How to Lower Homocysteine Levels

Heart Disease is a
Vitamin Deficiency

By Will Block

s the 20th century draws to a close, the American medical establishment stands at the brink of a cataclysmic self-revelation that promises to alter profoundly the way most doctors view - and treat - heart disease. Sometime within the next 2 or 3 years, accumulated findings from a line of scientific evidence going back at least 30 years will remove all doubt from a conclusion many people in the alternative medicine community reached a decade or more ago.

As soon as the results of this study are published, most likely in a high profile journal like the New England Journal of Medicine or the Journal of the American Medical Association, there will be a massive outbreak of news coverage, cover stories in Time and Newsweek, scores of books and pamphlets, specials on Nightline, Dateline, 60 Minutes, and 20/20, and expert interviews on Oprah, Larry King, and Crossfire.

One thing you won't find, though, is much enthusiasm for this new approach to heart disease from the pharmaceutical industry, and probably not much from the FDA either, at least not right away. The reason is simple.

Once that last piece of the scientific puzzle falls into place, no one will be able to deny that heart disease is due in a large part to nutritional deficiency. Just as too little vitamin C causes scurvy, too little folate (and to a lesser extent, vitamins B6 and B12) can cause your arteries to clog up. Many years of chronic folate deficiency can result in a heart attack or stroke.

This is the stuff of medical revolution. If low folate (an unnumbered B vitamin) levels lead directly to atherosclerosis, then simply increasing your dietary intake of the common and inexpensive folic acid, either from food or from supplements, should head off a significant number of heart attacks and strokes. If everyone were taking folic acid supplements, the need for expensive and dangerous drugs to lower cholesterol and blood pressure and even more expensive and dangerous surgical procedures, like coronary angiography, angioplasty, and coronary artery bypass, would likely plummet.


Just as too little vitamin C causes scurvy,
too little folate can cause your arteries to
clog up. Many years of chronic folate
deficiency can result in a
heart attack or stroke.

The folic acid story goes back to the late 1960s, when a young Harvard trained physician named Kilmer McCully, working at the prestigious Massachusetts General Hospital, became intrigued by a 35-year-old report of a boy diagnosed with a rare genetic disease - homocystinuria (homocysteine in the urine) - who had died of a stroke at the age of 8 years. What kinds of events could cause such a bizarre and devastating disruption of normal processes in someone so young, he wondered.

As he describes it in his recent book, The Homocysteine Revolution,1 McCully dug out the boy's original autopsy report and reexamined the old tissue samples under a microscope. He might as well have been looking at the arteries of an 80-year-old man. Looking at other cases of homocystinuria, he found similar pathological changes, including one infant who had died of a stroke at age 2 months!

These children had a gene mutation which interfered with the body's ability to break down (or remethylate) the amino acid homocysteine into another amino acid methionine. Could accumulating homocysteine have contributed to the premature atherosclerosis in these children's bodies, McCully wondered? Even more importantly, could elevated homocysteine be a factor in heart disease in adults, which accounts for more deaths in this country than any other disease?

If so, the implications would be staggering. It would mean that homocysteine levels - and presumably a high proportion of heart disease - could easily be controlled by consuming foods and/or supplements containing adequate amounts of vitamin B6, vitamin B12, riboflavin, and especially folic acid. If that doesn't constitute a vitamin deficiency, I don't know what does.

When Dr. McCully started presenting his potentially earthshaking ideas to the medical community in 1970, he met with a less than enthusiastic response. These were the days when the dangers of cholesterol were just starting to come into focus. The suggestion that elevated plasma homocysteine might be an equally important independent risk factor for heart disease seemed irrelevant, at best.


If everyone were taking folic acid
supplements, the need for expensive and
dangerous drugs to lower cholesterol
and blood pressure and even more
expensive and dangerous surgical procedures,
like coronary angiography, angioplasty, and
coronary artery bypass, would likely plummet.

McCully was denounced by a group of hostile researchers, who deliberately misinterpreted the results of their own study, tricking McCully into appearing to support their invalid conclusions. Had the results been interpreted properly, they would have supported his hypothesis. This lapse of scientific ethics helped call into question the connection between homocysteine and vascular disease.

Ultimately, Mass General "rewarded" McCully with the time-honored medical pioneer exit - the boot. Undaunted, he moved on to the Veterans Administration Hospital in Providence, where he remains to this day, finally vindicated and recognized for his insights and persistence.

