B Vitamins Reduce Homocysteine and Heart Disease

Recent scientific interest in blood levels of homocysteine as an independent risk factor in heart disease is now being reported in the media. Recently, TV and magazines have discovered the story behind the role of vitamin B-6, vitamin B-12 and folic acid in preventing homocysteine levels to build up in the blood. Homocysteine levels are associated with increased risk of heart disease. Although this line of research has been pursued since 1969, led by Harvard researcher, Dr. Kilmer McCully, the scientific community did not become widely interested until a great body of data was collected to confirm this linkage. The recent data are summarized in the following abstract from the New England Journal of Medicine and five press releases distributed by the American Heart Association.

A study reported in the July 24, 1997 issue of The New England Journal of Medicine (Volume 337, Number 4, pages 230-236) entitled "Plasma Homocysteine Levels and Mortality in Patients with Coronary Artery Disease" should remove any lingering doubts about the relationship to blood homocysteine level and the risk of heart disease. The level of homocysteine is dependent on several factors including dietary vitamin B-6, vitamin B-12 and folic acid. The amount of free methyl groups available in the body is also important and this too is related to dietary factors such as betaine (trimethylglycine). Of course, there is also a genetic factor involved.

The study was conducted in Norway by researchers Ottar Nygard, Jan Erik Nordrehaug, Helga Refsum, Per Magne Ueland, Mikael Farstad, and Stein Emil Vollset of the Division for Medical Statistics, Department of Public Health and Primary Health Care, the Department of Pharmacology, and the Division of Biochemistry, Department of Clinical Biology, University of Bergen; and the Department of Heart Disease, Haukeland University Hospital -- all in Bergen, Norway.

The Norwegian researchers prospectively investigated the relation between total homocysteine levels in the plasma and mortality among 587 patients with angiographically confirmed coronary artery disease. At the time of angiography in 1991 or 1992, risk factors for coronary disease, including homocysteine levels, were evaluated. The majority of the patients subsequently underwent coronary-artery bypass grafting (318 patients) or percutaneous transluminal coronary angioplasty (120 patients); the remaining 149 were treated medically.

After a median follow-up of 4.6 years, 64 patients (10.9 percent) had died. the researchers found a strong, graded relation between plasma homocysteine levels and overall mortality. After four years, 3.8 percent of patients with homocysteine levels below 9 micromol per liter had died, as compared with 24.7 percent of those with homocysteine levels of 15 micromol per liter or higher. The researchers report that homocysteine levels were only weakly related to the extent of coronary artery disease but were strongly related to the history with respect to myocardial infarction, the left ventricular ejection fraction, and the serum creatinine level. The relation of homocysteine levels to mortality remained strong after adjustment for these and other potential confounders. In an analysis in which the patients with homocysteine levels below 9 micromol per liter were used as the reference group, the mortality ratios were 1.9 for patients with homocysteine levels of 9.0 to 14.9 micromol per liter, 2.8 for those with levels of 15.0 to 19.9 micromol per liter, and 4.5 for those with levels of 20.0 micromol per liter or higher (P for trend = 0.02). The report noted that when death due to cardiovascular disease (which occurred in 50 patients) was used as the end point in the analysis, the relation between homocysteine levels and mortality was slightly strengthened.

The researchers concluded, "Plasma total homocysteine levels are a strong predictor of mortality in patients with angiographically confirmed coronary artery disease."

This report from the New England Journal of Medicine further strengthens the data from other studies. The following five press releases from the American Heart Association explain the body of evidence in more detail.


High homocysteine concentrations in blood warn of increased heart attack risk in young women
July 15, 1997

DALLAS, July 15: A twofold increased risk of heart attack was found among women who have higher than normal blood levels of the protein homocysteine and lower than normal blood levels of the vitamin folate, according to a study in today's American Heart Association Journal Circulation.

The new study, the first to investigate homocysteine as a risk factor in a large number of young women, provides evidence that high homocysteine may indicate increased heart attack risk, says lead author Stephen M. Schwartz, Ph.D.

Homocysteine, a product resulting from the metabolism of an amino acid methionine, is known to damage blood vessels, increasing the potential for cholesterol buildup in the bloodstream.

