B12, homocysteine, & heart disease

[Korn]

Here is some info that confirms that diets high in methionine, like meat, fish and dairy products, will increase methionine levels.


Animal studies suggest that diets high in methionine, in the presence of B-vitamin deficiencies, may increase the risk for atherosclerosis (hardening of the arteries) by increasing blood levels of cholesterol and a compound called homocysteine.15 This idea has not yet been tested in humans. Excessive methionine intake, together with inadequate intake of folic acid, vitamin B6, and vitamin B12, can increase the conversion of methionine to homocysteine—a substance linked to heart disease and stroke. Even in the absence of a deficiency of folic acid, B6, or B12, megadoses of methionine (7 grams per day) have been found to cause elevations in blood levels of homocysteine.16

Meat eaters who use the higher B12 levels in animal products as an argument pro their diet, because high B12 will decrease too high homocysteine levels, should be aware that the same diet also seem to create a need for more B12 (too keep homocysteine levels down), because it's higher concentrations of methionine.

More. (http://www.vitacost.com/science/hn/Supp/Methionine.htm)

[Korn]

More from http://www.nutritionreporter.com/B-vitamins.html


High blood levels of homocysteine, also known as hyperhomocysteinemia, pose a risk of cardiovascular disease independent of other risk factors, such as cholesterol, triglyceride, smoking, and so forth. Beresford estimated that up to 50,000 coronary heart disease deaths could be prevented by increasing folic acid intake-by eating more fruit and vegetables, fortifying foods with the vitamin, or taking supplements.

Large doses of folic acid are not needed to reduce hyperhomocysteinemia, according to Beresford. She wrote in JAMA (Oct 4, 1995;274:1049-57) that 650 mcg daily reduced homocysteine levels by 42 percent in men with hyperhomocysteinemia.[...]
Lead researcher Jacob Selhub, PhD, of the USDA Human Nutrition Research Center on Aging, Tufts University, analyzed data from 1,041 elderly participants in the well-known Framingham Heart Study. He and his colleagues found that people with high blood levels of homocysteine were twice as likely to suffer from clogged arteries than were people with low levels of the amino acid, according to an article in the New England Journal of Medicine (Feb. 2, 1995;332:286-91).[...]
At University Hospital in Lund, Sweden, Bo Israelsson, MD, reported that homocysteine levels increased in the weeks following a heart attack in 68 patients. Folic acid was far more effective than either B6 or B12 in lowering these homocysteine levels, Israelsson wrote in the Journal of Internal Medicine (April 1995;237:381-8).[...]
A number of studies have found widespread elevations of homocysteine and deficiencies of folic acid. One study found that 25 percent of middle-age men were deficient in vitamin B6, 56 percent in B12, and 59 percent in folic acid (Ubbink JB, American Journal of Clinical Nutrition, Jan 1993;57: 47-53.). A Tufts University analysis found 30 percent of elderly men and women to have elevated homocysteine levels.(Selhub J et al, JAMA, Dec. 8, 1993, 270:2693-2698.) In Atlanta, at the 1995 meeting of the Federation of American Societies for Experimental Biology, M. René Malinow, MD, of Oregon Health Sciences University commented that 30 to 40 percent of people with cerebrovascular and peripheral artery disease had high levels of homocysteine.

More recently, researchers from the United States, Germany, and Belgium reported that deficiencies of folic acid, B6, and B12 were far more common than previously thought. They measured homocysteine, methylmalonic acid (an indicator of B12 levels), and other indicators of vitamin status in 300 elderly subjects.

Although the people had apparently "normal" blood levels of vitamins, the researchers gave them intramuscular injections of folic acid, B6, and B12. Levels of homocysteine, methylmalonic acid, and the other vitamin markers began dropping - indicating that their vitamin levels had increased. "The response rate to vitamin supplements supports the notion that metabolic evidence of vitamin deficiency is common in the elderly, even in the presence of normal serum vitamin levels," Hans J. Naurath, MD, and his colleagues wrote in Lancet, (July 8, 1995;346:85-9).

Folic acid, which is water soluble and not stored by the body, is exceptionally safe. The Recommended Dietary Allowance (RDA) has been kept low (currently 200 mcg) because of a remote risk of folic acid masking some signs of B12 deficiency. Beresford, writing in JAMA suggested a simple and elegant solution: adding 1 mg (not mcg) of B12 to each 400 mcg tablet of folic acid.

Unlike cholesterol, homocysteine is not found in foods and, consequently, dieticians cannot recommend low-homocysteine diets. In contrast, folic acid is found in dark green leafy vegetables and organ meats. [...]
When consumption of folic acid or several other B vitamins is low and meat intake is high, the body cannot quench homocysteine, a byproduct of protein metabolism. Homocysteine attacks the walls of arteries and seems to set the stage for disease. It may even precede cholesterol as a causative factor. (McCully KS, Annals of Clinical & Laboratory Science, Nov.-Dec. 1993;23:477-93)

[Korn]

Wikipedia,org is an online encyclopedia that is being continuously updated.
Here is what it currently (May 2005) says about folic acid and heart disease:

Folic acid and heart disease


A deficiency of folate, vitamin B12, or vitamin B6 may increase your level of homocysteine, an amino acid normally found in your blood. There is evidence that an elevated homocysteine level is an independent risk factor for heart disease and stroke (30 - 41). The evidence suggests that high levels of homocysteine may damage coronary arteries or make it easier for blood clotting cells called platelets to clump together and form a clot (36). However, there is currently no evidence available to suggest that lowering homocysteine with vitamins will reduce your risk of heart disease. Clinical intervention trials are needed to determine whether supplementation with folic acid, vitamin B12 or vitamin B6 can lower your risk of developing coronary heart disease. If you know more than they do, please post what you know!

[Korn]

The American Heart Association on homocysteine:

The American Heart Association has not yet called hyperhomocysteinemia (high homocysteine level in the blood) a major risk factor for cardiovascular disease. We don't recommend widespread use of folic acid and B vitamin supplements to reduce the risk of heart disease and stroke. We advise a healthy, balanced diet that includes at least five servings of fruits and vegetables a day. For folic acid, the recommended daily value is 400 micrograms (mcg). Citrus fruits, tomatoes, vegetables and grain products are good sources. Since January 1998, wheat flour has been fortified with folic acid to add an estimated 100 micrograms per day to the average diet. Supplements should only be used when the diet doesn't provide enough.


What is homocysteine, and how is it related to cardiovascular risk?
Homocysteine is an amino acid in the blood. Too much of it is related to a higher risk of coronary heart disease, stroke and peripheral vascular disease (fatty deposits in peripheral arteries).


Evidence suggests that homocysteine may promote atherosclerosis (fatty deposits in blood vessels) by damaging the inner lining of arteries and promoting blood clots. However, a causal link hasn't been established.


How do folic acid and other B vitamins affect homocysteine levels?
Folic acid and other B vitamins help break down homocysteine in the body. Homocysteine levels in the blood are strongly influenced by diet and genetic factors. Dietary folic acid and vitamins B-6 and B-12 have the greatest effects. Several studies found that higher blood levels of B vitamins are related, at least in part, to lower concentrations of homocysteine. Other evidence shows that low blood levels of folic acid are linked with a higher risk of fatal coronary heart disease and stroke.


So far, no controlled treatment study has shown that folic acid supplements reduce the risk of atherosclerosis or that taking these vitamins affects the development or recurrence of cardiovascular disease. Researchers are trying to find out how much folic acid, B-6 and/or B-12 are needed to lower homocysteine levels. Screening for homocysteine levels in the blood may be useful in patients with a personal or family history of cardiovascular disease but who don't have the well-established risk factors (smoking, high blood cholesterol, high blood pressure, physical inactivity, obesity and diabetes).


Although evidence for the benefit of lowering homocysteine levels is lacking, patients at high risk should be strongly advised to be sure to get enough folic acid and vitamins B-6 and B-12 in their diet. They should eat at least five servings of fruits and green, leafy vegetables daily.

This is just one possible risk factor. A physician taking any type of nutritional approach to reducing risk should consider a person's overall risk factor profile and total diet.

[Korn]

http://www.y2khealthanddetox.com/truthchol.html

“People with these disorders frequently die of cardiovascular disease before reaching adulthood. In one case history report, a 16-year-old Japanese girl was unable to walk with or without support, and had severe peripheral neuropathy, muscle weakness and convulsions. Her vascular system was on the verge of collapse. B6 or B12 didn't help. Folic acid lowered homocysteine, but didn't improve her symptoms. Two months after adding TMG to the regimen, her homocysteine level dropped and she was able to walk with support. Seventeen months later, she was free from convulsions and able to walk normally again.

[Korn]

It seems to be a relationship between high folate levels, serum homocysteine and low risk of dementia.

From http://www.jr2.ox.ac.uk/bandolier/band67/b67-2.html :

The association between high serum homocysteine and low serum folate and dementia appears to be reproducible. Is it cause or effect? One suggestion is that people with dementia have poor diets - they may lose weight and have low serum albumin levels - because of their disease. So that could explain the low folate intake and high homocysteine levels. There is no easy answer to this, but the Oxford study demonstrated that homocysteine and vitamin levels were stable over several years while dementia got worse.