WHAT IS HOMOCYSTEINE?
Homocysteine is an amino acid formed naturally in the body and when broken down forms the amino acid methionine (commonly found in red meat). Small amounts of homocysteine cause no problems, because they are kept under control by a variety of enzymes. They may be either converted back into methionine or another amino acid, cysteine, they may be used for building new proteins, or they may be broken down and excreted via the kidneys before they can do any harm.

All too often, though, homocysteine levels rise too high, and that's when the trouble starts. In some people (about 1 in 300), hyperhomocystinemia (high levels of homocysteine in the blood) results from a genetic defect that causes a low concentration of one of the enzymes responsible for homocysteine's breakdown. This was the case with the two children McCully first observed.

In most people, though, excess homocysteine occurs because they ingest too much meat and/or too little folic acid and the other B vitamins. Since homocysteine levels tend to rise with age, it may be, along with smoking, LDL peroxidation, and a high fat diet, an important independent risk factor for vascular disease.


In general, people with high blood levels
of homocysteine are at significantly
greater risk for heart disease and stroke
than those with lower levels. This is true
even for people whose homocysteine
levels are within the normal range.

ACCUMULATING EVIDENCE
The evidence supporting the role of homocysteine in vascular disease and the preventive value of B vitamins began accumulating in the years after McCully's initial observations, but research didn't really take off until the mid-1980s. That's when well designed epidemiologic studies began to clearly demonstrate elevated homocysteine levels in as many as 40% of patients with vascular disease, heart attack, and stroke.

More than 20 epidemiologic studies of over 2000 patients have produced what the prominent Harvard epidemiologist Meir J. Stampfer, M.D., calls "remarkably consistent findings." In general, he notes, those with high blood levels of homocysteine were at significantly greater risk for heart disease and stroke than those with lower levels. This was true even for those whose homocysteine levels were within the normal range.2

Exciting as these results were, they were unconvincing, because they failed to answer the classic "chicken-and-egg" quandary: Which comes first, homocysteine or heart disease? If homocysteine causes heart disease, it opens up new avenues for treatment and prevention. But if homocysteine is just another biochemical marker of a diseased cardiovascular system, it would be interesting but hardly of therapeutic benefit.

The answer to this question demands two types of study. First, lab studies would demonstrate that homocysteine can damage arteries and promote atherosclerosis. Such data would supply the scientific rationale for therapeutically reducing homocysteine levels in the body. The second type, essential for scientific acceptance, would be prospective clinical trials, that follow well-controlled cohorts of subjects over many years.

HOW HOMOCYSTEINE CAUSES VASCULAR DISEASE
There is little doubt that homocysteine causes vascular pathology, although the precise mechanism(s) is not yet certain. At least three scenarios are currently being explored:

  • Increasing arterial endothelial cell proliferation. Homocysteine may directly damage the endothelial cells that line the inside of arteries by promoting excess cellular growth. In a sample of more than 15,000 asymptomatic men and women between 45 and 64 years of age, elevated plasma homocysteine was associated with a significant thickening of intimal-medial carotid artery walls.3 Other evidence suggests that homocysteine promotes excess growth of vascular smooth muscle cells,4 possibly by a pro-oxidant action on genes governing the cells' growth cycle.5 This kind of abnormal growth is a sign of atherosclerosis and may indicate the presence of (or potential for) hypertension, coronary heart disease, and stroke.
  • Promoting blood clotting. Homocysteine was shown to reduce cellular binding sites for tissue plasminogen activator (t-PA) by 65%.6 T-PA is a substance secreted by arterial endothelial cells to help reduce fibrinolytic activity (clot formation). T-PA has become an effective (and expensive) "clot dissolving" drug that could be used to stop a delayed or a secondary heart attack in its tracks.
  • LDL effects. According to the Dutch researcher Dr. Petra Verhoef, homocysteine may cause molecules of low-density lipoproteins (LDL), the "bad" cholesterol, to aggregate and be taken up by inflammatory cells in the arterial lining. Once inside the vascular wall, homocysteine is released, possibly permitting it to cause further damage and more coagulation. As noted above, several studies have shown that homocysteine is certainly capable of causing arterial damage.

Patients with the highest plasma homocysteine
concentrations had twice the presence of
carotid stenosis compared with those
with the lowest homocysteine levels. At the
same time, folate intake was inversely
correlated with carotid artery stenosis.

