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

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.

项目总结-稳定性心血管疾病（CVD）患者的风险升高， 第二个事件。在稳定的CVD患者中筛查风险的最简单方法是使用 生物标志物。然而，没有一个单一的标志物具有足够的预测能力。在这个项目中，我们将 确定未结合游离脂肪酸（FFAu）谱是否有助于预测以下风险： 稳定型心血管疾病（CVD）患者的不良结局。血浆游离脂肪酸 (FFA)其主要与白蛋白结合，长期以来与心脏缺血有关。 虽然仅以nM浓度存在，但FFAu是生理学相关级分 因为未结合的和未结合的被运输到细胞中。我们开发了荧光 探针（ADIFAB）测量FFAu，发现FFAu水平与 PTCA期间和TIMI II中STEMI患者的心血管缺血。人血浆 由大约30个独特的FFA组成。因为它们具有不同的生物学效应， 开发了一种方法来确定不同的FFAu（配置文件）。NHLBI为我们提供了 来自PEACE试验的1200例患者（有临床数据）的血浆，该试验试图确定 ACE抑制剂是否能改善心血管事件患者的预后。 我们使用我们的FFAu分析方法对200名PEACE患者进行分析。对于大多数FFAu 病例（事件）与对照（无事件）之间无显著差异。但是，对于Unbound α-亚麻酸（α-LNAu）的平均壳摩尔分数是对照的2倍以上 （p<0.0002）。200个FFAu曲线中αLNAu浓度的ROC分析得出C- 指数为0.702，其优于当前5种最佳生物标志物的组合，为上级。这一结果 表明αLNAu可能是一个新的风险因素，反映了与电流正交的事件 稳定CVD的最佳生物标志物。出乎意料的是，两种最弱的结合FFA，棕榈油酸酯， （POAu）和亚麻酸酯（αLNAu）的未结合率为“零”，尽管两者均与 白蛋白。重要的是，我们发现血液中POAu和α-LNAu的解离被阻断 但在由白蛋白和FFA组成的水性介质中不发生。在我们的FFAu档案中， 健康人和非心脏病患者的血液样本中未发现可测量的POAu和α-LNAu。 这意味着在白蛋白中存在POA和α-LNA解离的特异性抑制剂， 大多数血液样本，揭示了迄今为止未知的调节FFA代谢的机制 也是潜在的治疗靶点因此，FFAu图谱揭示了不可见的生物效应 总FFA的轮廓。在这个项目中，我们将完成测量和分析的 剩余的未分析的PEACE样品，并开始寻找释放抑制剂。