|
CAD AND VITAMIN K2
"It has been hypothesized that insufficient intake of vitamin K may increase soft-tissue
calcification owing to impaired gamma-carboxylation of the vitamin K-dependent protein matrix gamma-carboxyglutamic acid."
"In animal models, multiple forms of vitamin K have been shown to reverse the arterial
calcification created by vitamin K antagonists. The human data, however, are less consistent. Phylloquinone, the primary dietary
form, has not been associated consistently with the risk of cardiovascular diseases. High menaquinone intake may be associated
with lower risk of coronary heart disease mortality, but this needs to be confirmed".1
1. Erkkil AT, Booth SL.
Vitamin K intake and atherosclerosis.Curr Opin Lipidol. 2008 Feb;19(1):39-42.
HISTORY
1929: Vitamin K was discovered by Henrik Dam of Denmark. He noted that chickens started bleeding after several
weeks on a cholesterol-depleted diet.
Bleeding could only be stoppped when an essential compound from food added with the cholesterol. This new compound received
the letter "K" as the report was published as Koagulationsvitamin.
Dam H: Biochem Z, 215, 475,1929,
Dam, H. (1935). "The Antihmorrhagic Vitamin of the Chick.: Occurrence And Chemical Nature".
Nature 135 (3417): 652–653. doi:10.1038/135652b0
====
Chronological history obtained from:
MENAQ7. HISTORY:
"1929 – Dam discovers that young birds fed a fat-deficient diet experience lengthened blood clotting time,
anemia and hemorrhage. He postulates that there had to be a missing fat-soluble factor not previously known2
1934 – Dam and Schnheyder identify a factor in hempseed that prevents bleeding. Dam called it vitamin K from
"Koagulations-Vitamin" in German3. He also found vitamin K in other vegetables and in animal liver
1938 – Almquist et al show that vitamin K is formed also in bacteria in the intestinal canal4
1939 – Doisy et al succeed in determining the chemical structure of vitamin K as well as to synthesize vitamin
K
1943 – Dam and Doisy shared the Nobel Prize in medicine for their discovery of vitamin K
1974 – Stenflo and Nelsestuen discover that prothrombin – one of the important coagulation factors-
contains the unusual amino acid γ-carboxy glutamic acid (Gla) in the vitamin K-dependent region of the molecule. This
led to the understanding of how vitamin K could contribute to the activation of coagulation factors5, 6
1975 – Esmon et al discover a vitamin K-dependent protein carboxylation reaction in the liver7
1983 – Price et al describe Matrix Gla-protein (MGP); the strongest vitamin K-dependent inhibitor of tissue
calcification presently known8 GLA= gamma-carboxyglutamate
Price PA, Williamson MK.. Primary structure of bovine matrix Gla protein, a new vitamin K-dependent bone protein. J Biol Chem. 1985 Dec 5;260(28):14971-5.
The complete amino acid sequence of bovine bone matrix Gla protein (MGP) was determined by automatic sequence analysis
of the intact protein and of peptides isolated from tryptic and BNPS-skatole digests.
There is sufficient sequence homology between MGP and bone Gla protein (BGP) to indicate that these two bovine bone
proteins arose by gene duplication and subsequent divergent evolution.
MGP is the first vitamin K-dependent protein to be discovered which has several non-gamma-carboxylated residues to
the NH2-terminal side of its Gla residues.
1997 – Lou et al demonstrate the importance of MGP for vascular health by using MGP-deficient animals9
Calcification of the extracellular matrix (ECM) can be physiological as in bones or pathological.as occurs in
arteries and cartilage and other soft tissues.
What causes this pathological extracellular matrix calcification is not known. This paper identified
a molecule, matrix GLA protein (Mgp), a mineral-binding ECM protein synthesized by vascular smooth-muscle cells and chondrocytes,
that produce an uncalcified ECM. Mice that lacked Mgp,, though develop to term but die within months due to arterial
calcification resulting blood-vessel rupture. Mgp-deficient mice also developed pathological calcification of various cartilages
leading to short stature, osteopenia and fractures. This study indicted that ECM calcification must be actively inhibited
in soft tissues by Mgp to prevent calcification of arteries and cartilage..
2004 – Geleijnse et al publish a population-based study demonstrating that high dietary intake of vitamin
K2 influences cardiovascular health and reduced cardiovascular mortality. In this study dietary vitamin K2 appeared to be
superior to vitamin K1
2007 – Schurgers et al show that natural vitamin K2 as Menaquinone-7 (MK-7) is the most bioavailable, bioactive
and longest lasting form of vitamin K10
2008 – Gast el al publish another large population study confirming that natural dietary vitamin K2 is correlated
to improved cardiovascular health. Intake of vitamin K1 has no effect, while the benefits are specifically associated with
the longer menaquinones MK-7, MK-8 and MK-9"
2003:
H.M.H. Spronkb, B.A.M. Soutea, L.J. Schurgersa, H.H.W. Thijssenc, J.G.R. De
Meyc, C. Vermeera.Tissue-Specific Utilization of Menaquinone-4 Results in the
Prevention of Arterial Calcification in Warfarin-Treated Rats. J Vasc Res 2003;40:531-537 (DOI: 10.1159/000075344)
The warfarin-treated rat model were fed diets containing K1, MK-4, or both.
MK-4 and not K1 inhibited warfarin-induced arterial calcification.
The total hepatic K1 accumulation was threefold higher than that of MK-4, whereas aortic MK-4 was three times that of K1.
K1 and MK-4 were both equally utilized in the liver, but the aorta showed a more efficient utilization of MK-4.
2004: The Rotterdam study:
The effects of dietary intake of Vitamin K1 and K2 (mainly MK-4 from eggs and meat, and MK-8 and
MK-9 from cheese) were studied on following conditions:
1. The incidence of coronary heart disease (CHD)
2. All-cause mortality.
3. Aortic calcification.
4,800 healthy men and women werestudied and followed for over a 10 year period. It was shown that the highest vitamin K2
intake, 45mcg daily, resulted in 50% less arterial calcification and a 50% reduction CAD related death compared to the lowest
consumption group with intake of of K2, 12 mcg daily. Findings from the study indicate that eating foods rich in natural vitamin K2 (at least 32 mcg per day) results
in 50% reduction of arterial calcification, 50% reduction of cardiovascular death and 25% reduction of all cause mortality.
