Friday, November 7, 2008

Cardiovascular Disease and Vitamin K2

Vitamin K2 is intimately involved in calcium metabolism. Matrix Gla-protein (MGP) is a vitamin K-dependent protein that is secreted in cartilage, lung, heart, kidney and arteries. MGP prefers the MK-4 form of vitamin K2, the type that occurs almost exclusively in animal foods. Mice lacking MGP develop extensive arterial and soft tissue calcification (accumulation of calcium, as in bone). Same for humans with naturally occurring mutations in MGP (Keutel syndrome). It also happens in rats treated with warfarin, which inhibits vitamin K recycling. Let's hear what Dr. Cees Vermeer and his group have to say about MGP:
Among the proteins involved in vascular calcium metabolism, the vitamin K-dependent matrix Gla-protein (MGP) plays a dominant role. Although on a molecular level its mechanism of action is not completely understood, it is generally accepted that MGP is a potent inhibitor of arterial calcification. Its pivotal importance for vascular health is demonstrated by the fact that there seems to be no effective alternative mechanism for calcification inhibition in the vasculature. An optimal vitamin K intake is therefore important to maintain the risk and rate of calcification as low as possible.
So why do we care about vessel calcification? It associates strongly with the risk of heart attack and total mortality, better than traditional markers like the Framingham risk index*. That's because it's actually a measure of the disease process, rather than a marker with an unclear connection to it.

In my post on vitamin K2, I mentioned the Rotterdam study, which found that vitamin K2 intake is strongly associated with a lower risk of cardiovascular and total mortality. Vitamin K1, which is the type found in plants, was not associated with reduced mortality. I just came across another study in women selected from the PROSPECT cohort that showed something similar. Women with the highest K2 intake had the lowest level of coronary calcification. There was no association with K1. This suggests, yet again, that humans aren't very good at making the conversion from K1 to K2 MK-4. This is probably because during evolution, we always had a ready source of K2, so efficient conversion became unnecessary. Vitamin K2 MK-4 is found almost exclusively in animal foods.

Notably absent from the main text body is a discussion of where the K2 is coming from. It's tucked away in one sentence of the methods section: "cheese contributed 54%, milk products 22% and meat 15% of menaquinone intake." Oops! These are the foods that are supposed to cause heart disease! And do you remember where the K2 is? In the fat-- double oops! Yet another important nutrient that's found in animal fat.

Keep in mind that these Dutch women have an intake of K2 that is probably lower than what we would have eaten as hunter-gatherers. Most people in modern societies are verifiably K2 deficient. A focus on the organs (brain, pancreas) and fats of wild animals, shellfish, fish eggs and insects would have assured hunter-gatherers a high intake of vitamin K2 MK-4. This is precisely what Weston Price found in Nutrition and Physical Degeneration. He refers to vitamin K2 MK-4 as "activator X" in the book. In modern times, our most readily available source of vitamin K2 MK-4 is actually not a paleolithic food at all, it's butter from pasture-raised cows. It's how we can get away with not eating brain, pancreas and bugs.

*I plugged my numbers into this Framingham risk index calculator and it gave me the message "Please go back and enter an HDL value in the range of 20-100."!! I can imagine if you follow NCEP dietary guidelines your HDL would never break 100 mg/dL!


KKCorey said...

Hello Steven,
I've been reading your blog for a while now. It's one of my favorites.

I do want to point out the error in your post - K2 is available in the fermented forms of vegetables that naturally contain K1. Natto, a type of fermented soybean being the best known source. Sauerkraut and kim chee are minor sources.

Kathy Corey

Stephan Guyenet said...

Hi Kathy,

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.

Anonymous said...

Great blog! I'll be visiting on a regular basis.

I am interminably confused by the whole Vitamin K controversy.

For example, check this comparison of MK-4 versus MK-7.....

Also, stephen, aside from eating high quality butter, is there a way to supplement with MK-4?

Stan Bleszynski said...

Re: For example, check this comparison of MK-4 versus MK-7.....

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-:)

Lee said...

