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

描述（由申请人提供）：冠状动脉疾病每年导致超过50万美国公民猝死。在美国，开发预测主要不良冠状动脉事件风险增加的生物标志物是一项主要的公共卫生需求。血浆髓过氧化物酶（MPO）水平升高已被证明是急性冠状动脉综合征患者冠状动脉事件风险增加的预测因子。中性粒细胞释放MPO先于心肌损伤，并且MPO活性可能在一定程度上介导不良冠状动脉事件。因此，与血浆MPO水平相比，血浆MPO生成的氧化产物水平可能是不良冠状动脉事件的更好预测指标。我们发现了一种新的mpo生成的脂质氧化产物- 1-氯脂肪醛（1- ClFALD）。在过去的一年里，我们发现1-氯-脂肪酸（1-ClFA）和1-氯-脂肪醇（1-ClFOH）是1-氯-脂肪酸的稳定代谢物，从中性粒细胞释放，也存在于人血浆中。因此，本提案的具体目的是验证血浆1-ClFA和1-ClFOH水平预测冠心病患者主要不良冠状动脉事件风险增加的假设。克利夫兰诊所基金会的基因库将为这些研究提供广泛的临床数据库和人类血浆标本储存库。接受诊断性心导管插入术的受试者的广泛临床表型数据可用于本研究的所有受试者。可获得完整的病史、实验室、血管造影和结局数据，受试者已同意使用这些标本和匿名临床数据，以支持与心血管疾病相关的生化研究工作。病例队列设计将允许我们使用相同的对照人群评估多个结果。病例定义将包括遭受非致命性心肌梗死、中风或死亡的受试者。对照将从基因库登记的年龄和性别匹配的符合条件的受试者中随机抽取样本，证明没有心血管疾病的干预史。在圣路易斯大学，等离子体1-ClFA将通过LC-MS在三重四极杆仪器上使用电喷雾电离进行定量。血浆中1-ClFOH将在衍生成五氟苯甲酰酯后使用负离子化学电离的GC- MS进行定量。每个分析物将通过与合成制备的氘化内标进行比较来定量。将这些新的生物标记物的水平与其他生物标记物的水平进行比较，包括c反应蛋白、MPO、氯酪氨酸、硝基酪氨酸和肌钙蛋白T，这些生物标记物之前已经在这些标本中进行了量化。基因库中收集的这些人类样本的可用性提供了一个非凡的机会，可以在一组重点关注且定义明确的心脏病患者血浆中识别这些新型mpo催化氧化产物作为新型生物标志物。此外，这项研究将首次允许直接测量全身mpo催化的脂质氧化，并评估其与心血管疾病的潜在临床相关性。公共卫生相关性：大约1300万美国公民患有冠状动脉疾病，这是男性和女性死亡的主要原因。在拟议的研究中，我们将验证血浆中新型mpo生成的脂质氧化产物水平预测主要不良冠状动脉事件的假设。确定这些新的脂质氧化产物作为未来主要不良冠状动脉事件的预测因子，有可能显著影响冠状动脉疾病患者的护理和预后。

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.