Vitamin K2 and Heart Health

Vitamin K2 is important for optimal cardiovascular health (CVH). Vitamin K2 as menaquinone-7 (MK-7) is the vitamin K of choice for maintaining healthy blood vessels.

• MK-7 intake is associated with beneficial effects on cardiovascular health such as inhibition of vessel calcification. No such effects are found for dietary vitamin K1.
• Vitamin K2 deficiency, for instance induced by long term treatment with coumarins, results in calcification of vessels.
• MK-7, even in low concentrations, is far more effective in the body than vitamin K1 (and menaquinones-4, MK-4) for activation of matrix Gla-protein; an important inhibitor of vessel calcification.
• Western diet contains very little MK-7 and supplementation may be beneficial for support of optimal cardiovascular health.
• Vitamin K2 has been tested in clinical trials and documented to be safe.

Introduction

Cardiovascular diseases (CVD) are the number one cause of death globally; more people die annually from CVDs than from any other cause. An estimated 17.3 million people died from CVDs in 2008, representing 30% of all global deaths. Of these were an estimated 7.3 million due to coronary heart disease and 6.2 million due to stroke (American Heart Association 2011). CVD is closely related to life-style factors. Heart disease and stroke can to a large extent be prevented through a healthy diet, regular physical activity and avoiding tobacco smoke. The cost for the society is huge; in the US it has been estimated that in the next twenty years the cost of medical care for heart disease will rise from $273 billion (2010) to $818 billion (2030). In addition, heart disease will result in cost related to productivity; $172 billion in 2010 increasing to $276 billion in 2030 (WHO 2011).

In recent years growing evidence for an important role of vitamin K2 in prevention of CVD has appeared in the scientific literature (Gelijnse et al. 2004, Gast et al. 2009, Beulens et al. 2009). Since western diets contain very little vitamin K2, is a dietary supplementation of this important vitamin suggested in order to obtain beneficial effects on cardiovascular health (CVH).

 

Heart Health and cardiovascular calcification

Cardiovascular disease (CVD) is caused by disorders of the heart and blood vessels. CVD includes coronary heart disease (heart attacks), cerebrovascular disease (stroke), raised blood pressure (hypertension), peripheral artery disease, rheumatic heart disease, congenital heart disease and heart failure. Heart attacks and strokes are usually acute events and are mainly caused by a blockage that prevents blood from flowing to the heart or brain. The most common reason for this is a build-up of fatty and calcium rich deposits on and in the inner walls of the blood vessels that supply the heart or brain- known as atherosclerosis (Figure 1).

There are two major types of calcium mineralization;

• medial arterial calcification (in vascular smooth muscle cells, VSMC, in the arteries), and calcification associated atherosclerotic plaque (calcification of the tunica intima) (Doherty 2004). Arterial calcification was initially referred to as Mönckeberg’s sclerosis and both the media and internal
• elastic lamina (layer of elastic tissue layer between the intima and media tunica) are involved (Micheletti et al. 2008). For a review calcification of the arteries, see Dohorty 2004).

 

Figure 1: Development of atherosclerosis, from medmovie.com 2004

Calcification of the arteries is strongly linked to increased risk of cardiovascular disease (Chapman1960, Giachelli 2004, Johnson et al. 2006, Vattikuti and Towler 2004, Truong and Booth 2011,).  In patients, an inverse relationship between calcification of vessels and survival is demonstrated (Rosenhek et al. 2000). Vascular calcification is frequent in the general population and is increasing with age. The vascular calcification is complex, but may be preventable (Schurgers et al. 2007a, Trion and van der Laarse 2004).

 Matrix GLA Protein, MGP – A strong inhibitor of vessel calcification.

One of the strongest inhibitors of vessel calcification is the vitamin K dependent protein matrix Gla-protein (MGP) (Shearer and Newman 2008). Activated MGP binds calcium, preventing calcium deposits in arteries. The protein was first described by Price (Price 1983), and its presence in arteries and in atherosclerotic plaques have later been demonstrated (Price 1988, Shanahan et al. 1994, Fraser and Price 1988).

