Homocysteine and Cardiovascular Health
Cardiovascular diseases, especially myocardial infarction (heart attack) and stroke, kill at least 12 million people each year throughout the world. In the United States, cardiovascular diseases are the primary cause in about half of all deaths. In 1995 cardiovascular diseases killed about 455,000 men and 505,000 women.
None of this is news, of course. What is news is that in the U.S. between 13,500 to 50,000 of these deaths1 could easily be prevented by taking just 25 cents worth of vitamin supplements a day.
That's right for a mere quarter's worth of vitamins, you can significantly eliminate a major independent risk factor for heart attack or stroke. You can't even buy a candy bar for a quarter any more.
This is not hyperbole. This is not snake oil. This is not some quack cure. This is hard science, incontrovertible evidence, based on the results of hundreds of studies going back more than 30 years. Although conservative organizations like the American Heart Association (AHA) still refuse to endorse the conclusions of these studies and to recommend that people take these vitamin supplements, the conclusions are strongly supported by numerous articles and editorials that have appeared in the two most prestigious American medical journals, the Journal of the American Medical Association and the New England Journal of Medicine, as well as many other journals.2-7
We are referring to the link between the amino acid homocysteine and cardiovascular disease and the fact that supplements of vitamins B6 and B12, folic acid, and betaine (trimethylglycine, TMG) have been proven to sever that link.
Homocysteine is an amino acid formed from the metabolism of another amino acid, methionine, which is commonly found in meats-especially red meat. High homocysteine levels are now widely recognized as an independent risk factor for cardiovascular disease. This means that high homocysteine levels along with cigarette smoking, obesity, high blood pressure, high-fat diet, diabetes, and a sedentary life style increase your risk of developing cardiovascular disease and dying of a heart attack or stroke. Taking supplemental B6, B12, folic acid, and trimethylglycine quickly and effectively restores homocysteine to safe levels, essentially eliminating this very important risk, often within a few days (although the damage done by long-term elevated homocysteine takes longer to resolve).
Widespread acceptance by the medical community of the homocysteine-heart disease-vitamin connection has only recently begun to gain momentum. But the story really goes back to the late 1960s. At that time, a young Harvard-trained physician named Kilmer S. McCully, then employed by the Massachusetts General Hospital, first noticed the connection. What captured his interest were a few cases of children as young as two months of age, who had died of strokes. The children had been diagnosed with homocystinuria. Homocystinuria is a genetic condition in which the body lacks the ability to properly metabolize homocysteine. This leads to a build-up of homocysteine levels in the blood and urine. McCully found that the children"s arteries were severely clogged with atherosclerotic plaque, a condition usually seen only in elderly people with advanced atherosclerosis.
Over the next several years Dr. McCully and a handful of other investigators began building a scientific case for the role of elevated homocysteine. They found elevated homocysteine occurs not only in rare cases of genetic premature atherosclerosis but in garden-variety cardiovascular diseases as well. For his efforts, he was rewarded by the medical community with derision and near excommunication, a fate long known to medical pioneers who dare buck the established "wisdom." In 1979, McCully was fired by Mass General, but he eventually landed a position at the Veteran"s Administration Hospital in Providence, Rhode Island, where he was able to continue his research.
Fortunately, Dr. McCully"s
persistence paid off, and he has since been vindicated. Despite the existence of
a few notable holdouts, like the FDA and AHA, the medical community now widely
accepts the fact that homocysteine is a major independent cause of
cardiovascular disease, and that taking supplements of B vitamins and betaine
far in excess of the levels typically recommended by government guidelines
profoundly improves cardiovascular health. McCully himself was recently invited
to express these sentiments in an editorial in JAMA.8
Homocysteine Increases Cardiovascular Risk
More than 20 case-control and cross-sectional studies on more than 2,000 subjects have provided what Harvard epidemiologist Meir J. Stampfer, MD, calls "remarkably consistent" findings regarding the relationship between homocysteine levels and cardiovascular diseases. Specifically, patients with stroke and other cardiovascular diseases tend to have higher blood levels of homocysteine (hyperhomocysteinemia) than subjects without disease.