PROSPECTIVE PROOF
Several large prospective studies reinforce the message that excessive homocysteine is dangerous. In the Harvard-based Physician's Health Study, Stampfer and colleagues7 took blood from nearly 15,000 male physicians aged 40 to 84 years and measured the level of homocysteine, thus establishing a baseline. Up to that point, none of the doctors had ever suffered a myocardial infarction (MI, heart attack) or stroke.

Over the next 5 years, though, 271 of the doctors did have a heart attack. Stampfer et al found that these men had significantly higher baseline levels of homocysteine compared with matched controls whose hearts remained disease-free. Those with homocysteine levels in the top 5% had three times the risk of MI compared with those with lower levels, even after adjusting for other coronary risk factors, such as diabetes, hypertension, cholesterol levels, and accounting for those taking aspirin (known to reduce the incidence of heart attack). Stampfer and his coauthors concluded, "Because high levels [of homocysteine] can often be easily treated with vitamin supplements, homocysteine may be an independent, modifiable risk factor [italics added]."7

Where Stampfer's data found a significant effect of homocysteine only at the highest levels, the results of another study by a Tufts University team headed by Jacob Selhub, Ph.D., showed that the risk of heart disease increased across a wide range of homocysteine levels.8 Selhub et al's subjects included over 1000 elderly people (aged 67-96) participating in the long-running Framingham Heart Study. The researchers used ultrasound scans to examine the relationship between the degree of stenosis (arterial narrowing due to atherosclerotic buildup) of the carotid arteries, a reliable indication of the extent of cardiovascular disease. In addition, they measured the level of homocysteine in the subjects' blood, as well as their plasma concentrations and intakes of folate, vitamin B6 and vitamin B12.

Selhub and coworkers found a clearly graded increase in the prevalence of carotid artery stenosis with increasing plasma levels of homocysteine. Those patients with the highest plasma homocysteine concentrations had twice the presence of carotid stenosis (325% stenosis) compared with those with the lowest homocysteine levels. At the same time, folate intake and the plasma concentrations of folate and vitamin B6 were inversely correlated with carotid artery stenosis.

One large case-control study that included virtually every major homocysteine researcher in Europe as a co-author recently found a clear dose-response effect of homocysteine level and risk of atherosclerotic vascular disease. The authors reported that levels of folate and cofactors that modulate homocysteine metabolism were all inversely related to total homocysteine levels. "Compared with nonusers of vitamin supplements," they wrote, "the small number of subjects taking such vitamins appeared to have a substantially lower risk of vascular disease, a proportion of which was attributable to lower plasma homocysteine levels." In their startling conclusion, they stated, "An elevated plasma homocysteine level confers an independent risk of vascular disease similar to that of smoking or hyperlipidemia [italics added]."9


An elevated plasma homocysteine level was
found to confer an independent risk of vascular
disease similar to that of
smoking or elevated cholesterol.

How high is too high? It's not yet clear how much homocysteine is safe. A group of Dutch researchers headed by Dr. Petra Verhoef carried out a case control study of people (aged 25-65 years) who had undergone coronary angiography. Not surprisingly, they found that as homocysteine levels rose, so did the risk of severe coronary atherosclerosis. It may be that no level is completely safe. "The data suggest that the association exists over a wide range of [homocysteine] levels, without a clear cut off point below which there is no increased risk," they concluded (italics added).10

Many other studies have found similar relationships between homocysteine levels and MI,11 carotid artery thickening,3,12 coronary artery stenosis,13,14 deep-vein thrombosis,14,15 and stroke.16

A review of 35 human studies, in which the levels of plasma total homocysteine were measured in 4338 patients with atherosclerotic diseases and 22,593 controls, found homocysteine levels to be consistently higher in patients with atherosclerotic disease than in the controls. The average difference in homocysteine levels for those with disease vs controls in 23 case-control studies was 26%.17

A striking correlation with homocysteine levels was observed in a group of 170 relatively young men (mean age 50 years) with premature coronary artery disease. Those with clear evidence of coronary artery disease had plasma homocysteine levels 25% higher than matched controls whose hearts were disease-free.18

The response to homocysteine shown in most of these studies is similar to that long associated with cholesterol levels. It has been estimated that a 0.5-µL increment in homocysteine raises the risk of coronary artery disease to a degree equivalent to an increment in serum cholesterol of 20 mg/dL.19 Of particular interest in the study of men with premature heart disease, mentioned earlier, was the lack of difference between the two groups in total cholesterol or LDL levels. In the coronary disease group, there were significant differences in plasma levels of HDL cholesterol (the "good" cholesterol), which were lower and triglycerides which were higher.18 It is quite possible that homocysteine levels may be better (i.e., earlier) indicators of trouble to come than cholesterol.

