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Homocysteine and Heart Disease: A Culprit, or Just a Suspect?

A growing body of evidence links high levels of the circulating amino acid homocysteine with an increased risk of cardiovascular (CV) disease. But whether homocysteine will join the list of major risk factors or turn out to be a marker for some as-yet-unknown process remains in doubt.

The current consensus, embodied in a recent "science advisory" from the American Heart Association (1). is that it's too soon to start doing general screening for hyperhomocysteinemia. However, the AHA suggests that everyone be encouraged to consume recommended allowances of folate, vitamin B6, and vitamin B12, since these help prevent homocysteine elevation. In addition, measuring homocysteine in some patients at high risk for heart disease may make sense, according to the AHA.

Sizing Up the Evidence

Homocysteine is formed during the metabolism of methionine, an essential amino acid (2). The substance has been under suspicion as a possible player in CV disease for decades, and many studies have tied hyperhomocysteinemia to an increased risk (1). One meta-analysis (3) indicated that in 15 studies, hyperhomocysteinemia imparted a 70% increase in the risk of coronary artery disease. The same analysis found greater increments in risks for stroke and peripheral vascular disease.

However, five recent prospective studies failed to show a link between homocysteine and CV disease, the AHA report states. Perhaps more important, no randomized prospective trials have yet shown that lowering homocysteine will reduce the risk of CV disease (though such trials are underway).

Says Charles H. Hennekens, MD, a researcher who has cowritten several studies on homocysteine: "The totality of evidence on homocysteine is far less complete and conclusive than it is on the traditional risk factors. With the traditional risk factors, we have a much clearer picture of the large benefits we can get from modifying them." Hennekens is currently a visiting professor of epidemiology at the University of Miami.

Recent Findings

Imperfect though it is, the evidence continues to build. For example, a group from Australia recently examined 1,111 middle-aged men and women recruited randomly and found that increased homocysteine was an independent risk factor for carotid-artery-wall thickening and plaque formation (4). In addition, a recent case-control study (5) tied elevated homocysteine to a moderately increased risk of a CV event in postmenopausal women over a 3-year period.

But Hennekens remains cautious. He says the relative risks linking homocysteine with CV disease are generally higher in retrospective studies than in prospective studies—about 1.7 vs 1.2 to 1.3. "I think we shouldn't make the same mistake with homocysteine that we made with beta-carotene and we may be making with vitamin E," he adds. "We declare victory on an inadequate totality of evidence."

A Possible Mechanism

If hyperhomocysteinemia does promote atherogenesis, just how it does so is not yet clear. The main theory is that elevated homocysteine injures the endothelium, possibly by generating hydrogen peroxide, and the endothelial damage leads to platelet activation and thrombus formation (2).

Such theories, of course, presuppose that high homocysteine leads to atherosclerosis, not the other way around. There are signs, in fact, that homocysteine levels may rise after a stroke (6), which is consistent with the idea of "reverse causality." However, the authors of a recent editorial in Circulation (7) concluded that most evidence does not support reverse causality and there is no plausible mechanism for it.

Clinical Implications

Homocysteine elevation is readily prevented or treated with folate and vitamins B6 and B12. The AHA reports that folic acid supplementation ranging from 0.5 to 5.7 g/day lowers homocysteine levels 25%, and adding vitamin B12 brings a further 7% reduction. In addition, the report says, users of multivitamin supplements have lower homocysteine levels than nonusers.

Although the AHA report does not endorse general screening, it does say healthcare professionals should encourage people to get the recommended amounts of the three B vitamins by eating vegetables, fruits, legumes, meats, fish, and fortified grains and cereals. Beyond that, the report suggests that screening may be a good idea for patients who have a personal or family history of premature CV disease or have malnutrition or certain other conditions.

The normal range for homocysteine is 5 to 15 micromoles/L, according to the AHA panel. But the panel suggests that persons who have a level of 10 micromoles/L or higher may benefit from treatment if they have the risk factors mentioned above.

In contrast, Hennekens says he would not yet screen patients for homocysteine level in the clinical setting. "I think we need data from randomized trials of lowering homocysteine before we use screening as a clinical tool."

Victor Froelicher, MD, a cardiologist at Palo Alto (California) VA Health Care Systems, says that even though general screening isn't warranted, he advises patients to eat green leafy vegetables and take an occasional folic acid pill as a precaution. Froelicher is a senior associate editorial board member of the The Physician and Sportsmedicine.

