THE PHYSICIAN AND SPORTSMEDICINE - VOL 27 - NO. 7 - JULY 99
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.
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.
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%.
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.
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.
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.
FDA Issues Sunscreen Rules
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
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
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:
To request a free copy of the guidelines, send a postcard to CPSC, Washington, DC 20207.
Preventing Heart Disease in Women: Stronger Efforts Urged
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: