Novel MPO-derived plasma lipids as predictors of major adverse coronary events

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DESCRIPTION (provided by applicant): Coronary artery disease is responsible for the sudden death of over 500,000 U.S. citizens per year. The development of biomarkers that predict increased risk of major adverse coronary events is a major public health need in the United States. Elevated plasma myeloperoxidase (MPO) levels have been shown to be a predictor of increased risk of coronary events in patients with acute coronary syndromes. MPO release from neutrophils precedes myocardial injury, and it has been suggested that MPO activity may mediate, in part, adverse coronary events. Accordingly, in comparison to plasma MPO levels, plasma levels of MPO-generated oxidation products may be better predictors of adverse coronary events. We have discovered 1-chloro-fatty aldehyde (1- ClFALD) as a novel MPO-generated lipid oxidation product. In the past year, we have revealed that 1-chloro- fatty acid (1-ClFA) and 1-chloro-fatty alcohol (1-ClFOH) are stable metabolites of 1-ClFALD that are released from neutrophils and are also present in human plasma. Accordingly, the specific aim of this proposal is to test the hypothesis that plasma levels of 1-ClFA and 1-ClFOH predict increased risk of major adverse coronary events in patients with coronary artery disease. An extensive clinical database and repository of human plasma specimens from a study called Genebank at the Cleveland Clinic Foundation will be available for these studies. Extensive clinical phenotypic data from subjects undergoing diagnostic cardiac catheterization are available for all subjects enrolled in this study. Complete medical history, laboratory, angiographic and outcomes data are available, and subjects have provided consent for use of these specimens and anonymonized clinical data to support biochemical research efforts related to cardiovascular disease. A case-cohort design will allow us to evaluate multiple outcomes using the same control population. The case definition will include subjects that suffered non-fatal myocardial infarction, stroke or death. Controls will be drawn from a random sample of age and gender-matched eligible subjects from the Genebank registry demonstrating no inter- vening history of cardiovascular disease. At Saint Louis University, plasma 1-ClFA will be quantified by LC-MS on a triple quadrupole instrument using electrospray ionization. Plasma 1-ClFOH will be quantified using GC- MS with negative ion-chemical ionization following derivatization to its pentafluorobenzoyl ester. Each analyte will be quantified by comparisons to synthetically-prepared deuterated internal standards. Comparisons will be made between levels of these new biomarkers to that of other biomarkers including C-reactive protein, MPO, chlorotyrosine, nitrotyrosine and troponin T that have previously been quantified in these specimens. The availability of these collected human samples in Genebank provides an extraordinary opportunity to identify these novel MPO-catalyzed oxidation products in the plasma of a focused and well-defined group of heart patients as novel biomarkers. Furthermore, this study will allow a direct measure of systemic MPO-catalyzed lipid oxidation for the first time and evaluation of its potential clinical relevance to cardiovascular disease. PUBLIC HEALTH RELEVANCE: About 13 million U.S. citizens have coronary artery disease, and it is the leading cause of death among both men and women. In the proposed studies, we will test the hypothesis that plasma levels of novel MPO-generated lipid oxidation products predict major adverse coronary events. Identifying these novel lipid oxidation products as predictors of future major adverse coronary events has the potential to significantly impact care and outcomes of patients with coronary artery disease.