[Korn]

From Butler Hospital's website: (http://www.butler.org/body.cfm?id=125&chunkiid=38394)


Beginning in the late 1990s, medical researchers began to suspect that high levels of homocysteine (a substance produced when the body breaks down the amino acid methionine) may accelerate atherosclerosis, the primary cause of heart attacks, strokes, and intermittent claudication. During a brief period, it was widely proclaimed that homocysteine was an even more important risk factor for heart disease than cholesterol. However, it currently appears that homocysteine’s effect is slight at most.1 There is even some controversy regarding whether homocysteine causes atherosclerosis at all.

Most of the supporting evidence for a homocysteine-atherosclerosis connection comes from observational studies that found an association between high levels of homocysteine and increased atherosclerosis. Observational studies, however, cannot prove cause and effect. It is possible that certain underlying factors that increase homocysteine levels also accelerate atherosclerosis, rather than that high homocysteine causes accelerated atherosclerosis. For example, one large study found a stronger connection between vitamin B levels and heart disease than between homocysteine levels and heart disease.2 Since inadequate intake of vitamin B6 raises homocysteine levels, it may be that homocysteine levels may simply reflect vitamin B6 intake. Nonetheless, scientific investigation of the actions of homocysteine on the blood vessel wall suggests (but does not prove) that the apparent connection between homocysteine levels and atherosclerosis is more than coincidental.

Correlations have also been found between high homocysteine levels and numerous other diseases, including Alzheimer’s disease, complications of pregnancy, deep venous thrombosis, and pulmonary embolism.3–9 Again, however, most of the supporting evidence for this belief comes from observational studies, and therefore does not prove that homocysteine actually causes these illnesses.

Again: I'm not at all trying to suggest that high hcy-levels is not a bad thing. I find it very likely that low intake of folate, combined with the many B12-killers we're all exposed to will cause harm on our bodies, and that this needs to be addressed.

[Korn]

Is the following information right or wrong? It's from http://www.nationaldairycouncil.org/NationalDairyCouncil/Health/Digest/dcd69-2Page4.htm

More to follow....


Despite epidemiological findings linking high blood levels of homocysteine with increased risk for CVD, the mechanism(s) responsible for this association has yet to be clearly established. However, several possibilities are being investigated (39,45). There is no evidence from clinical trials that lowering blood levels of homocysteine by increasing intake of folic acid, vitamin B6, and/or vitamin B12, or by any other means, reduces the risk of CVD (3).

Sources:
39: Verhoef, P., F.J. Kok, D.A.C.M. Kruyssen, et. al. Arterioscler. Thromb. Vasc. Biol. 17: 989, 1997.
45: Wild, S.H., S.P. Fortmann, and S.M. Marcovina. Arterioscler. Thromb. Vasc. Biol. 17: 239, 1997.
3: Pasternak, R.C., S.M. Grundy, D. Levy, et. al. J. Am. Coll. Cardiol. 27: 978, 1996.

[Korn]

From thebody.com:


Many studies of non-HIV infected individuals have shown elevated serum homocysteine levels to be a risk factor for vascular disease. In particular, a review article by Boushey et al. (1995) highlighted homocysteine as a causal factor for arteriosclerotic vascular disease.(1) Individuals with a high level of serum homocysteine had 2.5 times the risk of developing vascular disease as those with a normal level; this makes serum homocysteine levels a stronger risk factor for vascular disease than serum cholesterol. In another study, Stubbs et al. (2000) demonstrated that for patients being admitted for acute cardiac events, serum homocysteine levels were an excellent predictor of later cardiac events such as another heart attack or death from a heart attack.(5)

The mechanism by which homocysteine acts is still unclear. However, research suggests that it affects the lining of blood vessels.(6) Increased serum homocysteine levels may damage this lining or make it hard for blood vessels to relax, making it easier for arteriosclerotic plaques to develop. Homocysteine may also change factors in blood itself so that the blood becomes more prone to clot.(1, 6) (1995)

[Korn]

http://pub50.bravenet.com/forum/4248179107/fetch/56536/ :

What is homocysteine, and how is it related to cardiovascular risk?




Homocysteine is an amino acid in the blood. Epidemiological studies have shown that too much homocysteine in the blood is related to a higher risk of coronary heart disease, stroke and peripheral vascular disease.




Two recent reports have strengthened the evidence for this relationship:

A large multi-center European trial, published in the June 11, 1997, issue of the Journal of the American Medical Association, found that among men and women younger than age 60, the overall risk of coronary and other vascular disease was 2.2 times higher in those with plasma total homocysteine levels in the top fifth of the normal range compared with those in the bottom four-fifths. This risk was independent of other risk factors, but was notably higher in smokers and persons with high blood pressure.


A Norwegian study, published in the July 24, 1997, issue of the New England Journal of Medicine, found that among 587 patients with coronary heart disease, the risk of death after four to five years was proportional to plasma total homocysteine levels. The risk rose from 3.8 percent in those with the lowest levels (below 9 ?mol per liter) to 24.7 percent with the highest levels (greater than 15 ?mol per liter).

Other evidence suggests that homocysteine may have an effect on atherosclerosis by damaging the inner lining of arteries, and promoting blood clots. However, a direct causal link hasn't been established.

How do folic acid and other B vitamins affect homocysteine levels?

Plasma homocysteine levels are strongly influenced by diet, as well as genetic factors. The dietary components with the greatest effects are folic acid and vitamins B6 and B12. Folic acid and other B vitamins help break down homocysteine in the body. Several studies, including the recent multi-center European trial, have found that higher blood levels of B vitamins are related, at least in part, to lower concentrations of homocysteine. Other recent evidence shows that low blood levels of folic acid are linked with a higher risk of fatal coronary heart disease and stroke.

As yet, however, no controlled treatment study has shown that folic acid supplements reduce the risk of atherosclerosis, or that taking these vitamins has an effect on the development or recurrence of cardiovascular disease. Researchers have studied varying amounts of folic acid to lower homocysteine levels, but it's still not clear what an optimal dose might be and to what extent a dietary supplement might be required to lower homocysteine levels.

Recent findings suggest that laboratory testing for plasma homocysteine levels can improve the assessment of risk. It may be particularly useful in patients with a personal or family history of cardiovascular disease, but in whom the well-established risk factors (smoking, high blood cholesterol, high blood pressure, physical inactivity, obesity and diabetes) don't exist. Although evidence for the benefit of lowering homocysteine levels is lacking, patients at high risk should be strongly advised to be sure to get enough folic acid and vitamins B6 and B12 in their diet.


This is just one risk factor. A physician taking any type of nutritional approach to reducing risk should consider a person's overall risk factor profile and total diet.

[Korn]

Is the problem homocysteine? Or is it cysteine and B6?
From http://www.diabetesnet.com/homocys.php :

Homocysteine - A heart risk you probably haven't heard of...


Homocysteine, a substance the body normally turns into two amino acids, came into the limelight several years ago. Researchers found some families had a genetic risk for early heart attacks, occurring between 10 and 45 years of age. Some of these heart attack-prone families were discovered to have an enzyme deficiency that created high blood levels of homocysteine.


Later researchers discovered that homocysteine can directly damage blood vessels and is strongly associated with heart attacks, strokes and peripheral vascular disease. Homocysteine attaches to LDL and modifies its structure, much like oxidation and glycosylation do. This modification of LDL by homocysteine seems to accelerate heart disease. One study found that homocysteine levels were four times as high in the LDL of men who had high cholesterol levels compared to those who did not. In another study of nearly 15,000 physicians, those with unhealthy blood levels of homocysteine were three and a half times more likely to have a heart attack than those with healthy levels.


The hereditary enzyme deficiency mentioned earlier is rare. However, homocysteine levels also rise when B vitamins are low, as they often are in diabetes. Excess urination caused by high blood sugars seems to cause the loss of the water-soluble B vitamins. Homocysteine is found at high levels in most people with diabetes who have kidney disease, and in 20 to 40 percent of the general population who have heart disease.


Vitamin B deficiencies also become more likely as we age. One study found a deficiency of one or more B vitamins in 63 percent of healthy Europeans over the age of 65, and in 83 percent of the elderly who were hospitalized for any reason.


A buildup of homocysteine also causes the loss of cysteine, an important antioxidant. In one study, women, ages 20-30, were given a vitamin B-6 supplement, and their cysteine levels rose 50 percent. High levels of homocysteine also lower copper levels in the blood. The activity of some antioxidants depends on copper.


Blood levels of homocysteine are easily lowered with a vitamin B complex supplement.

[Korn]

http://cats.med.uvm.edu/cats_teachingmod/family_practice/modules/nutrition/homocysteine/homocysteine.html

What is Homocysteine?


An elevated plasma total homocysteine concentration (generally described as >16 ?mol/L) has been associated with an increased risk of atherosclerotic and atherothrombotic vascular disease in numerous epidemiological studies.1-3* Homocysteine is a sulfur-containing amino acid that is not found in the diet but is produced during the normal metabolism of methionine (Figure 1).* The activated form of methionine, S-adenosylmethionine (SAM), is the donor of methyl groups for almost all transmethylation reactions in the body.4* Upon donating a methyl group, methionine becomes S-adenosylhomocysteine, which is then hydrolyzed to form homocysteine.* Homocysteine then has two potential fates.* It can be remethylated to generate methionine again, or it can condense with serine to generate cysteine in a 2-step reaction (the transsulfuration pathway).* If either of these pathways is limited in activity (i.e. decreased enzyme activity or inadequate cofactor), plasma homocysteine levels can rise.


