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The Cholesterol Times, Issue #010 -- Redefining Heart Disease: Discovering Vitamin K All Over Again
March 24, 2007
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In This Issue

Site Updates
It's Finally Here -- Launching Cholesterol-And-Health.Com Special Reports
Best of the 'Net
Research Watch

How to Link to This Newsletter
Copyright and Disclaimer
Search
Feedback

Site Updates

Is Dietary Cholesterol an Essential Nutrient?

Since the human body usually makes enough cholesterol to meet its needs, cholesterol is not considered an essential nutrient. Some people, however, have a genetic defect in the ability to make cholesterol. Although only one in 10,000 to 60,000 live births result in the severe form of this defect called Smith-Lemli-Opitz syndrome, between one and three percent of the population carry a copy of the defective gene and have a reduced rate of cholesterol synthesis and an increased risk of suicide. For this portion of the population, dietary cholesterol may in fact be an essential nutrient.

Debating the China Study: My Response to T. Colin Campbell

My latest response to Dr. T. Colin Campbell of Cornell University, author of The China Study in our ongoing debate about the significance of animal foods in the diet.

It's Finally Here -- Launching Cholesterol-And-Health.Com Special Reports

If you like the type of information you get from this newsletter, you'll love Cholesterol-And-Health.Com Special Reports. From now until March 31, members of this free newsletter can subscribe to Special Reports for only $20. Beginning on April 1, subscriptions will be opened to everyone at $30 per year and individual reports will be sold through Cholesterol-And-Health.Com for $15 per article. You'll receive four reports -- worth $60 -- jam-packed with extensively referenced and carefully reviewed information but with the unique perspective you find in my other articles. For an example of the typical quality and length that you can expect, see my recent Wise Traditions article on vitamin D. Topics covered will include the role of nutrition in heart disease, iron's dual role as both an oxidant and an antioxidant, the dark side of fish oils and beta-carotene, and much more.

(Note: If you have already subscribed to Special Reports, you should have recently received an update from me via email as well as an advanced copy of a yet-to-be-published article identifying the "activator X" of Weston Price. If you did not receive this, please contact me.)

Click here to subscribe to Special Reports today!

Best of the 'Net

T. Colin Campbell Responds to My Review

You can read Dr. Campbell's original response here. He numbers me among those who are "mischievously posing as qualified scientists" and states that I have shown "a serious lack of understanding not only of the fundamentals of scientific research but also of the principles of statistics, epidemiology and nutrition," by "superficially citing uncorrected crude correlations" that I have selected "to reflect an alternative agenda or bias that has nothing to do with objective science." I tried to focus on the science rather than the name-calling in my response.

Bill Sardi: It's the Calcification, Not the Cholesterol

"According to Dr. John Abramson of Harvard Medical School," Sardi writes, "in his article titled 'Are Lipid-Lowering Guidelines Evidence-Based?' in Lancet, no studies have shown statin cholesterol-lowering drugs to be effective for women at any age, nor for men 69 years of age or older, who do not already have heart disease or diabetes. Better than 50 adults have to take a cholesterol-lowering drug for 1 patient to avoid a mortal heart attack, and that figure only applies to high-risk patients. There is a vanishing benefit to lowering cholesterol for healthy adults. Dr. Abramson calls for cholesterol treatment guidelines to be revised." Sardi continues, exploring the new science revealing the importance of arterial calcification and the critical role of vitamins D and K as well as magnesium in preventing heart disease.

Dr. Daniel Steinberg on the Role of Oxidative Damage to Lipoproteins in Heart Disease

With over 400 published scientific articles, Daniel Steinberg, MD, PhD is an expert on cholesterol if there ever was one. In this interview with Richard A. Passwater, PhD, Dr. Steinberg discusses "the discovery that changed the direction of heart disease research" -- the role of oxidative damage to LDL in the development of heart disease. This interview is worth reviewing before moving on to the "Research Watch" section of this newsletter where I discuss the dramatic effect of carnosine -- a powerful antioxidant found in meat but destroyed by heat -- on the effect of oxidizing agents on LDL's ability to accumulate into macrophages to form the "foam cells" that characterize atherosclerosis. It's not all about lipoproteins, however. Other research cited below is showing that these macrophages accumulate exclusively in pockets of calcification that develop around dead smooth muscle cells -- whose death may be a result of a deficiency of a very misunderstood vitamin.

