脑小血管病新影像及生物标记物对心源型脑梗死复发风险的预测作用及其机制的探索性研究

Anticoagulation is the key of the most important second prevention treatment for cardioembolic stroke. However, because of easy brain hemorrhage as serious adverse events, anticoagulant usage is very low. More accurate prediction of the risk of stroke recurrence for different subtype (ischemia or hemorrhage) may help clinicians make decisions for the use of anticoagulants, which would make more patients benefit from largely decreased risk of stroke recurrence. Recent studies have found that small vessel disease is closely related to the prognosis and recurrence of stroke, and a new small vessel disease imaging marker - microinfarcts could be detected by 3T Magnetic Resonance (MRI) in vivo testing.Based on preliminary experiments, we have observed the microinfarcts successfully in patients with cardioembolism stroke and meanwhile found high mobility group protein B1 (HMGB1) played an important role as an inflammatory molecular in rats. We speculate that the brain microinfarcts may have great predictive value for ischemic stroke recurrence, and post-stroke inflammatory may contribute to the progress of stroke recurrence. In present study, we try to examine the prevalence and distribution (including the number, size, distribution, etc.) of microinfarts in cardioembolic stroke on high-resolution 3T 3D multi-modal MRI; and observe the dynamic change of the level of inflammatory markers (HMGB1, RAGE, INF-α, IL-6, etc. ) in peripheral blood, aiming to analyze the distribution features of the microinfarcts in patients within different cohorts and its relationship with HMGB1 levels, and clarifying the mechanism of cerebral small vessel disease and its predictive value for stroke recurrence in patients with cardioembolic stroke.

抗凝治疗是心源型脑梗死预防栓塞复发最重要的治疗手段。但因其易发生脑出血的严重不良事件，抗凝剂使用率非常低。增加对卒中复发类型（梗死或出血）风险预测的精确性可帮助临床从抗凝的获益方面指导抗栓策略的选择。近期研究发现小血管病与卒中预后及复发密切相关，而一种新小血管病影像标志物-微梗死可通过3T核磁共振（MRI）进行活体检测。我们前期研究在心源型脑梗死患者中发现了微梗死灶，同时在动物试验中发现高迁移率族蛋白B1（HMGB1）是一种重要的促炎因子。我们推测脑微梗死对心源型脑梗死复发具有预测价值，而急性脑梗死后炎症反应的程度可能促进卒中复发 。本研究拟采用薄层三维多模态MRI技术检测心源型脑梗死患者中微梗死等小血管病标志物，并定点监测外周血中炎性标志物水平，例如HMGB1通路相关因子，阐明脑小血管病变新影像及炎性标志物在心源型脑梗死复发中的机制及预测价值。

心源型脑梗死是脑梗死致死、致残率及复发率最高的亚型。增加对卒中复发类型（梗死或出血）风险预测的准确性能指导抗栓策略的选择。本研究拟采用薄层三维多模态MRI技术检测心源型脑梗死患者中微梗死等小血管病影像标志物，并监测外周血中HMGB等炎性标志物水平，探索脑小血管病变新影像及炎性标志物在心源型脑梗死复发中的机制及预测价值 。本研究共纳入脑梗死及TIA共158例，其中心源型梗死72例。心源型脑梗死平均年龄为67.2±13.6岁，男性占33.3%(24例)。微梗死是心源型梗死组最常见的脑小血管标志物，62.5%的患者（45/72）可见微梗死，微梗死个数为1-12个，其中仅累及皮层为33.3%（24/72），仅累及皮层下为9.7%（7/72），累及皮层及皮层下为18.1%（13/72）。48.6%（35/76）的微梗死位于梗死病灶同侧，2.8%（2/72）位于梗死病灶对侧，8.3%（6/72）位于双侧大脑半球。与非心源型脑梗死相比，两组在是否有微梗死（62.5% vs. 36.7%, p=0.002）、部位（p=0.001）、与梗死位置关系分布（p=0.02）以及微梗死个数（p=0.02）有显著性差异。与大动脉粥样硬化型梗死（34例）相比，微梗死（发生率、部位、与梗死部位分布关系、个数）均无显著性差异。与小血管闭塞型梗死（28例）相比，微梗死发生率更高（62.5% vs. 14.3%, p <0.001）、更多仅分布在皮层或者同时累及皮层和皮层下（p<0.001），与梗死部位位置分布关系（p=0.001）以及微梗死个数（p <0.001）均有显著性差异。多因素分析显示房颤（OR 2.647，95%CI 1.162-6.028，p=0.02）及心脏瓣膜病（OR 4.730，95%CI 1.194-18.735，p=0.027）是脑微梗死的显著性独立危险因素。HMGB1外周血表达水平在56例心源型梗死与非心源型梗死（143例）比较无统计学差异。 结果提示微梗死与其他脑小血管标志物（微出血、脑白质病变、扩大的血管周围间隙）不同，心源性或者动脉到动脉的栓塞可能是其主要的病因机制。结果有待继续扩大样本深入研究，对于伴有微梗死或者脑小血管病变总体负担高是否增加心源型脑梗死后卒中复发风险有待进一步分析研究。