The Role of Folate, Vitamin B12, and Vitamin B6
Both routes of homocysteine metabolism (remethylation and transsulfuration) require vitamins as cofactors or substrates (Figure 1).* The primary remethylation pathway, catalyzed by methionine synthase, requires both folate and vitamin B12.* The transsulfuration pathway, catalyzed by cystathionine ?-synthase, requires vitamin B6 as a cofactor.* An alternative, less significant hepatic remethylation pathway requires betaine, a derivative of choline.* Sub-optimal folate, vitamin B6, or vitamin B12 status, as well as genetic abnormalities of the enzymes involved in homocysteine metabolism [O1]can result in reduced enzyme function and elevated plasma homocysteine levels.* Conversely, adequate dietary intake of folate (400 ?g), or dietary supplementation of folate alone, or in combination with vitamin B6 and/or vitamin B12 is a safe, effective, and cost-efficient way to reduce plasma total homocysteine.5-8* It still remains to be determined, however, if lowering plasma homocysteine results in beneficial clinical outcomes.

Homocysteine and Cardiovascular Disease: How Strong is the Evidence?
An association between elevated plasma homocysteine and vascular disease was first hypothesized in 1969 when it was observed that individuals with genetic abnormalities (typically due to a deficiency of cystathionine ?-synthase) resulting in severely elevated plasma homocysteine were prone to premature atherosclerosis and thromboembolism.9* A large body of observational data since that time has supported the hypothesis that even modestly elevated plasma homocysteine increases the risk of atherosclerotic and/or atherothrombotic heart disease.1* By design, however, observational studies (both cross-sectional and case-control studies) determine plasma homocysteine levels after development of disease.* This type of study design cannot determine if a relationship is causal because it is not known if the exposure (elevated homocysteine) preceded the outcome (cardiovascular disease).* Prospective studies, such as cohort studies, are better able to establish a temporal relationship because baseline data (i.e. blood samples) are collected from healthy individuals who are then followed and later evaluated for the outcome.* Prospective studies cannot, however, determine cause and effect as there are no interventions and no way to control potentially confounding factors, such as exercise, smoking, and diet.* The most rigorous study design, the randomized, placebo-controlled, double-blinded study can establish both a temporal relationship and cause and effect.* In the case of homocysteine and cardiovascular disease, the observed associations weaken as the study design becomes more rigorous.10* Data from prospective studies have been inconclusive, and data from randomized trials are still lacking.10*

Is it Necessary to Take Folate, Vitamin B6, and Vitamin B12 Supplements?
Presently, there is not sufficient clinical evidence to recommend supplemental vitamins targeted at homocysteine reduction.* Furthermore, it is possible for most healthy individuals to consume adequate amounts of these vitamins from food.* The Recommended Dietary Allowance (RDA) for folate for adults is 400 ?g/day.* The RDA for adults <50 years old for vitamin B6 and vitamin B12 is 1.3 mg/day and 2.4 ?g/day, respectively.* Refer to Table 1 for dietary sources of these vitamins.*


In recent years, it has become easier to consume adequate folate, as most grains and cereals are now fortified with folic acid (synthetic folate).* In 1998, a Food and Drug Administration regulation requiring all enriched flour, rice, pasta, cornmeal, and other grain products to contain 140 ?g of folic acid per 100 g of product took effect.* While the intention of this fortification mandate was to increase the intake of folate by women of child-bearing age in order to reduce the risk of neural tube defects, a recent population-based study observed a significant improvement in folate status and a reduction in plasma homocysteine concentration since the fortification program took effect.11* The long-term implications of this fortification program are as of yet unknown.*


The level of fortification mandated by the FDA is conservative because excessive folate intake or supplementation (Tolerable Upper Level, UL = 1 mg/day) can mask the symptoms and delay the diagnosis of a potentially dangerous vitamin B12 deficiency, resulting in irreversible neurological damage.* Vitamin B12 deficiency is most common in the elderly, who may not absorb vitamin B12 as well as younger individuals, and in vegans, who do not consume any animal products or fortified foods, the only sources of vitamin B12.* These two populations should consume a vitamin B12 supplement, or foods supplemented with this vitamin.* Vitamin B12 supplementation is generally safe, with no adverse effects reported in healthy individuals.12* The UL for supplemental vitamin B6 is 100 mg/day.* Intakes from supplemental sources above this level are associated with potentially severe sensory neuropathies.12

The Bottom Line
To date, this is what is known for certain:
Impaired folate, vitamin B6, and/or vitamin B12 status can result in elevated plasma homocysteine levels.
Supplementation of folate, with or without vitamin B6 and/or vitamin B12 can safely reduce plasma homocysteine levels, even in individuals with genetic defects of homocysteine metabolism.
For most people, it is possible to obtain adequate amounts of these vitamins from food.


It is not known if reducing plasma homocysteine results in a decreased risk of atherosclerotic or atherothrombotic vascular disease, and thus, there is not sufficient evidence to recommend folate, vitamin B6, or vitamin B12 supplementation for the general population.* Exceptions to this may be individuals with a known genetic defect of homocysteine metabolism, individuals with a family history of premature cardiovascular disease, and individuals at risk for deficiencies of these vitamins, including those with a limited intake of fruits and vegetables and/or total avoidance of animal products.* Instead, individuals should aim to consume a varied diet that includes foods that are good sources of these vitamins (Table 1).* If an individual chooses to take a vitamin supplement, choose a supplement that provides no more than 100% of the RDA for these vitamins.*

[Korn]

http://www.abbottdiagnostics.com/Your_Health/Heart_Disease/Homocysteine/eat_your_heart_out.cfm

Victims of the rare genetic disorder known as homocystinuria usually die by age 20 from heart attack or stroke. They also have high blood levels of the amino acid homocysteine, a by-product of protein metabolism. That's highly suggestive of a cause-and-effect relationship, but after decades of investigation, the link between homocysteine and heart disease is still elusive. Says Dr. Andrew Bostom, co-director of the Cardiac Rehabilitative program at Memorial Hospital in Pawtucket, R.I.: "We have tantalizing suggestions that we might actually be dealing with a real risk factor, but we don't have smoking-gun evidence."

They do, however, have a plausible explanation for how homocysteine possibly works. If too much circulates in the blood, researchers believe, it may combine with LDL to form large molecules that are especially likely to attract the immune-system cells that help form plaques.

The good thing about homocysteine is that if it does prove to be a significant cause of heart disease, the treatment is in hand: studies have consistently shown that homocysteine can be easily controlled with B vitamins and folic acid, either in the diet or in supplements. The most recent study appeared two months ago in the New England Journal of Medicine: a government requirement that all flour, pasta and other grain products manufactured after Jan. 1, 1998, be enriched with folic acid (to stave off spinal-cord defects in newborns) has already measurably reduced homocysteine levels across the board.

[Korn]

From http://www.life-enhancement.com/LE/article_template.asp?ID=628 , a (non-vegan) site that sells supplements:


FOLATE IS A KEY TO HEART HEALTH
As we alluded to above, folate has come to be recognized as a key factor in heart health because of its ability - in conjunction with vitamin B12 - to reduce homocysteine levels. There is no longer any question regarding the strong statistical link between homocysteine and the risk for coronary heart disease (CHD),5 so ensuring that people get enough folic acid in their diet to reduce homocysteine levels has become a matter of public health policy. But how much folic acid is enough?

Since January 1998, the FDA has mandated that all refined cereal grains in the United States be fortified with 140 micrograms of folic acid per 100 grams of product (one microgram is one-thousandth of a milligram).6* Folic acid is found naturally in whole grains, citrus fruits, green vegetables, and beans (but cooking can destroy it). The FDA's Recommended Daily Allowance for folic acid is 400 mcg, and the mandated grain fortification is estimated to have increased the American consumer's average daily consumption of this nutrient by an increment of about 100 mcg (micrograms), or 0.1 mg.

*The primary impetus for this ruling was to reduce the incidence of neural tube defects in newborns, for which the value of folic acid is indisputable.


WOULD MORE FOLATE BE BETTER?
Data from the long-running Framingham Heart Study in Massachusetts show that homocysteine levels in the general population did, in fact, decrease - by 7% - in the first year after the FDA mandate took effect.7 That's good, but it raises three important questions:

1. Does reducing homocysteine levels cause a decrease in the incidence of coronary heart disease events, such as angina, heart attack, or cardiac arrest? The answer is not known, because there are as yet no clinical trial data demonstrating the efficacy of homocysteine-reducing therapy in preventing CHD events. It is widely assumed, however, that this will indeed prove to be the case.

2. What are the effects of the FDA's grain-fortification program likely to be in the longer run?

3. Would a much higher intake of folic acid (together with a correspondingly higher intake of vitamin B12 as well) be better, in terms of saving lives and saving medical costs to society?

MORE FOLIC ACID WOULD SAVE LIVES AND MONEY
To answer the second and third questions above would require a sophisticated analysis of many factors, based on an exhaustive survey of the world's scientific literature on folic acid, vitamin B12, homocysteine, and cardiovascular disease.

Just such a study, published recently in the Journal of the American Medical Association, was undertaken by a group of researchers from the University of California at San Francisco, Tufts University, the Harvard School of Public Health, and the Erasmus Medical Center in Rotterdam, The Netherlands.8

Incorporating powerful statistical tools in their computer model, the researchers crunched all the available data and came to the following conclusions about what would likely occur over the ten-year period from 2001 through 2010:

1. Morbidity/mortality reduced. The existing grain fortification with folic acid would lead to a 13% reduction in heart attacks in men and an 8% reduction in women, with comparable reductions in deaths due to CHD. As mentioned earlier, homocysteine levels increase with age in both men and women, but at any given age, both the homocysteine levels and the risk for CHD are lower in women than in men.

