A Novel Approach to Assessing Cryptogenic Stroke

评估隐源性中风的新方法

• 批准号: 8411031
• 负责人: FRANK R SHARP
• 金额: $ 56.11万
• 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/8411031
• 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. PUBLIC HEALTH RELEVANCE: This study will use gene expression profiles from blood of patients known to have ischemic cortical strokes due to paroxysmal atrial fibrillation (PAF) to predict which cryptogenic stroke patients have a PAF cause of their strokes. This novel approach has the capability of identifying PAF causes of cryptogenic strokes within days of the events and with early anticoagulation will prevent thousands of ischemic strokes per year. The study will also examine the immune and inflammatory factors that are different in PAF related stroke in women compared to men to search for factors associated with the increased risk of PAF related stroke in women.

描述（由申请人提供）：虽然缺血性中风的病因经常被确定，但约35%的病因不明的患者被标记为“隐源性中风”。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，并显示了已知由阵发性心房颤动（PAF）、非PAF心脏栓塞和大血管动脉粥样硬化引起的心脏栓塞导致中风的患者的全血中特定的基因表达谱。PAF通常会在心脏形成血块，并栓塞到大脑，从而导致中风。然而，在中风后进行心电图和/或动态心电图监测时，心律已恢复正常，无PAF迹象，中风被指定为“隐源性”。在以下目的中，我们测试已知PAF引起的心脏栓塞性中风的基因表达谱是否可以检测由PAF心脏栓塞引起的隐源性中风。此外，我们将检查PAF引起的中风后女性和男性的基因表达差异，因为女性发生PAF相关中风的风险明显高于男性，其生物学原因尚不清楚。目标# 1。预测哪些隐源性中风是由PAF引起的，使用qRT-PCR测量我们之前在PAF引起的中风的微阵列研究中鉴定的基因RNA水平。目标# 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)卒中后长期门诊心脏监测的PAF；(b)或中风后反复动态心电图监测PAF (c)或中风后反复心电图PAF。目标# 3。使用在Aim#2中证实患有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。的意义。前两个目标是预测PAF引起隐源性中风的原因，并通过心脏监测加以证实。第三个目标是研究女性和男性PAF患者之间不同的分子通路，从而开始确定与女性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26万例隐蔽性中风，相比之下，每年有27万例新的乳腺癌病例和5万例新的帕金森病例。我们的数据表明，50%的隐源性皮质中风可能是由于未被识别的心脏栓塞，其中一半是由于PAF。如果我们能够识别出所有的PAF心栓性隐源性中风，那么这些患者就可以用香豆素、达比加群或其他口服抗凝剂来代替抗血小板药物，或者什么都不用。这将每年预防数千例中风，相当于每年用tPA治疗中风的数量。