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）：最近认识到冠状动脉疾病（CAD）会因炎症反应而加重。已经表明鞘脂信号传导分子是炎症介质，特别是响应于炎前细胞因子如TNF α和IL 2。除了作为炎症反应的一部分的这些分子的推定释放之外，鞘脂的产生也可能是缺血本身的结果，因为最近的研究表明缺血性心脏细胞增加了鞘脂的产生。因此，我们推断由炎症或缺血过程产生的鞘脂可能指示心肌缺血。因此，我们设计了一项试验，目的是显示血清鞘脂，如鞘氨醇-1-磷酸（S1 P）的浓度上升，在接受负荷试验的患者，其核成像结果表明运动诱导的缺血。将在跑步机试验之前和之后多次采集系列血样，用于测定血清鞘脂。我们将比较血清鞘脂水平与炎症生物标志物，CRP和TNF α，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ETT阴性和核扫描阴性的患者。我们将评估我们假定的缺血标志物对活动性缺血的特异性和敏感性。该I期SBIR的另一个目的是开发适用于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第二阶段应用做好准备，在第二阶段应用中，我们将开发适用于临床实验室仪器和快速即时检测的商业测试平台。我们还打算对急诊室疑似AMI患者进行后续临床试验，以确定血清鞘脂是否可用于胸痛患者的分诊。鞘脂也可能促进急性冠状动脉综合征的病理生理学，并且它们是在血清TNF α水平升高的急性冠状动脉综合征患者中观察到的不良结局的原因。