Vitamin K2 MK-7: prevention and treatment of arterial calcification

Cardiovascular health is fundamental to the well-being of the individual, and has important implications for broader society. Arterial calcification, because of lifestyle, disease or simply the passage of time, will increase with the demographic greying of developed country populations

Arterial calcification or hardening of the arteries is a leading cofactor of cardiac incident and mortality.

Increases in the incidence of cardiovascular disease will only add further stress to already burdened healthcare systems.

Unfortunately, there are few courses of action that an individual can take to prevent or reverse arterial calcification, with one breakthrough exception: vitamin K2 MK-7, taken in adequate nutritional doses, has been shown to reduce the progression of vascular smooth muscle (arterial) calcification and even reverse existing levels of arterial calcification.

Vitamin K2 MK-7 offers an opportunity for people to make a positive contribution to their personal heart health and overall well-being, as well as offers brands and manufacturers a means to differentiate or extend product lines in the lucrative heart health category, especially with products that have high baseline levels of natural or fortified calcium.

Arterial calcification: common and highly detrimental to cardiovascular health

Coronary artery calcification is an independent predictor of cardiovascular disease.1 Arterial calcification is the result of calcium deposit build-up within the vascular smooth muscle cells in the tunica media, reducing the elasticity of the vessel and resulting in arterial stiffness. This type of arterial calcification is distinct from, and happens in addition to, the calcification associated with atherosclerotic plaques or calcification of the tunica intima.2

Clinical observations show that arterial calcification and atherosclerosis are progressive, accumulate with time and that early signs of arterial calcification have been observed in otherwise healthy children. Studies have also reported that calcium deposits in arterial walls affect nearly 30% of Americans over the age of 45.3 Although vascular stiffening commonly increases with age (arteriosclerosis), vascular calcification increases the risk of cardiovascular events independent of age (atherosclerosis).4

Arterial calcification leads to stiffness in the vessel wall, reducing the ability of the vessel to be flexible. The vessel loses the facility to expand outward to accommodate blood flow — a flow that is moving through an already reduced diameter vessel because of calcified plaque build-up within the vessel.

As a result, the heart must work harder to push blood through the rigid, reduced-diameter vessel, which increases the risk of cardiovascular events. A study in patients with cardiovascular disease showed that the degree of aortic-valve calcification was inversely associated with event-free survival. In other words, severe calcification resulted in a poor patient prognosis.5

Like this story? Subscribe to Nutraceutical Business Review magazine for incisive analysis, the latest news and expert-written articles from the functional food and drink industries. For more information click here.

Vitamin K2 MK-7 regulates the transport of calcium

Vitamin K2 MK-7 regulates the extrahepatic movement and uptake of calcium in the body; or, more simply, K2 regulates the distribution of calcium. MK-7 activates the proteins that incorporate calcium into bones (where it is needed) and activates the proteins that bind calcium to prevent deposits in arteries and smooth muscle walls (where it increases cardiovascular risk factors).

Vitamin K2 is an essential cofactor for the activation of proteins belonging to the Gla-protein family, of which one of the most studied is osteocalcin. Osteocalcin plays a role in the integration of calcium into the bone matrix, a function that defines vitamin K2 as essential to bone health.

Vitamin K2 MK-7 is also essential for the activation of matrix Gla-protein (MGP).6 After MGP is activated (in a carboxylation process initiated by vitamin K2), MGP binds free-floating calcium to prevent it from being deposited in vascular smooth muscle cells.7 Without MGP activation, unbound calcium is free for deposit in arteries and vascular smooth muscle walls. In plain language, K2 prevents calcium from being deposited in arteries, making it essential for heart health.

K2 activation of matrix Gla-protein (MGP) to prevent arterial calcification

High blood levels of non-activated MGP (dp-ucMGP) correlates with low vitamin K status and also with vascular calcification. In healthy adults, non-activated MGP levels correlate with age, with significantly higher levels of non-activated MGP measured in people 65 or older.7

In sum, low vitamin K status correlates with high levels of non-activated MGP and vascular calcification. We need more vitamin K as we age.

Higher levels of non-activated MGP (or uncarboxylated MGP) have also been observed in people at specific risk of vascular calcification, including those with rheumatoid arthritis, aortic valve disease, aortic stenosis, heart failure, chronic kidney disease (CKD) and patients taking vitamin K antagonists.