Americans who eat a normal diet are already getting extra folate in their food: In 1996 the US Food and Drug Administration ordered that all enriched grain products be fortified with folate to prevent neural tube defects. A recent study (8) indicates that this action may also help lower homocysteine levels in the general population. Researchers measured plasma folate and total homocysteine in a sizable cohort before and after the FDA action and found that the prevalence of high homocysteine (over 13 micromoles/L) dropped from 18.7% to 9.8%.

Supplementing Safely

Patients who do take folate supplements should also take vitamins B6 and B12, because a high folate intake alone can mask the development of megaloblastic anemia, which is linked to vitamin B12 deficiency (9). For high-risk patients in whom dietary measures fail to lower homocysteine, the AHA suggests a daily dose of 400 micrograms of folic acid, 2 mg of vitamin B6, and 6 micrograms of vitamin B12.

Robert Roos


  1. Malinow MR, Bostom AG, Krauss RM: Homocyst(e)ine, diet, and cardiovascular diseases: a statement for healthcare professionals from the nutrition committee, American Heart Association. Circulation 1999;99(1):178-182
  2. Welch GN, Loscalzo J: Homocysteine and atherothrombosis. N Engl J Med 1998;338(15):1042-1050
  3. Lowering blood homocysteine with folic acid based supplements: meta-analysis of randomised trials: Homocysteine Lowering Trialists' Collaboration. BMJ 1998;316(7135):894-898
  4. McQuillan BM, Beilby JP, Nidorf M, et al: Hyperhomocysteinemia but not the C677T mutation of methylenetetrahydrofolate reductase is an independent risk determinant of carotid wall thickening. Circulation 1999;99(18):2383-2388
  5. Ridker PM, Manson JE, Buring JE, et al: Homocysteine and risk of cardiovascular disease among postmenopausal women. JAMA 1999;281(19):1817-1821
  6. Lindgren A, Brattstrom L, Norrving B, et al: Plasma homocysteine in the acute and convalescent phases after stroke. Stroke 1995;26(12):2374-2375
  7. Bostom AG, Selhub J: Homocysteine and arteriosclerosis: subclinical and clinical disease implications, editorial. Circulation 1999;99(18):2361-2363
  8. Jacques PF, Selhub J, Bostom AG, et al: The effect of folic acid fortification on plasma folate and total homocysteine concentrations. N Engl J Med 1999;340(19):1449-1454
  9. Moustapha A, Robinson K: Homocysteine: an emerging age-related cardiovascular risk factor. Geriatrics 1999;54(April):49-63

News From the ACSM Annual Meeting

The 46th annual meeting of the American College of Sports Medicine (ACSM) was held in June in Seattle. Here are some highlights of the meeting as described in press releases from universities that had researchers presenting findings at the meeting.

  • A study presented by University at Buffalo exercise scientists suggests that dehydration may worsen exercise-induced asthma (EIA). The researchers compared eight persons who had EIA with eight age-matched controls who did not have EIA. Each subject's forced vital capacity (FEV1) was measured before and after exercise, both when fully hydrated and after 24 hours without fluid. Results showed that hydration status had no effect on nonasthmatics, whereas the FEV1 of dehydrated asthmatics was significantly lower both before and after exercise. Frank Cerny, PhD, coauthor of the study, said in the press release, "We need to investigate this condition further to determine how it affects pulmonary function."
  • A preliminary study from Pennsylvania State University suggests that menstrual disturbances in athletes are more likely to be linked with psychological stress signified by poor body image and excessive exercise than is the case in nonathletes. The study involved 143 women who were not taking oral contraceptives, including 88 athletes and 55 nonathletes. The women completed surveys on depression, eating disorders, "social physique anxiety," and exercise; tracked their diet; and underwent hormone monitoring. Twenty-four athletes (27%) and 15 nonathletes (27%) had irregular menstrual cycles. Among athletes, women with menstrual irregularities were more likely to have physique anxiety and engage in disordered eating and excessive exercise than were women of normal menstrual status; this pattern was not found in the nonathletes. In a news release from Penn State, study director Nancy Williams, PhD, said female athletes who have menstrual abnormalities are usually told simply to eat more and exercise less, but this study suggests that "psychological stress may exacerbate the effects of poor or inadequate diet and excessive exercise."
  • Surprise of the month: A scientific trial of thigh-reducing creams showed that the products do not reduce thigh circumference. In the 6-week study by researchers from the University of North Carolina at Chapel Hill and Florida Atlantic University, 11 women applied thigh cream to one leg and a placebo cream to the opposite leg. They did not diet or exercise. Researchers found no circumference differences, and the women said they did not see or feel any difference.