Geleijnse JM., et al. Dietary Intake of Menaquinone Is Associated with a Reduced Risk of Coronary
Heart Disease: The Rotterdam Study, Nutritional Epidemiology, 2004 134: 3100-3105.
----
Table from original study
Dietary Intake of Menaquinone Is Associated with a Reduced Risk of Coronary
Heart Disease: The Rotterdam Study
TABLE 3Association of coronary events and all-cause
mortality with intake of menaquinone in 4807 Dutch men and women aged 55 y and over1
|
Energy-adjusted menaquinone intake (g/d)
|
P for trend |
| <21.6 |
21.6–32.7 |
>32.7 |
|
| n |
1578 |
1605 |
1624 |
|
| Median intake, g/d |
15.1 |
26.9 |
40.9 |
|
| Nonfatal MI |
|
|
|
|
| Person-years |
11181 |
11549 |
11915 |
|
| Events, n |
51 |
57 |
36 |
|
| RR, model 12 |
1 |
1.15 (0.79, 1.69) |
0.74 (0.48, 1.14) |
0.18 |
| RR, model 23 |
1 |
1.08 (0.73, 1.62) |
0.67 (0.41, 1.09) |
0.12 |
| Incident CHD4 |
|
|
|
|
| Person-years |
11323 |
11556 |
11766 |
|
| Events, n |
86 |
89 |
58 |
|
| RR, model 1 |
1 |
1.05 (0.78, 1.42) |
0.71 (0.51, 1.00) |
0.048 |
| RR, model 2 |
1 |
0.96 (0.70, 1.31) |
0.59 (0.40, 0.86) |
0.007 |
| CHD mortality5 |
|
|
|
|
| Person-years |
11356 |
11747 |
12043 |
|
| Events, n |
41 |
35 |
23 |
|
| RR, model 1 |
1 |
0.84 (0.54, 1.33) |
0.59 (0.35, 0.99) |
0.045 |
| RR, model 2 |
1 |
0.73 (0.45, 1.17) |
0.43 (0.24, 0.77) |
0.005 |
| All-cause mortality |
|
|
|
|
| Person-years |
11356 |
11747 |
12043 |
|
| Events, n |
258 |
248 |
195 |
|
| RR, model 1 |
1 |
0.97 (0.82, 1.16) |
0.81 (0.67, 0.98) |
0.030 |
| RR, model 2 |
1 |
0.91 (0.75, 1.09) |
0.74 (0.59, 0.92) |
0.007 | |
1 RR obtained by Cox proportional hazard analysis, with 95% CI in parentheses and P for
linear trend across the tertiles.
2 Model includes age, gender, and total energy intake.
3 Model includes age, gender, total energy intake, BMI, smoking status, pack-years of cigarette smoking,
diabetes, education (3 categories), and intake of alcohol, SFA, PUFA, flavonols (quercetin, myricetin, and kaempferol), and
calcium.
4 CHD comprises fatal and nonfatal MI, sudden cardiac death, and other forms of acute and chronic
ischemic heart disease (ICD-10 codes I20–I25 and I46).
5 CHD events followed by death within 28 d after the onset of symptoms.
====
"Menaquinone intake was lower in subjects with severe aortic calcification (25.6 g/d) than in subjects with moderate
or mild calcification (28.6 and 28.8 g/d, respectively; P = 0.001).................
Menaquinone intake showed no significant association with moderate calcification ( Table 4). For severe calcification, however, a strong inverse relationship with menaquinone intake persisted after adjustment for
BMI, smoking, education, diabetes, and intake of alcohol, PUFA, SFA, flavonols, and calcium (Table 4). Additional adjustment for intake of fiber, vitamin C, vitamin E, and -carotene did not change these results."
Dietary Intake of Menaquinone Is Associated with a Reduced Risk of Coronary
Heart Disease: The Rotterdam Study
TABLE 4Association of aortic calcification with
intake of menaquinone in 4473 Dutch men and women aged 55 y and over,1, 2
|
Energy-adjusted menaquinone intake (g/d)
|
P for trend |
| <21.6 |
21.6–32.7 |
>32.7 |
|
| n |
1468 |
1493 |
1512 |
|
| Median intake, g/d |
15.1 |
26.9 |
40.9 |
|
| Moderate calcification |
|
|
|
|
| Controls, n |
916 |
958 |
1000 |
|
| Cases, n |
454 |
452 |
453 |
|
| OR, model 13 |
1 |
0.93 (0.79, 1.10) |
0.94 (0.80, 1.11) |
0.49 |
| OR, model 24 |
1 |
0.91 (0.77, 1.09) |
0.93 (0.76, 1.12) |
0.45 |
| Severe calcification |
|
|
|
|
| Controls, n |
916 |
958 |
1000 |
|
| Cases, n |
98 |
83 |
59 |
|
| OR, model 1 |
1 |
0.75 (0.54, 1.03) |
0.56 (0.39, 0.80) |
0.001 |
| OR, model 2 |
1 |
0.71 (0.50, 1.00) |
0.48 (0.32, 0.71) |
<0.001 | |
1 Aortic calcification was graded according to the length of the calcified area, i.e., no/mild (reference),
≤1 cm; moderate, >1 and <5 cm; severe, ≥5 cm.
2 OR obtained by multivariate logistic regression, with 95% CI in parentheses and P for
linear trend across the tertiles.
3 Model includes age, gender, and total energy intake.
4 Model includes age, gender, total energy intake, BMI, smoking status, pack-years of cigarette smoking,
diabetes, education (3 categories), and intake of alcohol, SFA, PUFA, flavonols (quercetin, myricetin, and kaempferol), and
calcium.