Schwartz, Associate Professor of Epidemiology at the University of Washington School of Public Health in Seattle, and his colleagues assessed homocysteine in women 18 to 44 years of age, almost 90 percent of whom were non-Hispanic whites. They interviewed and obtained blood samples from 79 women who had suffered a heart attack between July 1, 1991, and Feb. 28, 1995. As a control group, they used 386 women without coronary heart disease of the same age. All the study participants lived in Seattle's Washington, King, Pierce, or Snohomish counties.

Blood concentrations of total homocysteine, folates and vitamin B12 were determined. Because genetic factors also contribute to homocysteine, researchers measured a specific type of gene called MTHFR that helps regulate homocysteine. Other researchers had found that individuals who have a mutation on the gene have higher homocysteine levels.

Women in the top 10 percent of total homocysteine measurements had 2.3 times the heart attack risk of women in the lowest 50 percent. Women who had high homocysteine levels tended to have low folate levels and vice versa. The researchers found no difference in vitamin B12 concentration between heart attack survivors and the controls, and "little relationship between B12 concentration and heart attack risk."

Researchers took into account factors such as age, diabetes, cigarette smoking and obesity. This risk was actually lower than reported in the few small studies that had investigated homocysteine in women. This may have stemmed from the high influence of cigarette smoking and obesity, factors that are quite common among the heart attack cases and probably played a big role in causing their heart attacks, Schwartz says.

Women who carried two copies of the mutated gene tended to have a 25 percent or greater level of homocysteine than women with two copies of the standard MTHFR gene, a finding consistent with other studies. However, this held true only for those women who had low folate concentrations. This further fuels the question of the relationship between folic acid intake and homocysteine levels and what role the mutated gene may play in modifying it.

Interestingly, the Seattle study did not find that having two copies of the MTHFR gene variation increased a woman's risk of heart attack. The authors note that similar findings have emerged from the majority of recent studies of the MTHFR mutation and coronary heart disease, although three studies have reported a two to threefold increased risk for people with two copies of the mutated gene.

The reasons for these discrepancies are not clear, but Schwartz says that carrying double copies of the mutated gene may only increase the risk in people who fail to consume adequate folic acid. They urge a major study to determine the inter-relationship of B vitamin supplementation, genetic factors and homocysteine on the risk of cardiovascular disease.

Studies have shown that B vitamin supplements reduce the blood's concentrations of homocysteine, but no major study has yet addressed whether lowering homocysteine concentrations actually reduces cardiovascular risk.

"Our study adds support to the need for randomized trials to determine whether supplementation with folates (folic acid) and other B vitamins, such as B6 and B12, can prevent cardiovascular disease." Good sources of folic acid include orange juice, breakfast cereals, and fruits and vegetables. Vitamin B6 can be obtained from red meat.

The Seattle-area study also found, as other studies have, that women who inherit two mutated copies of the gene MTHFR had higher blood homocysteine concentrations. However, inheriting this common gene variation, which occurs in 10-13 percent of whites, did not in itself increase the risk of heart attack.

"Particularly among young women, we had expected that genetic factors would have played a stronger role in the relationship between homocysteine and heart attack risk," Schwartz says. "That we didn't see that was surprising."

In recent years, a growing body of evidence has linked high homocysteine to heart attacks, strokes, and other cardiovascular diseases. The all-male Physicians Health Study found that high homocysteine level increased the risk of heart attack 3.4 times. A study by Cleveland Clinic researchers found high homocysteine levels increased the heart attack risk among older men and women, particularly those over age 65. Among older people in the Framingham (Mass.) Heart Study, 21 percent had homocysteine levels that put them at increased risk of heart attack.

A Dutch team reported in the May issue of the AHA Journal Arteriosclerosis, Thrombosis and Vascular Biology that every 10 percent rise in homocysteine in its study participants was matched by almost the same increase in coronary heart disease risk.

