Background: Plasma homocysteine (tHCY) has been associated with coronary artery disease (CAD). We tested whether tHCY also increases secondary risk, after initial CAD diagnosis, and whether it is independent of traditional risk factors, C-reactive protein (CRP), and methylenetetrahydrofolate reductase (MTHFR) genotype.
Methods and results: Blood samples were collected from 1412 patients with severe angiographically defined CAD (stenosis >/=70%). Plasma tHCY was measured by fluorescence polarization immunoassay. The study cohort was evaluated for survival after a mean of 3.0+/-1.0 years of follow-up (minimum 1.5 years, maximum 5.0 years). The average age of the patients was 65+/-11 years, 77% were males, and 166 died during follow-up. Mortality was greater in patients with tHCY in tertile 3 than in tertiles 1 and 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-micromol/L increase in tHCY (P:<0.001). In multivariate Cox regression analysis, controlling for univariate clinical and laboratory predictors, elevated tHCY remained predictive 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 predictive of tHCY levels but not mortality.
Conclusions: In patients with angiographically defined CAD, tHCY is a significant predictor of mortality, independent of traditional risk factors, CRP, and MTHFR genotype. These findings increase interest in tHCY as a secondary risk marker and in secondary prevention trials (ie, with folate/B vitamins) to determine whether reduction in tHCY will reduce risk.