Possible mechanisms of increased risk are that hyperhomocystinemia may impair release of nitric oxide form endothelial cells, stimulate proferation of atherogenic smooth muscle cells, and contribute to thrombogenesis through activation of proteinC.

Homocysteine is derived from the sulfur-containing amino acid methionine and is metabolized through pathways associated with folic acid, vitamin B6, and vitamin B12 as cofactors. Deficiencies in the cofactors lead to elevated serum concentrations of homocysteine, although profound deficiencies are rare among persons with high homocysteine CAD.

Defects in the genes for 5,10-methylene tetrahydrofolate reductase (rare), cystathione B-synthase (0.5 per cent prevalence), methylene tetrahydrofolate homocysteine methyltransferase (rare), and methioine synthases (rare) can lead to increases in homocysteine.

Elevated plasma homocysteine levels (>15U/L) confer an independent risk for vascular disease, according to cross sectional and prospective case control studies.

The relative risk for stroke and MI is approxiametly 2.0 for homocysteine levels greater than 15 Umol/L compared with those less than 10 umol/L.

Secondary cause of increased homocysteine levels include age, male, sex, menopause, renal function and some medications (e.g., niacin, oral contraceptives with estrogen, phenytoin, methotrexate, theophyline). Thyroid function also is relevant.

No data are available to establish the vascular benefits homocysteine values. Treatment suggestions include 400μg (i.e., typical amount in multivitamins) to 2 mg of folate daily. Second line therapy includes 10 to 25 mg of pyridoxine (vitamin B6) daily with or without 400 μg vitamin B12 for patients with vitamin B12 deficiency. Use of folate in the setting of vitamin B12 deficiency can lead to megaloblastic anemia crisis. This suggests that vitamin B12 levels, albeit of low yield, should be measured for persons with high homocysteine values before initation of folate therapy.