title: A pipeline that integrates the discovery and verification of plasma protein biomarkers reveals candidate markers for cardiovascular disease.
abstract: We developed a pipeline to integrate the proteomic technologies used from the discovery to the verification stages of plasma biomarker identification and applied it to identify early biomarkers of cardiac injury from the blood of patients undergoing a therapeutic, planned myocardial infarction (PMI) for treatment of hypertrophic cardiomyopathy. Sampling of blood directly from patient hearts before, during and after controlled myocardial injury ensured enrichment for candidate biomarkers and allowed patients to serve as their own biological controls. LC-MS/MS analyses detected 121 highly differentially expressed proteins, including previously credentialed markers of cardiovascular disease and >100 novel candidate biomarkers for myocardial infarction (MI). Accurate inclusion mass screening (AIMS) qualified a subset of the candidates based on highly specific, targeted detection in peripheral plasma, including some markers unlikely to have been identified without this step. Analyses of peripheral plasma from controls and patients with PMI or spontaneous MI by quantitative multiple reaction monitoring mass spectrometry or immunoassays suggest that the candidate biomarkers may be specific to MI. This study demonstrates that modern proteomic technologies, when coherently integrated, can yield novel cardiovascular biomarkers meriting further evaluation in large, heterogeneous cohorts.
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
authors.forename: Terri A
authors.initials: TA
authors.lastname: Addona
authors.forename: Xu
authors.initials: X
authors.lastname: Shi
authors.forename: Hasmik
authors.initials: H
authors.lastname: Keshishian
authors.forename: D R
authors.initials: DR
authors.lastname: Mani
authors.forename: Michael
authors.initials: M
authors.lastname: Burgess
authors.forename: Michael A
authors.initials: MA
authors.lastname: Gillette
authors.forename: Karl R
authors.initials: KR
authors.lastname: Clauser
authors.forename: Dongxiao
authors.initials: D
authors.lastname: Shen
authors.forename: Gregory D
authors.initials: GD
authors.lastname: Lewis
authors.forename: Laurie A
authors.initials: LA
authors.lastname: Farrell
authors.forename: Michael A
authors.initials: MA
authors.lastname: Fifer
authors.forename: Marc S
authors.initials: MS
authors.lastname: Sabatine
authors.forename: Robert E
authors.initials: RE
authors.lastname: Gerszten
authors.forename: Steven A
authors.initials: SA
authors.lastname: Carr
mesh_terms: D015415:Biomarkers / Q000097:blood*; D001774:Blood Chemical Analysis / Q000379:methods*; D006801:Humans; D013058:Mass Spectrometry / Q000379:methods*; D009203:Myocardial Infarction / Q000097:blood*; D010449:Peptide Mapping / Q000379:methods*; D020543:Proteome / Q000032:analysis*; D018511:Systems Integration
chemical_list: D015415:Biomarkers; D020543:Proteome