Plant Poisons and Rotten Stuff

If you have any unexplained symptoms of inflammation, itching, blood pressure fluctuation, migraines, food intolerances, or gastrointestinal symptoms, it is possible that you are reacting to amines, salicylates, benzoates, glutamates or other naturally occuring or added chemicals in foods. This site is an excellent resource for learning about these sensitivities -- which according to three decades of research by the Australian Royal Prince Alfred Hospital Allergy Unit are much more common than true allergies.

From Seafood to Sunshine: A New Understanding of Vitamin D Safety

If you haven't already read it, my recent article on vitamin D published in Wise Traditions packs in everything you ever wanted to know about it's safety and toxicity into one report and makes critical points about it's interactions with vitamins A and K that you won't find discussed anywhere else.

Vitamin D Toxicity Redefined: Vitamin K and the Molecular Mechanism

My first peer-reviewed publication: a hypothesis on the molecular mechanism of vitamin D toxicity. In it, I propose that vitamin D toxicity is actually a relative deficiency of vitamin K, and suggest several possible molecular mechanisms by which it could induce this deficiency. The paper also proposes a mechanism by which vitamin A may protect against vitamin D toxicity, although vitamin A's role is likely to extend beyond that which I have discussed in this paper.

Research Watch

Vitamin K, Arterial Calcification and Atherosclerosis

Researchers at the University of Maastricht in the Netherlands recently published the results of an experiment in the journal Blood showing that vitamin K deficiency causes arterial calcification and the death of the smooth muscle cells that line the blood vessel wall. They have shown in previous research that atherosclerosis is characterized by deposits of calcium salts, lipids, white blood cells, and deformed vitamin K-dependent proteins manufactured by cells that do not have enough vitamin K to meet their needs. These deposits are not random -- they aggregate around the remnants of dead ("apoptotic") smooth muscle cells.

Vitamin K supports at least two proteins that are likely to protect against atherosclerosis: matrix Gla protein (MGP) and growth arrest specific gene product 6 (Gas6). MGP protects soft tissues from calcification, while Gas6 increases cell survival and helps clear away any fragments left behind by cells that do happen to die.

In this experiment, the researchers induced a vitamin K deficiency in Wistar Kyoto rats with warfarin, an oral anticoagulant that works by inhibiting the recycling of vitamin K. Warfarin caused arterial calcification, a marked increase in the death of smooth muscle cells, a loss of blood vessel elasticity, and a decreased ability of the blood vessels to accomodate changes in pressure. High-dose vitamin K supplementation reversed these changes even after they were induced by warfarin. Low-dose vitamin K supplementation not only did nothing to reverse the effects of warfarin but the calcification actually continued at the same rate in the animals that received the drug after it was discontinued, persisting for the entire duration of the study, showing that the vitamin K deficiency induced by oral anticoagulants persists long after their use is discontinued.

In this study and in an earlier one that the same researchers published, vitamin K1, found in plants, had no ability whatsoever to prevent warfarin-induced calcification when the drug and the vitamin were administered together, while vitamin K2, found in animal foods and fermented plant foods, completely inhibited warfarin-induced calcification. The researchers found, however, that after warfarin was discontinued, both vitamins were equally effective at reversing calcification.

The Wistar Kyoto rats that these researchers used convert vitamin K1 to vitamin K2 with great efficiency. Warfarin not only inhibits the recycling of vitamin K, but also the conversion of vitamin K1 to vitamin K2. Although it is not clear why this would be the case and the findings should therefore be treated with caution, the results strongly suggest that only vitamin K2 protects against heart disease, and that vitamin K1 is effective only insofar as it is converted to vitamin K2. How well humans make this conversion compared to rats is unknown. In The Rotterdam Study, intakes of vitamin K2 showed a powerful inverse association between calcification of the aorta, heart disease, and heart disease mortality. Intakes of vitamin K1 by contrast -- even though they were ten times higher than intakes of vitamin K2 -- had no relationship to any of these endpoints at all.

Schurgers LJ, Spronk HMH, Soute BAM, Schiffers PM, DeMey JGR, Vermeer C. Regression of warfarin-induced medial alastocalcinosis by high intake of vitamin K in rats. Blood. 2006; [Epub ahead of print].

Note: If you are reading this in email using AOL, you may encounter an error in which the text appears in subscript at this point. If so, you can continue reading the issue here.)

Statins Promote Vascular Cell Survival by Protecting Vitamin K-Dependent Proteins

Researchers from the University of Tokyo recently showed that statins, a class of drugs widely used to lower cholesterol, increase the survival of human arterial cells by protecting the vitamin K-dependent protein Gas6. The research was published in the journal Circulation Research.