2. Lives saved. If, in addition to grain fortification, all patients in the USA with known CHD were treated with 1 mg (1000 mcg) of supplemental folic acid and 0.5 mg (500 mcg) of vitamin B12 per day to further lower their homocysteine levels, approximately 310,000 fewer deaths due to CHD would occur over the ten-year period, compared with grain fortification alone. (The amount of supplemental folic acid in this treatment regimen is ten times the incremental amount by which the FDA mandate has increased the average daily consumption of folic acid through food.*) The absolute reduction in deaths would be greatest in the older age groups, and men would benefit more than women because men have the higher homocysteine levels and risk for CHD to begin with.

3. Lives improved. If the same treatment regimen just described were given to all men over 45 who did not have CHD, the projected gain over ten years would be more than 300,000 "quality-adjusted life-years" (QALYs). This concept is a statistical measure that tries to take the quality of life, not just its duration, into account (one QALY is defined as one year of perfect health). And if the treatment were given to all women over 55 (a higher threshold age than for the men, for statistical reasons) who did not have CHD, the projected savings would be more than 140,000 QALYs.

4. Money saved. For the treatment regimen just described for men over 45, the projected cost savings over the ten-year period would be $2 billion (in 1997 dollars). Inexplicably, the authors did not estimate the cost savings for the women over 55.

*Actually, it could be argued that the supplemental amount is about 20 times greater than the incremental food amount, because folic acid in supplement form is known to have about twice the bioavailability of folic acid in food, i.e., it is twice as likely to reach the body's cells, where it is needed. Either way, though, you'd have to be a sumo wrestler to eat as much as it would take to get an additional 1000 mcg of folic acid from food alone.


These figures, although they are all hypothetical, command our attention. The authors of the study concluded their report by saying:

The observational evidence supporting high homocysteine levels as a risk factor for CHD events is strong. Furthermore, clinical trial data demonstrate that homocysteine levels can be lowered by inexpensive and safe doses of folic acid and cyanocobalamin. . . . Ultimately, we would recommend homocysteine-lowering therapy routinely only if ongoing clinical trials demonstrate that vitamin therapy reduces clinically important CHD events. In the meantime, since combined therapy with folic acid and cyanocobalamin is well tolerated, it is reasonable to consider routine therapy in men older than 45 years and women older than 55 years.

[Korn]

From http://www.scienzavegetariana.it/rubriche/cong2002/vegcon_B12_en.html :

Heart disease


Two trials with folic acid, B12 and B6 have shown reductions in the development of atherosclerosis.

One, which had no control group, and may have a strong bias, showed reversal of atherosclerosis (Hackam, 2000).

A randomised, controlled trial showed a homocysteine reduction from 11.1 to 7.2 and a reduction in the rate of artery blocking after angioplasty. The number requiring further treatment was reduced by 50% (Schnyder, 2001).

A further trial with folic acid and B12 showed a reduction in abnormal ECGs on exercise (Vermeulen, 2000).

Other trials have shown increased artery flexibility with high dose folic acid, but this may be a pharmacological effect of folate rather than a homocysteine related effect.

[Korn]

From http://lib1.store.vip.sc5.yahoo.com/lib/newtimrx/vviews02b2.htm :


Homocysteine - Recent medical studies from the Framingham Heart Study in Massachusetts have concluded that high Homocysteine levels are an independent risk factor for heart disease. Without getting into the specific biochemistry let me state that homocysteine is an intermediate product in the normal metabolism of methionine. Methionine is an essential amino acid found in many of our food sources. We must receive methionine in our food (meat, eggs, fish, legumes, etc.) for proper functioning of many of our metabolic pathways. We convert the methionine in our diet first to homocysteine, then cysteine, then taurine. As long as this process occurs successfully there is no problem.
The rate limiting step in this process is the availability of certain B vitamins. The three B vitamins involved are Folic Acid(B9), B6 & B12. Recent studies have shown that the cause of B6 & B12 deficiency is usually a genetic factor while the missing folic acid is primarily from diet.


A high homocysteine level in the blood is a risk factor for heart disease, specifically heart attack. This risk is an independent risk similar in severity to smoking, high cholesterol and too much weight. Smokers increase their risk even more.


The way that homocysteine increases heart attack risk is by allowing LDL Cholesterol to oxidate. This causes the epithelial cells which line the arteries to become less stable. Researchers believe that this causes cholesterol plaques to break loose and cause an occlusion leading to a heart attack. The simple solution for removing this risk is to take a vitamin B supplement. Usually strong B-Complex such as B-100 will provide enough of B6, B12 and folic acid to reduce homocysteine levels to a normal level. During the study of homocysteine metabolism and heart disease it was noted that the group which took folic acid alone did not have a statistically significant higher risk then the group taking all three B vitamins. For this reason we recommend supplementing your diet with a single 400mcg folic acid tablet a day. If you are already taking any combination of vitamin tablets which deliver this 400mcg then you do not need any additional amount.

The study he/she refers to re. the lack of effect of taking three B vitamins instead of folic acid alone, could possibly be misunderstood (by vegans) as 'B12 is not important'.... remember, this study was not performed on long term vegans, but on meat eaters, who normally have higher levels of B12 than most vegans.

[Korn]

Here's an article about current analytical methods for measuring total homocysteine in plasma, from homocysteine.net, last updated in April 2005.

From the introduction:

Elevated concentration of plasma homocysteine has been a focus of research interest since it was established that it plays a major role in the cause and effect chain linking lifestyle, nutrition and cardiovascular disease (1). During the seven years following the publication of the first meta-analysis of the relationship between plasma total homocysteine and cardiovascular disease (2), the study has been cited 1255 times, reflecting the enormous research activity involved in the further clarification of the many questions that remain unanswered. While we wait for the results of the crucial intervention studies on the effect of vitamin supplementation in the prevention of cardiovascular disease (3), measurement of total homocysteine in plasma has found its way into risk assessment of individuals in many clinical settings.


This is the background for the steadily increasing demand for the analysis of total homocysteine in plasma meeting the research and clinical laboratories today. In this short review, the different laboratory methods in past, present and potential future use will be discussed critically.

The full article: http://www.homocysteine.net/pages/measuring/1/jmoller.html

[Korn]

From a discussion about homocysteine and Alzheimer, from Health On The Net Foundation (2002):


Blood Molecule Boosts Risk of Stroke, Alzheimer's
Study finds even moderate homocysteine levels raise odds

By Ed Edelson
HealthScoutNews Reporter

THURSDAY, Oct. 3 (HealthScoutNews) -- Moderately high blood levels of the amino acid homocysteine -- levels seen in a quarter of the adult population -- are linked to a substantial increase in the risk of Alzheimer's disease, other dementias and stroke.

"People deemed to have normal levels of homocysteine are in fact at elevated risk for stroke and dementia," says Stephen P. McIlroy, a lecturer in geriatric medicine at Queens University in Belfast, Northern Ireland. He reports the finding in the October issue of Stroke .


The research shows the need for a large-scale study to see whether taking supplements containing folic acid and B vitamins, which reduce blood levels of homocysteine, can lower the incidence of Alzheimer's disease and stroke, McIlroy says.


Other studies have linked elevated homocysteine levels to Alzheimer's disease, heart disease and stroke, but McIlroy's study finds a risk at lower levels than have been reported. He and his colleagues looked at homocysteine levels in 83 Alzheimer's patients, 78 patients with dementia caused by poor blood flow to the brain, 64 stroke patients and 71 healthy volunteers. All were in their 70s.


The study used a cutoff line of homocysteine levels found in the upper 25 percent of the healthy volunteers. After correcting for known risk factors such as smoking, blood cholesterol and blood pressure, the researchers say that readings above that level are associated with a 2.9 times greater risk of Alzheimer's disease, a 5.5 times greater risk of stroke, and a 4.9 times greater risk of dementia due to poor blood flow to the brain.


Laboratory studies have shown that homocysteine and molecules produced when it is metabolized can attack blood vessels and nerves. However, there has been a running debate about whether elevated homocysteine levels cause blood vessel and nerve damage or are just associated with processes that cause the damage. The case for cause-and-effect is compelling, McIlroy says.


"There are too many studies saying that high homocysteine levels are linked to dementia and stroke," he says. "I certainly think it is a cause, a very easily modifiable risk factor for dementia and stroke."


However, Bill Thies, vice president for medical and scientific affairs for the Alzheimer's Association, says it's too early to be recommending supplements for prevention.


"These kinds of studies don't give you cause-and-effect information," he says. "They just point you in a direction."


As for a prevention trial, Thies says it would be more difficult to do in the United States than in Northern Ireland. Many foods here are fortified with folic acid to prevent birth defects, something that's not done there, he says, and that might muddy the results of any American trial.


A study of Alzheimer's patients to see whether folic acid and vitamins B12 and B6 can slow progression of the disease is being started in the United States, Thies says. Positive results from that trial could lead to a bigger preventive study, he says.


The Alzheimer's Association has no official position on self-medication with folic acid and vitamin B, Thies says. A basic rule is that "anyone should not be taking anything without consulting their physician, and if you take anything, you should tell your physician," he says.