Lou and coworkers showed that mice lacking MGP developed to term, but die within two months as a result of arterial calcification which leads to blood-vessel rupture (Luo 1997). In accordance with this, Price was able to demonstrate that in warfarin treated rats, inhibiting vitamin K dependent MGP activation, the animals developed calcification of the elastic lamellae in arteries and heart valves (Price 1998). Figure 2 shows the structure of MGP with the five Gla residues (in red). In addition to glutamate carboxylation, MGP may also be phosphorylated (indicated in pink, fig. 2).

 

Figure2: Matrix Gla-protein- MGP- Activated by vitamin K –ready to bind calcium

 

Schurgers et al. discuss the effects of the different forms of MGP in maintaining healthy vessels (Schurgers et al. 2008). Significantly increased level of circulating non-phosphorylated, non-carboxylated MGP (dp-uc-MGP, inactive) was found in patients on anti-coagulation treatment compared to controls (Rennenberg et al. 2010). They conclude that active MGP is a potent inhibitor of arterial calcification.

The effects of preventing calcification by activated MGP have been demonstrated in animal models as well as humans (Proudfoot et al. 2006, Schurgers et al. 2008, Shanahan et al. 1998, Zebboudj et al. 2003).

Figure 3: Left: Healthy vessel with active MGP, cMGP.  Right: calcified vessels in the presence of inactive MGP, ucMGP

 An inverse relationship between under-caboxylated MGP (inactive) and survival in cardiovascular patients indicates an important role of MGP and vitamin K in preventing vessel calcification (Ueland et al. 2010). In a recent publication, it was found a 4.5 fold and 8.4 fold higher levels of undercarboxylated MGP and osteocalcin (OC), respectively in hemodialysis patients compared to controls (Westenfeld et al. 2012). The study confirms that hemolysis patients have a vitamin K deficiency and which may lead to vascular calcification.

Conclusion: MGP is a potent inhibitor of arterial calcification. Vitamin K2 is pivotal for activation of MGP.

 

Intake of Vitamin K2 – Positive effects on cardiovascular health

In a study in the Netherlands (The Rotterdam Study – 2004), involving 4807 Dutch men and women followed for 8-11 years, it was demonstrated that food intake of high amounts of vitamin K2 (menaquinones 4-10) dramatically reduced the risk of cardiovascular diseases and mortality (figure 4) (Geleijnse et al. 2004). Vitamin K1 had no effects on outcome in this large study.

In a follow-up study in 564 postmenopausal women using food-frequency questionnaire to estimate intake of vitamin K, it was demonstrated that high intake of menaquinones, but not vitamin K1 was associated with reduced coronary calcification (Beulens et al. 2009).

Figure 4: The Rotterdam study:Effect of vitamin K2 intake on heart and cardiovascular health (modified from Geleijnse et al. 2004

 

A similar study in 16057 women showed that there was an inverse correlation between intake of vitamin K2 (menaquinones MK7, MK-8 and MK-9) and the risk of coronary heart disease (CHD). Vitamin K1 intake was not associated with reduction of CHD (Gast et al. 2008). These data supports earlier findings that dietary vitamin K1 had no effect on coronary calcification (Villinus et al. 2005).

In a recent unpublished study in elderly women, treatment with daily dose of 180μg/day MK-7 for three years resulted in positive effects on several CVD-parameters including the pulse wave velocity (Homepage NattoPharma, press release).

Conclusion: Arterial calcification is linked to CVD and increased risk of death. MGP, activated by vitamin K2, inhibits calcification of vessels and may be an important factor for prevention of CVD. Supplementation of vitamin K2, and in particularly MK-7, may prevent arterial calcification and contribute to less cardiovascular disease such as CHD. No such association has been attributed to vitamin K1.