The scientists bathed isolated cells taken from human arteries in a solution very high in phosphate. The phosphate led to the death and calcification of the cells, similar to what is seen in cardiovascular disease. They showed that the death of the cells -- called apoptosis -- was a requirement for calcification, and that phosphate caused this death after being transported into the cell where it caused a decrease in the expression of Gas6, which is important to cell survival. Statins inhibited apoptosis and calcification by preserving the messenger RNA for Gas6, which is a molecule that helps "translate" the genetic information within the DNA into the real, live protein. The effect appears to be general rather than specific -- statins appear to increase the stability of all messenger RNA. However, these researchers showed that the ability of elevated levels of phosphate to induce apoptosis and calcification and the ability of statins to counter this effect was directly related to the preservation of the messenger RNA for this one specific vitamin K-dependent protein. Simply adding more Gas6 to the cell culture to make up for the phosphate-induced loss of Gas6 achieved the same result as adding the statin.

Perhaps it is time to consider whether vitamin K might be a lower-cost, safer and more effective alternative to statin drugs.

Son B-K, Kozaki K, Iijima K, Eto M, Kojima T, Hidetaka O, Senda Y, Maemura K, Nakano T, Akishita M, Ouchi Y. Statins Protect Human Aortic Smooth Muscle Cells From Inorganic Phosphate-Induced Calcification by Restoring Gas6-Axl Survival Pathway. Circulation Research. 2006; 98: 102-1031.

High Estrogen Levels Increase the Risk of Stroke in Men -- A New Role for Fruits and Vegetables?

In a study published last month in the journal Neurology, researchers reported an association between high levels of estrogen and stroke among two thousand male participants in the Honolulu Heart Program. The researchers measured the men's blood levels of estrogen between 1991 and 1993 and followed them until 1998, recording the incidence of stroke. Among all hormones tested, only estradiol, the main form of estrogen, was associated with the risk of stroke. Among the 80 percent of men with low, moderate or moderately high levels of estrogen, there was no difference in the risk of stroke. Among the 20 percent of men with the highest levels of estrogen, however, the risk of stroke was doubled. Higher estrogen levels were also associated with an increase in the prevalence of atrial fibrillation (when the upper chambers of the heart quiver rather than pumping effectively) and dementia and lower levels of cholesterol.

This finding raises the question of whether inverse associations between fruits and vegetables and the risk of stroke may be related to their anti-estrogenic properties. The most effective anti-estrogenic plant compounds are flavones and flavanones, which inhibit the conversion of testosterone to estrogen. (These compounds are members of a broader group called flavonoids, other forms of which have weaker anti-estrogenic properties. For a comprehensive review of the actions of flavonoids, see here.) Flavones are found in parsley, thyme, celery, sweet red peppers, honey and propolis (a waxy substance found in unfiltered honey), while flavanones are found in citrus fruits. In human males (in a study cited in the aforementioned review), twenty-one days of consuming honey and propolis, which contain a flavone called chrysin, resulted in the inhibition of estrogen synthesis and a resultant increase in testosterone levels.

Abbott RD, Launer LJ, Rodriguez BL, Ross GW, Wilson PWF, Masaki KH, Strozyk D, Curb JD, Yano K, Popper JS, Petrovitch H. Serum estradiol and risk of stroke in elderly men. Neurology. 2007; 68: 563-568.

Low Cholesterol Increases the Risk of Mortality Among the Very Old

A small study of 23 subjects between the ages of 85 and 94 living in Troina, a rural village of Sicily, found that over the course of two years, low cholesterol levels increased the risk of mortality. Cholesterol levels ranged from 116 mg/dl to 239 mg/dl. Sex, age, body mass index and high cholesterol were not risk factors for total mortality in this study. Thirty percent of the study population died by the end of two years, but the authors did not report the magnitude of increased risk posed by low cholesterol.

The subjects were selected from a random sample of the 103 elders living in the village who were over the age of 84. The initial sample numbered forty people; after 17 of the forty were excluded due to dementia, malnutrition, acute or chronic diseases, or the use of lipid-lowering therapy, 23 remained. The study was small and the data reported was not very thorough; nevertheless, Troina should be congratulated for its robust elderly population, in whom the majority of people over the age of 84 are healthy and drug-free.

Spada RS, Toscano G, Cosentino FII, Iero I, Lanuzza B, Tripodi M, Ferri R. Low total cholesterol predicts mortality in the nondemented oldest old. Arch Gerontol Geriatr Suppl. 2007; 1: 381-384.

Does Television Cause Heart Disease After All?

