This meta-analysis of observational studies suggests that elevated homocysteine is at most a modest independent predictor of IHD and stroke risk in healthy populations. Studies of the impact on disease risk of genetic variants that affect blood homocysteine concentrations will help determine whether homocysteine is causally related to vascular disease, as may large randomized trials of the effects on IHD and stroke of vitamin supplementation to lower blood homocysteine concentrations.

Premature arteriosclerosis and thromboembolic events are well-known complications of homozygous homocystinuria due to cystathionine synthase deficiency. It is unknown whether heterozygosity for homocystinuria predisposes to premature vascular disease. We explored the frequency of excessive homocysteine accumulation after standardized methionine loading in 75 patients presenting with clinical signs of ischemic disease before the age of 50:25 with occlusive peripheral arterial disease, 25 with occlusive cerebrovascular disease, and 25 with myocardial infarction. In seven patients in each of the first two groups but in none of the patients in the third group, heterozygosity for homocystinuria was established on the basis of pathological homocysteinemia after methionine loading and cystathionine synthase deficiency in skin fibroblast cultures. Because the frequency of heterozygosity for homocystinuria in the normal population is 1 in 70 at the most, we conclude that this condition predisposes to the development of premature occlusive arterial disease, causing intermittent claudication, renovascular hypertension, and ischemic cerebrovascular disease.

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Abstract-An inborn error of metabolism, homocystinuria due to cystathionine ␤-synthase deficiency, results in markedly elevated levels of circulating homocysteine. Premature vascular events are the main life-threatening complication. Half of all untreated patients have a vascular event by 30 years of age. We performed a multicenter observational study to assess the effectiveness of long-term homocysteine-lowering treatment in reducing vascular risk in 158 patients. Vascular outcomes were analyzed and effectiveness of treatment in reducing vascular risk was evaluated by comparison of actual to predicted number of vascular events, with the use of historical controls from a landmark study of 629 untreated patients with cystathionine ␤-synthase deficiency. The 158 patients had a mean (range) age of 29.4 (4.5 to 70) years; 57 (36%) were more than 30 years old, and 10 (6%) were older than 50 years. There were 2822 patient-years of treatment, with an average of 17.9 years per patient. Plasma homocysteine levels were markedly reduced from pretreatment levels but usually remained moderately elevated. There were 17 vascular events in 12 patients at a mean (range) age of 42.5 (18 to 67) years: pulmonary embolism (nϭ3), myocardial infarction (nϭ2), deep venous thrombosis (nϭ5), cerebrovascular accident (nϭ3), transient ischemic attack (nϭ1), sagittal sinus thrombosis (nϭ1), and abdominal aortic aneurysm (nϭ2). Without treatment, 112 vascular events would have been expected, for a relative risk of 0.09 (95% CI 0.036 to 0.228; PϽ0.0001). Treatment regimens designed to lower plasma homocysteine significantly reduce cardiovascular risk in cystathionine ␤-synthase deficiency despite imperfect biochemical control. These findings may be relevant to the significance of mild hyperhomocysteinemia that is commonly found in patients with vascular disease.