In an editorial in the New England Journal of Medicine, Stampfer argues that these results suggest that elevated homocysteine is not simply a marker for another risk factor. On the contrary, he writes, "A variety of conditions can lead to elevated homocysteine levels, but the relation between high levels and vascular disease is present regardless of the underlying metabolic cause."2 This conclusion is supported by a study in baboons that developed vascular lesions after just 3 months of homocysteine infusions.20


Men with clear evidence of coronary artery
disease had plasma homocysteine levels 25%
higher than matched control men
whose hearts were disease-free.

REDUCING HOMOCYSTEINE LEVELS WITH VITAMIN SUPPLEMENTS
Perhaps the most remarkable aspect of the homocysteine-vascular disease connection is the ease with which the situation can be normalized - and the risks reduced. In most people with elevated homocysteine levels, the cause is simply inadequate intake of folic acid (and, to a lesser extent, the other relevant B vitamins). Selhub et al21 showed this most clearly in a 1993 cross-sectional analysis of 1160 elderly people (aged 67-96 years) drawn from the Framingham population. Among their key findings:

  • Homocysteine levels increased with age.
  • As plasma folate levels fell, plasma homocysteine levels rose.
  • Inadequate plasma concentrations of one or more B vitamins appear to contribute to 67% of cases of high homocysteine levels.

But, as before, "correlation" does not necessarily mean that homocysteine is causal. Even the best-controlled epidemiologic study cannot tell you definitively whether increasing B vitamin intake will reduce elevated homocysteine levels. You need a double-blind, placebo-controlled prospective study for that. Just such a study was carried out in Germany, and the results confirm what was becoming pretty obvious: taking vitamin supplements containing folate, vitamin B6, and vitamin B12 can significantly reduce levels of homocysteine in the blood. Homocysteine levels returned to normal in 92% of the supplement group vs 20% of the placebo group.22

And it didn't take long to see a difference: the maximal benefit of taking the vitamin supplements occurred within 5 to 12 days.

Verhoef's group in the Netherlands may have provided the strongest support yet for the value of vitamin supplements for preventing heart disease. They compared 130 Boston area patients, on in years but not older than 76, hospitalized with their first MI, with 118 match controls, who had not suffered a heart attack. A questionnaire was used to estimate the people's dietary intake of vitamins B6, B12, and folate. The authors found that:23

  • Plasma homocysteine was 11% higher in the MI patients.
  • Dietary and plasma levels of vitamin B6 and folate were lower in the MI patients.
  • Intake of vitamin B6 and folate was inversely associated with the risk of MI, independently of other potential risk factors.
  • The relationship with vitamin B12 was less clear, but it appeared that low intake impaired the natural conversion of homocysteine to methionine. The homocysteine that accumulated as a result was the primary cause of hyperhomocysteinemia in the MI patients.
  • The most important determinant of plasma homocysteine was folate level, although it was not the only determinant. Some people who apparently had adequate intake of this vitamin did not have sufficient plasma levels.

In most people with elevated homocysteine
levels, the cause is simply
inadequate intake of folic acid.

WAITING FOR THE MISSING LINK
So what's missing? Why hasn't the medical establishment leaped aboard the folate bandwagon, with horns blaring out the good news that a substantial percentage of heart attacks and strokes could be easily prevented by taking a few common, safe, inexpensive vitamin supplements? According to one estimate, merely increasing daily folate intake to 400 µg (twice the current RDA) would reduce plasma homocysteine levels enough to save a minimum of 13,500 deaths annually from coronary artery disease.19

The most obvious missing link in the chain of evidence is a large, long term, double-blind, placebo-controlled prospective clinical trial in which one group of healthy people takes supplements and the other does not. The results would have to clearly demonstrate that taking B vitamin supplements reduces the risk of developing serious atherosclerotic vascular disease. Given this kind of evidence, even resistance from the FDA and the AMA would certainly melt away.