Other co-authors of the report are David S. Siscovick, M.D.; Frits R. Rosendaal, M.D., Ph.D.; R. Kevin Beverly, M.S.; Bruce M. Psaty, M.D., Ph.D.; W. T. Longstreth, Jr., M.D. and Thomas D. Koepsell, M.D., of the University of Washington; M. Rene Malinow, M.D. and David L. Hess, Ph.D., of the Oregon Regional Primate Research Center, Beaverton; T. E. Raghunathan, Ph.D., of the University of Michigan, Ann Arbor; Frits R. Rosendaal, M.D., of the Leiden University, Leiden; and Pieter H. Reitsma, Ph.D., now at the Academic Medical Center, Amsterdam.


Homocysteine new 'risk factor' for coronary heart disease, says Dutch team
May 20, 1997

DALLAS, May 20 -- While not as potent a predictor of heart disease as cholesterol, homocysteine, an amino acid found in the blood, runs a close second, a new Dutch study finds.

The May issue of the American Heart Association Journal Arteriosclerosis, Thrombosis and Vascular Biology that for every 10 percent rise in homocysteine, there is almost exactly the same rise in the risk of developing severe coronary heart disease. Cholesterol elevations of 10 percent confer a 20 percent increased risk for heart disease.

There is still debate about whether certain subgroups, for example, middle-aged men, should take an extra tablet of vitamin B; we are waiting for a big trial to look at this; so we only advise that individuals try to increase folic acid intake by increasing consumption of green leafy vegetables and fruit.

Individuals from families with a history of heart disease at an early age may want to have their homocysteine levels checked by their physician, suggests Verhoef, who calls homocysteine, a 'new risk factor.'

The study included 131 patients who had severe blockages in two coronary arteries. A second group included 88 patients who had only moderate blockages in one coronary vessel. Another group consisted of healthy individuals without heart disease. Researchers found a linear relationship between the homocysteine levels and severity of coronary artery blockages.

Heart attacks occur when the blood vessels to the heart become blocked. Scientists use the amount of occlusion as a way to determine the severity of heart disease.

While scientists know that cholesterol can contribute to fatty build-up in the arteries, they don’t know exactly why elevations in homocysteine are dangerous. Scientists speculated that homocysteine may destroy the inner layer of the blood vessel or that it makes it easier for clots to forms. “But,” says Verhoef, “these observations were made in laboratory (test tube) studies and we still have to do many more human studies.”

High amino acid levels combined with genetic disorder increases relative risk of vein clots
March 31, 1997

DALLAS, March 31 -- Men with high blood levels of an amino acid called homocysteine and a hereditary blood clotting disorder called Factor V Leiden have a far greater relative risk of forming potentially life-threatening blood clots in leg veins that can travel to the lungs than men who have neither or either condition, Boston researchers report in the current issue of the American Heart Association Journal Circulation. Such clots can cause medical conditions known as deep venous thromboses, characterized by blood-clots in leg veins, and pulmonary emboli, a potentially fatal condition when a blood clot travels to a lung artery.

About one in every 400 healthy individuals is likely to be affected by high levels of homocysteine and Factor V Leiden, the authors of the study say. But, they add, the absolute risk of developing blood clots associated with the two conditions remains low, so the value of long-term treatment with drugs that keep clots from forming needs to be evaluated in future studies. The scientists also suggest that people with Factor V Leiden disorder be screened to determine their blood levels of homocysteine.

Previous studies have suggested that folic acid, found in oranges, bananas, beans and broccoli, may protect against heart and blood vessel disease by lowering blood levels of homocysteine. The data in this study “raise the possibility that simple dietary interventions might be adequate to reduce long-term risks in some patients,” the researchers write.

Paul Ridker, M.D., of Brigham and Women’s Hospital, and his colleagues determined homocysteine levels and the presence or absence of Factor V Leiden in 145 initially healthy men participating in the Physicians’ Health Study who later developed these wandering blood clots, and in 646 men who did not develop such blood clots during the 10-year follow-up.

Normally, men have homocysteine levels of 10-11 micromoles per liter of blood. In this study, men with homocysteine levels of at least 17.25 micromoles per liter were at least three times more likely than men with normal homocysteine levels to develop a venous blood clot that was not attributed to any other medical condition. Men with high homocysteine levels who also had Factor V Leiden had a 20-fold increased risk of developing these blood clots.

Co-authors of the study are: Charles H. Hennekens, M.D., Dr.P.H.; Jacob Selhub, Ph.D.; Joseph P. Miletich, M.D.; M. Rene Malinow, M.D.; and Meir J. Stampfer, M.D. Circulation is one of five scientific journals published by the Dallas-based AHA.


