A Novel Approach to Assessing Cryptogenic Stroke

描述(申请人提供)：尽管缺血性中风的病因经常被确定，但约35%的无已知病因的患者被标记为“隐源性中风”。由于目前还没有确定隐源性中风原因的方法，我们实验室使用了分子方法来尝试解决这个问题。我们使用全基因组微阵列检测了全血中的基因表达，并显示了已知因阵发性房颤(PAF)、非阵发性房颤(PAF)心脏栓塞症和大血管动脉粥样硬化而导致中风的患者的全血中特异的基因表达谱。PAF通常会导致心脏中的血块，进而栓塞到大脑，从而导致中风。然而，在卒中后进行EKG和/或Holter监测时，心律已恢复正常，没有PAF的证据，卒中被指定为“隐源性”。在以下目标中，我们测试我们的已知PAF心源性卒中原因的基因表达谱是否将检测由PAF心源性栓塞症引起的隐源性卒中。此外，我们将研究PAF引起的中风后女性和男性的基因表达差异，因为女性患PAF相关中风的风险明显高于男性，而造成这种差异的生物学原因尚不清楚。目的#1.通过qRT-PCR测量我们先前对PAF引起的中风的微阵列研究中确定的基因的RNA水平，预测哪些隐源性中风是由PAF引起的。目的#2.证明AIM#1中预测由PAF引起的隐源性皮质卒中实际上有：(A)卒中后门诊长时间心脏监测的PAF；(B)卒中后重复Holter监测的PAF；(C)卒中后重复EKG的PAF。目的#3.利用在AIM#2中被证实患有PAF的受试者，确定由PAF引起的隐源性卒中后女性与男性的基因表达差异。前两个目标将预测隐源性中风的PAF原因，并通过心脏监测确认这些原因。第三个目标将解决PAF女性和男性之间不同的分子途径，以开始确定与女性PAF相关中风风险增加相关的生物因素。美国每年有超过26万例隐源性中风，相比之下，每年有27万例乳腺癌新发病例和5万例帕金森氏症新发病例。我们的数据表明，50%的隐源性皮质卒中可能是由于未被识别的心源性栓塞症，其中一半可能是由于PAF。如果我们能确定所有的PAF心脏栓塞性隐源性卒中，那么这些患者将接受Coumadin、Dabigatran或其他口服抗凝剂治疗，而不是抗血小板药物或什么都不用。这将每年预防数千次中风，相当于每年接受tPA治疗的中风数量。

DESCRIPTION (provided by applicant): Though the causes of ischemic stroke are often identified, the ~35% of patients without a known cause are labeled as "cryptogenic strokes." Since there are no current methods for identifying causes of cryptogenic strokes, our laboratory has used a molecular approach in an attempt to solve this problem. We have examined gene expression in whole blood using whole genome microarrays and shown specific gene expression profiles in whole blood of patients who have known causes of stroke due to cardioembolism due to paroxysmal atrial fibrillation (PAF), non-PAF cardioembolism and large vessel atherosclerosis. PAF often causes a blood clot in the heart that embolizes to brain to produce a stroke. However, by the time an EKG and/or Holter monitor are performed after the stroke, the heart rhythm has returned to normal with no evidence of PAF and the stroke is designated as "cryptogenic." In the following aims we test whether our gene expression profiles for known PAF causes of cardioembolic stroke will detect cryptogenic strokes caused by PAF cardioembolism. In addition, we will examine gene expression differences in women and men following strokes caused by PAF because women are at a significantly higher risk for PAF related stroke than men, and the biological reasons for this are not understood. Aim #1. Predict which cryptogenic strokes are caused by PAF using qRT-PCR measurement of RNA levels of genes identified in our previous microarray studies of strokes caused by PAF. Aim #2. Demonstrate the cryptogenic cortical strokes predicted to be caused by PAF in Aim #1 have in fact: (a) PAF on prolonged outpatient cardiac monitoring after the stroke; (b) or have PAF on repeated Holter monitoring after the stroke(c) or PAF on repeat EKGs after the stroke. Aim #3. Determine the gene expression differences in women compared to men following cryptogenic strokes caused by PAF using the subjects proven to have PAF in Aim#2. significance. The first two aims will predict PAF causes of cryptogenic strokes and confirm these by cardiac monitoring. The third aim will address molecular pathways that are different between women and men with PAF to begin identifying the biological factors associated with the increased risk of PAF related stroke in women. There are over 260,000 cryptogenic strokes/ year in the US which compares to 270,000 new breast cancer cases/ year and 50,000 new Parkinson's cases/year. Our data suggest that >50% of cryptogenic cortical strokes may be due to unrecognized cardioembolism and half of these would be due to PAF. If we could identify all of the PAF cardioembolic cryptogenic strokes, then these patients would be treated with coumadin, Dabigatran or other oral anti-coagulant instead of anti-platelet agents or nothing. This would prevent thousands of strokes per year and is equivalent to the number of strokes treated with tPA per year.