Vitamin K2: An emerging story
TRACK YOUR PLAQUE
Along with vitamin D, recent studies put vitamin K2 in the spotlight as a major factor in calcium control in the body. Long considered a passive accompaniment of atherosclerotic plaque growth, calcium deposition in coronary arteries, evidenced by your CT heart scan score, is increasingly looking more like an active component that may be under your control.
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Measuring coronary calcium is the basis for CT heart scanning. The heart scan score provides a measure of the volume of calcium in coronary arteries, and thereby yields an indirect index of total plaque volume. This useful insight originated with the observations of Dr. John Rumberger and his Mayo Clinic team, who discovered this relationship in the mid-1990s. Calcium consistently occupies 20% of total plaque volume. Thus, 2 mm3 of calcium translates into 10 mm3 of total plaque—hard, soft, and everything in between.
For years, we've therefore viewed calcium as just a convenience, a tool that is easy to visualize, but just a passive marker and not an active participant in the disease. Some have even argued that calcium is nothing more than a remnant of prior "rupture," a scar from the dangerous activity of a soft plaque. They claim that calcium is, in fact, a reflection of increased stability of a plaque, since the "hard" element is not itself prone to rupture. Thus, some believe that, while it serves a practical purpose, calcium plays no true role in causing atherosclerotic plaque.
Those arguments are being dashed by new observations into phenomena behind vitamin K and its role in causing calcium deposition and coronary plaque.
For several years since its discovery in 1929, vitamin K has been known to play a crucial role in maintaining normal blood clotting. Vitamin K is required by the human liver to manufacture several blood clotting proteins (clotting factors II, VII, IX, X, and proteins S and C). This is the basis for administering the vitamin K-blocking drug, Coumadin (warfarin) to people who have blood clots or risk for blood clot formation, since clot formation is effectively blocked by the drug.
Determination of the human need for vitamin K was therefore based on the amount necessary to maintain normal balance between blood clotting and thinning. We don't want to have our blood excessively "thinned" and prone to bleeding, nor do we want "thick" blood prone to clots. Vitamin K deficiency that disturbs normal clotting is somewhat unusual, often prompted by antibiotics, since bacteria that normally reside in the colon are responsible for producing approximately 75% of the vitamin K needed every day.
Research has uncovered the fact that vitamin K also plays a crucial role in maintaining bone health. It was found that the amount of vitamin K required to halt bone absorption leading to osteoporosis requires much greater intakes than that required for blood clot regulation. Further, it appears that bone and vascular tissue (like coronary arteries) maintain a preference for a different form of vitamin K than that required for blood clotting regulation. Rather than vitamin K1 needed for clotting, vitamin K2 is the form preferred by bones and arteries (Schurgers LJ et al 2001). It appears that much of the information generated over the years for vitamin K focused on the K1 form, ignoring the K2 form necessary for bone and vascular health.
Normal deposition of calcium occurs only in bone and in teeth. Abnormal deposition of calcium in the body occurs in three places: the inner lining of the arteries of the body (the intima) that causes atherosclerotic plaque; the muscle layer of arteries ("medial calcification"); and heart valves. K2 appears to be the form of vitamin K responsible for controlling these phenomena.
How is vitamin K2 involved in coronary atherosclerotic plaque?
The possible role of vitamin K2, also known as the menaquinones (since there are several subtypes), as a contributor to coronary plaque development emerged from several unrelated observations:
* Osteocalcin, a protein located in human bone, is under control of vitamin K2. A deficiency of vitamin K2 permits unrestrained calcium absorption from bone tissue by osteocalcin, leading to osteoporosis. This led researchers to wonder whether a similar protein in vascular (blood vessel) tissue, matrix Gla-protein (MGP) was also under similar vitamin K2 control.
* MGP occurs at unusually high concentration at the edge of calcium and atherosclerotic plaque, suggesting an active role in depositing calcium in plaque (Schurgers LJ et al 2001). In addition, people with coronary disease with reduced levels of vitamin K2 show more advanced atherosclerotic plaque (Schurgers LJ et al 2005).
* A special genetic mutant of mice that lack a protein that uses vitamin K2 displays unrestrained calcium deposition in the arteries (aorta and coronary) of their body, so powerfully rampant that they die within a few weeks of birth.
* A similar mutation in the human gene for the vitamin K epoxide reductase complex subunit 1 (VKORC1) doubles the likelihood of atherosclerotic diseases like coronary disease, stroke, and aortic disease (Wang Y et al 2006).
* In certain regions of Japan, a native dish called natto, or fermented soybean, is a staple, commonly eaten several times per week. Natto is unusually rich in vitamin K2. People indulging in natto have several-fold greater blood levels of K2 and have much less heart disease, osteoporosis, and bone fractures (Kaneki M et al 2001).
