, et al. Inactive matrix Gla protein is causally related to adverse health outcomes: a Mendelian randomization study in a Flemish population. Hypertension. 2015;65(2):463–70.CrossRefPubMed
37.
• Mayer O Jr, Seidlerova J, Bruthans J, Filipovsky J, Timoracka K, Vanek J, et al. Desphospho-uncarboxylated matrix Gla-protein is associated with mortality risk in patients with chronic stable vascular disease. Atherosclerosis. 2014;235(1):162–8. This long-term prospective study among CVD patients indicates that low vitamin K status is associated with mortality risk. CrossRefPubMed
38.
Knapen MH, Braam LA, Drummen NE, Bekers O, Hoeks AP, Vermeer C. Menaquinone-7 supplementation improves arterial stiffness in healthy postmenopausal women. A double-blind randomised clinical trial. Thromb Haemost. 2015;113(5):1135–44.CrossRefPubMed
39.
Thompson S, James M, Wiebe N, Hemmelgarn B, Manns B, Klarenbach S, et al. Cause of death in patients with reduced kidney function. J Am Soc Nephrol. 2015;26(10):2504–11.CrossRefPubMedPubMedCentral
40.
Blacher J, Guerin AP, Pannier B, Marchais SJ, London GM. Arterial calcifications, arterial stiffness, and cardiovascular risk in end-stage renal disease. Hypertension. 2001;38(4):938–42.CrossRef
41.
Holden RM, Morton AR, Garland JS, Pavlov A, Day AG, Booth SL. Vitamins K and D status in stages 3–5 chronic kidney disease. Clin J Am Soc Nephrol. 2010;5(4):590–7.CrossRefPubMedCentral
42.
Pilkey RM, Morton AR, Boffa MB, Noordhof C, Day AG, Su Y, et al. Subclinical vitamin K deficiency in hemodialysis patients. Am J Kidney Dis. 2007;49(3):432–9.CrossRefPubMed
43.
Schurgers LJ. Vitamin K: key vitamin in controlling vascular calcification in chronic kidney disease. Kidney Int. 2013;83(5):782–4.CrossRefPubMed
44.
Cranenburg EC, Brandenburg VM, Vermeer C, Stenger M, Muhlenbruch G, Mahnken AH, et al. Uncarboxylated matrix Gla protein (ucMGP) is associated with coronary artery calcification in haemodialysis patients. Thromb Haemost. 2009;101(2):359–66.PubMed
45.
Delanaye P, Krzesinski JM, Warling X, Moonen M, Smelten N, Medart L, et al. Dephosphorylated-uncarboxylated matrix Gla protein concentration is predictive of vitamin K status and is correlated with vascular calcification in a cohort of hemodialysis patients. BMC Nephrol. 2014;15:145.CrossRefPubMedCentral
46.
Meuwese CL, Olauson H, Qureshi AR, Ripsweden J, Barany P, Vermeer C, et al. Associations between thyroid hormones, calcification inhibitor levels and vascular calcification in end-stage renal disease. PLoS One. 2015;10(7):e0132353.CrossRefPubMedPubMedCentral
47.
Thamratnopkoon S, Susantitaphong P, Tumkosit M, Katavetin P, Tiranathanagul K, Praditpornsilpa K, et al. Correlations of plasma desphosphorylated uncarboxylated matrix Gla protein with vascular calcification and vascular stiffness in chronic kidney disease. Nephron. 2016;135(3):167–72.CrossRefPubMed
48.
Schurgers LJ, Barreto DV, Barreto FC, Liabeuf S, Renard C, Magdeleyns EJ, 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;5(4):568–75.CrossRefPubMedPubMedCentral
49.
Schlieper G, Westenfeld R, Kruger T, Cranenburg EC, Magdeleyns EJ, Brandenburg VM, et al. Circulating nonphosphorylated carboxylated matrix gla protein predicts survival in ESRD. J Am Soc Nephrol. 2011;22(2):387–95.CrossRefPubMedPubMedCentral
50.
•• Keyzer CA, Vermeer C, Joosten MM, Knapen MH, Drummen NE, Navis G, et al. Vitamin K status and mortality after kidney transplantation: a cohort study. Am J Kidney Dis. 2015;65(3):474–83. This longitudinal study with long-term follow-up provides evidence that vitamin K status is associated with a strong risk of mortality after kidney transplantation. CrossRefPubMed
51.
Fu X, Wang XD, Mernitz H, Wallin R, Shea MK, Booth SL. 9-Cis retinoic acid reduces 1alpha,25-dihydroxycholecalciferol-induced renal calcification by altering vitamin K-dependent gamma-carboxylation of matrix gamma-carboxyglutamic acid protein in A/J male mice. J Nutr. 2008;138(12):2337–41.CrossRefPubMed
52.
Arbour NC, Darwish HM, DeLuca HF. Transcriptional control of the osteocalcin gene by 1,25-dihydroxyvitamin D-2 and its 24-epimer in rat osteosarcoma cells. Biochim Biophys Acta. 1995;1263(2):147–53.CrossRef
53.
Seyama Y, Horiuch M, Hayashi M, Kanke Y. Effect of vitamin K2 on experimental calcinosis induced by vitamin D2 in rat soft tissue. Int J Vitam Nutr Res. 1996;66(1):36–8.PubMed
54.
Breen EC, van Wijnen AJ, Lian JB, Stein GS, Stein JL. In vivo occupancy of the vitamin D responsive element in the osteocalcin gene supports vitamin D-dependent transcriptional upregulation in intact cells. Proc Natl Acad Sci U S A. 1994;91(26):12902–6.CrossRefPubMedPubMedCentral
55.
Fraser JD, Price PA. Induction of matrix Gla protein synthesis during prolonged 1,25-dihydroxyvitamin D3 treatment of osteosarcoma cells. Calcif Tissue Int. 1990;46(4):270–9.CrossRefPubMed
56.
Miyake N, Hoshi K, Sano Y, Kikuchi K, Tadano K, Koshihara Y. 1,25-Dihydroxyvitamin D3 promotes vitamin K2 metabolism in human osteoblasts. Osteoporos Int. 2001;12(8):680–7.CrossRefPubMed
57.
Braam LA, Hoeks AP, Brouns F, Hamulyak K, Gerichhausen MJ, Vermeer C. 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(2):373–80.PubMed
58.
Shea MK, O'Donnell CJ, Hoffmann U, Dallal GE, Dawson-Hughes B, Ordovas JM, et al. Vitamin K supplementation and progression of coronary artery calcium in older men and women. Am J Clin Nutr. 2009;89(6):1799–807.CrossRefPubMedPubMedCentral
59.
Kurnatowska I, Grzelak P, Masajtis-Zagajewska A, Kaczmarska M, Stefanczyk L, Vermeer C, et al. Effect of vitamin K2 on progression of atherosclerosis and vascular calcification in nondialyzed patients with chronic kidney disease stages 3–5. Pol Arch Med Wewn. 2015;125(9):631–40.
60.
Kurnatowska I, Grzelak P, Masajtis-Zagajewska A, Kaczmarska M, Stefanczyk L, Vermeer C, et al. Plasma desphospho-uncarboxylated matrix Gla protein as a marker of kidney damage and cardiovascular risk in advanced stage of chronic kidney disease. Kidney Blood Press Res. 2016;41(3):231–9.CrossRefPubMed
Metadata
Title
The Role of Vitamin K Status in Cardiovascular Health: Evidence from Observational and Clinical Studies
Authors
A. J. van Ballegooijen
J. W. Beulens
Publication date
01-09-2017
Publisher
Springer US
Published in
Current Nutrition Reports / Issue 3/2017
Electronic ISSN: 2161-3311
DOI
https://doi.org/10.1007/s13668-017-0208-8

