Sphingolipids as Markers of Cardiac Ischemia

描述（由申请人提供）：最近人们认识到冠状动脉疾病（CAD）因炎症反应而加重。有人认为鞘脂信号分子是炎症的介质，特别是在对炎性前细胞因子如TNFalpha和il - 2的反应中。除了这些分子的释放可能是炎症反应的一部分，鞘脂也可能是缺血本身产生的结果，因为最近的研究表明缺血心脏细胞产生的鞘脂增加。因此，我们推断炎症或缺血过程产生的鞘脂可以指示心肌缺血。因此，我们设计了一项试验，目的是显示在接受核成像结果显示运动引起缺血的应激测试的患者中，血清鞘脂浓度（如鞘鞘醇-1-磷酸（S1P））升高。在跑步机测试之前和之后，将获得连续的血液样本，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TNFalpha，以及缺血的标准评估，包括心电图和核成像阳性。缺血阴性患者是指ETT阴性和核扫描阴性的患者。我们将评估我们假定的缺血性标志物的特异性和敏感性。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II期应用做好准备，在II期应用中，我们将开发适合临床实验室仪器和快速护理点测试的商业测试平台。我们还打算对疑似急性心肌梗死的急诊室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。也有可能鞘脂有助于急性冠状动脉综合征的病理生理，并且它们是急性冠状动脉综合征患者血清TNFalpha水平升高的不良预后的原因。

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.