Alterations in Unbound Free Fatty Acid Profiles in CVD

CVD 中未结合游离脂肪酸谱的变化

• 批准号: 10761556
• 负责人: Alan Kleinfeld
• 金额: $ 29.3万
• 依托单位: MEMBRANE SCIENCES, LLC
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10761556
• 关键词: Adult; Affinity; Albumins; Angiotensin-Converting Enzyme Inhibitors; Binding; Biological; Biological Markers; Blood; Blood specimen; Cardiac; Cardiovascular Diseases; Cardiovascular system; Cells; Cessation of life; Clinical Data; Data; Detection; Disease; Dissociation; Equilibrium; Event; Female; Fluorescent Probes; Future; Goals; Human; Ischemia; Lipids; Liquid substance; Maps; Measurable; Measurement; Measures; Methods; Mole the mammal; Myocardial Ischemia; National Heart, Lung, and Blood Institute; Nonesterified Fatty Acids; Patients; Percutaneous Transluminal Coronary Angioplasty; Phase; Physiological; Plasma; Predictive Factor; Publishing; ROC Curve; Recording of previous events; Reference Standards; Reporting; Risk; Risk Assessment; Risk Factors; Role; Sampling; Small Business Innovation Research Grant; Sudden Death; Sum; adverse outcome; aqueous; comparison control; fatty acid metabolism; improved; improved outcome; indexing; individual patient; inhibitor; male; meter; mortality; new therapeutic target; novel; palmitoleate; pi bond; profiles in patients; prognostic; prognostic value; protein biomarkers; risk prediction; risk stratification; screening; therapeutic target; Adult; Affinity; Albumins; Angiotensin-Converting Enzyme Inhibitors; Binding; Biological; Biological Markers; Blood; Blood specimen; Cardiac; Cardiovascular Diseases; Cardiovascular system; Cells; Cessation of life; Clinical Data; Data; Detection; Disease; Dissociation; Equilibrium; Event; Female; Fluorescent Probes; Future; Goals; Human; Ischemia; Lipids; Liquid substance; Maps; Measurable; Measurement; Measures; Methods; Mole the mammal; Myocardial Ischemia; National Heart, Lung, and Blood Institute; Nonesterified Fatty Acids; Patients; Percutaneous Transluminal Coronary Angioplasty; Phase; Physiological; Plasma; Predictive Factor; Publishing; ROC Curve; Recording of previous events; Reference Standards; Reporting; Risk; Risk Assessment; Risk Factors; Role; Sampling; Small Business Innovation Research Grant; Sudden Death; Sum; adverse outcome; aqueous; comparison control; fatty acid metabolism; improved; improved outcome; indexing; individual patient; inhibitor; male; meter; mortality; new therapeutic target; novel; palmitoleate; pi bond; profiles in patients; prognostic; prognostic value; protein biomarkers; risk prediction; risk stratification; screening; therapeutic target

Project Summary- Patients with stable cardiovascular disease (CVD) have an elevated risk of a second event. The easiest method for screening risk in stable CVD patients would use biomarkers. However, no single marker has sufficient prognostic power. In this project we will determine whether profiles of unbound free fatty acids (FFAu) can help predict the risk of adverse outcomes in patients with stable cardiovascular disease (CVD). Plasma free fatty acids (FFA) which are mostly bound to albumin have long been associated with cardiac ischemia. Although present at only nM concentrations, the FFAu are the physiologically relevant fraction because the unbound and not the bound are transported into cells. We developed fluorescent probes (ADIFAB) to measure FFAu and found that FFAu levels were associated with cardiovascular ischemia during PTCA and in patients with STEMI in TIMI II. Human plasma is composed of about 30 unique FFA. Because they have distinct biological effects, we have developed a method to determine the different FFAu (profiles). The NHLBI provided us with plasma from 1200 patients (w/ clinical data) from the PEACE trial which sought to determine whether ACE inhibitors would improve outcomes in patients who had a cardiovascular event. We used our FFAu profiling method to profile 200 of the PEACE patients. For most of the FFAu there were no significant case (event) vs. control (no event) differences. However, for unbound alpha linolenate (αLNAu) the average case mole fractions were more than twice controls (p<0.0002). ROC analysis of the αLNAu concentrations in the 200 FFAu profiles yielded a C- index of 0.702, which is superior to the current 5 best biomarkers combined. This result suggests that αLNAu might be a novel risk factor that reflects events orthogonal to the current best biomarkers of stable CVD. Unexpectedly, two of the weakest binding FFAus, palmitoleate (POAu) and linolenate (αLNAu) had “zero” unbound, although both were present bound to albumin. Importantly, we found that blocking dissociation of POAu and α-LNAu occurs in blood but does not occur in aqueous media composed of albumin and FFA. In our FFAu profiles of healthy blood samples and non-cardiac diseases we found no measurable POAu and α-LNAu. This implies that there are specific inhibitors of POA and α-LNA dissociation from albumin in most blood samples, revealing a hitherto unknown mechanism for regulating FFA metabolism and a potential therapeutic target. Thus, FFAu profiles reveal biological effects that are invisible to total FFA profiles. In this project we will complete the measurement and analysis of the remaining unanalyzed PEACE samples and begin the search for the inhibitor of release.

稳定心血管疾病（CVD）的项目摘要患者的风险较高 第二个事件。稳定CVD患者筛查风险的最简单方法是使用 生物标志物。但是，没有单个标记具有足够的预后能力。在这个项目中，我们将 确定未结合的游离脂肪酸（FFAU）的概况是否可以帮助预测 稳定心血管疾病（CVD）患者的不良预后。缺乏血浆脂肪酸 （FFA）大多与白蛋白绑定在一起，长期以来一直与心脏缺血有关。 尽管仅以NM浓度存在，但FFAU是物理相关的部分 因为未结合而非结合被转运到细胞中。我们开发了荧光 问题（ADIFAB）测量FFAU并发现FFAU水平与 PTCA期间的心血管缺血和TIMI II的STEMI患者。人血浆是 由大约30个独特的FFA组成。因为它们具有独特的生物学作用，所以我们有 开发了一种确定不同FFAU（配置文件）的方法。 NHLBI为我们提供了 来自和平试验的1200名患者的血浆（带临床数据），这是确定的 ACE抑制剂是否会改善患有心血管事件的患者的预后。 我们使用FFAU分析方法来介绍200个和平患者。对于大多数FFAU 没有明显的情况（事件）与控制（无事件）差异。但是，对于未结合 α亚麻酸含量（αlnau）平均情况摩尔分数超过两次对照 （p <0.0002）。 ROC对200 FFAU谱的αLNAU浓度的分析产生了C- 指数为0.702，优于当前5个最佳生物标志物的合并。这个结果 表明αlnau可能是反映事件正交的新风险因素 稳定CVD的最佳生物标志物。出乎意料的是，两个最弱的绑定ffaus，棕榈酸 （POAU）和亚麻酸盐（αlnau）的“零”未结合，尽管两者都与 白蛋白。重要的是，我们发现阻塞POAU和α-LNAU的解离发生在血液中 但不发生在由白蛋白和FFA组成的水性介质中。在我们的ffau个人资料中 健康的血液样本和非心脏疾病我们没有发现可测量的POAU和α-LNAU。 这意味着有特定的POA抑制剂和α-LNA从白蛋白解离 大多数血液样本，揭示了调节FFA代谢的隐藏未知机制 以及潜在的治疗靶标。这是FFAU概况揭示了无形的生物学作用 总体FFA配置文件。在这个项目中，我们将完成对 仍然是未分析的和平样本，并开始寻找释放的抑制剂。