Do high homocysteine levels magnify stroke risk in young women?
January 26, 1996

SAN ANTONIO, Jan. 26 -- A disorder characterized by deficiencies in B vitamins may be associated with a woman's increased risk of developing premature stroke, Maryland scientists reported here today at the American Heart Association's Annual Conference on Stroke.

The disorder, called hyperhomocysteinemia, refers to elevations of a plasma amino acid called homocysteine. Like cholesterol, plasma homocysteine levels are determined by a mix of genetic and nutritional factors. In its extreme form hyperhomocysteinemia may cause life-threatening blood clotting disorders, even leading to strokes and deep vein thromboses (clots in the blood vessels of the limbs) during childhood.

Severe hyperhomocysteinemia was identified more than 30 years ago, and found to be a genetic disease. Lately, researchers have found moderate hyperhomocysteinemia can also be caused by a deficiency in forms of vitamin B (folic acid, vitamins B6 and B12.)

Steven Kittner, M.D., M.P.H, associate professor of neurology, epidemiology and preventive medicine at the University of Maryland School of Medicine in Baltimore, who reported the study's findings, says in the last 10 years, moderate hyperhomocysteinemia has been given more prominence as a contributing factor for vascular disease. "Prospective studies, such as the well-known Physicians Health Study and the British Regional Heart Study, have confirmed its linkage to heart attack and stroke in middle-aged and elderly men."

To determine if homocysteinemia might be associated with premature stroke in women, Kittner and his colleagues studied a group of young women who were participating in a research project looking at the causes of stroke in women between the ages of 15 and 44.

"There have been only a few studies looking at the link between homocysteine and vascular disease among young women," says Kittner, "and none in a representative, biracial American population."

Sixty women who had suffered stroke and 125 randomly selected, age-matched control subjects were enrolled in the study. The women had their blood levels of homocysteine measured and were assessed for high blood pressure, smoking status, cholesterol and other cardiovascular risk factors. After adjusting for these risk factors, researchers found that women who were in the top fourth for homocysteine levels had a 2.3-fold increased risk of stroke compared to those in the lower groups. Among those in whom no cause of stroke could be determined, the association was even higher -- 3.4-fold.

The median blood levels of homocysteine for women in the study were 6.5 nanomoles per millimeter (nmol/ml). But risk of stroke began to rise in women whose levels were above 8.5 nmol/ml.

Vitamin B supplements, particularly folic acid, can lower homocysteine when taken at the recommended dietary allowance (RDA). The RDA for folic acid is 200 mg/day for men and 180 mg/day for women; the RDA for vitamin B6 is 2 mg/day for men and 1.6 mg/day for women. Sources of folic acid include fruits and vegetables, and vitamin B6 is obtained from red meat.

However, Kittner says the optimal dosage is unknown. And, while there's no harm in taking a daily multivitamin, high doses of folic acid can mask vitamin B12 deficiency (which can result in anemia or neurologic problems), and extremely high doses of B6 can cause peripheral nerve damage.

And, Kittner says, the big question remains: "Will reducing homocysteine modify risk?"

"We are where we were with high blood pressure many years ago; we knew we could lower blood pressure with drugs, but whether it reduced risk was still unknown. "We first learned there was an association. Then we learned later that risk was reduced with therapy."

Kittner's co-authors are R. Macko, M.D.; J.R. Hebel, Ph.D.; B. Feeser, M.P.H.; J. Rohr, B.A.; M.R. Malinow, M.D.; B. Upson; D. Buchholz, M.D.; C. Earley, M.D., Ph.D.; C. Johnson, M.D.; T.R. Price, M.D.; M. Sloan, M.D.; B. Stern, M.D.; R. Wityk, M.D.; M. Wozniak, M.D., Ph.D.; R. Sherwin, M.D.; P. Stolley, M.D., M.P.H.


