Sphingolipids as Markers of Cardiac Ischemia

鞘脂作为心脏缺血的标志物

• 批准号: 6736436
• 负责人: Roger A Sabbadini
• 金额: $ 15.16万
• 依托单位: LPATH THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-03-01 至 2006-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6736436
• 关键词: acute disease /disorder; angina pectoris; angiography; biomarker; blood lipid; blood tests; cardiovascular stress test; clinical research; clinical trials; cytoskeletal proteins; diagnosis design /evaluation; electrocardiography; enzyme linked immunosorbent assay; heart disorder diagnosis; heart imaging /visualization /scanning; high performance liquid chromatography; human subject; inflammation; laboratory mouse; mass spectrometry; monoclonal antibody; myocardial ischemia /hypoxia; pathologic process; sphingolipids; sphingosine; tumor necrosis factor alpha

DESCRIPTION (provided by applicant): It has recently been appreciated that coronary artery disease (CAD) is aggravated by the inflammatory response. It has been suggested that sphingolipid signaling molecules are mediators of inflammation, particularly in response to pre-inflammatory cytokines such as TNFalpha and IL2. In addition to the putative release of these molecules as part of the inflammatory response, it is possible that sphingolipids are produced as a consequence of ischemia itself, since recent studies demonstrate increased sphingolipid production by ischemic heart cells. Thus, we reasoned that sphingolipids produced either by the inflammatory or ischemic processes could indicate myocardial ischemia. Accordingly, we have designed a trial with the aim of showing that the concentrations of serum sphingolipids such as sphingosine-1-phosphate (S1P) rise in patients undergoing a stress test whose nuclear imaging results indicate exercise-induced ischemia. Serial blood samples will be obtained before and several times after treadmill testing for the determination of serum sphingolipids. We will compare serum sphingolipid levels with inflammatory biomarkers, CRP and TNFalpha, and standard assessments of ischemia, including positive electrocardiographic and nuclear imaging. Ischemia-negative patients are those with a negative ETT and negative nuclear scans. We will evaluate the specificity and sensitivity of our putative ischemic markers with active ischemia. An additional aim of this Phase I SBIR is to develop monoclonal antibodies suitable for serum testing of patients suspected of cardiac ischemia. The anticipated success will prepare us for a Phase II application in which we will develop the commercial test platform suitable for both clinical laboratory instruments and rapid point-of-care testing. We also intend to conduct follow-on clinical trials of emergency room patients suspected of AMI to determine if serum sphingolipids may be useful in triaging chest pain patients. It is also possible that sphingolipids contribute to the pathophysiology of acute coronary syndrome and that they are responsible for the poor outcomes observed in acute coronary syndrome patients who have elevated serum levels of TNFalpha.

描述（由申请人提供）：最近人们认识到炎症反应会加剧冠状动脉疾病（CAD）。有人认为，鞘脂信号分子是炎症介质，特别是对炎症前细胞因子（如 TNFα 和 IL2）的反应。除了假定的炎症反应一部分释放这些分子外，缺血本身也可能产生鞘脂，因为最近的研究表明缺血性心脏细胞鞘脂的产生增加。因此，我们推断炎症或缺血过程产生的鞘脂可能表明心肌缺血。因此，我们设计了一项试验，目的是证明在接受应激测试的患者中，其核成像结果表明运动引起的缺血，血清鞘脂如 1-磷酸鞘氨醇 (S1P) 的浓度会升高。在跑步机测试之前和之后多次采集连续血样以测定血清鞘脂。我们将比较血清鞘脂水平与炎症生物标志物、CRP 和 TNFα，以及缺血的标准评估，包括阳性心电图和核成像。缺血阴性患者是指 ETT 和核扫描均为阴性的患者。我们将评估我们假定的缺血标志物与活动性缺血的特异性和敏感性。 I 期 SBIR 的另一个目的是开发适合疑似心脏缺血患者血清检测的单克隆抗体。预期的成功将为我们的二期应用做好准备，我们将开发适用于临床实验室仪器和快速现场护理测试的商业测试平台。我们还打算对疑似 AMI 的急诊室患者进行后续临床试验，以确定血清鞘脂是否有助于对胸痛患者进行分类。鞘脂也可能促进急性冠脉综合征的病理生理学，并且是导致血清 TNFα 水平升高的急性冠脉综合征患者预后不良的原因。