Stampfer points out that homocysteine levels do not have to be elevated by very much to increase risk, since most of the patients in these studies had levels that were within what is generally regarded to be the normal range.3 A meta-analysis found a positive association between hyperhomocysteinemia and thrombosis (formation of clots in blood vessels) in eight out of 10 studies involving 2,400 patients. In these eight studies, the risk of thrombosis was two to 13 times greater in people with hyperhomocysteinemia.9
Another meta-analysis of 35 studies found consistently higher homocysteine levels in patients with atherosclerotic diseases. In 23 case-control studies, homocysteine levels were on average 26% higher among subjects with atherosclerosis compared with healthy subjects.10
One cross-sectional study conducted by Dr. Jacob Selhub of Tufts University and his associates, involved more than 1,000 elderly people from the long-running Framingham Heart Study. The investigators examined the relationship between the degree of carotid artery blockage (stenosis) and plasma homocysteine levels. After adjusting for other risk factors, they found that those individuals with the highest levels of homocysteine had twice the risk of a carotid stenosis than those with the lowest levels. Moreover, the authors reported that those patients who had the most carotid artery stenosis had the lowest intake of folic acid and vitamin B6.5
The Physicians" Health Study, a Harvard-based study that tracked nearly 15,000 male physicians (aged 40-84 years) for up to five years, came to a similar conclusion. At the start of the study, none of the physicians had ever suffered a heart attack or stroke. During the course of the study, 271 of the men subsequently suffered a heart attack. When the researchers compared the homocysteine levels in these men with those of matched controls who had remained healthy, they found that the men whose homocysteine levels were in the highest five percent had about three times the risk of heart attack as those with the lowest levels. "Because high levels [of homocysteine] can often be easily treated with vitamin supplements, homocysteine may be an independent, modifiable risk factor," the authors concluded.4
Homocysteine"s role as an independent risk factor for cardiovascular diseases was confirmed in a large multicenter European study that included researchers from nine different countries. The results showed a 2.2-fold greater incidence of cardiovascular disease in those whose homocysteine levels were in the top 20%. Although only a small number of the subjects in this study were taking vitamin supplements, the authors noted that those who were taking supplements appeared to have a "substantially lower risk of vascular disease, a proportion of which was attributable to lower plasma homocysteine levels."11
In a recent prospective study of homocysteine and heart disease conducted in the United Kingdom, serum samples were collected from 21,520 people between the ages of 35 and 64 years. Homocysteine levels were significantly higher in men who haddied of a heart attack than in those who had not, and those with the highest levels of homocysteine had three to four times the risk of those with the lowest levels. The investigators also found a continuous dose-response relationship, with the risk increasing by 41% for each 5 mM/L increase in homocysteine level.12
Why Homocysteine Levels Rise
High homocysteine in the blood can arise from three primary causes. The first is a genetic defect that impairs homocysteine metabolism. Actually, several different genetic defects related to the formation of the various enzymes required to metabolize homocysteine have been identified. The most serious defects may result in premature death, as in the cases McCully encountered early in his investigations. More common are less severe defects, which may produce mild or moderate elevations of homocysteine. These defects are quite common, occurring in perhaps 30% of the population, and may account, at least in part, for the inheritability of cardiovascular disease.3
You can also elevate your homocysteine levels by consuming too much methionine-rich food. Recall that the converts methionine directly into homocysteine.
Although the high fat content of certain meats is usually blamed for increasing the risk of heart disease and stroke, the high methionine content of meat may be equally culpable.
Probably the most important contribution to elevated homocysteine levels for most people is inadequate intake of folic acid, vitamins B6 and B12, and betaine. No matter what the cause of hyperhomocysteinemia, even when there is a genetic defect, it is almost always possible to reduce levels to the healthy range by taking sufficient quantities of these nutrional supplements.
Given the deadly consequences of elevated homocysteine, the ease with which homocysteine levels can be brought down and maintained within the safe range by taking vitamin supplements containing folic acid (folate), vitamin B6 (pyridoxine), vitamin B12, and betaine is truly remarkable.
The reason these nutrients are so important is that they all act as cofactors in the metabolism of homocysteine. When they are present in appropriate amounts, homocysteine formed from methionine is immediately converted either to cysteine, a benign amino acid, or back to methionine. When sufficient amounts are not present, homocysteine can accumulate and begin to damage blood vessels.
The conversion of homocysteine to cysteine, known as transsulfuration, requires an enzyme called cystathionine b-synthase (CBS) along with vitamin B6 as a cofactor. In the absence of vitamin B6, transsulfuration cannot proceed, and homocysteine begins to build up and damage blood vessels.
The conversion of homocysteine back to methionine is called remethylation. Folic acid and vitamins B6 and B12 are required for this reaction. Betaine can also facilitate remethylation. When levels of these nutrients are low, remethylation cannot proceed efficiently, allowing homocysteine to accumulate.
