Statins augment small vessel function and improve stroke outcomes

项目总结/摘要 迫切需要安全有效的预防和治疗中风的新策略， 减轻中风后残疾的负担。他汀类药物广泛用于二级中风预防;然而， 迄今为止，对潜在的长期副作用的担忧阻止了他汀类药物在患者中的预防性使用 中风的高危人群在急性缺血性卒中（AIS）中， 与微血管功能障碍有关，在脑MRI上表现为白色高信号（WMH）。WMH 负荷与梗死生长、出血性转化和更差的AIS临床结局相关。在AIS中， 他汀类药物的血管保护作用可减轻微血管功能障碍的程度， 脑组织和临床结果，但这需要进一步调查。我们假设中风前 晚期WMH患者使用他汀类药物可改善脑灌注并降低血脑屏障 (BBB)在AIS期间中断。此外，晚期WMH患者可能会从以下方面获得额外的益处： 脑灌注和功能结果AIS与早期卒中后他汀类药物治疗。我们建议 研究他汀类药物使用对卒中后结局的影响，使用WMH严重程度作为临床模型， 微血管功能障碍使用协作的方法，我们建议：（1）确定是否中风前 他汀类药物的使用改变了微血管功能障碍和缺血组织的神经影像学和血浆生物标志物 晚期WMH和AIS受试者的结局;（2）评估他汀类药物暴露是否改善生存率， 患有晚期WMH的AIS受试者的功能结局。获得神经影像学和血浆生物标志物 AIS和晚期WMH受试者开始他汀类药物治疗前后的数据将提供概念验证数据 他汀类药物治疗对微血管功能障碍的影响，以及其在脑组织对 急性缺血这项研究将弥补他汀类药物治疗的效果和时机方面的知识空白。 中风的演变它提出了先发制人的治疗AIS策略，以改善卒中后结局。如果 成功，这项研究将提供数据，以支持预防性使用他汀类药物的患者谁是高风险的， 中风的基础上，他们的WMH负担，并最终，它可能会导致改变我们的实践标准， 一级预防卒中，明确启动他汀类药物治疗的最佳窗口，并减少 中风后残疾

PROJECT SUMMARY/ABSTRACT Novel strategies to prevent and treat stroke that are both safe and effective are desperately needed in order to alleviate the burden of post-stroke disability. Statins are widely used for secondary stroke prevention; however, concerns with regard to potential long-term side effects to date prevented prophylactic use of statins in patients at high-risk for stroke. In acute ischemic stroke (AIS), cerebral tissue damage and clinical outcomes have been linked to microvascular dysfunction, manifesting as white matter hyperintensity (WMH) on brain MRI. WMH burden is associated with infarct growth, hemorrhagic transformation, and worse clinical AIS outcomes. In AIS, vascular protective effects of statins may alleviate the degree of microvascular dysfunction and improve cerebral tissue and clinical outcomes, but this requires further investigation. We hypothesize that pre-stroke statin use in subjects with advanced WMH improves cerebral perfusion and decreases blood-brain barrier (BBB) disruption during AIS. In addition, patients with advanced WMH may derive additional benefits in cerebral perfusion and functional outcomes after AIS with early post-stroke statin initiation. We propose to investigate the effect of statin use on outcomes after stroke, utilizing WMH severity as a clinical model of microvascular dysfunction. Using a collaborative approach, we propose to: (1) determine whether pre-stroke statin use modifies the neuroimaging and plasma biomarkers of microvascular dysfunction and ischemic tissue fate in subjects with advanced WMH and AIS; and (2) assess whether statin exposure improves survival and functional outcomes in AIS subjects with advanced WMH. Neuroimaging and plasma biomarkers obtained before and after initiation of statin in subjects with AIS and advanced WMH will provide proof-of-concept data on the impact of statin therapy on microvascular dysfunction, and its role in cerebral tissue susceptibility to acute ischemia. This study will bridge a critical gap in knowledge about the effect and timing of statin therapy in the evolution of stroke. It addresses pre-emptive therapeutic AIS strategies to improve post-stroke outcomes. If successful, this study will provide data to support prophylactic use of statins in patients who are high-risk for stroke based on their WMH burden, and ultimately, it may lead to change in our standard of practice for primary stroke prevention, clarify the optimal window for initiation of statin therapy, and decrease the burden of post-stroke disability.