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(Circulation. 2005;112:3868-3875.)
© 2005 American Heart Association, Inc.

Coronary Heart Disease

Metabolomic Identification of Novel Biomarkers of Myocardial Ischemia

Marc S. Sabatine, MD, MPH; Emerson Liu, MD; David A. Morrow, MD, MPH; Eric Heller, MD; Robert McCarroll, PhD; Roger Wiegand, PhD; Gabriel F. Berriz, PhD; Frederick P. Roth, PhD; Robert E. Gerszten, MD

From the Cardiovascular Division (M.S.S., D.A.M.), Brigham and Women’s Hospital, and the Donald W. Reynolds Cardiovascular Clinical Research Center on Atherosclerosis at Harvard Medical School (M.S.S., E.L., R.E.G.), Boston, Mass; CANTATA Pharmaceuticals (R.M., R.W.), Cambridge, Mass; the Department of Biological Chemistry and Molecular Pharmacology (G.F.B., F.P.R.), Harvard Medical School, the Cardiology Division and Center for Immunology and Inflammatory Diseases (E.L., E.H., R.E.G.), Massachusetts General Hospital, and the Donald W. Reynolds Cardiovascular Clinical Research Center (M.S.S., E.L., R.E.G.), Harvard Medical School, Boston, Mass.

Correspondence to Robert E. Gerszten, MD, Cardiology Division and Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Room 8307, 149 13th St, Charlestown, MA 02129. E-mail rgerszten{at}partners.org

Received April 14, 2005; de novo received June 16, 2005; revision received September 14, 2005; accepted September 19, 2005.

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.

Methods and 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.

Key Words: exercise • ischemia • metabolism

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