In some people, the enzymes required to facilitate transsulfuration or folate-based methylation are deficient, leading to homocysteine elevation despite adequate folate and/or vitamin B6 intake. Betaine has been shown to be quite effective in reducing high homocysteine levels in these cases.19
Keeping Homocysteine Levels Low
Study after study has demonstrated beyond the shadow of a doubt that the risks associated with elevated homocysteine can be quickly and easily eliminated by taking adequate amounts of folic acid, vitamins B6 and B12, and betaine. Selhub"s 1993 cross-sectional analysis of people from the Framingham study, for example, found that (1) homocysteine levels increased with age, (2) plasma homocysteine levels dropped as folate intake increased, and (3) 67% of the cases of hyperhomocysteinemia were related to inadequate plasma concentrations of one or more of the B vitamins.20
In a German study, injections of folate and vitamin B6 reduced homocysteine concentrations in 175 elderly people, with maximum effect seen within five to 12 days. Homocysteine levels returned to normal in 92% of the vitamin-treated group compared with only 20% of those treated with placebo.21 Another study compared 130 Boston area patients hospitalized with their first heart attack with 118 matched controls who had never had a heart attack. The authors found that (1) homocysteine levels were 11% higher in the heart attack patients, (2) dietary and plasma levels of vitamin B6 and folate were lower in the heart attack patients, and (3) as intake of folate and vitamin B6 increased, the risk of heart attack decreased, independently of other risk factors.17
Data from the large Harvard-based Nurses" Health Study also supports the use of B vitamins. Beginning in 1980, more than 80,000 women with no previous history of cardiovascular disease began filling out detailed food questionnaires. During a 14-year follow-up, there were 658 cases of nonfatal and 281 cases of fatal heart attack among these women. Analysis of the data revealed that higher intakes of folate and vitamin B6 from either food or supplements were associated with a lower risk of heart attack. The levels of folate required to produce a beneficial effect were "well above the current RDA of 180 mg/day."7
While most studies have concentrated on using the B vitamins to normalize homocysteine metabolism, some people do not respond to this regimen, possibly because of a genetic defect. Studies have shown that by adding betaine to the standard B vitamin regimen, homocysteine can be reduced to safe levels in nearly everyone.22, 23
How Much Do You Need?
To sum up the homocysteine-cardiovascular disease-B-vitamin story, there is no doubt that:
Diet or Supplements?
Sounds pretty convincing, doesn't it? How is it then, that the American Heart Association and the FDA the same "guardians of our health" that have already endorsed such valuable heart protective measures as Cheerios and margarine refuse to endorse vitamin supplements for lowering homocysteine?
According to official AHA policy, "The American Heart Association does not recommend widespread use of folic acid and B vitamins to reduce the risk of heart disease and stroke (brain attack)." Instead, along with the FDA, they recommend getting all your vitamins from a "balanced diet that includes at least five servings of fruits and vegetables a day."
If this doesn"t sound much like your diet, you"re not alone. It has been estimated that for 88 to 90% of the population, dietary intake of folate is less than 400 mcg per day, which is currently thought to be the minimum necessary to achieve optimal homocysteine control.7
The FDA"s response to addressing neural tube birth defects has been to mandate that grain products sold in the US be "fortified" with 140 mcg per 100 gm of grain. It is estimated that this would increase average intake by only 100 mcg per day and probably less. Even after fortification, only 25% of adult women would have dietary folate intakes above 400 mcg per day.7, 24-26
It is clear to those scientists who have done the major research on homocysteine and cardiovascular disease that the only way to optimally neutralize the homocysteine threat is by taking vitamin supplements. In an editorial in JAMA, earlier this year, Kilmer McCully, who started it all over 30 years ago, wrote, "…the current recommended dietary allowances for these nutrients [folate and vitamin B6] are too low to provide optimal protection against cardiovascular disease and need to be revised accordingly for the population as a whole." McCully also predicted that "…supplementation, fortification, improved dietary intakes of folate and vitamin B6, and better food processing and distribution" should all contribute to general improvement in cardiovascular health.8
In an editorial in the New England Journal of Medicine in 1995, Dr. Meir Stampfer, who supervised many of the large epidemiologic studies on cardiovascular health, strongly endorsed vitamin supplements. Wrote Stampfer, "The studies of genetic defects and epidemiologic data linking high blood homocysteine levels with vascular diseases are consistent; persuasive, plausible biologic mechanisms have been described; and safe, inexpensive, and effective intervention folate supplementation is available."3
Optimal Dosing Regimen
The optimal dosing regimen is still uncertain, although it is certain that high levels of folate should not be an obstacle. The current folate RDA of 400 mcg per day was recently increased from 180 mcg. But this increase was for prevention of neural tube birth defects, not for preventing cardiovascular disease. The Nurses" Health Study found that 400 mcg per day was the minimum necessary to achieve optimal coronary protection.7
Stampfer argues that doses up to five times that level should not be out of the question. "Folate supplements in the range of one to two mg [1,000 to 2,000 mcg] per day, which are generally innocuous, are usually sufficient to reduce or normalize high homocysteine levels, even if the elevation is not due to inadequate folate consumption (<400 mcg per day)," wrote Stampfer in 1995.3
The Nurses" Health Study also found that a minimum of 3 mg per day of vitamin B6 (in addition to 400 mcg of folate) was enough to reduce the risk of coronary disease to a minimum. This very low dose is still about double the current RDA for vitamin B6. It is not uncommon for people to be taking daily doses of 100 mg of vitamin B6.