Several leading researchers have already called for such a definitive study. Unfortunately, this type of research is extremely expensive. Pharmaceutical companies do it all the time for their new drugs, but with no hope of an exclusive patent on the natural - and therefore unpatentable - B vitamins, there is no incentive to invest the hundreds of millions of dollars required to do the crucial studies that would gain FDA's endorsement, regarded by most physicians as the green light needed to try a new treatment.

Given the magnitude of the issues involved, the demonstrated safety and probable efficacy of folic acid and the other B vitamins, as well as the enormous cost savings possible, such a study, as indicated earlier, will likely get done somehow, perhaps with government funding, in the next few years.

Most researchers who have studied this area, however, need no further convincing. They know what these vitamins can do and openly advocate taking them. Dr. Jacob Selhub, of Tufts, points out that as much as 40% of the population is not consuming enough folate to keep their homocysteine at a safe level.21


According to one estimate, merely increasing
daily folate intake to 400 µg (twice the current
RDA) would reduce plasma homocysteine
levels enough to save a minimum of 13,500
deaths annually from coronary artery disease.

Notes Meir Stampfer in his New England Journal editorial, "Because the weight of the evidence is substantial and the intervention appears to be benign, it may be possible to make broad preliminary recommendations based on trials of secondary prevention or disease progression (e.g., thickening of the carotid-artery wall) rather than wait for large, expensive, and prolonged trials of primary prevention. In the meantime, it will be prudent to ensure adequate dietary intake of folate [italics added]."2

HOW MUCH IS ENOUGH?
The question then arises, What is "adequate dietary intake?" First, forget what the federal government says. The RDA (recommended daily allowance) - a mere 200 µg - was never intended to prevent vascular disease. In fact, in 1989, the RDA was actually reduced from 400 µg to 200 µg, despite growing evidence that at least 400 µg was needed, not only to prevent heart disease, but to prevent neural tube defects (e.g., spina bifida) in newborns. Surveys have found that most people consume far less than 200 µg/day from natural sources like green leafy vegetables.

The FDA's approach to ensuring that people, especially pregnant women, get the RDA of folic acid is to mandate fortification of foods like bread and pasta. Oddly, they have virtually ignored the issue of homocysteine and heart disease and still refuse to recommend supplements, even to people at risk.

Meir Stampfer, who is typically very conservative when it comes to recommending vitamin supplements, loudly endorsed them in his NEJM editorial more than 2 years ago. He defines inadequate folate intake as less than 400 µg per day. He suggests that doses as high as 1000 to 2000 µg (1-2 mg) might be more appropriate, pointing out that such doses are "innocuous" and "usually sufficient to reduce or normalize high homocysteine levels, even if the elevation is not due to inadequate amounts of folate consumption."2

At a meeting of the Federation of American Societies of Experimental Biology (FASEB), Stampfer stated, "Public health considerations often require taking protective action even before all the proof is in." And his coauthor of the NEJM editorial, Dr. M. René Malinow, of the Oregon Regional Primate Research Center, proclaimed the coming revolution: "Scientists are on the threshold of the most important extension of the diet/health hypothesis since the discovery of the relationship of cholesterol to heart disease."24


The only way to get enough B vitamins to
provide adequate protection is to take
supplements, either individually, or preferably
in a balanced multinutrient
formulation
 

Enhance Your Vitamin B Status
Clearly, even eating a balanced diet, loaded with fruits and vegetables, will never give you enough folate to reach significant levels, nor would food fortification. The only way to get enough B vitamins to provide adequate protection is to take supplements, either individually, or preferably in a balanced multinutrient formulation. A recommended dose is 800 µg of folate, along with 36 mg of vitamin B6, and 600-µg of vitamin B12. One of the advantages of these amounts over those in inferior multinutrient formulations is that a person can take half the standard dose and still get protection against homocysteine induced vascular damage, and you can double your dose and still be within the safe range.