Folic acid and vitamin B supplements are generally agreed to be innocuous, Thies says, but "there is no such thing as a completely safe drug." Since various studies have suggested that taking aspirin, other anti-clotting drugs, estrogen or other medications might reduce the risk of Alzheimer's, "you could end up taking a fair collection of pills without evidence that they might be effective or what the risk is," he says.

http://www.hon.ch/News/HSN/509450.html

[Korn]

http://www.abbottdiagnostics.com/Your_Health/Heart_Disease/Homocysteine/Clinical_Insights/chdrisk.cfm


The authors found that 10% of the population's risk for CHD appears attributable to homocysteine and that a 5 µmol/L homocysteine increment elevates CHD risk by an amount equivalent to a 20 mg/dL increase in serum cholesterol. Hyperhomocysteinemia has also been shown to have a high prevalence in patients with both cerebrovascular and large artery disease.


In studies performed after Boushey's meta-analysis, similar findings have been described. Malinow and associates measured plasma homocysteine concentrations in survivors of myocardial infarction (MI) and in control subjects from Northern Ireland and France. They reported that plasma homocysteine levels were higher in the Irish than in the French and that subjects with MI had higher levels than controls. They concluded that a "global excess of risk for MI was graded across the distribution of plasma homocysteine concentration" and that the elevated homocysteine levels in the Irish may explain that population's increased incidence of CHD.


As explained by Dr. Genest, one of the problems in interpreting the data on homocysteine and CHD is that many of the studies are of the case-controlled type, a valuable methodology that has inherent limitations. Among prospective, nested, case-control studies, the association has not been as consistent.


Top of page


For example, while the British Regional Heart Study and the British United Provident Association (BUPA) trial showed an increased relative risk of CHD in patients with hyperhomocysteinemia (RR = 2.8 and 2.9, respectively), other studies have not. In fact, the Atherosclerosis Risk in Communities (ARIC) study questioned the role of homocysteine as a causative risk factor for HD in men (but not women). Confounders that may limit the role of homocysteine as an independent risk factor variable include vitamin B6 intake, renal function, smoking, fibrinogen, D-dimer, and C-reactive protein. Although univariate analysis shows a strong and consistent association between homocysteine and cardiovascular disease in case-control studies, this does not prove a causal relationship. According to Dr. Genest, the exact role of homocysteine in CHD awaits the results of prospective trials currently in progress.


Jacques Genest, Jr, MD
Associate Professor, University of Montreal
Director, Cardiovascular, Genetics Laboratory
Clinical Research Institute of Montreal
Montreal, Quebec, Canada
[...]Page last modified: June 16, 2005

[Korn]

This (http://www.mercola.com/2000/oct/1/insulin_homocysteine.htm) site refers to 'Diabetes Care 2000;23:1348-1352', and writes:

Insulin May Raise Homocysteine

Overweight children with high levels of the hormone insulin in their blood are also likely to have high levels of homocysteine, a substance that appears to raise the risk of heart disease, stroke, and birth defects, as well as possibly other adverse effects as well.


In addition, these children and adolescents appear to have lower levels of folate, a vitamin that can lower homocysteine levels.


The combination of elevated homocysteine and reduced folate could put these children at increased risk for developing heart disease, explain researchers from the University of Graz in Austria, who studied the link in 84 children and adolescents.


"The implication of our finding might be that reduction of cardiovascular risk factors (such as) body fat and insulin -- by dieting and/or physical activity -- might improve homocysteine metabolism," Dr. Siegfried Gallistl, the study's lead author, explained in an interview with Reuters Health. He also noted that that insulin appears to inhibit enzymes that play a role in homocysteine metabolism.


Insulin is the hormone responsible for getting glucose (sugar) in the blood into cells throughout the body to use as fuel. The cells of people with type 2 diabetes do not respond adequately to insulin. As a result, levels of both glucose and insulin in the blood remain high.


"Our study demonstrates for the first time that insulin is a main correlate of homocysteine in obese children and adolescents and suggests that (high insulin) may contribute to impairment of homocysteine metabolism in childhood obesity," the researchers conclude.

[Korn]

An excerpt from The American Journal of Clinical Nutrition (http://www.ajcn.org/cgi/content/full/72/2/315)



Homocysteine and cardiovascular disease: cause or effect?
Lars Brattström and David EL Wilcken

Abstract
Both markedly and mildly elevated circulating homocysteine concentrations are associated with increased risk of vascular occlusion. Here we review possible mechanisms that mediate these effects. Inborn errors of homocysteine metabolism result in markedly elevated plasma homocysteine (200–300 µmol/L) and thromboembolic (mainly venous) disease: treatment to lower but not to normalize these concentrations prevents vascular events. Mild homocysteine elevation (>15 µmol/L) occurs in 20–30% of patients with atherosclerotic disease. Usually, this is easily normalized with oral folate and ongoing trials are assessing the effect of folate treatment on outcomes. Although there is evidence of endothelial dysfunction with both markedly and mildly elevated homocysteine concentrations, the elevated homocysteine concentration in atherosclerotic patients is also associated with most standard vascular risk factors, and importantly, with early decline in renal function, which is common in atherosclerosis. Decline in renal function alone causes elevated plasma homocysteine (and cysteine). These observations suggest that mild hyperhomocysteinemia could often be an effect rather than a cause of atherosclerotic disease. Data on the common C677T methylenetetrahydrofolate reductase polymorphism supports this, in that, although homozygosity is a frequent cause of mild hyperhomocysteinemia when plasma folate is below median population concentrations, it appears not to increase cardiovascular risk. Indeed, there is recent evidence suggesting an acute antioxidant effect of folic acid independent of its effect on homocysteine concentrations. This antioxidant mechanism may oppose an oxidant effect of homocysteine and be relevant to treatment of patients with vascular disease, especially those with chronic renal insufficiency. Such patients have moderately elevated plasma homocysteine and greatly increased cardiovascular risk that is largely unexplained.

INTRODUCTION

Despite the impressive epidemiologic evidence that mild hyperhomocysteinemia is an independent risk factor for atherosclerotic and atherothrombotic vascular disease, we have become increasingly doubtful as to whether modest elevations of plasma homocysteine may be causally involved in the pathogenesis of atherosclerosis. As will be outlined in this review, there are now substantial indications that a modest elevation of plasma homocysteine is usually benign and is a consequence rather than a cause of atherosclerosis.
[...]
CONCLUSIONS

It has been established that lowering the markedly elevated circulating homocysteine concentrations found in patients with the inborn error of homocystinuria due to CBS deficiency, even to suboptimal concentrations, greatly reduces cardiovascular risk (20, 139). This finding defines a key role for grossly elevated homocysteine concentrations in the pathogenesis of vascular disease. The relevance to vascular risk of mild hyperhomocysteinemia is, however, still undetermined. The results of the many ongoing homocysteine-lowering trials with folic acid in vascular patients may certainly clarify whether folate therapy is relevant to cardiovascular risk in the general population and will provide much important information (38). However, if the trials show a positive effect of supplementation they will not of course separate the effects of oral folate supplementation from those of lowering homocysteine concentration. This might be done by comparing folic acid and betaine therapy in such patients because both lower circulating homocysteine but by different mechanisms. This would be an extremely interesting study but one that is unlikely to be done.

American Journal of Clinical Nutrition, Vol. 72, No. 2, 315-323, August 2000

[Korn]

From the University of Kuopio:


Homocysteine and other CVD risk factors
High circulating Hcy concentrations may increase the risk of CVD when present with other CVD risk factors. For example, there is some evidence that in hypercholesterolemic patients the risk of an atherosclerotic event was about three times higher in patients with high plasma tHcy concentrations compared to those with low tHcy concentrations. Another study done in subjects with elevated LDL cholesterol concentrations suggests that even mildly increased plasma tHcy levels are of crucial importance for deterioration of endothelial function. Increased risk of mortality in the subjects with both elevated cholesterol and tHcy concentrations may at least partly be explained by deterioration of endothelial function.


Similar findings to those found in hypercholesterolemic patients have also been reported in case of increased plasma fibrinogen levels or in smokers. The increased risk with increased fibrinogen and tHcy concentrations could be explained by their complementary roles in the platelet activation-aggregation cascade. Fibrinogen represents a major step in platelet aggregation while homocysteine impairs nitric oxide production and also contributes to the generation of oxidized species. In some studies smoking has been shown to increase plasma tHcy concentrations, but in the KIHD study population this is not seen. Smokers have an increased risk of vascular disease in general and according to some recent research the risk is greatly increased in the presence of a raised plasma tHcy concentration when compared with non-smokers.


Currently Jyrki Virtanen is studying the effects of high plasma tHcy concentration on CVD risk in men of the KIHD study, who also have other CVD risk factors. These include smoking, high serum total and LDL cholesterol and apo-B apolipoprotein concentrations and high plasma fibrinogen concentration. Preliminary results would seem to indicate that although tHcy alone is not a risk factor for CVD in this study population, it may increase the risk when present with above mentioned risk factors.


Homocysteine and methionine
Since Hcy is formed from an essential dietary amino acid methionine, high intakes of methionine increase the plasma tHcy concentrations. This happens because the capacity of the transsulfuration pathway is exceeded and Hcy is excreted from cells. Elevation of plasma tHcy occurs, for example, in the oral methionine loading test, in which a large dose of methionine (0.1 g/kg body weight of L-methionine) is ingested to diagnose hyperhomocysteinemia. It could be speculated that a long-term high methionine intake from diet could lead to modest but chronic plasma tHcy concentrations, which in turn could increase the risk of CVD.


