Prospective study of serum homocysteine and risk of ischemic stroke among patients with preexisting coronary heart disease

Background and Purpose - Substantial evidence is accumulating suggesting that hyperhomocysteinemia may be a risk factor for ischemic stroke. Results of prospective studies are, however, conflicting, and the role of hyperhomocysteinemia in patients with preexisting atherosclerotic vascular disease is not clear. Our aim was to assess prospectively the risk of incident ischemic stroke conferred by serum total homocysteine among patients with preexisting stable coronary heart disease (CHD). Methods - We obtained baseline fasting serum samples from patients with chronic CHD enrolled in the Bezafibrate Infarction Prevention (n=3090) secondary prevention study cohort. With a nested case-control design, we measured baseline total homocysteine concentration by a high-performance liquid chromatography- based method in sera (n= 160) of matched case-control pairs: patients who developed ischemic stroke during a mean follow-up of 8.2 years (cases) and age- and sex-matched controls without subsequent cardiovascular events. Results - An increase of 1 natural log unit in homocysteine concentration was associated with a >3-fold increase in relative odds of incident ischemic stroke (3.3; 95% CI, 1.2 to 10.2). Homocysteine concentrations at the highest quartile (> 17.4 μmol/L) were associated with significantly higher odds of ischemic stroke compared with the lowest quartile in matched-pair analysis (3.1; 95% CI, 1.1 to 9.8) and after multivariable adjustments (4.6; 95% CI, 1.3 to 18.9). Adding fibrinogen or soluble intercellular adhesion molecule-1 concentrations, markers of inflammation, to the model did not attenuate this association. The linear trends across the quartiles were significant for all models (P<0.05). Conclusions - Serum total homocysteine concentration is a strong predictor for incident ischemic stroke among patients at increased risk because of chronic CHD. The graded association observed is independent of traditional risk factors or inflammatory markers and indicates the importance of serum homocysteine levels in patients with preexisting vascular disease.