"For menaquinone (MK-n), dietary data are scanty in the literature. We therefore analyzed foods and beverages
frequently consumed in the Netherlands for MK-4 through MK-10 and linked these data to the dietary database of the Rotterdam
Study (19). Intake of menaquinone comprised 10% of the total vitamin K intake, but its bioavailability is probably higher than for
phylloquinone that is strongly bound to vegetable fiber (14). Menaquinone in our Dutch population was mainly derived from dairy products, especially cheese (19). Interestingly, in this respect, cheese has not been established as a dietary risk factor for cardiovascular disease in
epidemiological studies, despite its high levels of saturated fat and salt. We hypothesize that menaquinones in cheese (MK-8
and MK-9) could exert a beneficial effect in the cardiovascular system and that the high cheese consumption in France and
the Mediterranean countries may possibly account for lower prevalences of CHD. Menaquinone is also produced by the intestinal
flora, but the absorption seems to be limited (27). In our study, however, it was not possible to quantify endogenous menaquinone synthesis. Dietary intake of menaquinone
is reflected in serum levels. In healthy Japanese subjects who consumed fermented soybean (natto) high in menaquinone (especially
MK-7), serum concentrations of MK-7 and carboxylated osteocalcin were significantly increased (28).
Vascular tissue and calcified plaques contain MGP, a vitamin K–dependent protein known to prevent excessive calcium
deposition in bone (1–4,7,8).
Lack of vascular MGP resulted in excessive aortic and coronary calcification in knockout mice (9). The inverse association of menaquinone with aortic calcification and CHD in our study may be explained by undercarboxylation
of vascular MGP and consequently enhanced calcification of atherosclerotic lesions. Calcified plaques are more prone to rupture,
which will elicit a thrombotic response, thereby increasing the risk of a coronary event (29).
Another vitamin K–dependent protein found in the vessel wall is protein S (30). Together with activated protein C, this anticoagulant plays an important role in preventing clot formation at the inner
surface of the vessel wall. However, the quantitative contribution of extrahepatic protein S synthesis to hemostasis is probably
small.
There is evidence for a differential effect of vitamin K subtypes in the cardiovascular system. Rats at our laboratory
were fed diets containing phylloquinone, menaquinone, or both after treatment with high doses of warfarin. Despite similar
in vitro cofactor activity for γ-carboxylase, menaquinone but not phylloquinone supplementation prevented warfarin-induced
arterial calcification (31). The tissue-specific use of phylloquinone and menaquinone in rats was assessed by measuring the ratios of quinone over epoxide
(K:KO ratios) during warfarin treatment. In the arterial vessel wall, K:KO ratios were substantially lower for phylloquinone
than for menaquinone whereas the reverse was observed for the liver, suggesting a tissue-specific utilization of vitamin K
subtypes (31). In a recent trial in humans, phylloquinone was almost exclusively incorporated into the triacylglycerol-rich lipoprotein
(TGRLP) fraction after intestinal absorption, whereas a substantial part of the menaquinones was recovered from the LDL fraction
(32). The TGRLP fraction is mainly cleared by the liver, whereas LDL forms a transport system to extrahepatic tissues. Menaquinone
supplementation lowered serum cholesterol levels in a study of 17 dialysis patients (33). In our population of healthy older subjects, we confirmed the favorable effect of menaquinone on blood lipids but effects
were small and could not explain the inverse relation that we observed between dietary menaquinone and CHD.
In conclusion, our findings suggest a protective effect of menaquinone intake against CHD, which could be mediated by inhibition
of arterial calcification. Adequate intake of foods rich in menaquinones, such as curds and (low-fat) cheese, may contribute
to CHD prevention."
=====
"This information proves that Vitamin K2 is a critical nutrient
for patients with arteriosclerosis as it has the potential to prevent and remove calcium from arteriosclerotic plaques thus
making plaques easier to dissolve and less dangerous."1
VITAMIN K
Vitamin K is found
in plants as phylloquinone K1 and in animals as menaquinone K2
and synthetic form K3.
Functions:
1. Helps blood coaguation (K1)
2. Influences bone formation and tissue calcification and atherosclerosis (K2).
Vitamin D3, calcium, and magnesium are important for maintaining and promoting bone health. Vitamin
K plays a vital role in bone metabolism and healthy bone formation and density.
Vitamin K helps osteoblastic cell that generates or lays down bone and osteocalcin production.
Osteocalcin, a protein, acts as the structural framework holding calcium in place in bones. Vitamin K converts osteocalcin
to an active bone-building form before it can perform its bone building function.
Vitamin K is also important for transportation of calcium in bloodstream into bones.
Osteoclasts as opposed to osteoblast, breaks down bone and remove bone tissue.
Vitamin K2 has also been shown to inhibit osteoclasts and help maintain bones.
Vitamin K2-7 stimulates carboxylation (gamma-carboxylated osteocalcin), which plays
an important role in bone formation.
References:
Y. Koshihara and K Hoshi. shows that vitamin K2 increased Gla-containing osteocalcin,
which accumulated osteocalcin in the extracellular matrix, and facilitated mineralization in vitro.Journal
of Bone and Mineral Research, 1997.
ZJ Ma and M Yamaguchi.These results suggested that MK-7 (K2-7) has a suppressive effect on osteoclasts.
Molecular and Cellular Biochemistry. 2001
M Yamaguchi et al1. This study demonstrates that MK-7 (K2-7) has an anabolic effect on bone tissue and osteoblastic
(MC3T3-E1) cells in vitro, suggesting that the compound can stimulate osteoblastic bone formation. Molecular
and Cellular Biochemistry, 2001.
3. Supports hearts
4. Support skin
5. An antioxidant and helps cells against oxidative damage
6. Supports immune system
7. Supports normal blood sugar levels
K1(phylloquinone, or phytomenadione or phytonadione)
K2 ( (MK-n, menaquinone)
There is no good vitamin K2 test.
Three synthetic vitamin K are known: vitamins K3, K4,
and K5.
The natural K1 and K2 forms are nontoxic.
The synthetic form K3 (menadione) has shown toxicity.[1]
Vitamin K is heat-stable and water soluble. It is destroyed by strong acids or alkalis
and gamma-irradiation of foods.
Vitamin K.
Fat absorbable vitamins are A D E K.
Sources:
K1 in plants mainly in green leafy vegetables but only 10-15% gets absorbed even
if consumed with dietary fat.
K2 in animals from meat,
eggs, and dairy products and made by bacteria in the human gut.16
Japanese natto: A fermented soybea containing a good bacteria called bacillus subtilus
that may also be a probiotic.
