A Novel Approach to Assessing Cryptogenic Stroke

描述（由申请人提供）：虽然缺血性卒中的病因经常被确定，但约35%的病因不明的患者被标记为“隐源性卒中”。“由于目前还没有确定隐源性中风原因的方法，我们的实验室已经使用分子方法试图解决这个问题。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心房颤动（PAF）、非PAF心源性栓塞和大血管动脉粥样硬化导致的心源性栓塞所致中风患者全血中的特定基因表达谱。PAF通常会导致心脏中的血凝块栓塞到大脑中，从而导致中风。然而，在中风后进行EKG和/或霍尔特监测时，心律已恢复正常，没有PAF的证据，中风被指定为“隐源性”。“在以下目标中，我们测试我们已知的PAF心源性栓塞性中风原因的基因表达谱是否能检测到PAF心源性栓塞引起的隐源性中风。此外，我们将研究女性和男性在PAF引起的中风后的基因表达差异，因为女性患PAF相关中风的风险显著高于男性，其生物学原因尚不清楚。目标1。使用qRT-PCR测量我们先前对PAF引起的中风的微阵列研究中鉴定的基因的RNA水平，预测哪些隐源性中风是由PAF引起的。目标2。证明目标#1中预测由PAF引起的隐源性皮质卒中实际上：（a）卒中后长期门诊心脏监测中的PAF;（B）或卒中后重复霍尔特监测中的PAF（c）或卒中后重复EKG中的PAF。目标3。使用目标#2中证实患有PAF的受试者，确定PAF引起的隐源性卒中后女性与男性的基因表达差异。 意义前两个目标将预测PAF原因的隐源性中风，并确认这些心脏监测。第三个目标是解决女性和男性PAF患者之间不同的分子途径，以开始确定与女性PAF相关卒中风险增加相关的生物学因素。在美国，每年有超过260，000例隐源性中风，相比之下，每年有270，000例新发乳腺癌病例和50，000例新发帕金森病病例。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，其中一半是由于PAF。如果我们能够识别所有PAF心源性栓塞隐源性卒中，那么这些患者将接受香豆素、达比加群或其他口服抗凝剂治疗，而不是抗血小板药物或不治疗。这将防止每年数千次中风，相当于每年使用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.