Clinical Chemistry 56: 194-201, 2010. First published December 18, 2009; 10.1373/clinchem.2009.127878
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(Clinical Chemistry. 2010;56:194-201.)
© 2010 American Association for Clinical Chemistry, Inc.

Mini-Reviews

Integration of Proteomic-Based Tools for Improved Biomarkers of Myocardial Injury

Robert E. Gerszten1,2,a, Steven A. Carr3,a and Marc Sabatine4

1 Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Charlestown and Harvard Medical School, Boston, MA; 2 Cardiology Division, Massachusetts General Hospital, Boston and Harvard Medical School, Boston, MA; 3 Broad Institute of MIT and Harvard, Cambridge, MA; 4 Cardiovascular Division, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA.

aAddress correspondence to: R.E.G. at Cardiology Division and Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital East-8307, 149 13th Street, Charlestown, MA 02129. Fax 617-726-5651; e-mail rgerszten{at}partners.org. S.A.C. at Broad Institute of MIT and Harvard, 7 Cambridge Center, Cambridge, MA 02142. Fax 617-252-1902; e-mail scarr{at}broad.mit.edu.


Abstract

Background: Given the mounting evidence in favor of early pharmacologic and catheter-based interventions for patients across the spectrum of acute coronary syndromes, discovering novel diagnostically sensitive and specific biomarkers that provide biochemical proof of early or reversible myocardial injury could have a substantial positive impact on patient care.

Content: To address unmet needs in disease biomarkers, investigators have turned to proteomics approaches. We describe advances in proteomics discovery technologies based on liquid chromatography–tandem mass spectrometry that facilitate the unbiased analysis of low-abundance blood proteins. We detail the development of emerging techniques to enhance the biomarker verification process, such as accurate inclusion mass screening, stable isotope dilution–multiple reaction monitoring–mass spectrometry (SID-MRM-MS), and stable isotope standards with capture by antipeptide antibodies, which combines the advantages of specific immunoaffinity enrichment of a target peptide with the structural specificity and quantitative capabilities of SID-MRM-MS. We highlight new assays incorporating these techniques for troponin I, a representative low-abundance cardiac biomarker, and interleukin-33, an emerging novel marker of myocardial stress for which no existing ELISA exists. We demonstrate that troponin I and interleukin-33 peptides have a linear, dynamic range spanning 4 orders of magnitude and limits of detection of approximately 0.5 µg/L back-calculated to the protein concentration.

Conclusions: There remain important unmet diagnostic and prognostic needs in cardiology. Advances in technology may allow proteomics to play a vital role in the discovery and validation of novel biomarkers to help fill those needs.