A prospective study of plasma homocyst(e)ine and risk of ischemic stroke.


Verhoef P, Hennekens CH, Malinow MR






BACKGROUND AND PURPOSE: Several studies have reported elevated circulating homocyst(e)ine levels in subjects with cerebral atherosclerosis. We assessed prospectively whether high plasma levels of homocyst(e)ine affect risk of ischemic stroke and evaluated whether high blood pressure modifies any such effect. METHODS: The study sample was drawn from the Physicians' Health Study, a randomized, double-blind, placebo-controlled trial of aspirin and beta-carotene in 22,071 US male physicians. A total of 14,916 subjects 40 to 84 years old with no prior history of stroke, transient ischemic attack, or myocardial infarction provided blood samples at baseline and were followed for 5 years, with 99.7% morbidity and 100% mortality follow-up. Using a nested case-control design, we assayed homocyst(e)ine in samples from 109 subjects who subsequently developed ischemic stroke and 427 control subjects. RESULTS: The mean plasma concentration of homocyst(e)ine was slightly higher in subjects with stroke (11.1 +/- 4.0 [+/- SD] nmol/mL) than in control subjects (10.6 +/- 3.4 nmol/mL), but the difference was not statistically significant (P = .12). The crude odds ratio of ischemic stroke for subjects in the upper 20% (> 12.7 nmol/mL) compared with those in the bottom 80% of homocyst(e)ine levels was 1.4 (95% confidence interval, 0.8 to 2.2). The odds ratio was 1.2 (95% confidence interval, 0.7 to 2.0) after controlling for several risk factors and other potential confounders. In subgroup analyses, elevated homocyst(e)ine levels appeared to be more strongly predictive of ischemic stroke in normotensive subjects and in men 60 years or younger. Although not statistically significant, in these subgroups increases in risks of 100% and 70%, respectively, were observed for men in the upper 20% of homocyst(e)ine values. CONCLUSIONS: In this study, the data were compatible with a small but nonsignificant association between elevated plasma homocyst(e)ine and risk of ischemic stroke. However, since the sample size is small and the confidence intervals are wide, either no association or a moderate increase in risk cannot be excluded, particularly in subgroups otherwise at low risk, eg, younger men and those with normal blood pressure.