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Am Fam Physician. 2000;62(3):643

Elevated homocysteine levels have been associated with an increased risk of atherosclerosis. High homocysteine levels appear to interfere with cellular function in the endothelium and smooth muscles of blood vessels. Vermeulen and colleagues evaluated the effect of lowering homocysteine levels with folic acid and vitamin B6 supplementation on atherosclerosis in patients at very high risk.

Healthy siblings of patients who were diagnosed with severe atherosclerotic disease before the age of 56 years were recruited for the two-year prospective randomized study. All siblings were screened for a history of arterial disease and tested for renal and hepatic function before enrollment. Methionine-loading tests were used to identify siblings who had hyperhomocysteinemia (HHC). Those with HHC were randomized to receive treatment for two years with folic acid (5 mg daily) and vitamin B6 (250 mg daily) or an identical placebo. Siblings without HHC also were invited to participate in the study and were randomized to receive treatment or placebo. Vitamin supplements were not permitted during the study period. Follow-up assessments were conducted after year 1 and again at the end of the study. Serum levels of cholesterol, lipids, vitamin B6 and hepatic enzymes were obtained at each assessment. Data on blood pressure, exercise electrocardiography (ECG), ultrasonographic measurement of femoral and carotid artery diameters, and clinical development of any atherosclerotic condition also were assessed.

Results of assessments in siblings treated with vitamins were comparable in all important variables to those receiving a placebo. Treatment was well tolerated, and compliance was 100 percent. Twenty-four participants did not complete the study, but no serious side effects were noted in any groups. Mean plasma folate and B6 concentrations increased significantly in the treatment groups. Fasting total homocysteine levels and postmethionine homocysteine levels decreased significantly in the treatment groups compared with those taking the placebo. The rate of abnormal exercise ECG test results was significantly lower in the treatment groups. However, blood pressure and arterial-diameter measurements did not differ between groups during the two-year follow-up period.

The authors conclude that lowering homocysteine levels in healthy persons at high risk of atherosclerosis resulted in decreased abnormal exercise ECG tests, but not with changes in arterial diameter. They urge that further research and trials with clinical end points be conducted to quantify the effect of vitamin therapy on atherosclerosis.

editor's note: Family physicians have urged patients for years to eat balanced diets, including generous portions of green leafy vegetables, and to avoid vitamin deficiencies. This advice is rapidly moving from being considered simple common sense to seen as an active strategy to prevent heart disease. The evidence is particularly compelling in patients from the Indian subcontinent. The rates of coronary heart disease in immigrants to Europe from the Indian subcontinent are very high (as noted in the Chambers editorial) and appear to be related to homocysteine concentrations as well as the more conventional risk factors.—a.d.w.

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