 

Vitamin K and the «calcium paradox»

Calcification of vessels is a process resembling the bone formation process. Many recent publications indicate a link between CVD and osteoporosis (Booth 2009, Fujita et al. 2000, Kidd et al. 2010, Szulc et al. 2009, Hamerman, review, 2005). The link is mainly based on epidemiological studies showing that people with arterial calcification also had increased bone loss (Jørgensen et al. 2004, Wiklund et al. 2011, Hofbauer et al. 2007).

The findings are supported by studies looking at mechanisms, which may explain why risk for vascular disease may be related to risk of osteoporosis (Hamerman 2005, Eastell et al. 2010, Vattikuti and Towler 2004). The mineral composition of bone (hydroxyapatite) is chemically very similar to that observed in calcific deposits in atherosclerotic arteries (Duer et al. 2008, Doherty et al. 2004). Vitamin K is involved in both processes; as a cofactor for activating osteocalcin associated with building calcium into bone and for activating MGP, inhibiting calcium accumulation in vessel  (Newman and Shearer 2008, Rishavy et al.2004, Schurgers et al. 2008). This is the so-called “the Calcium Paradox”.

Conclusion: Research points to an important link between bone and cardiovascular health and the regulation of calcium in body tissue. Vitamin K2 is one pivotal key; activating Gla-proteins such as osteocalcin and matrix Gla-protein, for calcium binding and regulation.

 

Vitamin K deficiency – result of anti-coagulant treatment – negative effects on CVD

Oral anti-coagulants or vitamin K-antagonists like the coumarins are used globally for primary and secondary prevention of both arterial and venous thrombosis (Ansell et al. 2004). Coumarins interfere with the activation of vitamin K-dependent coagulation factors, thereby lowering the ability for blood clotting. While warfarin may prevent stroke and pulmonary embolism, it may possibly contribute to complications associated with low vitamin K activity, such as osteoporosis, bone fractures, and calcification of arteries (Barnes et al. 2005, Caraballo et al. 1999, Cranenberg et al. 2007, Hylek et al. 2003, Lerner et al. 2009, Rennenberg et al. 2010, Weijs et al. 2010.)

Danzinger has given a review of the effects of warfarin treatment on Gla-proteins. The coagulation factors are activated in the liver, while for instance MGP is activated in the vasculature. As warfarin inhibits the vitamin K-cycle, both processes are inhibited (Danziger 2008). This implies that warfarin may lead to vitamin K deficiency in peripheral tissue, potentially giving serious side-effects (Figure 5).

Figure 5: Hepatic carboxylation, vitamin K1 and peripheral carboxylation, vitamin K2. In the presence of warfarin little or no carboxylation takes place in the periphery. Modified from Danziger 2008.

 

In a cross sectional study in middle aged long term coumarin users and a matched control group, it was demonstrated that chronic coumarin therapy is associated with enhanced vascular calcification (Rennenberg et al. 2010). It was suggested that the effects were related to the inhibition of MGP activation, resembling vitamin K2 deficiency.

In a recent study, use of anti-coagulants was associated with negative effects on cardiovascular health (Weijs et al. 2011). The authors suggest that chronic use of vitamin K antagonist may enhance potentially harmful coronary calcification in elderly low-risk atrial fibrillation patients.

Conclusion: Current research indicates that long term therapy with anti-coagulants, i.e. blocking vitamin K2 activity, may result in negative effects on bone health and calcification of blood vessels.

 

Vitamin K2, MK-7 Superior to Vitamin K1

Vitamin K comprises a number of structurally related compounds including phylloquinone (vitamin K1) and menaquinones (vitamin K2s); menaquinone-4 (MK-4) and menaquinone-7 (MK-7) being the most important. Basically, the K vitamins act in the same manner by activating the Gla-proteins. However, there are a large differences in absorption, transport in blood and tissue distribution (Schurgers et al. 2002). The half-life for MK-7 is extremely much longer than for vitamin K1; 72hours vs. 1-2 hours and is more efficient for activation of Gla-proteins in extra hepatic tissue (i.e. bone and vessels) (Schurgers et al. 2007b).

The biological activity of K vitamins are dependent on the three-dimensional configuration; the molecule can be in a cis or a trans form. Studies have demonstrated that only the all-trans form is biological active (Lowenthal et al. 1979)¸ probably due to the requirement for the trans structure to interact with the enzymes in the vitamin-K cycle (Li et al. 2010).

 

Vitamin K2 – is there a deficiency in general population?

Phylloquinone is found in green/leafy vegetables such as green salads, broccoli and spinach. Vitamin K1 is considered as the major dietary source of vitamin K, accounting for approximately 90% of total vitamin K intake (Schurgers and Vermeer 2000). Based on different studies of content in food worldwide, Suttie has given a summary of estimated an intake of vitamin K in the general population to be between 70 to 250 mcg/day (Suttie, ed. “Vitamin K”, 2009). However the bioavailability of vitamin K1 from food is low; less than 20% is absorbed (Garber and Vermeer 1999).

Vitamin K2, menaquinones, are found in animal products, meat, dairy, eggs (mainly MK-4) and fermented food, e.g. cheese, yoghurt, and fermented soybean products such as the Japanese dish natto (mainly MK-7), (Schurgers and Vermeer 2000). In the Netherlands the average intake of MK-4 and long-chain menaquinones from eggs and cheese has been reported to be in the range 7μg/day and 22μg/day, respectively (Schurgers et al. 1999). Limited knowledge exists regarding intake of menaquinones; fermented cheeses may be the most important source (Schurgers and Newman 2009).

The intake of K vitamins is sufficient for 100% activation of the clotting factors in the liver in the healthy population (Schurgers et al. 2007b, Theuwissen et al. 2012)

In contrast to the coagulation factors, several studies have demonstrated that both OC and MGP in serum are not fully activated in the general population (10- 40%) and that supplementation increases the degree of activation (Booth 2009, Sokoll et al. 1997, Shea et al. 2011, Westenfeld et al. 2012, Theuwissen et al. 2012). Potentially, extra-hepatic caroxylation of Gla-proteins contribute to better health (Theuwissen et al. 2012).

In studies in healthy volunteers it has been demonstrated that only doses from 90μg and above significantly improved the carboxylation of OC or MGP (Tsukamoto et al., Brugè et al.2011, Theuwissen et al. 2012, own unpublished data). In a small study in 12 volunteers, only the 90 μg dose was able to produce a significant biological effect, measured as increase of the cOC:ucOC ratio (well-recognized index of the functionality of OC) (Brugè et al.2011). In a small study giving placebo or 45- 180μg MK-7 for six weeks, a significant linear dose response relationship for plasma level of MK-7 was found. Only at the highest dose, 180μg, a significant increase in cOC and decrease in ucOC from baseline was found (own data, unpublished). In a recent publication, Theuwissen et al. (2012) demonstrated that after intake of MK-7 in doses around Recommended Daily Intake, RDA, (i.e. 90μg and above) a significant increased circulation of carboxylated OC and MGP was demonstrated .

 

Recommendations:                                                                                                                         

Vitamin K2’s relation to cardiovascular health is a new field with interesting perspectives for public health. The strong link between the silent arterial calcification and increased risk for cardiovascular events suggests needs for preventive actions. Research points a pivotal role for the matrix Gla protein (MGP), one of the strongest natural inhibitors of vascular calcification. Vitamin K2 is a key factor for MGP activation.

Vitamin K2 deficiencies are quite common in the general population, except for people eating natto and a few other foods. Recent published data indicates that doses of vitamin K2 in the range of RDA (90μg/day) are needed for sufficient activation of MGP and osteocalcin (in bone). Important: Patients on oral anticoagulant therapy using coumarins/warfarin should always consult their physician before taking vitamin K2.

 Buy Vitamin K2 here

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