Homocysteine in 'normal' range may raise CHD risk
November 14, 1995

DALLAS, Nov. 15 -- A high level of the amino acid homocysteine is fast becoming recognized as a new risk factor for premature coronary artery disease, but the precise amount that signals danger isn't known. Scientists searching for this "threshold" now say that risk may actually extend to many, including some women and elderly, whose homocysteine levels are in a range heretofore considered to be normal. And the investigators say their findings suggest that low levels of vitamin B6 should be added to the growing heart disease (CHD) risk list. After studying homocysteine and B-complex vitamin levels including B6, B12 and folic acid in 304 patients with coronary disease and in 231 healthy controls, researchers at the Cleveland Clinic report:

"The results show that homocysteine concentrations now widely accepted as normal are associated with an increased likelihood of coronary artery disease and that this risk increases with rising homocysteine concentrations." Their findings appear in the Nov. 15 issue of the American Heart Association scientific journal Circulation.

The scientists also found "an independent increased risk of coronary disease" in patients with a vitamin B6 deficiency, defined as pyridoxal phosphate levels below 20 nanomoles per liter of blood. Vitamin B6 levels were low in 10 percent of patients and only 2 percent of controls --yielding, the authors say, a four-times-higher risk of coronary disease ("odds ratio" 4.3) for those with B6 deficiency after adjusting for other risk factors including high homocysteine.

In the study of 201 male and 103 female patients, each 5-micromoles-per- liter increase in homocysteine more than doubled the overall risk of coronary disease (odds ratio 2.4). The risk was also high for women (odds ratio 3.5) and for all patients over age 65 (odds ratio 2.9).

Homocysteine concentrations were higher in patients than in controls (14.4 vs. 10.9 micromoles per liter). The researchers found homocysteine levels of 14 micromoles per liter more than quadrupled risk of coronary disease, conferring an odds ratio of 4.8.

Many previous studies of homocysteine have used "very arbitrary" levels to define normality, notes Killian Robinson, M.D., staff cardiologist at the Cleveland Clinic and principal investigator for the new study. "Now, additional research is clearly needed to define more precisely what range of values for homocysteine should be considered normal."

The balance of scientific evidence now favors a "graded" association between elevated homocysteine and increasing CHD risk, a theory the Cleveland researchers say has now been confirmed by the results of their study.

Basic research has shown that excess homocysteine appears to be "toxic" to cells lining the inner wall of arteries and increases "stickiness" of blood clotting components including platelets. Experimental doses of folic acid and B6 bring drops in homocysteine levels, leading scientists to infer that increased intake of these B vitamins will have beneficial effects. But this remains to be proved in long-term trials.

In the study published today, Robinson and his colleagues report they found vitamin B6 deficiency was more prevalent in patients than in controls. Deficiencies in folic acid and B12 were not observed, and folic acid levels actually were higher in the patients. The researchers emphasized: "the elevated homocysteine in our patients was not entirely explained by low vitamin concentrations . . ."

Their data led the scientists to conclude that both high homocysteine concentrations and low B6 levels are "independent risk factors" for CHD. They write: "The risk associated with homocysteine rises with increasing concentrations, has no threshold, and is evident in women and the elderly."

Older patients, say the investigators, have received little attention in CHD research, even though they form a large portion of the population at risk for coronary disease. And they say that while the mechanisms involved aren't fully understood, "increased plasma homocysteine is a common risk factor for coronary disease in older people." More than 50 percent of the patients in their study over 65 were rated as "hyperhomocysteinemic."

Similarly, say the researchers, the effects of high homocysteine levels on women haven't received much study despite evidence that larger amounts of the amino acid are present in women with vascular disease. The prevalence of hyperhomocysteinemia was greater in women than in men in their study, the authors point out. They write: "It is now clear that hyperhomocysteinemia also increases the risk for coronary disease in women."

Other co-authors of the report with Robinson are Ellen L. Mayer, M.D.; Dave P. Miller, M.S.; Ralph Green, M.D.; Frederick van Lente, Ph.D.; Anjan Gupta, M.D.; Kandice Kottke-Marchant, M.D., Ph.D.; Susan R. Savon, M.S.; Jacob Selhub, Ph.D.; Steven E. Nissen, M.D.; Michael Kutner, Ph.D.; Eric J. Topol, M.D., and Donald W. Jacobsen, Ph.D. Circulation is one of five scientific journals published by the Dallas-based AHA.