Low fat Dutch gouda
Edam cheese
Curd cheese is lower in animal fat than regular cheese, in equal portions, natto contains over 27 times more vitamin
K2 than curd cheese.
Antibiotics
and the non-steroidal anti-inflammatory drugs kill many of these good intestinal bacteria.
Vitamin K1
was less effective than Vitamin K2 in preventing bone loss.
Vitamin K2 (MK-7) is absorbed better and is 6 times
more potent than Vitamin K1.
There is a lower incidence of calcification
of the aorta if on long term K2 therapy.
High K2 level is associated with number of lower
plaque in the arteries and more elastic are the arteries.
K2 lack causes calcium to deposit in arteries, aorta,
soft tissues including muscle, breast, kidneys and in heel spurs instead of bones.
In Japan, osteoporosis is treated by K2.
========
---
From
The secret to avoiding calcium-related osteoporosis and atherosclerosis by Dr.
Kate Rheaume-Bleue.
Calcium and Vitamin D supplementation without the addition of Vitamin K2 could be dangerous.
Benefits of vitamin K2
The vitamin K2 activates its dependent proteins: Osteocalcin and MGP
a) Osteocalcin in bone building cells needs to be activated in order to bind calcium to the surface of bones.
b) Matrix Gla (gamma-carboxyglutamate) Protein (MGP) in the vasculature to get activated in and inhibit calcium deposition
in the arteries.
MGP is the most powerful inhibitor of soft tissue calcification.
Americans as a society, consume far more calcium than most other populations, but suffer from far more osteoporosis ("calcium
paradox").
The american diets are often very low in K2MK7.
Without Vitamin K2 , calcium is not transported to the bones for depostion
instead, the calcium get deposited in soft tissue and arteries resulting to a combination of osteoporosis and atherosclerosis.
If calcium isn’t absorbed properly, instead of going to bones, it accumulates
in arteries and soft tissues leading to high blood pressure, atherosclerosis, heart attack, strokes, and arthritis.
Megumi Natto. You Need More MK7-type Vitamin K2
There are other health benefits of Vitamin K2:
Reduction of dental cavities, heart disease, prostate cancer, liver cancer, diabetes,
wrinkles, obesity, varicose veins, and other ailments.
K2 and the Calcium Paradox: How a Little-Known Vitamin Could Save Your Life
References:James Howenstine. ARTERIOSCLEROSIS CAN BE REVERSED.PART 1 of 2 July 24, 2008
NewsWithViews.com
http://www.newswithviews.com/Howenstine/james67.htm
===============
Vitamin K1 had no effect on vascular health, and is primarily taken-up by the liver. K2 is transported
to extra-hepatic tissues, such as vessel wall and bones-tissue, especially sub types MK7, MK8 and MK9 and are important for
cardiovascular health.3, 4.
VITAMIN K2 REDUCES WOMEN'S RISK OF CORONARY HEART DISEASE.
The Prospect-EPIC cohort Study:
16,057 women, aged 49 - 70 years and free of cardiovascular disease at baseline were followed over
a period of more than 8 years.
The data confirmed that higher consumption of natural vitamin K2 (especially subtypes menaquinone-7,
8 & 9) - but not vitamin K1 - was associated with significantly reduced prevalence of CHD.
The study confirmed findings in the Rotterdam study [2].
The Gast et al.1 showed that a 9% reduction in risk of developing CHD for every 10 mcg of natural vitamin
K2 consumed.
The researchers (Gast et.al) found that for every 10mcg vitamin K2 (MK-7, MK-8 and MK-9) consumed,
the risk of coronary heart disease was reduced by 9%.
Vitamin K2 and prevention of calcification discussed by Schurgers LJ., et al. [3] in the Rotterdam study. ====
==
How vitamin K2 prevents blood vessels calcification?
Matrix Gla-protein (MGP), is the most potent inhibitor of vascular calcification known. MGP has
a high affinity for calcium. MGP is vitamin K dependent, and without adequate vitamin K, MGP is inactive. Inactive
MGP may lead to increased calcium-deposition on the blood vessels and atherosclerosis.
---
Stephan Guyenet . Cardiovascular Disease and Vitamin K2. http://wholehealthsource.blogspot.com/2008/11/cardiovascular-disease-and-vitamin-k2.html
MGP is secreted in cartilage, lung, heart, kidney and
arteries. Mice lacks MGP and develop extensive arterial and soft tissue calcification.
Humans with naturally occurring mutations in MGP (Keutel
syndrome).
Rats treated with warfarin, which inhibits vitamin K
recycling.
There seems to be no effective alternative mechanism to MGP for calcification inhibition
in the vasculature.
====
MGP prefers the MK-4 form of vitamin K2.
The effects of vitamin K1 and K4 (MK4) on vascular calcification and their utilization in the arterial vessel wall were
compared in the warfarin-treated rat model for arterial calcification.
Warfarin-treated rats were fed diets containing K1, MK-4, or both.
MK-4 and not K1 inhibits warfarin-induced arterial calcification.
The total hepatic K1 accumulation was threefold higher than that of MK-4, whereas aortic MK-4 was three times that of K1.
K1 and MK-4 were both equally utilized in the liver, but the aorta showed a more efficient utilization of MK-4.
"K2 can be produced by bacterial fermentation, but an argument can be made that K2 MK-4, the animal form, is the most natural
for humans and the most effective.
MK-4 is the type that mammals synthesize for themselves, whereas the MK-7 in natto
and other bacterial menaquinones are different.
The form of K2 that Weston Price described in Nutrition and Physical
Degeneration was almost certainly MK-4."
http://www.menaq7.com/index.php?s=Links
"Interesting. They suggest that MK-7 is superior because it stays in bloodstream
20 times longer (100h vs 5h). I am not sure about the interpretation of this fact - is it positive or negative? If it stays
longer in the blood stream perhaps because it is not being readily absorbed by bone and other tissue then is is not so good
(thus MK-4 should be better). If on the other hand MK-4 stays so short because it is getting destroyed too quickly then MK-7
should be more benefitial in smaller doses!