To demonstrate that correlation does not prove causation, many authors point out that countries with high rates of television ownership have high rates of heart disease, and that we would not necessarily conclude from this that television causes heart disease. Correlations never prove causation, but they are more compelling reasons to look for true causation when they are shown at the level of the individual rather than the level of the population and if confounding variables are eliminated -- for example, people who watch more TV may exercise less.

An interesting study conducted by researchers from Tufts University and published this month in the journal Diabetes Care found an association between television watching and metabolic syndrome among Peurto Ricans and Dominicans living in Massachusetts. The association persisted even after adjusting for confounding varaibles such as physical activity.

Metabolic syndrome is a group of symptoms including abdominal obesity, insulin resistance, glucose intolerance, disturbed lipid levels and high blood pressure, and is associated with diabetes, cardiovascular disease and mortality. Incidence of the metabolic syndrome was over fifty percent in the study population, and the risk was more than doubled for those watching more than 5.6 hours of television per day, even after adjusting for age, sex, ethnicity, body mass index, education, alcohol use, smoking, household arrangement, physical activity, total energy intake, and intake of saturated, polyunsaturated and trans fatty acids. Each hour watching television was associated with a 19 percent increased risk of metabolic syndrome.

When the researchers looked at components of the metabolic syndrome on an individual basis, television watching was associated with a greater waist-to-hip ratio, lower HDL, higher total-to-HDL cholesterol, and higher blood pressure, although the association with high blood pressure did not withstand adjustment for physical activity, energy and fat intakes.

The researchers cited evidence that the metabolic rate of individuals is higher when they read than when they watch television. It will be interesting to see whether reading increases the metabolic rate, television decreases the metabolic rate, or both.

Although a continued search for confounding variables and an examination of the possible health-promoting effects of more mentally engaging activities certain deserve our attention, we should also consider whether exposure to certain visual patterns, wavelengths of light, or even electromagnetic energy may have adverse effects on our metabolism. In his 1985 book, The Body Electric: Electromagnetism and the Foundation of Life, Robert O. Becker extensively documented the effects of electromagnetic energy on metabolism.

"Electromagnetic energy has other effects on blood composition and tissue function," Becker wrote. "Yuri D Dumansky, one of many Soviet biophysicists who have done detailed work on microwave hazards, found changes in carbohydrate metabolism, including a rise in human blood-sugar levels, resulting from 100 and 1,000 microwatts. Power-frequency (50-hertz) fields were also linked to altered sugar and protein metabolism in rats, as well as decreased muscular strength in rabbits. Like many other Russian results, these were questioned because of American failure to corroborate them. In this case a research team headed by NS Mathewson of the Armed Forces Radiobiology Research Institute in Bethesda, Maryland, reported no such metabolic changes in response to the Sanguine-Seafarer 45-hertz frequency.

"However, the Mathewson group made a fundamental mistake. They neglected to account for the 60-hertz background field near the test cages in their lab, even though they'd measured it when setting up the work station. When we reanalyzed their data in light of this omission, the experiment showed exactly the same changes in blood levels of glucose, globulins, lipids and triglycerides as the Russians found."

Becker also cites disturbances in trace mineral metabolism and the utilization of vitamins B2 and B6 produced by electromagnetic radiation and metabolic effects produced by levels of radiation within the range of typical offiice appliances such as computers and overhead lighting.

It would certainly be an interesting turn of events to find out that watching too much television actually does cause heart disease after all!

Goa X, Nelson ME, Tucker KL. Television Viewing Is Associated With Prevalence of Metabolic Syndrome in Hispanic Elders. Diabetes Care. 2007; 30: 694-700.

Vitamin A Protects Against Vitamin D Toxicity But Does Not Antagonize Its Anti-Carcinogenic Effects

Dr. Heather Mernitz and her colleages at Tufts University recently showed that vitamin A protects against vitamin D toxicity without antagonizing its ability to prevent lung cancer in mice. The research will be published in the April issue of the International Journal of Cancer.

The researchers used the active hormone forms of these vitamins: calcitriol, the active form of vitamin D, and 9-cis-retinoic acid, one of the active forms of vitamin A. The mice were injected with 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), a carcinogen from tobacco smoke. The dose of NNK was sufficient to produce 10-12 lung tumors in 100 percent of the mice. Activated vitamin D at 2.5 micrograms per kilogram of food produced a 36 percent reduction in tumor incidence and an 85 percent reduction in the number of tumors each mouse developed, but also produced a 20 percent decrease in body weight and a 29 percent incidence of gross kidney calcification. 15 milligrams of activated vitamin A completely protected against these toxic effects without producing any antagonistic effect on vitamin D's ability to inhibit lung cancer.

