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Am Fam Physician. 2004;70(7):1372-1374

The value of elevated plasma homocysteine in identifying patients at high risk for adverse coronary heart disease (CHD) events currently is being clarified. Results of studies in patients with type 2 diabetes have shown a relationship only between elevated homocysteine and all-cause mortality, not specifically with cardiac events. Soinio and associates used a long-term, prospective study to determine the predictive value of moderately elevated plasma homocysteine levels for CHD in 830 patients with type 2 diabetes.

Participants were adults with measurements of plasma homocysteine performed retrospectively on stored baseline samples obtained between 1982 and 1984. Data on cardiac events were obtained in 1990 by questionnaire and medical records. The modified World Health Organization definition for definite or possible myocardial infarction was used as the primary outcome.

Coronary artery disease
Peripheral arterial disease
Aortic atherosclerosis
Deep venous thrombosis
Hypertension (probably)
Dementia in older adults (possibly)
Alzheimer’s disease (possibly)

During the seven-year follow-up period, the mean plasma homocysteine concentration was statistically significantly higher in patients who had myocardial infarction than in those who did not. This was true whether or not the coronary event was fatal. The CHD event rate was significantly higher in patients with plasma homocysteine levels of 15 μmol per L or more. The latter was true also after adjustment for sex, age, calculated creatinine clearance, and other CHD risk factors.

The authors conclude that in patients with type 2 diabetes, elevated plasma homocysteine levels are associated independently with higher rates of CHD events and CHD mortality. This finding appears to be true among patients with and patients without preexisting CHD. It is uncertain whether lowering homocysteine levels reduces CHD risk in diabetic patients.

editor’s note: Elevated plasma homocysteine levels clearly are an independent risk factor for multiple diseases in the general population and in patients with type 2 diabetes (see accompanying table).1,2 Because the mechanism remains uncertain, direct causality has not yet been determined. The most probable mechanism by which homocysteine may have toxic effects is oxidation, but other biochemical processes may be involved. Because elevated homocysteine levels probably result in impaired vascular endothelial and smooth muscle cell function by decreasing vasodilation by nitric oxide and altering the elastic properties of the vascular wall, it also may contribute to blood pressure elevation.1 Betaine, a homocystinuric agent, folic acid, vitamin B12, and vitamin B6 are being investigated as agents to reduce the plasma homocysteine level and possibly decrease atherosclerotic vascular risk and serve as adjuvant therapy for hypertension. Until primary and secondary prevention studies of homocysteine reduction and cardiovascular disease provide more specific advice, plasma homocysteine measurement probably should be reserved for use in patients with unexplained premature cardiovascular disease and patients with known cardiovascular risk factors who need further stratification for treatment planning or obtaining compliance.—r.s.

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