Statins augment small vessel function and improve stroke outcomes

描述(由申请人提供)：迫切需要安全有效的预防和治疗中风的新策略，以减轻中风后残疾的负担。他汀类药物被广泛用于二级卒中预防；然而，到目前为止，对潜在的长期副作用的担忧阻碍了他汀类药物在卒中高危患者中的预防性使用。在急性缺血性卒中(AIS)中，脑组织损伤和临床结果与微血管功能障碍有关，在脑MRI上表现为脑白质高信号(WMH)。WMH负荷与梗塞扩大、出血性转化和较差的临床AIS结局相关。在AIS中，他汀类药物的血管保护作用可能会减轻微血管功能障碍的程度，改善脑组织和临床结果，但这还需要进一步研究。我们假设卒中前应用他汀类药物可改善晚期WMH患者的脑血流灌注，减少AIS期间血脑屏障(BBB)的破坏。此外，晚期WMH患者在AIS后早期应用卒中后他汀类药物可能会在脑血流灌注和功能结果方面获得额外的好处。我们建议研究他汀类药物的使用对术后预后的影响。 中风，利用WMH严重性作为微血管功能障碍的临床模型。使用一种协作方法，我们建议：(1)确定卒中前使用他汀类药物是否改变了晚期WMH和AIS受试者微血管功能障碍和缺血组织命运的神经影像和血浆生物标记物；以及(2)评估他汀类药物暴露是否改善了晚期WMH AIS受试者的存活率和功能预后。在AIS和晚期WMH患者开始应用他汀类药物前后获得的神经影像和血浆生物标记物将提供有关他汀类药物治疗对微血管功能障碍的影响及其在脑组织对急性缺血易感性中的作用的概念验证数据。这项研究将弥合他汀类药物在卒中演变中的作用和时机的认识上的一个关键差距。它解决了先发制人的治疗AIS战略，以改善中风后的结果。如果成功，这项研究将提供数据，支持基于WMH负担的卒中高危患者预防性使用他汀类药物，最终可能导致我们一级卒中预防实践标准的改变，阐明开始他汀类药物治疗的最佳窗口，并减轻卒中后残疾的负担。

DESCRIPTION (provided by applicant): 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.