This study is of monumental importance. I have found research dating back to 1934 showing that vitamins A and D protect against each other's toxicity, but this is the first study I am aware of showing a simultaneous mitigation of toxicity without an antagonism of beneficial actions in live animals. The implications of the finding for nutritional policy and recommendations are enormous: if the simultaneous administration of vitamins can mitigate their toxicity without antagonizing their beneficial effects, the entire models by which optimal requirements and upper limits are determined need to be revised to take these interactions into account.

Mernitz H, Smith DE, Wood RJ, Russell RM, Wang X-D. Inhibition of lung carcinogenesis by 1alpha,25-dihydroxyvitamin D3 and 9-cis retinoic acid in the A/J mouse model: Evidence of retinoid mitigation of vitamin D toxicity. Int J Cancer. 2007; 120: 1402-1409.

Carnosine -- Meat's Antioxidant -- Prevents the Uptake of LDL into "Foam Cells"

A dangerous process called glycation occurs when sugars, amino acids or polyunsaturated fatty acids oxidize. These "glycating agents" can damage LDL and greatly increase the rate at which it is taken up by white blood cells called macrophages to form the so-called "foam cells" that characterize atherosclerosis. Carnosine is a compound found exclusively in meat. It is a dipeptide -- that is, a combination of two amino acids -- composed of l-histidine and beta-alanine. It is a powerful anti-glycation agent.

Australian researchers published a report in FEBS Letters, a publication of the Federation of European Biochemical Societies, showing that carnosine completely inhibits the effect of glycation on LDL accumulation into foam cells. The researchers incubated macrophages with LDL or with LDL and glycoaldehyde, a potent glycating agent. The glycoaldehyde more than doubled the rate at which LDL was taken up into the macrophages. The addition of carnosine completely abolished the effect. The concentrations used of these substances were higher in the study than what is found in our bodies, but the proportions between the glycating agent and the carnosine were similar to what we would encounter in the human body. This suggests that meat may be a powerful inhibitor of atherosclerosis -- but as we'll see below, it all depends on how you cook it.

Rashid I, van Reyk DM, Davies MJ. Carnosine and its constituents inhibit glycation of low-density lipoproteins that promotes foam cell formation in vitro. FEBS Letters. 2007; 581: 1067-1070.

High-Heat Cooking Converts Carnosine Into Acrylamide -- It's Not Just in Potatoes Anymore

If you think blackened and barbequed steak is going to protect you from atherosclerosis, think again. Unfortunately high temperatures convert carnosine into acrylamide, a potent carcinogen and neurotoxin.

Acrylamide is most famous for its presence in baked and especially fried potatoes, in which the amino acid asparagine reacts with sugars in the potato to form this nasty toxin under conditions of high heat. Unfortunately, acrylamide in meat products has largely escaped our attention because it is mostly present as acrylamide derivitives like N-methylacrylamide, which is just as toxic but doesn't show up on tests for plain old acrylamide.

This is actually old news by now in the scientific literature, but it was news to me when I happened upon this study several weeks ago. In 2004, researchers from McGill University in Quebec, Canada published a report in the Journal of Agricultural and Food Chemistry showing that acrylamide forms in meat under conditions of high heat even more rapidly than it does in potatoes -- even in the absence of sugar. Whereas the formation of acrylamide from asparagine in potatoes requires sugar, the formation of acrylamide from carnosine in meat does not. The reason, however, that acrylamide levels in cooked meat are 200 times lower than those in cooked potatoes is because the acrylamide reacts with another meat constituent, carnitine, to form N-methylacrylamide, another toxin just as potent.

High heat thus not only forms toxic acryalmide derivatives in meat, but also destroys the carnosine and creatine.

It should therefore not be difficult to see how something as simple as the method of cooking can turn meat from a health-promoting and heart disease-fighting super-food into a charred slab of toxic trash. Hopefully future research can clarify just what types, temperatures and lengths of cooking best retain the health-promoting creatine and carnosine while avoiding the formation of toxic acrylamides.

This finding also makes it clear why epidemiological evidence associating "meat" with disease that does not distinguish between cooking methods (among many other quality factors) is woefully inadequate to address the question of what types of food constitute an optimal diet.

Yaylayan VA, Locas CP, Wnorowski A, O'Brien J. The Role of Creatine in the Generation of N-Methylacrylamide: A New Toxicant in Cooked Meat. J Agric Food Chem. 2004; 52: 5559-5565.

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