Sphingolipids as Markers of Cardiac Ischemia

描述(由申请人提供)：最近人们认识到炎症反应会加重冠状动脉疾病(CAD)。已有研究表明，鞘脂信号分子是炎症的介质，特别是在对炎症前细胞因子如TNFpha和IL2的反应中。除了这些分子的释放可能是炎症反应的一部分，也可能是由于缺血本身的结果，因为最近的研究表明，缺血的心脏细胞增加了鞘脂的产生。因此，我们推断，炎症或缺血过程产生的鞘磷脂可能表明心肌缺血。因此，我们设计了一项试验，目的是证明接受负荷测试的患者的血清鞘氨醇浓度上升，这些患者的核成像结果表明运动诱导的缺血。在跑台试验之前和之后多次采集连续血样，以测定血清神经鞘脂脂。我们将比较血清鞘脂水平与炎症生物标志物、C反应蛋白和肿瘤坏死因子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。这一第一阶段SBIR的另一个目标是开发适用于疑似心肌缺血患者的血清检测的单抗。预期的成功将使我们为第二阶段的应用做好准备，在这一阶段中，我们将开发既适用于临床实验室仪器又适用于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。鞘磷脂也可能参与了急性冠脉综合征的病理生理过程，并可能是血清肿瘤坏死因子α水平升高的急性冠脉综合征患者预后不良的原因。

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.