* Pregnant women taking the potent blood-thinning agent and vitamin K blocker, Coumadin (warfarin), gave birth to babies with severe abnormalities of bone structure. Likewise, people who take Coumadin suffer more osteoporosis (a lack of calcium in bones). They also show substantially more abnormal calcium deposition in other areas, such as heart valves—twice as much as non-Coumadin takers (Schurgers LJ et al 2004; Gage BF et al 2006).
The above observations prompted investigators to conduct the Rotterdam Heart Study, a large Dutch trial reported in 2004. The Rotterdam Heart Study was the first substantial trial in humans that suggested a genuinely powerful association of vitamin K2 dietary intake and heart disease. 4,800 participants were tracked for 7 years. Participants who ingested the greatest quantities of vitamin K2, or menaquinone, in their diet experienced 57% fewer heart attacks than people who ingested the least. The same relationship did not hold for vitamin K1.
Higher intakes of vitamin K2 also corresponded to less calcium deposited on the aorta (an indirect measure of atherosclerosis), while participants who ingested less K2 were more likely to show moderate or severe calcification. The lowest risk of heart attack and aortic calcification was seen in participants who included more than 32.7 mcg of vitamin K2 per day in their diet (Geleijnse JM et al 2004).
For the first time, a solid connection was made between vitamin K2 levels and heart disease. The size and quality of the study lends credibility to the concept. The Rotterdam Heart Study also confirmed that the observations connecting vitamin K2 and atherosclerotic calcium may indeed translate into a real-world relationship that carries therapeutic implications.
How about vitamin K2 and heart scan scores? While an 800 participant study among U.S. Army personnel revealed no relationship of vitamin K1 and heart scan scores (Villines TC et al 2005), vitamin K2 proves a different story. A recent Japanese study, for instance, revealed that people with the greatest deficiency of vitamin K2 tended to have higher heart scan scores (Jono S et al 2004). Higher blood levels of the MGP protein were also associated with higher heart scan scores (116.7 u/l in participants with scores of zero, compared to 81.9 u/l in those with scores >400), indirectly implicating vitamin K deficiency as a culprit in causing higher heart scan scores (Jono S et al 2004).
Vitamin K2 in food and supplements
While vitamin K1 is found naturally in green leafy vegetables, vitamin K2 is found in cheese (though not the industrialized cheese product passed off as cheese in the grocery), some meats, egg yolks, as well as natto. Few Americans would be willing to eat the hard-to-stomach natto—it's a pretty horrendous looking and tasting dish, sort of like haggis is to the Scottish. It's one of those native dishes that you've got to be raised on it to like it. Most of us therefore get little of these foods, since they've acquired reputations as less healthy foods avoided in low fat diets, or they're simply unappetizing. Some have suggested that the greater native cheese content of the Mediterranean diet might be partly response for the substantial reduction in heart attack seen on this diet.
In addition, much of the body's vitamin K originates with the natural bacteria in the human intestine, which produce a large proportion of the body's K. However, this is nearly all vitamin K1 and little K2.
There is an emerging notion in vitamin K2 research that the daily requirement is far greater than previously suspected. Of total vitamin K intake, only about 10% is the K2 form. Unfortunately, the present recommended daily allowance of vitamin K is based only on the blood-clotting effects of vitamin K1. Deficiency of vitamin K1 is relatively uncommon. Vitamin K2 deficiency may be far more common.
Vitamin K1 is cleared from the blood rapidly. Interestingly, vitamin K2 when taken orally lingers in the blood for an extended period and can rise to much greater levels in the blood than K1. Vitamin K2 also appears to be safe, with no side effects identified even with high doses. In Japan, both vitamin K2 as a high-dose supplement (45 mg per day) and in natto have been used in the treatment of osteoporosis, with or without vitamin D supplementation, and results in substantial increases in bone density (Iwamoto J et al 2004; Katsuyama H et al 2004).
The majority of vitamin K supplements contain only K1, or contain both K1 and K2 with a very small proportion of K2. Thus, if vitamin K2 is to be taken as a supplement, specific K2 generally needs to be taken.
Should vitamin K2 be added to your plaque control program? The experience is clearly not fully developed. However, the science behind vitamin K2 is becoming increasingly compelling and argues for supplementation as a method to augment your vitamin D strategy. Bone health will likely benefit and you may have an inhibiting effect on coronary calcification.
What dose of vitamin K2 is best? This is entirely unexplored. However, supplements generally contain between 50 mcg and 5 mg. (Carlson makes the high potency 5 mg capsule of menetetrenone.) Even the low end of supplement dose of 50 mcg per day would likely at least double or quadruple the K2 intake of the average American. We've been suggesting a dose of 100 mcg twice per day. But we'll have to wait and see whether this has an impact on heart scan scores.
Note: If you take Coumadin (warfarin), use of vitamin K should be discussed with your doctor before you begin supplementation, since substantial changes in blood thinning (protime or INR) will occur. Note that, however, there are data to suggest that modest supplementation of vitamin K1 adds to long term stability of blood coagulation.
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