Statins augment small vessel function and improve stroke outcomes

项目摘要/摘要 迫切需要安全有效的预防和治疗中风的新策略，以便 减轻中风后残疾的负担。他汀类药物被广泛用于二级中风预防；然而， 到目前为止，对潜在长期副作用的担忧阻碍了他汀类药物在患者中的预防性使用 中风的高危人群。在急性缺血性中风(AIS)中，脑组织损害和临床结果 与微血管功能障碍有关，在脑MRI上表现为白质高信号(WMH)。WMH 负荷与梗死灶扩大、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减轻微血管功能障碍的程度，改善 脑组织和临床结果，但这需要进一步的研究。我们假设中风前 晚期WMH患者应用他汀类药物可改善脑血流灌注并降低血脑屏障 (Bbb)在AIS期间中断。此外，患有晚期WMH的患者可能会在 卒中后早期应用他汀类药物的AIS患者的脑血流灌注和功能结果。我们建议 以WMH严重程度为临床模型，研究他汀类药物对卒中后预后的影响 微血管功能障碍。使用协作方法，我们建议：(1)确定卒中前 应用他汀类药物改变微血管功能障碍和缺血组织的神经影像和血浆生物标记物 晚期WMH和AIS受试者的命运；以及(2)评估他汀类药物暴露是否提高存活率和 晚期WMH的AIS受试者的功能结局。获得神经成像和血浆生物标记物 AIS和晚期WMH受试者服用他汀类药物前后将提供概念验证数据 他汀类药物对微血管功能障碍的影响及其在脑组织易感性中的作用 急性缺血。这项研究将弥合关于他汀类药物治疗效果和时机的关键知识空白。 中风的演变。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 这项研究的成功将为预防使用他汀类药物提供数据，这些患者是高血压的高危人群。 中风基于他们的WMH负担，并最终可能导致我们的实践标准改变 初级卒中预防，明确开始他汀类药物治疗的最佳窗口，并减轻 中风后的残疾。

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.