Other articles of this Issue 3/2017

Current Nutrition Reports 3/2017 Go to the issue

Gastroenterology, Critical Care, and Lifestyle Medicine (SA McClave, Section Editor)

Nutritional Risk Factors in the Pathogenesis of Parenteral Nutrition-Associated Liver Disease

Cardiovascular Disease (JHY Wu, Section Editor)

Evidence of the Potential Effectiveness of Centre-Based Childcare Policies and Practices on Child Diet and Physical Activity: Consolidating Evidence from Systematic Reviews of Intervention Trials and Observational Studies

Gastroenterology, Critical Care, and Lifestyle Medicine (SA McClave, Section Editor)

Nutrition at the End of Life: It’s Not What You Say, It’s How You Say It

Cardiovascular Disease (JHY Wu, Section Editor)

Novel Online or Mobile Methods to Assess Eating Patterns

Gastroenterology, Critical Care, and Lifestyle Medicine (SA McClave, Section Editor)

Protein Intake in Chronic Kidney Disease

Cardiovascular Disease (JHY Wu, Section Editor)

Inflammation: a New Player in the Link Between Mediterranean Diet and Diabetes Mellitus: a Review
Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Reserve your place

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin
Prof. Florian Limbourg
Prof. Anoop Chauhan
Developed by: Springer Medicine
Obesity Clinical Trial Summary

At a glance: The STEP trials

Read more

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine
Image Credits