Clinical observations show that arterial calcification and atherosclerosis are progressive, accumulate with time and that early signs of arterial calcification have been observed in otherwise healthy children

Studies have also shown that non-activated MGP is inversely correlated with poor dietary vitamin K intake. Further, an inverse relationship between non-activated MGP (dp-ucMGP) and cardiovascular patient survival indicates the importance of activated MGP in preventing vascular calcification.8 Non-activated MGP (and low vitamin K2 status) have also been found to be directly associated with cardiac-related mortality in aortic stenosis and chronic kidney disease patient populations.8–10

A recent publication supports these findings. In a study of 577 older individuals, non-activated MGP (dp-ucMGP) was associated with increased risk of cardiovascular disease, independent of other risk factors and vitamin D status. The effect was attributed to low vitamin K status.11

In summary, several studies have demonstrated that high levels of non-activated MGP (and activation can only be initiated by K2) are correlated with vascular calcification.

Shifting to the positive, studies have also shown that vitamin K2 supplementation produces a strong and significant decrease in non-activated MGP in healthy adults.7,12,13 Vitamin K2 doses from 90µg and higher significantly improve the carboxylation (activation) of MGP in healthy adults.14,15 Theuwissen and coworkers showed that after intake of vitamin K2 MK-7 in doses close to the Recommended Daily Allowance (90µg and greater), levels of carboxylated (activated) MGP increased significantly.14

MK-7: the optimal K2 format for the prevention of arterial calcification

The vitamin K family comprises phylloquinone (vitamin K1) and menaquinones (vitamin K2). Vitamin K1 primarily plays a role in blood coagulation, with a limited role in the regulation of calcium.

Menaquinones are classified according to the length of their side-chain, with menaquinone-4 (MK-4) and menaquinone-7 (MK-7) being the most important. MK-4, however, has the same short half-life as vitamin K1, one that is measured in just a few hours. MK-7, by contrast, has a half-life of several days, making it the optimal format for dietary supplementation.

Studies have also documented that MK-7 is the most potent of the K-vitamins.12 As the diets of most western populations contain little MK-7, assumptions of deficiencies can be made for this essential vitamin.16

A pivotal study on the intake of vitamin K from food, frequently referred to as the Rotterdam Study, demonstrated the effect of vitamin K2 in a study of 4807 Dutch men and women, aged 55 and older, during a period of 8–11 years.17

The study showed that diets high in vitamin K2 (MK-4 to MK-10) dramatically reduced the risk of cardiovascular disease and mortality (arterial calcification by 50%, cardiovascular death by 50% and all-cause mortality by 25%).

A study of more than 16,000 women (age 40–79) with a long follow-up period, known as the Prospect Study, allowed for the study of vitamin K2 menaquinones based on the length of their side-chain.18 The Prospect Study demonstrated an inverse correlation between intake of K2 (MK-7, MK-8 and MK-9) and the risk of coronary heart disease. The long-chain forms of K2 (MK-7 and higher), were shown to have the most beneficial effects on the prevention of coronary heart disease, with a mortality risk reduction of 9% for each extra 10µg/day intake.

Reversal of arterial calcification

The 2015 Knapen study provides some of the strongest evidence of the cardiovascular benefits of vitamin K2 MK-7. This placebo-controlled study of 244 postmenopausal women demonstrated that a high intake of vitamin K2 MK-7 was associated with reduced arterial calcification.19

The study showed that after 3 years, arterial stiffness significantly decreased among the MK-7 group (180µg/day), compared with a slight increase in stiffness among the placebo group. MK-7 not only inhibited the age-related stiffening of the vessel walls but also reversed and reduced it.

A path forward

Vitamin K2 MK-7 has been shown to reduce and even reverse arterial calcification, offering individuals a path to make a positive contribution to their personal heart health and overall well-being. Vitamin K2 Mk-7 offers brands and manufactures a means to differentiate products or extend product lines in the lucrative heart health category, especially with products that have high baseline levels of natural or fortified calcium.