Homocysteine and stroke
Although high plasma tHcy has been suggested to be a risk factor for CVD, its role as a risk factor for stroke is more controversial. Although most case-control studies suggest it to be a risk factor for stroke, the results from prospective studies are conflicting. Two recent meta-analyses, however, have concluded that Hcy might increase the risk of stroke. The mechanisms through which Hcy could cause stroke are its hypercoagulative effects in ischemic stroke and promotion of plaque rupture in hemorrhagic stroke. Jyrki Virtanen's next paper will concern the role of high plasma tHcy concentration in the risk of overall and ischaemic stroke in the KIHD study population.


Conclusion
Although folate or folic acid intake could lower the risk of CVD through reducing plasma tHcy concentrations, elevated homocysteine may also be only a marker for low folate and/or vitamin B6 status or an indicator of an unhealthy lifestyle rather than a causal risk factor per se. Ongoing intervention trials will indicate whether homocysteine-lowering through vitamin supplementation prevents heart diseases, or are the measured circulating high homocysteine and low folate levels just markers of unhealthy lifestyle.


More information about our studies:
sari.voutilainen@uku.fi, jyrki.virtanen@uku.fi

More: http://www.uku.fi/nutritionepidemiologists/folate.htm

[Korn]

From http://www.quackwatch.org/03HealthPromotion/homocysteine.html :




Homocysteine: A Cardiovascular Risk
Factor Worth Considering


Stephen Barrett, M.D.



At least nine well-known risk factors can help predict the likelihood of heart attacks and strokes: heredity, being male, advancing age, cigarette smoking, high blood pressure, diabetes, obesity (especially excess abdominal fat), lack of physical activity, and abnormal blood cholesterol levels. The more of these risk factors a person has, the greater the likelihood of becoming ill. Heredity, gender, and age cannot be modified, but the others can be influenced by the individual's behavior. Modifying these factors can lower the risk of having a heart attack.


During the past few years, elevated blood levels of homocysteine (a sulfur-containing amino acid) have been linked to increased risk of premature coronary artery disease, stroke, and thromboembolism (venous blood clots), even among people who have normal cholesterol levels. Abnormal homocysteine levels appear to contribute to atherosclerosis in at least three ways: (1) a direct toxic effect that damages the cells lining the inside of the arteries, (2) interference with clotting factors, and (3) oxidation of low-density lipoproteins (LDL).


A recent study compared 131 patients with severe blockages in two coronary arteries, 88 patients with moderate blockage of one coronary artery, and another group of healthy individuals without heart disease. The researchers found a linear relationship between blood homocysteine levels and severity of the coronary blockages: For every 10% elevation of homocysteine, there was nearly the same rise in the risk of developing severe coronary heart disease [1]. Another study has found that postmenopausal women with elevated homocysteine levels had a higher incidence of coronary heart disease [2]. Another study found that homocysteine levels were much higher in people who developed vein clots than in similar people who did not [3]. Yet another study found that elevated homocysteine levels may ne associated with an increased risk of stroke in people who already have coronary heart disease [4]


Blood for measuring serum homocysteine levels is drawn after a 12-hour fast. Levels between 5 and 15 micromoles per liter (µmol/L) are considered normal. Abnormal concentrations are classified as moderate (16-30), intermediate (31-100), and severe (greater than 100 µmol/L). [5]


The connection between homocysteine and cardiovascular disease was suspected about 25 years ago when it was observed that people with a rare condition called homocystinuria are prone to develop severe cardiovascular disease in their teens and twenties. In this condition, an enzyme deficiency causes homocysteine to accumulate in the blood and to be excreted in the urine. Recent studies suggest that elevated blood homocysteine levels are as important as high blood cholesterol levels and can operate independently. Some 10% to 20% of cases of coronary heart disease have been linked to elevated homocysteine levels. Both hereditary and dietary factors may be involved.


Homocystinuria is transmitted by a recessive gene. If both parents transmit the gene, the resultant offspring have very high plasma homocysteine levels. People who receive the defective gene from only one parent do not develop the disease but often have a mildly elevated plasma level of homocysteine. About one person in 100 carries one such gene. Abnormal elevation also occurs among people whose diet contains inadequate amounts of folic acid, vitamin B6, or vitamin B12. Regardless of the cause of the elevation, supplementation with one or more of these vitamins can lower plasma levels of homocysteine.


Dietary supplementation with folic acid can reduce elevated homocysteine levels in most patients. The usual therapeutic dose is 1 mg/day. When this is not effective, vitamins B6 and/or B12 can be added to the regimen, which should be continued permanently. Some doctors routinely recommend that patients known to have atherosclerosis take B-vitamin supplements without being tested to determine whether their homocysteine level is elevated. They reason that since supplementation is harmless and since elevated homocysteine levels might be a factor, testing is not worth bothering with. Even though some patients may be helped with this "shotgun" strategy, I believe it is far better to (a) find out whether a problem exists and (b) to be certain that if homocysteine levels are elevated, the vitamin regimen is adjusted to be sure that lowering is achieved.


A recent study that followed 80,000 women for 14 years found that the incidence of heart attacks was lowest among those who used multivitamins or had the highest intake of folic acid and B6 from dietary sources [6]. This data parallels the finding that elevated homocysteine levels are associated with a higher incidence of heart disease. However, the researchers measured folic acid blood levels but did not measure homocysteine or B12 levels. Rather, they assumed that low folic acid levels were caused by inadequate dietary intake. Victor Herbert, M.D., a leading expert on B12 metabolism, has pointed out that the low folic acid levels among the experimental subjects could have been caused by decreased B12 absorption related to getting older.


Lowering the serum concentration of homocysteine has been proven to reduce the risk of adverse cardiovascular events among people with homocystinuria. Studies have not yet determined whether lowering homocysteine levels reduces the incidence of heart attacks or strokes among people with mildly elevated homocysteine levels [7,8], but many experts believe that scientific studies will prove that it does. This belief has been strongly supported by a four-year study in which 101 men with vascular disease were given supplementary doses of folic acid, B6 , and B12. Ultrasound examinations of their carotid arteries found a decrease in the amount of carortid plaque in their arteries, with the greatest effect in those whose homocyteine levels had been highest before the treatment began [9].


Screening for elevated homocysteine levels is advisable for individuals who manifest coronary artery disease that is out of proportion to their traditional risk factors or who have a family history of premature atherosclerotic disease. Levels above 9 or 10 µmol/l warrant treatment. The effect of supplementation is usually apparent within a month. The laboratory test can be obtained for about $40. Some physicians recommend that all patients with atherosclerotic disease be screened. A recent study of the effect on homocysteine of either folic acid or B12 alone found that the body adjusts its reliance on one or the other and that supplementing with both provides a more certain way to improve homocysteine levels [10].


At least a dozen large-scale studies following a total of more than 60,000 people are underway in the United States, Canada, and Europe to examine the effects of lowering blood homocysteine levels on the incidence of heart attacks and/or strokes [9,11]. The longest one so far involved 553 patients who had had successful angioplasty has found that lowering homocysteine levels significantly decreased the incidence of major cardiac events after angioplasty. The participants were randomly assigned to receive a combination of folic acid, vitamin B12, and vitamin B6 or a placebo for 6 months and were followed for about six more months. The study found that the incidence of heart attacks, death and need for repeat revascularization were about one third less in the vitamin group than in the control group [12].


Since folic acid is nontoxic, it seems prudent to treat elevated homocysteine levels based on current knowledge. The process should be supervised by a well-informed physician.


Caution: Elevated homocysteine levels can be caused by vitamin B12 deficiency due to impaired absorption of B12 caused by gastric atrophy (damage to the lining of the stomach). B12 deficiency leads to anemia and, if not corrected in time, will permanently damage the nervous system. Folic acid supplements will correct the anemia (which can serve as a warning sign before nerve damage develops), but they do not prevent the damage. For this reason, people over 50 who take folic acid supplements should also take at least 25 micrograms of vitamin B12 per day, a dose large enough to enable adequate amounts to be absorbed. Dr. Herbert believes that everyone over age 50 should take B12 supplements anyway, because gastric atrophy is common as people age. Products containing 100 mcg per pill are readily available.


References


Verhoef P and others. Plasma total homocysteine, B vitamins, and risk of coronary atherosclerosis. Arteriosclerosis, Thrombosis, and Vascular Biology 17:989-995, 1997.
Ridker PM and others. Homocysteine and risk of cardiovascular disease among postmenopausal women. JAMA 281:1817-1821, 1999.
Loralie J and others. Hyperhomocyst(e)inemia and the Increased Risk of Venous Thromboembolism. Archives of Internal Medicine 160:961-964, 2000.
Tanne D and others. Prospective study of serum homocysteine and risk of ischemic stroke among patients with preexisting coronary heart disease. Stroke 34:632-636, 2003.
Kang SS and others. Hyperhomocyst(e)inemia as a risk factor for occlusive vascular disease. Annual Review of Nutrition 12:279-298, 1992.Rimm EB and others. Folate and Vitamin B6 from Diet and Supplements in Relation to Risk of Coronary Heart Disease among Women. JAMA 279:359-364, 1998.
Malinow MR and others. Homocyst(e)ine, diet, and cardiovascular diseases: A statement for healthcare professionals from the nutrition committee, American Heart Association. Circulation 99:178-182, 1999.
Eikelboom JW and others. Homocyst(e)ine and cardiovascular disease: A critical review of the epidemiologic evidence. Annals of Internal Medicine 131:363-375, 1999.
Hackam DG and others. What level of plasma homocyst(e)ine should be treated? Effects of vitamin therapy on progression of carotid atherosclerosis in patients with homocyst(e)ine levels above and below 14 micromol/L. American Journal of Hypertension 13:105-100, 2000.
Genest J Jr and others. Homocysteine: To screen and treat or wait and see? Canadian Medical Association Journal 163:37-38, 2000. [PDF}
Quinlivan EP and others. Importance of both folic acid and vitamin B12 in reduction of risk of vascular disease. Lancet 359:227-228, 2002. [PDF]
Booth GL, Wang EL, with the Canadian Task Force on Preventive Health Care. Preventive health care, 2000 update: screening and management of hypohomocysteinemia for the prevention of coronary artery disease events. Canadian Medical Association Journal 163:21-29, 2000. [PDF]
Schnyder G and others. Homocysteine-lowering therapy with folic acid, vitamin B12, and vitamin B6 on clinical outcome after percutaneous coronary intervention. The Swiss Heart Study: A randomized controlled trial. JAMA 288:973-979, 2002






This article was revised on March 29, 2003.