Hello Stephen

Do you have any figures on quantities of vitamin K in brain and pancreas? This might help us to estimate optimal amounts for our consumption. Price said that his healthy isolated groups ate ten times the fat soluble vitamins of westerners. Perhaps that equates to

Vitamin A 10-20,000iu
Vitamin D 5000iu
Vitamin K 500mcg

I am happy to eat liver once a week for the vitamin A but I don't think I can reach high levels of D and K from food, especially since I am somewhat skeptical of the quality of our modern butter. In the UK, I think most cows are pasture fed when possible ie from Spring to late Summer but the butter produced does not have the deep yellow expected from this.


Stephan Guyenet said...

Hi Micawber,

Stan pretty much summed up my thinking about MK-4 vs MK-7. When mammals synthesize K2 from K1 for their own use, they make MK-4. That's the type that's found in eggs and milk, designed to nourish a growing animal. A lot of the people promoting MK-7 over MK-4 are trying to sell MK-7. I'm not trying to sell either one.

That's not to say MK-7 is bad or that it can't behave like MK-4 in some ways, but we just don't know at this point. Humans probably didn't consume large amounts of MK-7 until we invented natto, so I'm skeptical that it's the "best" form of K2, or that it can substitute for MK-4.


I know there are data out there in rodents, but it would take me a while to get to them. I'm not sure if there are data in animals that a hunter-gatherer would be likely to eat.

Those numbers look about right, except the vitamin D. I think Americans in Price's time were eating less D than we do today (milk fortification), so the number might be closer to 2,000 IU or even less.

The vitamin K2 number may be a little high as well. I'd guess very roughly from 200-500 micrograms per day. You can get that much from pastured butter and organs. By the way, sweetbreads are sometimes pancreas. They are either thymus or pancreas, and a good butcher should be able to tell you which he's selling as sweetbreads.

Anonymous said...

Thanks Stephen,

Is vitamin K from green leafies synthesized into MK-4?

Stephan Guyenet said...


The vitamin K in plants is K1, also called phylloquinone. It's made into K2 MK-4 by some animals, but humans seem to be bad at making the conversion.

K1 is important for other reasons. It's required for proper blood clotting. It's particularly rich in greens.

Debs said...

K2 MK-4 keeps seeming more essential the more we learn about it. It's ironic that people avoid crucial animal fats like delicious butter because they're afraid of getting cardiovascular disease.

It's true our typical butter isn't the kind of MK-4 rich, yellow stuff whose praises Weston Price sang, although you can get good quality, pastured butter if you look for it.

Oh, and not only are we eating worse quality butter, we're eating less of it. Here
is a chart showing our consumption of butter between 1912 and 2006. If these data are accurate, we're eating less than a quarter of what we did in 1912. Even during the Depression, when Weston Price was working, we were eating over three times as much butter as now. The same was true during World War II, when butter was rationed. It started plummeting in the 1950s, and kept going down. Today, we eat only a little over four lbs/capita annually.

Maybe I shouldn't say "we" considering the roughly six pounds of butter in my freezer, but you know what I mean.

Food Is Love/Seattle Local Food

Anonymous said...

Hey Debs,

I'm in Boston. I haven't seen grass-fed butter yet; not even in the grass-fed beef specialty butchers we have around here.

Ideally, I'd like to get grass-fed + raw butter.

Any suggestions?

Scott W said...

I know that it is best to get vitamins, etc. from food, but supplments can step in here for people who do not have access to pasture-fed butter, or who travel (like me) and really can't take along bottles of cod liver oil.

I get Vitamin A from from a Now brand supplement, 10,000 IU per softgel, source is fish liver oil. I get vitamin D3 from a Carlson softgel, 2000 IU per gel. And K2 MK-4 also comes from Carlson, 5 mg per softgel, so one a week or so is about right. Yes there is a miniscule amount of soybean or suflower oil in the A and D, basically the amount of a large drop of water in each softgel, whic is offset by the fish oil capsules I also take.

Like I said, natural food is better, but if circumstances or budget don't allow it, then supplementation is very inexpensive and certainly better than forgoing these critical nutrients.


Debs said...