On the other hand the natural animal form of K2 is MK-4 thus, I suspect
but have no proof, that we should probably stick to the natural MK-4 rather than fungal MK-7 from natto. We just had cooked
pork tongues last week, added benefit was that it has lots of fat and cholesterol. Very cheap too. 8-:)" -----
[1] Gast G.C.M., et al. A high menaquinone reduces the incidence
of coronary heart disease in women, Nutrition, Metabolism and Cardiovascular Diseases, Available online 28 January 2009.
doi:10.1016/j.numecd.2008.10.004
[2] Geleijnse JM., et al. Dietary Intake of Menaquinone Is Associated with a Reduced Risk of Coronary Heart Disease:
The Rotterdam Study, Nutritional Epidemiology, 2004 134: 3100-3105.
[3] Schurgers LJ., et al., Regression of Warfarin-Induced Medial Elastocalcinosis by High Intake of Vitamin K
in Rats, Blood, 2007. 109(7): 2823-2831
-----
Cardiovascular health
22. Schurgers, LJ. Cranenburg, ECM and Vermeer, C. Matrix Gla –protein: The calcification inhibitor in need of vitamin K.
Theme issue article. Thromb Haemost 2008; 100: 593-603
23. Geleijnse JM, Vermeer C, Grobbee DE, Schurgers LJ, Knapen MH, van der Meer IM, Hofman A, Witteman JC. Dietary intake of menaquinone
is associated with a reduced risk of coronary heart disease: the Rotterdam Study. J Nutr. 2004;134(11):3100-5.
24. Beulens et al: High dietary menaquinone intake is associated with reduced coronary calcification. Atherosclerosis. 2008 Jul
19.
25. Beulens JW, Bots ML, Atsma F, Bartelink ML, Prokop M, Geleijnse JM, Witteman JC, Grobbee DE, van der Schouw YT. High dietary
menaquinone intake is associated with reduced coronary calcification. Atherosclerosis. 2008
26. Gast G.C.M., et al. A high menaquinone reduces the incidence of coronary heart disease in women, Nutrition, Metabolism and
Cardiovascular Diseases, Available online 28 January 2009. doi:10.1016/j.numecd.2008.10.004
27. Bolland MJ, Barber PA, Doughty RN, Mason B, Horne A, Ames R, Gamble GD, Grey A, Reid IR. Vascular events in healthy older
women receiving calcium supplementation: randomised controlled trial.BMJ. 2008;336(7638):262-6.
28. Schurgers, LJ: Unpublished data
29. Iribarren C, Sidney S, Sternfeld B, Browner WS. Calcification of the aortic arch: risk factors and association with coronary
heart disease, stroke, and peripheral vascular disease. JAMA. 2000;283(21):2810-5
30. Shaw LJ, Raggi P, Berman DS, Callister TQ. Coronary artery calcium as a measure of biologic age. Atherosclerosis. 2006;188(1):112-9
=====
http://www.menaq7.com/index.php?page=cardiovascular-health
Another study24 which looked at the relation between vitamin K1 and vitamin K2 intake and coronary calcification among 564 post-menopausal
women showed decreased calcification associated with vitamin K2 intake (specifically MK-7, MK-8 & MK-9) but not with vitamin
K1 intake.25
An interesting double blind placebo-controlled bone health study from New Zealand where 1471 postmenopausal women received
1000 mg calcium daily reported a high frequency of cardiovascular events. Judged from the information given, it seems that
the daily intake of vitamin K2 was very low in these women. Inadequate vitamin K2 supplementation seems to be a contributing
factor to this cardiovascular problem27.
Unfortunately, the western diet does not contain sufficient vitamin K2 and supplementing with MenaQ7, the natural vitamin
K2, is therefore recommended by experts.
Arterial calcification
Calcification was once believed to be an irreversible process and a result of aging. However, it is now known that calcium
accumulation is an actively regulated process also involving vitamin K2-dependent MGP. Healthy arterial tissues have shown
to contain 20-50 times more vitamin K2 than unhealthy arteries28. The amount of calcium in the arteries is a risk factor for cardiovascular health29. Significant calcification makes one older than what the birth certificate states; while with little or no calcification
one can deduct up to 10 years from one's chronological age.30
In short, you are as old as your arteries.
===========
The Calcium Paradox
Impaired calcium metabolism results in simultaneous bone tissue degradation and excessive calcium accumulation
in the vessel walls. This is known as the Calcium Paradox. While bones are in need of calcium, excessive calcification may
occur in arteries and soft tissues including skin. Vitamin K2 is an essential co-factor involved in calcium utilization by
activating proteins responsible for removing circulating mineral from the arteries and binding it to the bone matrix.
Matrix Gla Protein’s role
Matrix Gla Protein (MGP) is a key inhibitor of soft vascular tissue calcification – it can be measured
in blood, but exerts its effect in tissues where it binds calcium, preventing it from depositing in the vessel walls. In collaboration
with other soluble factors and cells MGP thus helps remove calcium from the arteries, and thereby keep them elastic and flexible.
In order to properly perform its inhibitory function, MGP must be activated by vitamin K during a process
called carboxylation. Vitamin K2 deficiency results in undercarboxylation of MGP (ucMGP) and impairs their biological function.
Without adequate vitamin K2 in the vessel walls ucMGP accumulates at the sites of calcium deposition but is basically inert
as it cannot inhibit calcification, which in turn increases the risk of fatal cardiovascular events.
----
Vitamin K
From Wikipedia, the free encyclopedia.
http://en.wikipedia.org/wiki/Vitamin_K
--
http://www.vitamink2.org/?znfAction=referencesKeyStudies
---
1939:
Discovery of K2.
Almquist H J: Early history of vitamin K. Am. J.Clin. Nutrition. 28, 656-659, 1975
http://www.ajcn.org/content/28/6/656.full.pdf
The first crystalline antihemorrhagic vitamin K was discovered from rottting (inoculated with bacteria) fish meal
by E.A. Doisy and his group by and named as K2.
Dam and Doisy shared the 1943 Nobel Prize for medicine for their work on vitamin K (K1 and K2) published in 1939.
========
VITAMIN K DEFICIENCY
Average diets have enough vitamin K.
Primary vitamin K deficiency is rare in healthy adults.
Newborns are at an increased risk of deficiency.
