A Novel Approach to Assessing Cryptogenic Stroke

评估隐源性中风的新方法

• 批准号: 8533056
• 负责人: FRANK R SHARP
• 金额: $ 54.14万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8533056
• 关键词: Address; Adopted; Angiotensins; Anticoagulants; Anticoagulation; Aspirin; Atherosclerosis; Atrial Fibrillation; Biological; Biological Factors; Blood; Blood Clot; Blood Platelets; Blood coagulation; Brain; Cardiac; Cardiovascular system; Cause of Death; Cells; Coagulants; Coagulation Process; Data; Electrocardiogram; Evaluation; Event; Gender; Gene Expression; Genes; Genetic Transcription; Genome; Heart; Heart Atrium; Holter Electrocardiography; Immune; Incidence; Inflammation; Inflammatory; Ischemic Stroke; Label; Laboratories; Measurement; Methods; Molecular; Molecular Profiling; Monitor; New Agents; Oral; Outcome; Outpatients; Parkinson Disease; Pathogenesis; Pathway interactions; Patients; Peripheral; Play; Prevention; Problem Solving; RNA; Recurrence; Renin; Risk; Role; Signal Transduction; Stroke; Testing; Thrombin; Thrombopoietin; Thromboxane A2; Time; Vascular remodeling; Waran; Whole Blood; Woman; Women' s Health; base; disability; heart rhythm; high risk; malignant breast neoplasm; men; novel; novel strategies; prevent; transcription factor

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.

描述（由申请人提供）：尽管经常发现缺血性中风的原因，但约35％的没有已知原因的患者被标记为“隐性中风”。由于目前尚无识别隐性中风原因的方法，因此我们的实验室使用了分子方法来解决此问题。我们已经使用全基因组微阵列检查了全血中的基因表达，并显示了由于阵发性心房颤动（PAF），非PAF心脏栓塞和大动脉粥样硬化而导致的心脏栓塞引起的患者的全血的特定基因表达谱。 PAF通常会引起心脏中的血块，该血块栓塞到大脑产生中风。但是，到中风后执行了心电图和/或抛光剂监测器时，心律已经恢复正常，没有PAF的证据，并且中风被指定为“隐态性”。在下面的目标中，我们测试了我们的基因表达谱是否是针对心脏符号中风的已知PAF原因的基因表达谱是否会检测到由PAF心脏栓塞引起的隐源性中风。此外，我们将检查由PAF引起的中风的男女中的基因表达差异，因为女性患PAF相关的中风的风险明显高于男性，并且尚不清楚其生物学原因。目标＃1。预测使用PAF使用QRT-PCR测量的RNA水平在我们先前的微阵列研究中鉴定出的对PAF引起的中风的基因的RNA水平引起了哪些隐性中风。目标＃2。证明了AIM＃1中PAF预测的隐源性皮质中风实际上是：（a）中风后长时间门诊心脏监测； （b）或中风后重复监测的重复抛光监测或中风后的PAF。目标＃3。与男性相比，与男性相比，通过PAF引起的女性使用受试者在AIM＃2中具有PAF，确定女性的基因表达差异。 意义。前两个目的将预测PAF的造成隐性中风的原因，并通过心脏监测确认这些。第三个目标将解决患有PAF的男女之间不同的分子途径，以开始识别与女性中PAF相关的中风风险增加相关的生物学因素。在美国，/年有超过260,000个隐性中风，相比之下，每年270,000例新的乳腺癌病例和50,000例新帕金森氏病例。我们的数据表明，> 50％的隐态皮质中风可能是由于未识别的心脏栓塞引起的，其中一半是由于PAF所致。如果我们能够鉴定所有PAF心脏符号隐性中风，那么这些患者将接受香豆素，dabigatran或其他口服抗凝血剂而不是抗植物剂或任何一无所有的治疗。这将预防每年数千次中风，相当于每年用TPA处理的中风数量。