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）：最近人们对冠状动脉疾病（CAD）的炎症反应加剧。已经提出，鞘脂信号分子是炎症的介体，特别是在炎性前细胞因子（如TNFALPHA和IL2）的响应中。除了推定这些分子作为炎症反应的一部分外，由于缺血本身，还可能产生鞘脂，因为最近的研究表明，缺血性心脏细胞的鞘脂产生增加。因此，我们认为由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，目的是表明接受压力测试的患者的血清鞘脂浓度，例如鞘氨醇1-磷酸盐（S1P），其核成像结果表明运动诱导的缺血性。在跑步机测试测定血清鞘脂之前，将获得连续血样。我们将比较血清鞘脂水平与炎症生物标志物，CRP和TNFalpha以及缺血的标准评估，包括阳性心电图和核成像。缺血性阴性患者是患有负ETT和阴性核扫描的患者。我们将评估具有活性缺血的假定缺血标志物的特异性和敏感性。 I阶段I SBIR的另一个目的是开发适合涉嫌心脏缺血的患者的血清测试的单克隆抗体。预期的成功将使我们为II期应用程序做好准备，在该应用程序中，我们将开发适合临床实验室工具和快速护理测试的商业测试平台。我们还打算对怀疑AMI的急诊室患者进行后续临床试验，以确定血清鞘脂是否可能有助于分类胸痛患者。鞘脂还可能有助于急性冠状动脉综合征的病理生理学，并导致急性冠状动脉综合征患者在血清TNFALPHA水平升高的情况下观察到的不良预后。