Plasma homocysteine predicts mortality independently of traditional risk factors and C-reactive protein in patients with angiographically defined coronary artery disease

Background-Plasma homocysteine (tHCY) has been associated with coronary art ery disease (CAD). We tested whether tHCY also increases secondary risk, af ter initial CAD diagnosis, and whether it is independent of traditional ris k factors, C-reactive protein (CRP), and methylenetetrahydrofolate reductas e (MTHFR) genotype. Methods and Results-Blood samples were collected from 1412 patients with se vere angiographically defined CAD (stenosis greater than or equal to 70%). Plasma tHCY was measured by fluorescence polarization immunoassay. The stud y cohort was evaluated for survival after a mean of 3.0 +/- 1.0 years of fo llow-up (minimum 1.5 years, maximum 5.0 years). The average age of the pati ents was 65 +/- 11 years, 77% were males, and 166 died during follow-up. Mo rtality was greater in patients with tHCY in tertile 3 than in tertiles 1 a nd 2 (mortality 15.7% versus 9.6%, P = 0.001 [log-rank test], hazard ratio [HR] 1.63). The relative hazard increased 16% for each 5-mu mol/L increase in tHCY (P(0.001). In multivariate Cox regression analysis, controlling for univariate clinical and laboratory predictors, elevated tHCY remained pred ictive of mortality (HR 1.64, P = 0.009), together with age (HR 1.72 per 10 -year increment, P < 0.0001), ejection fraction (HR 0.84 per 10% increment, P = 0.0001), diabetes (HR 1.98, P = 0.001), CRP (HR 1.42 per tertile, P = 0.004), and hyperlipidemia. Homozygosity for the MTHFR variant was weakly p redictive of tHCY levels but not mortality. Conclusions-In patients with angiographically defined CAD, tHCY is a signif icant predictor of mortality, independent of traditional risk factors, CRP, and MTHFR genotype. These findings increase interest in tHCY as a secondar y risk marker and in secondary prevention trials tie, with folate/B vitamin s) to determine whether reduction in tHCY will reduce risk.