Risk factors:
1.Liver damage or disease (e.g. alcoholics).
2. Cystic fibrosis.
3. Inflammatory bowel diseases.
4. Recent abdominal surgeries.
Secondary reasons:
5. Bulimics
6.Dieting.
DRUGS
7. Anticoagulants.
8. Salicylates. Vitamin K2 is not affected.
9. Barbiturates.
10. Cefamandole and other broad spectrum antibiotics
11. Malabsorption causes.
12. Reduced production among elderly.
Symptoms of deficiency:
Heavy menstrual bleeding in women, anemia, bruising, and bleeding of the gums or nose.
Osteoporosis[60][61] and coronary heart disease[62][63] are strongly associated with lower levels of K2 (menaquinone).
As Menaquinone is not inhibited by salicylates, its supplementation may alleviate the chronic vitamin K deficiency
caused by long term aspirin use.[citation needed]
===
WHICH MK2 IS NEED TO BE SUPPLEMENTED?
MK4 or MK7
Vitamin K2 (Menaquinone-4) is synthesized by animal tissues and is found in meat, eggs, and dairy products.[57] Menaquinone-7 is synthesized by bacteria during fermentation and is found in fermented soybeans (natto).[58] In natto 0% of vitamin K is from MK-4 and in cheese 2–7%.[59]
Vitamin K2 (MK4) and bone health
In contrast, MK4 has been shown in numerous studies to reduce fracture risk, stop and reverse bone loss. In Japan, MK4
in the dose of 45 mg daily is recognized as a treatment for osteoporosis[85][88] under the trade name Glakay.[89] MK4 has been shown to decrease fractures up to 87%.[13] In the amount of 45 mg daily MK4 has been approved by the Ministry of Health in Japan since 1995 for the prevention
and treatment of osteoporosis.[14]
MK4 (but not MK7 or vitamin K1) prevented bone loss and/or fractures in the following circumstances:
[edit] Vitamin K2 (MK7) and bone health
Menaquinone-7 (MK7), which is abundant in fermented soybeans (natto), has been demonstrated to stimulate osteoblastic bone
formation and to inhibit osteoclastic bone resorption.[90] In another study, use of MK-7 caused significant elevations of serum Y-carboxylated osteocalcin concentration, a biomarker of bone formation. MK-7 also completely inhibited a decrease in the calcium content of bone tissue
by inhibiting the bone-resorbing factors parathyroid hormone and prostaglandin E2.[91] On 19 February 2011, HSA (Singapore) approved a health supplement that contains vitamin K2 (MK7) and vitamin
D3 for increasing bone mineral density.[92]
==
Vitamin K and cancer
While researchers in Japan were studying the role of vitamin K2 as the menaquinone-4 (MK-4) form in the prevention
of bone loss in females with liver disease, they discovered another possible effect. This two-year study that involved 21
women with viral liver cirrhosis found that women in the supplement group were 90% less likely to develop liver cancer.[94][95] A German study performed on men with prostate cancer found a significant inverse relationship between vitamin K2 consumption and advanced prostate cancer.[96]
===
Toxicity
Although allergic reaction from supplementation is possible, there is no known toxicity associated with high doses of the phylloquinone (vitamin K1)
or menaquinone (vitamin K2) forms of vitamin K and therefore no tolerable upper intake level (UL) has been set.[49]
Blood clotting (coagulation) studies in humans using 45 mg per day of vitamin K2 (as MK4)[25] and even up to 135 mg/day (45 mg three times daily) of K2 (as MK4),[50] showed no increase in blood clot risk. Even doses in rats as high as 250 mg/kg body weight did not alter the tendency
for blood-clot formation to occur.[51]
However, a synthetic form of vitamin K, vitamin K3 (menadione), is demonstrably toxic. In fact, the FDA has
banned this synthetic form of the vitamin from over-the-counter supplements because large doses have been shown to cause allergic
reactions, hemolytic anemia, and cytotoxicity in liver cells.[1]
[edit] Drug interactions
Phylloquinone (K1)[52][53] or menaquinone (K2) are capable of blocking the blood thinning action of anticoagulants like warfarin, which work by interfering with the action of vitamin K. They also reverse the tendency of these drugs to cause
arterial calcification in the long term.
==
There are three synthetic forms of vitamin K, vitamins K3, K4, and K5, which
are used in many areas including the pet food industry (vitamin K3) and to inhibit fungal growth (vitamin K5).[41]
==
And in an animal model MK4 was shown to prevent arterial calcifications, pointing to its potential role in
cardiovascular disease prevention.[40] I
--
Subtypes of vitamin K2
Vitamin K2 (menaquinone) includes several subtypes. The two subtypes of vitamin K2 that
have been most studied are menaquinone-4 (menatetrenone, MK4) and menaquinone-7 (MK7).
MK4 is produced via conversion of vitamin K1 in the body, in the testes, pancreas and arterial
walls.[3] While major questions still surround the biochemical pathway for the transformation of vitamin K1 to MK4,
studies demonstrate that the conversion is not dependent on gut bacteria, occurring in germ-free rats[4][5] and in parenterally-administered K1 in rats.[6][7] In fact, tissues that accumulate high amounts of MK4 have a remarkable capacity to convert up to 90% of the available
K1 into MK4.[8][9]
In contrast to MK4, menaquinone-7 (MK7) is not produced by humans but is converted from phylloquinone in the
intestines by gut bacteria.[10] However, bacteria-derived menaquinones (MK7) appear to contribute minimally to overall vitamin K status.[11][12] MK4 and MK7 are both found in the United States in dietary supplements for bone health.
The US FDA has not approved any form of vitamin K for the prevention or treatment of osteoporosis; however, MK4 has been shown to decrease fractures up to 87%.[13] In the amount of 45 mg daily MK4 has been approved by the Ministry of Health in Japan since 1995 for the prevention
and treatment of osteoporosis.[14]
Vitamin K2 (MK4, but not MK7 or vitamin K1) has also been shown to prevent bone loss
and/or fractures in the following circumstances:
- caused by corticosteroids (e.g., prednisone, dexamethasone, prednisolone),[15][16][17][18]
- anorexia nervosa,[19]
- cirrhosis of the liver,[20]
- postmenopausal osteoporosis,[14][21][22][23][24][25]
- disuse from stroke,[26]
- Alzheimer's disease,[27]
- Parkinson disease,[28]
- primary biliary cirrhosis[29]
- and leuprolide treatment (for prostate cancer).[30]
- ==
-
Vitamin K2 is involved in bone metabolism.