Micawber, Organic Valley makes a 100% grass-fed butter called Pasture Butter. It comes in a green wrapper and looks looks like this. It also has a high butterfat content. Check a local co-op or Whole Foods. It's produced May - Sept, but is still on the shelves in Seattle.

Also, check out That site lists raw milk producers in each state, and may have some leads for grass-fed butter. Here's the link for Massachusetts.

Food Is Love/Seattle Local Food

Anna said...

I'm in the process of writing up a grass-fed butter post now that I have found more options. In addition to the brand Debs mentioned, a locally owned small chain of "natural" foods stores near me is now selling Natural by Nature tubs of whipped GF butter.

Also, in CA (or perhaps online for out of state "for pet use" sales) there is raw butter from Organic Pastures, which we use a lot, but it has a stronger taste that some might need to get used to (I prefer it for topping savory dishes and veggies). Claradale raw milk dairy in No Cal might make raw butter, too.

Clover and Strauss organic creameries indicate their herds have significant access to pasture, but not all the time due to weather, muddy conditions, etc. But at least they address the issue and leave less guessing for the consumer.

For travel (and reduction of rattling supplement capsules to swallow), I like the tiny glass bottles of Carlson D drops, in doses of 1000 or 2000 iU D3 per drop (about 365 drops per bottle). I add the drops to a bite of food or in my morning coffee. Carlson also makes an infant dose and 400iU dose.

Anonymous said...

Debs, thanks so much. I'll see if I can get it locally - my butcher here in the south end is extremely accommodating. Otherwise, I guess I'll order it online.

Anna, looking forward to your post. I didn't know that about raw butter - to be honest, I've never tried it. I've had a lot of raw cheese (have family in Paris), so thought it would be worth trying. I'm a bit curious I guess - and believe that raw milk products have the enzymes necessary for digestion.

Really good stuff here on this blog.



Yuneek said...

"Notably absent from the main text body is a discussion of where the K2 is coming from. It's tucked away in one sentence of the methods section: "cheese contributed 54%, milk products 22% and meat 15% of menaquinone intake." "

Stephan, there an inconsistency in what you are saying. Cheese comprised, by far, the largest percentage of K2 consumption but cheese in relatively low in MK-4 while high in MK-5 through MK10.

Hard Cheeses
76.3 (6% MK-4)
Soft Cheeses
56.5 (6.5% MK-4)

"Menaquinone was present in meats and eggs (MK-4 only), fish, sauerkraut, cheese, and other dairy produce (MK-5 through MK-10)."

"Both the phylloquinone and menaquinones (MK-4 to MK-10) were quantified from a few animal food items; the summarised vitamin K amounts of fish, meat and dairy products were generally very low (1-10 m g/100 g). Long-chain menaquinones (>MK-8) were found only in pig and bovine livers, Edam type cheese and soured whole milk in the range of 0.2-30 m g/100 g. Among the fish samples analysed the best vitamin K source was rainbow trout, which contained 3.1 m g/100 g mainly in the form of MK-4. Similarly MK-4 was the dominant vitamin K form in different meats (beef, pork, chicken); the highest amount (60 m g/100 g) was found in chicken meat. Among the dairy products various cheeses contained vitamin K in the range of 7.8-49.4 m g/100 g; the distribution of menaquinones varied significantly between cheese types. The sum of different forms in soured whole milk was 8.4 m g/100 g, whereas yoghurt contained vitamin K only as phylloquinone and MK-4 (0.7 m g/100 g)."

I think it is fair to say that animal sources, rather than just MK-4, are good sources of health giving vitamin K2.

I also think it is interesting that chicken, among animal meats, has a high vitamin K2 content.

As an aside: I know that pig liver is high enough in K2 to affect INR /Pro Time readings for people on warfarin therapy.

Stephan Guyenet said...

Hi Yuneek,

MK-4 is the animal form of K2. The longer-chain menaquinones in cheese are the result of fermentation.

The epidemiological association in the two studies I linked to did include longer menaquinones, but it remains to be seen whether they contribute to the (possible) effect.

Judging by the fact that arteries accumulate MK-4 preferentially, along with several other tissues, and MK-4 is the type of K2 that mammals synthesize from K1, I would say the evidence points to MK-4 being the important form of K2.

