Metabolomic identification of novel biomarkers of myocardial ischemia.
BACKGROUND
Recognition of myocardial ischemia is critical both for the diagnosis of coronary artery disease and the selection and evaluation of therapy. Recent advances in proteomic and metabolic profiling technologies may offer the possibility of identifying novel biomarkers and pathways activated in myocardial ischemia.


RESULTS
Blood samples were obtained before and after exercise stress testing from 36 patients, 18 of whom demonstrated inducible ischemia (cases) and 18 of whom did not (controls). Plasma was fractionated by liquid chromatography, and profiling of analytes was performed with a high-sensitivity electrospray triple-quadrupole mass spectrometer under selected reaction monitoring conditions. Lactic acid and metabolites involved in skeletal muscle AMP catabolism increased after exercise in both cases and controls. In contrast, there was significant discordant regulation of multiple metabolites that either increased or decreased in cases but remained unchanged in controls. Functional pathway trend analysis with the use of novel software revealed that 6 members of the citric acid pathway were among the 23 most changed metabolites in cases (adjusted P=0.04). Furthermore, changes in 6 metabolites, including citric acid, differentiated cases from controls with a high degree of accuracy (P<0.0001; cross-validated c-statistic=0.83).


CONCLUSIONS
We report the novel application of metabolomics to acute myocardial ischemia, in which we identified novel biomarkers of ischemia, and from pathway trend analysis, coordinate changes in groups of functionally related metabolites.
Sabatine
Marc S
MS
Cardiovascular Division, Brigham and Women's Hospital, Donald W. Reynolds Cardiovascular Clinical Research Center on Atherosclerosis, Harvard Medical School, Boston, Massachusetts, USA.
Liu
Emerson
E
Morrow
David A
DA
Heller
Eric
E
McCarroll
Robert
R
Wiegand
Roger
R
Berriz
Gabriel F
GF
Roth
Frederick P
FP
Gerszten
Robert E
RE
D000249:Adenosine Monophosphate / Q000378:metabolism; D000368:Aged; D015415:Biomarkers / Q000097:blood / Q000378:metabolism; D016022:Case-Control Studies; D002851:Chromatography, High Pressure Liquid; D019343:Citric Acid / Q000378:metabolism; D005080:Exercise Test; D005260:Female; D006801:Humans; D019344:Lactic Acid / Q000097:blood; D008297:Male; D008660:Metabolism / Q000502:physiology*; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000378:metabolism; D017202:Myocardial Ischemia / Q000175:diagnosis*; D012306:Risk; D021241:Spectrometry, Mass, Electrospray Ionization
D015415:Biomarkers; D019343:Citric Acid; D019344:Lactic Acid; D000249:Adenosine Monophosphate