Barry A. Franklin, PhD, is the new president and Priscilla M. Clarkson, PhD, is president-elect of the American College of Sports Medicine (ACSM). Their 1-year terms began in June at the ACSM meeting in Seattle. Franklin is director of cardiac rehabilitation and exercise laboratories at William Beaumont Hospital in Royal Oak, Michigan, and professor of physiology at Wayne State University in Detroit. Clarkson is associate dean of the School of Public Health and Health Sciences and a professor in the Department of Exercise Science at the University of Massachusetts. She will become ACSM president at the 2000 annual meeting in Indianapolis. Franklin is an editorial board member of The Physician and Sportsmedicine.

Field Notes

FDA Issues Sunscreen Rules
New sunscreen regulations, issued by the US Food and Drug Administration (FDA) in May, seek to streamline labeling and assist consumers in making sun protection decisions. According to an FDA press release, the regulations include:

  • A uniform, streamlined labeling system for all products that contain sunscreen;
  • Three categories of protection: "minimum" (sun protection factor [SPF] 2 to 12), "moderate" (SPF 12 to 29), and "high" (SPF 30 and higher);
  • A ban on the listing of specific SPF values above 30; labels can only say "30 plus";
  • A requirement that manufacturers test their products' sun-protection factors;
  • A list of 16 allowed active ingredients (zinc oxide and avobenzone are the most recent additions);
  • Banning the use of "unsupported, absolute, and/or misleading terms such as 'sunblock,' 'waterproof,' and 'all-day protection,'" and
  • A warning label for tanning products that do not contain sunscreen ingredients.

Sunscreen makers have 24 months to comply with the new requirements. Manufacturers of cosmetic tanning products that do not contain sunscreen have 12 months to include a warning statement on their label.

High-Altitude Hikers Lack Emergency Awareness
Many wilderness hikers and backpackers don't know how to prepare for medical emergencies or respond when one occurs, according to a press release detailing the work of researchers from the University of Colorado Health Sciences Center in Denver.

In a survey of 126 hikers on a 15-mile round-trip trail at an elevation above 10,000 ft in Rocky Mountain National Park, researchers found that 30% were not using sunscreen and that fewer than 1% were carrying the recommended amount of water (6 to 8 L) for the length and difficulty of the hike. The hikers also knew little about the risks involved in high-altitude hiking, such as dehydration, hypothermia, heat illness, altitude illness, and fatigue. Fewer than half recognized the early symptoms of hypothermia, and 30% did not know how to treat it.

The National Park Service and Wilderness Medical Society recommend that people who plan to hike above 8,000 ft acclimate themselves at that elevation for 2 nights beforehand. The groups recommend consuming 0.5 to 1 L of water per hour of exercise or 7 to 8 L per day.

Soccer-Goal Safety Standards Announced
To reduce the risk of potentially fatal soccer-goal tip-overs, the US Consumer Product Safety Commission (CPSC) and the soccer-goal industry have developed safety standards to make the goals more stable. According to a CPSC press release, the new standard requires that movable soccer goals, except very lightweight goals, remain stable when the goal is weighted in a downward or horizontal direction. The standard also specifies warning labels that must be attached to goals.

Since 1979, the CPSC has recorded 23 deaths and 38 serious injuries from soccer goals that tipped over and crushed people who climbed on them or hung from the crossbar. Most of the accidents involved unanchored homemade goals.

The CPSC notes that the number and type of anchors needed depend on soil type and goal weight. Anchor types include:

  • augers that screw into the ground;
  • semipermanent anchors that require a permanent underground base and are tethered or bolted to the goal;
  • pegs, stakes, or j-hooks that are driven into the ground; and
  • sandbags or counterweights for indoor goals.

To request a free copy of the guidelines, send a postcard to CPSC, Washington, DC 20207.

Preventing Heart Disease in Women: Stronger Efforts Urged
A panel representing the American College of Cardiology (ACC), the American Heart Association, and four other professional health organizations has found that heart disease prevention efforts are less aggressive for women than for men, according to a press release from the ACC.

The panel recently released a scientific statement that identifies the most important strategies for lowering heart disease risk in women. The recommendations, published in the May issues of the Journal of the American College of Cardiology and Cardiology, include:

  • Consider a statin or cholesterol-lowering drug instead of hormone replacement therapy for first-line treatment of hypercholesterolemia in postmenopausal women.
  • Raise the target blood level of high-density lipoprotein above current national recommendations.
  • Address the increased heart disease risk in women who have diabetes. Diabetes multiplies a woman's heart disease risk three to seven times, compared with a twofold to threefold risk increase in men.