Debs said...

Another tip for butter-seekers: go to your local farmers market. If there's not someone there selling butter, talk to whoever is selling dairy products or even meats. They may know of someone who is selling grass-fed butter locally.

On my last trip to NYC, I found local, cultured, grass-fed butter made from sheep and cow milk at the farmers market. So good.

Dave said...

I would very much love to find a local source for grass-fed butter, but haven't had any luck yet (the county I live in bans sale of raw milk, which is annoying). I've been getting Anchor butter, which comes from New Zealand. Very tasty, and comes in 8 oz. blocks which are more convenient than 1 lb. I get mine from Grass Fed Traditions:

Related note: I made up a new batch of beef stock, and for the first time was able to use 100% grass fed bones. The fat I skimmed was an incredible golden color, which presumably indicates good K2 content (apparently the color comes from carotenes in the grass, and is correlated with the Vitamin K content).

Chris Masterjohn has a nice detailed article on K2 here:

Stephan Guyenet said...

Hi Dave,

Check out for dairy in your area. You can also order from US Wellness Meats. It's pretty expensive though.

Sounds like a delicious bone stock! I've read Chris Masterjohn's great article; it's what got me interested in K2.

Unknown said...


Just tried to order the Organic pastures butter and the shipping was over $40.

Had to pass

Anna said...

I just remembered to check the label of the ghee I use Purity Farms, which says the cows are pastured and organic. It's in the dairy chill-case at the store, but I store it in an unchilled cupboard for several months without problem.

I also like to save and reuse the straight sided glass jars Purity Farms packs their ghee in for storing other things, like homemade mayo.

http://www dot purityfarms dot com/faq.html
(remove the spaces and "dot")

Debs said...

Sverlyn, talk to the food buyer at a co-op or natural foods store in your area. If they buy from a distributor who carries that butter, they may be able to order a whole box - 6 lbs - for you. I ordered it that way from my co-op in Seattle, and even got a discount.

Unknown said...

Yes Debs- good idea
I just found a local organic food coop and their distributor carries the Purity Farms ghee and the Organic Valley pastured butter. I'll check @ Whole Foods next time I get there

Paul Mcgrath said...

I wonder if grass-fed beef (just the meat) has much higher K2 MK4 than conventional grain-fed beef?

I take warfarin due to a DVTE five months ago. On occasion, I would eat grass-fed beef over these five months.

To prevent spoilage, I would consume 1 to 1 1/2 pounds of the beef within a three day period. Every time I had my INR/PT tested a day or two afterward, my clotting time was shortened significantly.

My GP has gone so far as to strongly recommend that I stop eating any grass-fed beef while taking warfarin, which I've done.

My experience would indicate that the grass-fed beef I consumed did have a lot of K2.

Anonymous said...

What is the role of K2/MK-4 in blood clotting?

Stephan Guyenet said...

Hi pmpctek,

Thanks for your experience. I have a friend who recently had a pulmonary embolism and was on coumadin.

Grass-finished beef muscle should have more K2 than grain-finished beef, but neither has very much. I'm surprised to hear it affected your clotting time.

I hope your doctor has told you about the risk of arterial calcification on warfarin/coumadin. You should ensure a high K2 intake as soon as the clot is dissolved. I sent my friend a bottle of cod liver oil with K2 MK-4 (Thorne) added in drop-wise, as soon as she was off coumadin.

I'll be posting about the coumadin/calcification link tonight.

Paul Mcgrath said...


Unfortunate, my GP had no knowledge of any connection between vascular calcification, osteoporosis, and vitamin K antagonist coumarin therapies.

In fact, it took some educating and quarreling to convince him that it would be in my best interest that I not stay on warfarin therapy for life. He conceded only after I agreed to see a hematologist [a second time] to see if they can't determine why I had the DVTE.

Here's some links that appear interesting to this subject:

Stephan Guyenet said...


I'm glad you're up to speed. Long-term warfarin therapy is potentially very dangerous, because it can exacerbate K2 deficiency (already a widespread problem in modern societies).

