Metabolomics studies identify elevated plasma levels of specific analytes that are associated with increased risk for CVD
In initial studies we sought to discover unbiased small molecule metabolic profiles in plasma that predict increased risk for cardiovascular disease (CVD). An initial “Learning Cohort” was used comprised of plasma from stable patients undergoing elective cardiac evaluation who subsequently experienced a heart attack (myocardial infarction, MI), stroke or death over the ensuing three year period versus age- and gender-matched subjects who did not. Liquid chromatography with on-line mass spectrometry (LC/MS) analysis of plasma was performed to define analytes associated with cardiac risk as described in Methods. Of an initial 2000+ analytes monitored, 40 met all acceptability criteria within the Learning Cohort. Subsequent studies within an independent “Validation Cohort” led to identification of 18 analytes that met acceptability criteria in both Learning and Validation Cohorts (Fig. 1a,b, Supplementary Fig. 1a, Supplementary Table 1).
The structural identity of the 18 small molecules in plasma whose levels track with cardiac risks was not known since the compounds were screened based upon their retention time and mass-to-charge ratio (m/z) when analyzed by LC/MS. Among the 18 analytes, those with m/z 76, 104 and 118 demonstrated significant (p<0.001) correlations amongst one another, suggesting their potential relationship via a common biochemical pathway (Supplementary Fig. 1b). We therefore initially sought to structurally define these three analytes.