Stroke & cognition in surgical aortic stenosis

背景：钙化性主动脉瓣狭窄（AS）是美国最主要的瓣膜疾病。随着人口的老龄化，这种诊断和需要主动脉瓣置换术（AVR）的患者数量正在迅速增长。栓子与大多数中风和心脏手术后认知功能障碍（POCD）有关。因AS而出现AVR的患者被定义为术后卒中“特别”风险（10%）的亚组，40%的患者患有多发性脑栓塞事件。这些患者在短期内也有继发于这些多发性脑梗死的POCD和/或血管性认知障碍的风险，并且可能有加速发展为长期血管性痴呆的风险。这是研究卒中和POCD发病机制的关键人群，也是神经保护干预的成功或失败可能有效证明的关键人群。目的：目的1)确定老年AS患者AVR后脑卒中和脑短暂性缺血事件的发生率；目的2)利用术前和术后弥散加权MRI（DWI）确定AVR术后脑缺血事件替代成像生物指标的有效性；目的-3)与年龄/疾病匹配的对照组相比，确定老年AS患者AVR后认知表现的变化。相关性：术后中风预示着早期死亡率增加5-10倍，而69%的患者患有严重残疾。一般中风患者的治疗进展，早期诊断和有组织的早期干预方法对预后产生了深远的影响。奇怪的是，在“捕获”人群中，心脏手术后中风监测的有组织方法很少存在，这些人群中风的发生不仅频繁而且可预测。（AVR后报道的中风发生率的5倍差异非常说明问题。）相反，有了密切监测的机会，快速干预/神经保护的好处可以合理地预期超过在普通人群中看到的。由于设计不足，神经保护试验以惊人的速度失败。设计适当的动力研究的一个关键因素是准确地知道要研究的结果的频率。准确计算两个重要的缺血性终点（卒中和POCD）的风险，将为未来的试验奠定基础。AVR后卒中的潜在成像替代物DWI-MRI病变的验证，可能允许在更小的人群中有效地进行“概念验证”研究。先进的影像学方法与详细的认知分析相结合，可能使我们加深对POCD发病机制的理解。最后，研究数据库将使我们能够仔细检查心脏手术期间栓塞过程导致认知障碍和痴呆的长期风险。

DESCRIPTION (provided by applicant): Background: Calcific aortic stenosis(AS) is the leading valvular disease in the United States. The number of patients with this diagnosis and requiring aortic valve replacement(AVR) is growing rapidly with the aging of our population. Emboli are implicated in most strokes and in postopertive cognitive dysfunction(POCD) after heart surgery. Patients presenting for AVR for AS define a subgroup at "extraordinary" risk(10%) for postoperative stroke, and 40% suffer multiple cerebral embolic events. These patients also are at risk for POCD and or vascular cognitive impairment secondary to these multiple cerebral infarctions in the short- term, and may be at risk for an acceleration toward long-term vascular dementia. This is a key population in which to study not only the pathogenesis of stroke and POCD, but also one in which the success or failure of neuroprotective interventions may be efficiently demonstrable. Aims: Aim-1) To determine the incidence the outcomes of stroke and cerebral transient ischemic events in an aged population, after AVR for AS; Aim-2) To determine the validity of a surrogate imaging biomarkertor postoperative cerebral ischemic events after AVR, using pre and postoperative Diffusion-Weighted MRI(DWI); Aim-3)Jo determine the change in cognitive performance in the aged patient after AVR for AS as compared to age/disease matched controls over time. Relevance:Post-surgical stroke portends a 5-10-fold increase in early mortality, while 69% suffer severe disability. Advances in the treatment of patients in the general stroke population, where early diagnosis, and an organized approach to early intervention has profoundly impacted outcome. Oddly, an organized approach to stroke surveillance after heart surgery, in a "captured" population, where the occurrence of stroke is not only frequent but predictable, rarely exists. (The 5-fold variance in the reported incidence of stroke after AVR is very telling.) Conversely, with the opportunity for close surveillance, benefits of rapid intervention/neuroprotection could reasonably be expected to surpass those seen in the general population. Neuroprotection trials have failed at an alarming rate due to inadequate design. A key element in designing properly powered studies is knowing accurately the frequency of the outcome to be studied. An accurate accounting of the risk of two important ischemic endpoints, stroke and POCD, will serve as a foundation for future trials. Validation of a potential imaging surrogate for stroke after AVR, DWI-MRI lesions, may allow for the efficient conduct of "proof of concept" studies in much smaller populations. Advanced imaging approaches paired with detailed cognitive analyses may allow us to deepen our understanding of the pathogenesis of POCD. Finally, the study database will allow us to closely examine the long-term risks for cognitive impairment & dementia from embolic processes during heart surgery..