-
Vitamin K2 are characterized by the number of isoprenoid residues comprising the side
chain. Menaquinones are abbreviated MK-n, where n represents the number of isoprenoid side chains. Thus, menaquinone-4 abbreviated MK-4, has 4 isoprene residues in the side chain. Bacteria can produce a range of vitamin K2
forms, including the conversion of K1 to K2 (MK-7) by bacteria in the small intestines.
-
-
---------------
-
http://www.genoprice.com/vitamin_k2.htm
-
-
The Special Effects of
Vitamin K2
1. Treatment of haemorrhage caused by VK2 deficiency;
-
promotes thrombin formation,
-
accelerates blood clotting,
-
maintains clotting time;
-
a quick coagulant in surgeries or first aids
2. Treatment of osteoporosis;
-
VK2 produces osteocalcin which can bind calcium, deposits on bone increasing bones density and to prevent
fracture.
3. Prevention of hepatocellular
carcinoma in women with viral cirrhosis.
4. Diuresis, detoxifcation of liver and lowering the blood pressure.
-
==
-
Vitamin K is a stronger antioxidant than vitamin E or coenzyme Q10，
-
Vitamin K2 deficiency can have effects similar to diabetes.And n
-
Vitamin K2 may be helpful in treating certain cancers and Alzheimer's disease.
-
---
-
THROMBIN DEFICIENCY
-
1. Newborn. At 1-2 weeks age, newborns often have low thrombin. The placenta is a difficult
barrier to transport fat. It takes several weeks for newborn to have normallevel of thrombin. If the thrombin rate
is lower than normal level by 10%, infant can have hemorrhagic disease.
-
Some senior citizens
may lack of vitamin K2.
-
Drugs such as dicarboxylic
coumarin.
-
------
Vitamin K2
Benefits of vitamin K2
The vitamin K2 activates its dependent proteins: Osteocalcin and MGP
a) Osteocalcin in bone building cells needs to be activated in order to bind calcium to the surface of bones
b) Matrix Gla (glutamic acid) Protein (MGP) in the vasculature to get activated in and inhibit calcium deposition
in the arteries.
MGP is the most powerful inhibitor of soft tissue calcification.
Healthy adults are insufficient in vitamin K as 30% of their MGP is synthesized in an inactive form. This figure increases
at increasing age.
Protection against cardiovascular calcification is 70% in the young healthy person and diminishes as ages, unless
K2 is suplemented.
Best references:
http://www.lef.org/Vitamins-Supplements/Item01224/Super-K-with-Advanced-K2-Complex.html
http://www.lef.org/Vitamins-Supplements/References/2011/Vitamins.htm
Vitamins
=====
http://www.westonaprice.org/fat-soluble-activators/x-factor-is-vitamin-k2#fig4
http://www.westonaprice.org/fat-soluble-activators/x-factor-is-vitamin-k2
-----
http://www.thorne.com/Products/Vitamins/prd~K170.jsp
Vitamin K2 Liquid
concentrated vitamin K2 in a convenient liquid form
- effective in maintaining bone health*
- supports a healthy cardiovascular system*
- provides nutritional support for oncology patients*
Product Information
Vitamin K2 exerts a more powerful influence on bone than does vitamin K1.* Vitamin K2 is a series of molecules known as
menaquinones. The most common and well studied of the menaquinones is MK-4. Thorne's vitamin K2 is MK-4.
Vitamin K2
appears to offer significant benefit for supporting bone health.* Although much of the vitamin K2 research has been conducted
on postmenopausal support for bones, because vitamin K2 does not have any estrogenic effects, vitamin K2 also offers bone
support for other populations, including anorexics, dialysis patients, individuals with Parkinson's disease, those who have
cirrhosis of the liver, individuals who have had a bone marrow transplant, those immobilized after a stroke, and individuals
on chronic steroid therapy.*
Thorne's Vitamin K2 Liquid supplies 1 mg of vitamin K2 per drop. Research shows doses
up to 15 mg three times daily may be used.*
===
http://thorne.com/Products/Circulatory-Support/Cardiovascular_Health/prd~KD500.jsp
Vitamin D / K2 Liquid
liquid vitamins D3 and K2 in a balanced formula
- 10 drops contain 5,000 IU vitamin D3 and 1 mg vitamin K2
- vitamins K and D for support of healthy bones*
- in liquid for ease of dosing and titration
- both vitamins support a healthy cardiovascular system*
- provides nutritional support for oncology patients*
Product Information
Vitamin K2 exerts a more powerful influence on bone than does vitamin K1.* Vitamin K2 is a series of molecules known as
menaquinones. The most common and well studied of the menaquinones is MK-4. Thorne's vitamin K2 is MK-4 and is derived from
bacterial fermentation; thus, there is no soy in the product. Vitamin K is also essential for normal cell formation and maintenance
of a healthy cardiovascular system.*
It is essential to maintain healthy vitamin D levels throughout all stages of
life, from fetal development to old age.* Vitamin D helps protect a number of important systems in the body, including healthy
bones, immunity, and cardiovascular function.*
Combining vitamins D and K may provide even better protection of these
systems.* One study in postmenopausal women found a combination of minerals with vitamins D and K maintained healthy artery
elasticity, compared to two other groups of women who received either minerals with vitamin D but not K, or placebo.*
Thorne's
Vitamin D / K2 Liquid is in medium chain triglyceride oil, preserved with mixed tocopherols.
---
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Nature
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Synthetic
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Natural
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Source
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Vitamin K2 MK4 is only found in animal products.
The best sources: Grass-fed butter from cows eating rapidly growing grass, and foie
gras.
K2 MK7 is found abundantly in natto, a
type of fermented soybean, and it may be partially converted to MK-4.
Oil, butter,eggs, meats and dairy.
"Perigord, France is the world's capital of foie gras, or fatty goose liver.