[Korn]

From http://www.homocysteine.com/bkchap2.html

Carotid artery intimal-medial wall thickening and plasma homocyst(e)ine in asymptomatic adults. The Atherosclerosis Risk in Communities Study.
Malinow MR; Nieto FJ; Szklo M; Chambless LE; Bond G: Circulation* (United States), Apr 1993, 87(4) p1107-13

Editor's Comment:
I remember meeting Dr. Malinow in New York City in Dr. Victor Herbert's apartment. This was followed by a great Thai dinner on 59th street. I took the opportunity to discuss Dr. Malinow's homocysteine studies and found him to be a credible, brilliant researcher who was ahead of his time. The following work is a landmark study of great importance.

Dr. Malinow constructed a rather simple, noninvasive study using ultrasound to measure the thickness of the wall of the carotid arteries, the vessels that pipe all of the blood to the head. It is these vessels that when thickened and narrowed lead to strokes and the so-called TIA (transient ischemic attack). The study as presented below shows that if your homocysteine level is high, in the upper twenty percent, the chances for a thickened artery wall are more than three times greater than for someone having a level in the lowest 20%.

Plasma levels of homocysteine are elevated in certain patients with occlusive arterial diseases. We extended these findings to asymptomatic adults. METHODS AND RESULTS. We determined plasma homocysteine levels in 287 pairs of asymptomatic adults. Cases and controls were defined on the basis of intimal-medial thickness of the carotid wall as measured by B-mode ultrasound. Study subjects had no history of atherosclerotic disease and were selected from a probability sample of 15,800 men and women between 45 and 64 years old. Subjects with thickened intimal-medial carotid walls (cases) had higher plasma homocysteine levels than controls (p 0.001). The odds ratio for having a thickened carotid artery wall was 3.15 (p 0.001) for subjects in the top quintile of plasma homocysteine levels ( 10.5 mumol/L) compared with those in the bottom quintile ( 5.88 mumol/L). CONCLUSIONS: The present study as well as observations on the common occurrence of elevated plasma homocysteine levels in patients with occlusive arterial diseases suggest that clinical trials should be conducted to determine whether normalization of hyperhomocysteinemia may prevent progression of atherosclerosis.

romotion of vascular smooth muscle cell growth by homocysteine: a link to atherosclerosis.*
Tsai JC; Perrella MA; Yoshizumi M; Hsieh CM; Haber E; Schlegel R; Lee ME: JProc Natl Acad Sci U S A* (United States), Jul 5 1994, 91(14) p6369-73 Cardiovascular Biology Laboratory, Harvard School of Public Health, Boston, MA.

Editor's Comment:
This study by Tsai and associates from a prominent laboratory is very provocative. Modern theories of the mechanisms of atherosclerosis propose that an initial toxic event leads to damage of the innermost blood vessel lining cells, the intimal or endothelial cells. After this comes the monocyte scavenger cells and sticky granulocytes (both white blood cells) in an attempt to repair the damage. This is to no avail for the repair mechanism itself becomes a confounding damaging force.

Monocytes change shape as they bore their way into the blood vessel wall and secrete materials that help turn on other cells to grow. They, in concert with other cells, start to imbibe oxidized lipoprotein-cholesterol forming what have been called "foam cells". The following study points to homocysteine's ability to not only damage endothelial cells (the initial event of atherosclerosis) but also to stimulate the overgrowth of blood vessel smooth muscle cells, a hallmark of atherosclerosis.

Plasma homocysteine levels are elevated in 20-30% of all patients with premature atherosclerosis. Although elevated homocysteine levels have been recognized as an independent risk factor for myocardial infarction and stroke, the mechanism by which these elevated levels cause atherosclerosis is unknown. To understand the role of homocysteine in the pathogenesis of atherosclerosis, we examined the effect of homocysteine on the growth of both vascular smooth muscle cells and endothelial cells at concentrations similar to those observed in clinical studies. As little as 0.1 mM homocysteine caused a 25% increase in DNA synthesis, and homocysteine at 1 mM increased DNA synthesis by 4.5-fold in rat aortic smooth muscle cells (RASMC). In contrast, homocysteine caused a dose-dependent decrease in DNA synthesis in human umbilical vein endothelial cells. Homocysteine increased mRNA levels of cyclin D1 and cyclin A in RASMC by 3- and 15-fold, respectively, indicating that homocysteine induced the mRNA of cyclins important for the reentry of quiescent RASMC into the cell cycle. Furthermore, homocysteine promoted proliferation of quiescent RASMC, an effect markedly amplified by 2% serum. The growth-promoting effect of homocysteine on vascular smooth muscle cells, together with its inhibitory effect on endothelial cell growth, represents an important mechanism to explain homocysteine-induced atherosclerosis.

Association between plasma homocysteine concentrations and extracranial carotid-artery stenosis.* Selhub J; Jacques PF; Bostom AG. D'Agostino RB; Wilson PW; Belanger AJ; O'Leary DH; Wolf PA; Schaefer EJ; Rosenberg IH: Comment in: N Engl J Med 1995 Feb 2; 332(5):328-9* Department of Agriculture Human Nutrition Research Center on Aging, Tufts University, Boston, MA 02111.

Editor's Comment:
Dr. Selhub has written extensively on homocysteine and atherosclerosis. Here is a study that not only confirms the results of Malinow's work cited above but also correlates high blood levels of homocysteine with decreased ingestion of vitamins B6 and folic acid. The authors were also able to correlate lower serum levels of these vitamins in patients with thickened carotid arteries and high homocysteine.

Later, in another chapter, I will present evidence revealing that it is next to impossible to ingest enough folic acid from a healthy diet to suppress homocysteine to its lowest and safest level. The roles played by* vitamin B6 and folic acid are critical and will be explained in detail in the chapter on homocysteine metabolism.

Epidemiological studies have identified hyperhomocysteinemia as a possible risk factor for atherosclerosis. We determined the risk of carotid-artery atherosclerosis in relation to both plasma homocysteine concentrations and nutritional determinants of hyperhomocysteinemia. METHODS. We performed a cross-sectional study of 1041 elderly subjects (418 men and 623 women; age range, 67 to 96 years) from the Framingham Heart Study. We examined the relation between the maximal degree of stenosis of the extracranial carotid arteries (as assessed by ultrasonography) and plasma homocysteine concentrations, as well as plasma concentrations and intakes of vitamins involved in homocysteine metabolism, including folate, vitamin B12, and vitamin B6. The subjects were classified into two categories according to the findings in the more diseased of the two carotid vessels: stenosis of 0 to 24 percent and stenosis of 25 to 100 percent. RESULTS. The prevalence of carotid stenosis of or = 25 percent was 43 percent in the men and 34 percent in the women. The odds ratio for stenosis of or = 25 percent was 2.0 (95 percent confidence interval, 1.4 to 2.9) for subjects with the highest plasma homocysteine concentrations ( or = 14.4 mumol per liter) as compared with those with the lowest concentrations ( or = 9.1 mumol per liter), after adjustment for sex, age, plasma high-density lipoprotein cholesterol concentration, systolic blood pressure, and smoking status (P 0.001 for trend). Plasma concentrations of folate and pyridoxal-5'-phosphate (the coenzyme form of vitamin B6) and the level of folate intake were inversely associated with carotid-artery stenosis after adjustment for age, sex, and other risk factors. CONCLUSIONS. High plasma homocysteine concentrations and low concentrations of folate and vitamin B6, through their role in homocysteine metabolism, are associated with an increased risk of extracranial carotid-artery stenosis in the elderly.

Serum total homocysteine and coronary heart disease.* Arnesen E, Refsum H, Bonaa KH, Ueland PM, Forde OH, Nordrehaug JE Int J Epidemiol 1995 Aug;24(4):704-9* Institute of Community Medicine, University of Tromso, Norway.

Editor's Comment:
This study evaluated 21,826 subjects and confirmed the association of high homocysteine levels with heart attack. It also found the absence of a threshold value for homocysteine above which heart attacks occur. This means that those with lower homocysteine levels will have a lower chance of having a heart attack. As we shall discuss in another chapter, therapy with appropriate doses of vitamins will lower serum homocysteine levels by up to 50%.