25 Cent-a-Day Protection
A simple simple, effective, and inexpensive way to restore and maintain homocysteine at safe levels. Nutrients demonstrated to normalize homocysteine metabolism. Per day amounts.
Those who may have extreme hyperhomocysteinemia may need to increase this dose, perhaps doubling it to six capsules per day. This would still keep all nutrients within the safe range.
1. Boushey CJ, Beresford SA, Omenn GS, Motulsky AG. A quantitative assessment of plasma homocysteine as a risk factor for vascular disease. Probable benefits of increasing folic acid intakes [see comments]. JAMA. 1995; 274:1049-57.
2. Russell R. Contempo 1996: Nutrition. JAMA. 1996;275.
3. Stampfer M, Malinow M. Can lowering homocysteine levels reduce cardiovascular risk? N Engl J Med. 1995; 332:328-329.
4. 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.
5. 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.
6. Verhoef P, Stampfer MJ, Rimm EB. Folate and coronary heart disease. Curr Opin Lipidol. 1998; 9:17-22.
7. Rimm EB, Willett WC, Hu FB, et al. Folate and vitamin B6 from diet and supplements in relation to risk of coronary heart disease among women [see comments]. JAMA. 1998; 279:359-64.
8. McCully K. Homocysteine, folate, vitamin B6, and cardiovascular disease (Editorial). JAMA. 1998; 279:392-393.
9. Selhub J, D'Angelo A. Relationship between homocysteine and thrombotic disease [In Process Citation]. Am J Med Sci. 1998; 316:129-41.
10. 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.
11. Graham IM, Daly LE, Refsum HM, et al. Plasma homocysteine as a risk factor for vascular disease. The European Concerted Action Project. JAMA. 1997; 277:1775-81.
12. Wald NJ, Watt HC, Law MR, Weir DG, McPartlin J, Scott JM. Homocysteine and ischemic heart disease: results of a prospective study with implications regarding prevention. Arch Intern Med. 1998; 158:862-7.
13. Tsai J, Perrella M, Yoshizumi M, et al. Promotion of vascular smooth muscle cell growth by homocysteine: a link to athersclerosis. Proc Natl Acad Sci. 1994; 91:6369-6373.
14. 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.
15. Wilcken DE, Dudman NP. Mechanisms of thrombogenesis and accelerated atherogenesis in homocysteinaemia. Haemostasis. 1989; 19:14-23.
16. Hajjar K. Homocysteine-induced modulation of tissue plasminogen activator binding to its endothelial cell membrane receptor. J Clin Invest. 1993; 91:2873-2879.
17. Verhoef P, Stampfer MJ, Buring JE, et al. Homocysteine metabolism and risk of myocardial infarction: relation with vitamins B6, B12, and folate. Am J Epidemiol. 1996; 143:845-59.
18. Stamler JS, Osborne JA, Jaraki O, et al. Adverse vascular effects of homocysteine are modulated by endothelium-derived relaxing factor and related oxides of nitrogen. J Clin Invest. 1993;91:308-18.
19. Dudman NP, Guo XW, Gordon RB, Dawson PA, Wilcken DE. Human homocysteine catabolism: three major pathways and their relevance to development of arterial occlusive disease. J Nutr. 1996;126:1295S-300S.
20. 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.
21. Naurath HJ, Joosten E, Riezler R, Stabler SP, Allen RH, Lindenbaum J. Effects of vitamin B12, folate, and vitamin B6 supplements in elderly people with normal serum vitamin concentrations [see comments]. Lancet. 1995;346:85-9.
22. Wilcken DE, Wilcken B, Dudman NP, Tyrrell PA. Homocystinuria–the effects of betaine in the treatment of patients not responsive to pyridoxine. N Engl J Med. 1983; 309:448-53.
23. Wilcken DE, Dudman NP, Tyrrell PA. Homocystinuria due to cystathionine beta-synthase deficiency–the effects of betaine treatment in pyridoxine-responsive patients. Metabolism. 1985; 34:1115-21.
24. Appel LJ. Folic acid fortification of food [letter; comment]. JAMA. 1996;275:681-2; discussion 682-3.
25. Bendich A. The RDA process: time for a change [letter]. J Nutr. 1994;124:911-2.
26. Subar AF, Block G, James LD. Folate intake and food sources in the US population. Am J Clin Nutr. 1989;50:508-16.
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