Good news for the bon vivants: foie gras turns out to be the richest known source of K2. Perigord also has the lowest rate of cardiovascular mortality
in France, a country already noted for its low CVD mortality."
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Healthy colon bacteria
Japanese natto
Low fat Dutch gouda
Edam cheese
Bacteria in the colon
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Converson of Vitamin K1 to K2 subtype MK4.
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The vitamin K in plants is K1. It's made into K2 subtype MK4 by some animals.
Bacteria can convert K1 to K2 by bacteria in the small intestines.
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Bacteria can convert of K1 to K2(MK7) by bacteria in the small intestines
Humans are not good at making this conversion.
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K2 in Europe
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MK7 is the only approved as food supplement and fortified food.
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The number of isoprene units attached to the molecules ring structure.
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MK4, has 4 isoprene residues in the side chain.
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MK7, has 7 isoprene residues in the side chain.
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MK4 is synthesized by animals for their own use
from K1 (and from MK7 in rats).
Animals concentrate MK4 (with smaller amounts of K1)
in the brain, pancreas and salivary gland.
MK4 is produced via conversion of vitamin K1 in the body, in the testes, pancreas and arterial
walls.[3] While major questions still surround the biochemical pathway for the transformation of vitamin K1 to MK4,
studies demonstrate that the conversion is not dependent on gut bacteria, occurring in germ-free rats[4][5] and in parenterally-administered K1 in rats.[6][7] In fact, tissues that accumulate high amounts of MK4 have a remarkable capacity to convert up to 90% of the available
K1 into MK4.[8][9]
It appears that MK4 is capable of performing all
the functions of vitamin K including activating blood clotting factors (function of Vitamin K1).
Newborns are often born clotting deficient, so,
vitamin K1 injections is given to them after birth in the U.S. to prevent hemorrhaging.
In Japan, they children receives MK4 to prevent
hemorrhage.
Japan has half the
infant mortality rate of the U.S.
Some countries utilize predominanantly MK4 over
other forms of vitamin K in the diet ( dairy such as Masai)
Infants receive most of vitamin K from MK4. Colostrum,
the first milk to come out, is rich in MK4.
Vitamin K is required to activate Gla proteins (gamma-carboxyglutamic acid), a modified amino acid that's synthesized
using vitamin K (by gamma-carboxylation reaction).
Gla proteins are important: the class includes:
MGP, ( to keep arteries clean)
osteocalcin ( bones strong) and
blood clotting factors( to keep blood clotting
correctly).
Vitamin K2:
It acts like hormone, activating a nuclear receptor called the steroid and xenobiotic receptor (SXR) and influencing the
expression of a number of genes.
It also acts as an antioxidant, a cofactor for sphingolipid synthesis in the brain, and an activator of protein kinase A signaling.
These functions have been studied in the context of MK4 not yet with MK7 has
equivalent effects.
.
SXR-independent
effects of vitamin K2 on gene expression.
MK4 activates transcription of two specific genes in
osteoblast cells (create bone tissue).
The genes are GDF15 and STC2 and they're involved in
bone and cartilage formation.
They tested K1, MK-7, and MK-4.
Only MK4 has effects on gene expression in bone
tissue.
Vitamin K2 MK4 seems to be able to perform all the
functions of vitamin K:
1. Activates Gla proteins
2. Participates in sphingomyelin synthesis.
3. Binds SXR.
4. Activates transcription through protein kinase
A.
No investigations with MK7 is done yet
in these respects.
MK4 is the only form of vitamin K2 that's been shown
to reduce fracture risk in clinical trials. by Stephan Guyenet
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MK7 is made in large amounts by the bacterium Bacillus subtilis that ferments the Japanese condiment natto.
MK7 can activate clotting factors and osteocalcin. It can function as a cofactor
for gamma-carboxylation.
MK7 stays in the blood for longer than MK4 in
humans.
These findings were conducted by MK7 supplement vendors and the results have not been
published.
MK4 and MK7 have the exact same plasma
half-life in rats. The human experiment should be done.
|
MK5 through MK14 are synthesized by bacteria.
The liver, in some animals, including humans, concentrates longer menaquinones to a
greater extent than MK4, if they're present in the diet.
Newborns are often born clotting deficient, and in USA they
received Vitamin K1 injections after birth to prevent hemorrhaging.
In Japan, newborns receive MK4 to prevent.
Japan has half the infant mortality rate of the U.S.
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Fracture prevention
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"all the studies showing lowered fracture risk with K2 supplementation used MK-4, not MK-7. MK-7 has never been
directly shown to reduce fracture risk in humans."
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Coronary artery disease
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x
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Data from the Prospect-EPIC cohort study:
16,057 women studied between 1993 and 1997aged 49-70 years. After adjustment for traditional risk and dietary factors,
an inverse association between vitamin K2 and risk of CHD was observed with per 10mug/d vitamin K2 intake and mainly due to
vitamin K2 subtypes MK-7, MK-8 and MK-9 and not Vitamin K1.
Reference:
Gast GC, de Roos NM, Sluijs I, Bots ML, Beulens JW, Geleijnse JM, Witteman JC, Grobbee DE, Peeters
PH, van der Schouw YT.
A high menaquinone reduces the incidence of coronary heart disease in women. Nutr Metab Cardiovasc
Dis. 2009 Jan 27.
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Prevention of fractures
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MK4 supplements can reduce fracture risk.
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MK7 hasn't been tested yet.
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Add your content here
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Calcification nreversal.
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MK-4 reverses arterial calcification in rats?
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Add your content here
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Half life duration.
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The reason MK-4 has a shorter half-life:
It is less lipid-soluble due to its shorter tail and resides more towards the surface of the lipoprotein and is therefore
more easily absorbed into cells.
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The reason MK7 has a longer half-life:
This may be due to that it has a longer side-chain, so more fat-soluble, and thus is located more in
the core of the lipoproteins thus having less interaction with enzymes that would bring it into the cells.
.
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Cost and dose.
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MK4 is cheaper than MK-7!
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MK7s are being sold comes in much lower doses.
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Add your content here
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x
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whereas vitamin K 2 has an unsaturated side chain [ 1].
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Add your content here
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How Vitamin K2 helps Heart?