Several studies have observed high plasma levels of homocysteine among patients with coronary heart disease (CHD). The only prospective study was based on US physicians, and concluded that homocysteine was associated with subsequent myocardial infarction (MI). However, the association was limited to those above a threshold level of homocysteine. METHODS. We conducted a nested case-control study among the 21,826 subjects, aged 12-61 years, who were surveyed in the municipality of Tromso, Norway. Among those free from MI at the screening, 123 later developed CHD. Four controls were selected for each case. RESULTS. Level of homocysteine was higher in cases than in controls (12.7 +/- 4.7 versus 11.3 +/- 3.7 mumol/l (mean +/- SD); P = 0.002). The relative risk for a 4 mumol/l increase in serum homocysteine was 1.41 (95% confidence interval (CI): 1.16-1.71). Adjusting for possible cofounders reduced the relative risk to 1.32 (95% CI: 1.05-1.65). There was no threshold level above which serum homocysteine is associated with CHD events. CONCLUSIONS. In the general population serum total homocysteine is an independent risk factor for CHD with no threshold level.

[Korn]

Excerpts from http://www.medic8.com/healthguide/articles/homocysteine.html



HOMOCYSTEINE AND VASCULAR DISEASE - a patient's guide
Dr Michael Crooke - Biochemistry Pathologist



What is Homocysteine?

Homocysteine is an amino acid found in blood and other body fluids. It is a breakdown product of another amino acid (methionine). Once homocysteine is formed it can be further broken down and excreted or it can be reconverted to methionine. This reconversion is important, as methionine is an essential amino acid.


If the excretory or recycling processes are not functioning efficiently then levels of homocysteine in the blood will increase. Both the breakdown and recycling processes are controlled by enzymes and these enzymes require adequate levels of vitamins for proper activity. In the case of the breakdown process vitamin B6 is important, and for recycling of homocysteine to methionine, vitamin B12 and folate are necessary. The overall evidence is that folate may be most important in keeping homocysteine at lower levels.


What is the significance of homocysteine?

The importance of homocysteine is that higher levels in blood have been linked to a higher chance of developing vascular disease (heart attacks, strokes and blockage of the arteries to the legs). High homocysteine is also associated with a higher frequency of venous thrombosis (clots).


These associations of homocysteine with vascular disease do not prove that homocysteine is a cause of the disease. They are in the category of circumstantial evidence, qualifying homocysteine as a strong risk factor and allowing the reasonable hypothesis that it is a cause of cardiovascular disease. The final link in proving a cause is to show that reducing levels of a risk factor leads to reduction in disease and these studies have not yet been completed for homocysteine.

[...]

The current situation for homocysteine is much the same as existed for cholesterol 10-15 years ago, i.e. it is only a risk factor although there are plausible reasons that it may be a cause of vascular disease. The strength of the association of high homocysteine with vascular disease, especially coronary artery disease, is just as high as that for cholesterol, so it is important that the final research studies are completed. These will show whether or not lowering homocysteine does decrease the risks of vascular disease and should also help to define safe methods of lowering homocysteine. Despite the high risk association of homocysteine, there is no guarantee that the trials will be successful. Associations can easily be questionable.

[...]
Further studies have confirmed that the risk associated with homocysteine is also seen in the general population, at much lower levels of homocysteine than found in homocystinuria. In fact, the risk is graded over the whole range of homocysteine levels found in what would be regarded as normal populations. The usual range of homocysteine found in the plasma (blood) of 95% of people is 5- 15 umol/L. The evidence suggests that any increase of 5 umol/L, even within this so called normal range, inreases the risk of a clinical event related to heart disease by about 1.5 fold.


The evidence is even stronger when those with the top 20% of homocysteine levels within the range of 5-15 umol/L are compared with those with the bottom 80% of homocysteine levels. The increased risk is then up to two fold. The magnitude of this increased risk is similar to that seen for the top 20% of cholesterol levels and for smokers versus non-smokers. Levels of homocysteine over 15 umol/L confer even higher risk.



These risk associations are sustained, and may be even stronger, in these people who are already known to have arterial disease. For example, in one study of people known to have coronary artery disease, 25% of those with homocysteine over 15 umol/L died over a five year period, compared with only 4% of those with homocysteine under 9 umol/L.


These studies of populations (epidemiology) have all been consistent in showing the risk association of vascular disease with homocysteine, across over 20 studies. The overall conclusion is that homocysteine is confirmed as a risk factor for vascular disease, completely independent of any other risk factors. While consistent, these studies do not prove cause and effect. However, there is a strong possibility that homocysteine is likely to be a contributing cause of arteriosclerotic vascular disease (hardening of the arteries).


[...]


The final biological evidence is that homocysteine causes damage to the cells which line blood vessels when these cells are grown in cell cultures to which homocysteine is added. This damage, if it occurs in the body, would be expected to promote the formation of atheroma and thrombosis.


What causes homocysteine to be higher than may be desirable?

The chemical reactions determining homocysteine levels in the blood are complex. The key point to understand is that a deficiency of folate may result in higher levels.


A number of factors affect these reactions but there is a wealth of evidence to suggest that levels of blood (serum)folate are most important. Normally about 50% of homocysteine is reconverted to methionine by the enzyme methionine synthase in steps which also require folate, vitamin B12 and the enzyme methylenetetrahydrofolate reductase (MTHFR). Folate acts as a methyl donor for the overall reaction and thus deficiency of folate would be expected to impair the conversion of homocysteine to methionine, thus causing increased levels of homocysteine.


There is consistent evidence that plasma homocysteine is inversely related to serum folate, i.e. higher folate gives lower homocysteine and vice versa. This relationship holds at levels of folate which have previously been considered to be normal.


Furthermore, the risk of coronary heart disease has been clearly linked to lower levels of serum folate and long term studies have shown an inverse association between a high folate diet and both coronary and carotid artery disease. Most notable is the Nurses Study in which 80,000 women were followed up for 14 years. The risk of heart attack was reduced by 30-50% in those who consumed the most folate/folic acid, compared with those who consumed the least. This reduced risk was considered to be most likely due to the effects of high folate consumption to reduce homocysteine, although the study was not set up to prove this point.


A number of other clinical trials have shown that supplementation of the diet with folic acid does lower homocysteine and a summary of all studies indicates that, on average, 0.5mg of folic acid reduces homocysteine by about 25% (e.g. from 12 to 9). Greater reductions were seen if the subjects had initially high pre-treatment levels of homocysteine or lower initial levels of serum folate. Small additional effects to lower homocysteine were seen when the diets were also supplemented with vitamin B12. These were all short term dietary studies and there was no attempt to study any changes in vascular disease.


[n]The conclusion from all these dietary studies is that up to 40-50% of the population have insufficient intake of natural food folate to lower homocysteine to the levels associated with lower vascular risk (homocysteine under 9 umol/L).


Furthermore, it is probable that the currently stated reference (normal) ranges for serum folate are set too low. The usual lower limit stated is around 7 umol/L, but to minimise homocysteine levels the lower level should be around 15 umol/L and some people will need much higher levels than this to minimise homocysteine.[/b]

[...]

Higher homocysteine levels are also found, on average, in men compared with woman, in smokers, and there is a tendency for levels to increase with age. This latter effect may be related to poorer diet in older people i.e. less folate and vitamin B12. Excessive coffee drinking also tends to increase homocysteine.

[...]

It is of interest that in the United States it has been mandatory, since 1st January 1998, that all cereal based foods be supplemented by the manufacturers with folic acid, at 140mg/100g. This will add about 100 mg of folic acid (equivalent to 200 mg of food folate) to the average diet. (Note 100 mg equals 0.1mg). The reason for this legislation was not related to possible prevention of heart disease but rather to the fact that this level of supplementation will help prevent neural tube defects (spina bifida and anencephaly). It has been clearly shown that when pregnant woman consume folic acid supplements, in addition to natural food folate, a large proportion of cases of spina bifida are prevented. It is difficult, even with the best diet, to reach the daily amount of folate/folic acid required so supplementation is necessary. In New Zealand it is recommended that all pregnant women take folic acid supplements.


The legislation caused controversy in the United States with some health authorities arguing that the supplementation should have been greater, not only to prevent spina bifida, but also to reduce the risk of vascular disease in the whole population by lowering average levels of homocysteine in response to adequate folic acid.


The critics, the prestigious Centre for Disease Control among them, argue that since there is clear evidence that a substantial proportion of the population consume insufficient folate in food, the cereal based foods should have been supplemented with a minimum of 0.35mg/100g of folic acid and that 0.7mg/100g would be safe [...].



It can certainly do no harm to increase folate containing foods in the diet. Examples of these are green/leafy vegetables such as [b]broccoli, or spinach, starch beans such as kidney beans, butter beans, peas, corn, cauliflower, nuts, avocado, wheat bran, wholegrain cereals and most fruits, especially citrus fruits. Most nutritional authorities would recommend at least five daily servings of foods from this group as part of a healthy diet, also likely to benefit cholesterol levels. If this level of intake can be achieved it is arguable that most people would not benefit further from supplementation with folic acid.


[...]

The only known risk of folic acid is in people who might have vitamin B12 deficiency. Folic acid supplements can mask the symptoms of vitamin B12 deficiency. The elderly are especially at risk, as vitamin B12 deficiency is relatively common in this group. Even so, only doses of folic acid of over 0.8mg are likely to cause a problem. The obvious solution is to measure both serum folate and vitamin B12 before folic acid supplements are taken and, if appropriate, to also take vitamin B12.

You've probably read - a lot of times - that it's almost impossible to get enough B12 to keep the homocysteine levels down on a vegan diet. Non-vegans who read about folate and homocysteine have probably have seen, equally many times, that it's almost impossible to get enough folate (to keep the homocysteine levels 'safe') on a non-vegan diet.