Homocysteine and reclassification of cardiovascular disease risk

J Am Coll Cardiol. 2011 Aug 30;58(10):1025-33. doi: 10.1016/j.jacc.2011.05.028.


Objectives: The purpose of this study was to examine whether adding homocysteine (Hcy) to a model based on traditional cardiovascular disease (CVD) risk factors improves risk classification.

Background: Data on using Hcy to reclassify individuals in various risk categories beyond traditional approaches have not been adequately scrutinized.

Methods: We performed a post hoc analysis of the MESA (Multi-Ethnic Study of Atherosclerosis) and NHANES III (National Health and Nutrition Examination Survey III) datasets. Hcy was used to predict composite CVD and hard coronary heart disease (CHD) events in the MESA study and CVD and CHD mortality in the NHANES III survey using adjusted Cox-proportional hazard analysis. Reclassification of CHD events was performed using a net reclassification improvement (NRI) index with a Framingham risk score (FRS) model with and without Hcy.

Results: Hcy level (>15 μmol/l) significantly predicted CVD (adjusted hazard ratio [aHR]: 1.79, 95% confidence intervals [CI]: 1.19 to 1.95; p = 0.006) and CHD events (aHR: 2.22, 95% CI: 1.20 to 4.09; p = 0.01) in the MESA trial and CVD (aHR: 2.72, 95% CI: 2.01 to 3.68; p < 0.001) and CHD mortality (aHR: 2.61, 95% CI: 1.83 to 3.73; p < 0.001) in the NHANES III, after adjustments for traditional risk factors and C-reactive protein. The level of Hcy, when added to FRS, significantly reclassified 12.9% and 18.3% of the overall and 21.2% and 19.2% of the intermediate-risk population from the MESA and NHANES cohorts, respectively. The categoryless NRI also showed significant reclassification in both MESA (NRI: 0.35, 95% CI: 0.17 to 0.53; p < 0.001) and NHANES III (NRI: 0.57, 95% CI: 0.43 to 0.71; p < 0.001) datasets.

Conclusions: From these 2 disparate population cohorts, we found that addition of Hcy level to FRS significantly improved risk prediction, especially in individuals at intermediate risk for CHD events.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Aged
  • Aged, 80 and over
  • Cardiovascular Diseases / blood
  • Cardiovascular Diseases / epidemiology*
  • Female
  • Homocysteine / blood*
  • Humans
  • Male
  • Middle Aged
  • Nutrition Surveys
  • Risk Assessment / methods
  • United States / epidemiology


  • Homocysteine