Omega-3 fatty acids also thin the blood. Have you ever tried using fish oil to reduce your INR? Just an idea.

Stephan Guyenet said...


I'm not sure. K2 supplements come with warnings not to take them while on coumadin/warfarin therapy, which suggests they may affect coagulation. But I haven't been able to find any data on it, so it could just be an attempt to avoid being sued (because it's related to K1, which does affect coagulation). It sounds like according to pmpctek's experience, it might affect coagulation.

Paul Mcgrath said...


I take 3gs EPA/DHA's fish oil daily. I'd like to take even more, but I could be getting a double whammy from using too much fish oil and the warfarin concomitantly. What's too much fish oil? Who knows? I would assume it would depend on the individual. I've had no adverse effects, that I can tell, so far.

As you probably know, the prothrombin time (PT/INR) test measures functionality of coagulation factors II, VII, IX, and X, and that these factors require vitamin K in order to become biologically active. The PT/INR test protocol is used to assess the affects of only these clotting Factors. Vitamin E (>1000 gms) may block some vitamin K absorption/bioavailability, but results are mixed.

Fish oil suppresses platelet aggregation which uses an entirely different anti-coagulation pathway than a vitamin K antagonist. Platelet function can be assessed using the old, very crude bleeding time test, platelet aggregation assays, or a new platelet function test using a PFA-100 instrument.

There is no one test to measure the combined effect of these two anti-coagulation pathways (that I'm aware of.)

I'm finding it hard enough searching for a local doctor familiar with the calcification/warfarin literature. It's probably going to be impossible to find a local GP actually praticing in alternative anti-coagulation therapies.

Paul Mcgrath said...
This comment has been removed by the author.
Paul Mcgrath said...

I meant to write >1000mgs of vitamin E.

Stephan Guyenet said...


I think I understand. You're saying the PT/INR test won't see the effect of n-3 on platelet aggregation. So they titrate the warfarin therapy without taking platelet aggregation into account? How complicated. Well good luck finding a doctor who suits your needs.

Paul Mcgrath said...

"So they titrate the warfarin therapy without taking platelet aggregation into account?" - stephan

That's correct, because vitamin K antagonist warfarin has no affect on platelets, just as fish oil has no affect on coagulation factors II, VII, IX, and X.

Aaron Blaisdell said...


I take two 1200 mg capsules of fish oil daily for a total dose of 2400mg. I always bring my capsules with me when I travel. On a recent trip from LA to Argentina, the very dry air on the airplane dried up my nasal passages and caused a nosebleed. I stopped taking the capsules for two days and the nosebleeds stopped. Then, I started taking them again and the nosebleeds returned, but stopped when I immediately stopped taking the fish oil. I waited until a few days after returning to LA before resuming the fish oil and have experienced no nosebleeds since. I guess 2400mgs of fish oil is enough to thin my blood to the point of inducing nose bleeds under very dry conditions.

Paul G. Rollis said...

My understanding is that mk4 removes calcium from arterial plaque and that mk7 puts it into the bones and teeth.
About fish oil dosages: the size of the pill (1,000 mg., or 1200 mg.) is not what is important. What IS important is the combined total of EPA and DHA mg. per softgel. The other "stuff" in the gel doesn't matter. You need a minimum of 1,200 mg./day of EPA and DHA. It is safe to go as high as 4,000 mg./day.
Paul G. Rollis

Anonymous said...

Just a quick thanks for this and your other blogs regarding K2. Thanks especially for your unyielding scientific approach to this and other critically important nutritional and health topics.

earthgirl said...

@ "Paul G. Rollis said...
My understanding is that mk4 removes calcium from arterial plaque and that mk7 puts it into the bones and teeth." Can anyone reference this please?

earthgirl said...

Re "In modern times, our most readily available source of vitamin K2 MK-4 is actually not a paleolithic food at all, it's butter from pasture-raised cows. It's how we can get away with not eating brain, pancreas and bugs."
Point (well) made.
I think our ancestors did not starve themselves by following the doctrine of unobtainable nutrition, but instinctively (?) sourced alternatives and if they survived to reproduce then so did the alternatives as dietary sources.