Atrial Fibrillation Precursors May Be Novel Stroke Risk Factors

标题：房颤前兆可能是新的卒中危险因素 项目总结/摘要 这是一份K23重新提交申请，申请人是神经科医生、年轻的研究者Hooman Kamel博士。 对心律失常引起的缺血性中风进行以病人为中心的临床研究。K23奖项将 为他提供在三个关键职业发展领域获得关键技能的方法：1）流行病学 和临床试验设计，2）心脏诊断技术，和3）生物标志物的开发和评估。通过 获得这些技能后，Kamel博士将实现成为一名独立的临床医生的长期职业目标。 调查员为了实现这一目标，Kamel博士招募了一位主要的导师Richard Devereux博士， 具有心血管流行病学和心脏诊断技术专业知识的心脏病专家，以及两名合作者 导师，米切尔埃尔金德博士，神经学家与中风流行病学和临床试验设计的专业知识， 博士Costantino Iadecola是一位在缺血性脑损伤和生物标志物方面具有专长的神经学家。 根据最近的证据和他自己的初步数据，卡梅尔博士的中心假设是， 室上性心律失常甚至在心房颤动/扑动（AF）发展之前就增加了中风风险， 这是目前唯一被认为会导致中风的心律失常。检验这一假设将解决一个 关于室上性心律失常导致中风的知识存在根本性的空白。直到这些知识 如果没有填补这一空白，就不能完全确定预防心脏病引起中风的最佳策略。通过 为了实现以下具体目标，申请人将测试其假设并收集人口数据- 基于室上性心律失常卒中风险的研究（将在R 01申请中提出， K23奖期）。具体目标1将检验心电图P波离散度， 心房电功能障碍的早期标志物和室上性心律失常的易感性， 中风的风险也会增加这一目标将通过分析入组研究的无AF队列来实现。 强心研究，一项基于人群的流行病学研究，包括基线心电图数据和 >375例经裁定和分类的中风病例。具体目标2将检验室上性心动过速 异位与隐源性中风有关。在一项前瞻性入组的患者系列中， 将比较75例隐源性室上性早搏患者在心脏监测期间的室上性异位， 中风和75例中风患者的小血管闭塞或大动脉粥样硬化。二次 分析将比较两组之间心脏栓塞的生物标志物， 室上性异位与这些生物标志物。具体目标3将检验以下假设： 阵发性室上性心动过速与短暂性脑缺血发作后卒中的风险相关。 将使用经验证的ICD-9-CM编码来实现这一目标，用于阵发性室上性心动过速， 链接来自加州州住院病人数据库和急诊部数据库的医疗记录。 这项拟议中的研究意义重大，因为积极的结果将揭示新的中风风险因素， 虽然阴性结果将抵消未经证实的抗凝治疗的标签外使用的增加， 隐源性卒中后的非特异性室上性心律失常该研究具有创新性 因为它试图通过识别一个新的大类来改变当前的研究和临床实践范式， 中风高危患者，可能受益于现有的抗凝药物，并寻求 通过心脏病学工具在中风研究中的新应用，架起心脏病学和神经病学的桥梁。

TITLE: Atrial Fibrillation Precursors May Be Novel Stroke Risk Factors PROJECT SUMMARY/ABSTRACT This is a K23 resubmission application for Dr. Hooman Kamel, a neurologist and young investigator pursuing patient-oriented clinical research on ischemic stroke caused by cardiac arrhythmias. A K23 award will provide him with the means to acquire critical skills in three key career development areas: 1) epidemiology and clinical trial design, 2) cardiac diagnostic techniques, and 3) biomarker development and assessment. By acquiring these skills, Dr. Kamel will fulfill his long-term career goal of becoming an independent clinical investigator. To pursue this goal, Dr. Kamel has recruited a primary mentor, Dr. Richard Devereux, a cardiologist with expertise in cardiovascular epidemiology and cardiac diagnostic techniques, and two co- mentors, Dr. Mitchell Elkind, a neurologist with expertise in stroke epidemiology and clinical trial design, and Dr. Costantino Iadecola, a neurologist with expertise in ischemic brain injury and biomarkers. Based on recent evidence and his own preliminary data, Dr. Kamel's central hypothesis is that supraventricular arrhythmias increase stroke risk even before the development of atrial fibrillation/flutter (AF), which is currently the only cardiac arrhythmia thought to cause stroke. Testing this hypothesis will address a fundamental gap in knowledge about which supraventricular arrhythmias cause stroke. Until this knowledge gap is filled, optimal strategies for preventing stroke from cardiac disease cannot be fully determined. By pursuing the following specific aims, the applicant will test his hypothesis and gather data for a population- based study of stroke risk from supraventricular arrhythmias (to be proposed in an R01 application during the K23 award period). Specific Aim 1 will test the hypothesis that electrocardiographic P-wave dispersion, an early marker of atrial electrical dysfunction and predisposition to supraventricular arrhythmias, is associated with an increased risk of stroke. This aim will be pursued by analyzing a cohort without AF enrolled in the Strong Heart Study, a population-based epidemiological study with baseline electrocardiographic data and >375 adjudicated and classified cases of stroke. Specific Aim 2 will test the hypothesis that supraventricular ectopy is associated with cryptogenic stroke. In a prospectively enrolled series of patients, rates of supraventricular ectopy during cardiac monitoring will be compared between 75 patients with cryptogenic stroke and 75 patients with stroke from small-vessel occlusion or large-artery atherosclerosis. Secondary analyses will compare biomarkers of cardiac embolism between the two groups, and correlate rates of supraventricular ectopy with these biomarkers. Specific Aim 3 will test the hypothesis that clinical diagnoses of paroxysmal supraventricular tachycardia are associated with the risk of stroke after transient ischemic attack. This aim will be pursued using a validated ICD-9-CM code for paroxysmal supraventricular tachycardia and linked medical records from the California State Inpatient Database and Emergency Department Database. The proposed research is significant because positive results will uncover novel stroke risk factors, while negative results will counter the increasing off-label use of unproven anticoagulant therapy for nonspecific supraventricular arrhythmias after cryptogenic stroke. The proposed research is innovative because it seeks to shift current research and clinical practice paradigms by identifying a large new class of patients who are at high risk for stroke and may benefit from existing anticoagulant drugs, and also seeks to bridge cardiology and neurology via the new application of cardiology tools to stroke research.