References

1. P. Greenland, et al., “ACCF/AHA 2007 Clinical Expert Consensus Document on Coronary Artery Calcium Scoring by Computed Tomography in Global Cardiovascular Risk Assessment and in Evaluation of Patients with Chest Pain: A Report of The American College Of Cardiology Foundation Clinical Expert Consensus Task Force (ACCF/AHA Writing Committee to Update the 2000 Expert Consensus Document on Electron Beam Computed Tomography) Developed in Collaboration with the Society of Atherosclerosis Imaging and Prevention and the Society of Cardiovascular Computed Tomography,” J. Am. Coll. Cardiol. 49, 378–402 (2007).

2. W. Karwowski, et al., “The Mechanism of Vascular Calcification: A Systematic Review,” Med. Sci. Monit. 18(1), 1–11 (2012).

3. D.E. Bild, et al., “Ethnic Differences in Coronary Calcification: The Multi-Ethnic Study of Atherosclerosis (MESA),” Circulation 111, 1313–1320 (2005).

4. C. Iribarren, et al., “Calcification of the Aortic Arch: Risk Factors and Association with Coronary Heart Disease, Stroke and Peripheral Vascular Disease,” JAMA 283, 2810–2815 (2000).

5. R. Rosenhek, et al., “Predictors of Outcome in Severe, Asymptomatic Aortic Stenosis,” N. Engl. J. Med. 343(9), 611–617 (2000).

6. G.W. Dalmeijer, et al., “Matrix Gla Protein Species and Risk of Cardiovascular Events in Type 2 Diabetic Patients,” Diabetes Care 36(11), 3766–3771 (2013).

7. E.C. Cranenburg, et al., “Characterisation and Potential Diagnostic Value of Circulating Matrix Gla Protein (MGP) Species,” Thromb. Haemost. 104(4), 811–822 (2010).

8. T. Ueland, et al., “Undercarboxylated Matrix Gla Protein is Associated with Indices of Heart Failure and Mortality in Symptomatic Aortic Stenosis,” J. Intern. Med. 268(5), 483–492 (2010).

9. H.M. Spronk, et al., “Tissue-Specific Utilization of Menaquinone-4 Results in the Prevention of Arterial Calcification in Warfarin-Treated Rats,” J. Vasc. Res. 40, 531–537 (2003).

10. J. Keutel, G. Jorgensen and P. Gabriel, “A New Autosomal-Recessive Hereditary Syndrome. Multiple Peripheral Pulmonary Stenosis, Brachytelephalangia, Inner-Ear Deafness, Ossification or Calcification of Cartilages,” Dtsch Med. Wochenschr. 96, 1676–1681 (1971).

11. E.G.H.M. van den Heuvel, et al., “Circulating Uncarboxylated Matrix Gla Protein: A Marker of Vitamin K Status as a Risk Factor of Cardiovascular Disease,” Maturitas 77, 137–141 (2014).

12. L.J. Schurgers, et al., “Vitamin K-Containing Dietary Supplements: Comparison of Synthetic Vitamin K1 and Natto-Derived Menaquinone-7,” Blood 109. 3279–3283 (2007).

13. E. Theuwissen, 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. 108(9), 1652–1657 (2012).

14. E. Theuwissen, et al., “Vitamin K Status in Healthy Volunteers,” Food Funct. 5, 229–234 (2014).

15. R. Westenfeld, et al., “Effect of Vitamin K(2) Supplementation on Functional Vitamin K Deficiency in Hemodialysis Patients: A Randomized Trial,” Am. J. Kidney Dis. 59(2), 86–95 (2012).

16. C. Vermeer, “Vitamin K: The Effect on Health Beyond Coagulation: An Overview,” Food Nutr. Res. 56 (2012): doi: 10.3402/fnr.v56i0.5329.

17. J.M. Geleijnse, et al., “Dietary Intake of Menaquinone is Associated with a Reduced Risk of Coronary Heart Disease: The Rotterdam Study,” J. Nutr. 134(11), 3100–3105 (2004).

18. G.C.M. Gast, et al., “A High Menaquinone Intake Reduces the Incidence of Coronary Heart Disease,” Nutr. Metab. Cardiovasc. Dis. 19(7), 504–510 (2009).

19. M.H. Knapen, et al., “Menaquinone-7 Supplementation Improves Arterial Stiffness in Healthy Postmenopausal Women. A Double-Blind Randomised Clinical Trial,” Thromb. Haemost. 113(5), 1135–1144 (2015).

Featured Companies

Kappa Bioscience (more information, website)