References

  1. McCully K. The Homocysteine Revolution. New Canaan, CT: Keats Publishing, Inc.; 1997.
  2. Stampfer M, Malinow M. Can lowering homocysteine levels reduce cardiovascular risk? N Engl J Med. 1995;332:328-329.
  3. Malinow M, Nieto F, Szklo M, Chambless L, Bond G. Carotid artery intimal-medial wall thickening and plasma homocyst(e)ine in asymptomatic adults. The Atherosclerosis Risk in Communities Study. Circulation. 1993;87:1107-1113.
  4. Tsai J, Perrella M, Yoshizumi M, et al. Promotion of vascular smooth muscle cell growth by homocysteine: a link to atherosclerosis. Proc Natl Acad Sci. 1994;91:6369-6373.
  5. Gunby P. Lipoprotein patterns, plaque, homocysteine, and hormones among ongoing cardiology studies. JAMA. 1996;October 9.
  6. Hajjar K. Homocysteine-induced modulation of tissue plasminogen activator binding to its endothelial cell membrane receptor. J Clin Invest. 1993;91:2873-2879.
  7. Stampfer M, Malinow M, Willett W, et al. A prospective study of plasma homocyst(e)ine and risk of myocardial infarction in US physicians. JAMA. 1992;268:877-881.
  8. Selhub J, Jacques P, Bostom A, et al. Association between plasma homocysteine concentrations and extracranial carotid-artery stenosis. N Engl J Med. 1995;332:286-291.
  9. Graham I, Daly L, Refsum H, et al. Plasma homocysteine as a risk factor for vascular disease. The European Concerted Action Project. JAMA. 1997;277:1775-1781.
  10. Verhoef P, Kok F, Kruyssen D, et al. Plasma total homocysteine, B vitamins, and risk of coronary atherosclerosis. Aterioscler Thromb, Vasc Biol. 1997;17:989-995.
  11. Nygard O, Nordrehaug J, Refsum H, Ueland P, Farstad M, Vollset S. Plasma homocysteine levels and mortality in patients with coronary artery disease. N Engl J Med. 1997;337:230-236.
  12. Clarke R, Fitzgerald D, O'Brien C, et al. Hyperhomocysteinemia: a risk factor for extracranial carotid artery atherosclerosis. Ir J Med Sci. 1992;161:61-65.
  13. Stamler J, Osborne J, Jaraki O, et al. Adverse vascular effects of homocysteine modulated by endothelium-derived relaxing factor and related oxides of nitrogen. J Clin Invest. 1993;91:308-318.
  14. Fermo I, Vigano' D'Angelo S, Paroni R, Mazzola G, Calori G, D'Angelo A. Prevalence of moderate hyperhomocysteinemia in patients with early onset venous and arterial occlusive disease. Ann Intern Med. 1995;123:747-753.
  15. den Heijer M, Koster T, Blom H, et al. Hyperhomocysteinemia as a risk factor for deep-vein thrombosis. N Engl J Med. 1996;334:759-762.
  16. Perry I, Refsum H, Morris R, Ebrahim S, Ueland P, Shaper A. Prospective study of serum total homocysteine concentration and risk of stroke in middle-aged British men. Lancet. 1995;346:1395-1398.
  17. Moghadasian M, McManus B, Frolich J. Homocyst(e)ine and coronary artery disease. Clinical evidence and genetic and metabolic background. Arch Intern Med. 1997;157:2299-2308.
  18. Genest JJ, McNamara J, Salem D, Wilson P, Schaefer E, Malinow M. Plasma homocyst(e)ine levels in men with premature coronary artery disease. J Am Coll Cardiol. 1990;16:1114-1119.
  19. Boushey C, Beresford S, Omenn G, Motulsky A. A quantitative assessment of plasma homocysteine as a risk factor for vascular disease: probable benefits of increasing folic acid intakes. JAMA. 1995;274:1049-1057.
  20. Ueland P, Refsum H, Brattstrom L. Plasma homocysteine and cardiovascular disease. In: Francis RJ, ed. Atherosclerotic Cardiovascular Disease, Hemostasis, and Endothelial Function. New York: Marcel Dekker; 1992:183-236.
  21. Selhub J, Jacques P, Wilson P, Rush D, Rosenberg I. Vitamin status and intake as primary determinants of homocysteinemia in an elderly population. JAMA. 1993;270:2693-2698.
  22. Naurath H, Joosten E, Riezler R, Stabler S, Allen R, Lindenbaum J. Effects of vitamin B12, folate, and vitamin B6 supplements in elderly people with normal serum vitamin concentrations. Lancet. 1995;346:85 89.
  23. Verhoef P, Stampfer M, Buring J, et al. Homocysteine metabolism and risk of myocardial infarction: relation with vitamins B6, B12, and folate. Am J Epidemiol. 1996;143:845-859.
  24. Anonymous. Homocysteine and folate: new implications for heart attack prevention. Center for Cardiovascular Education. 1997;http://www.heartinfo.com/homocystbg.html.

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