摘要
评估颅内动脉瘤的不稳定风险(破裂和生长风险)对于指导未破裂颅内动脉瘤(UIA)的治疗决策具有重要意义.本研究自2017年1月-2022年1月前瞻性地纳入了UIA患者,进行了2年的随访,并进一步分为发掘队列和验证队列,主要终点事件是UIA的不稳定事件,定义为在随访期内,动脉瘤出现破裂、大小生长或者形态学改变.基于758个UIA患者的发掘队列,联合影像特点和多组学分析,发现大小指数、形态不规则、油酸、花生四烯酸、白细胞介素-1β(IL-1β)和肿瘤坏死因子-α(TNF-α)是UIA出现不稳定事件的危险因素.进一步分析显示,组织中和血清中油酸和花生四烯酸的表达水平有一致性趋势.运用机器学习算法,本研究构建了不稳定分类器,并能较好地识别发掘队列中的不稳定UIA(曲线下面积(AUC)为0.94).在含492个UIA患者的验证队列中,该分类器也能很好地识别不稳定UIA(AUC为0.89).基于大鼠颅内动脉瘤模型,发现干预油酸、IL-1β和TNF-α能预防UIA破裂.本研究基于中国人群揭示了UIA不稳定风险的标志物,并提供了一个风险分层模型,有望指导UIA的临床决策.
Intracranial aneurysm is the leading cause of nontraumatic subarachnoid hemorrhage.Evaluating the unstable(rupture and growth)risk of aneurysms is helpful to guild decision-making for unruptured intracranial aneurysms(UIA).This study aimed to develop a model for risk stratification of UIA instability.The UIA patients from two prospective,longitudinal multicenter Chinese cohorts recruited from January 2017 to January 2022 were set as the derivation cohort and validation cohort.The primary endpoint was UIA instability,comprising aneurysm rupture,growth,or morphology change,during a 2-year follow-up.Intracranial aneurysm samples and corresponding serums from 20 patients were also collected.Metabolomics and cytokine profiling analysis were performed on the derivation cohort(758 single-UIA patients harboring 676 stable UIAs and 82 unstable UIAs).Oleic acid(OA),arachidonic acid(AA),interleukin 1β(IL-1β),and tumor necrosis factor-a(TNF-a)were significantly dysregulated between stable and unstable UIAs.OA and AA exhibited the same dysregulated trends in serums and aneurysm tissues.The feature selection process demonstrated size ratio,irregular shape,OA,AA,IL-1β,and TNF-a as features of UIA instability.A machine-learning stratification model(instability classifier)was constructed based on radiological features and biomarkers,with high accuracy to evaluate UIA instability risk(area under curve(AUC),0.94).Within the validation cohort(492 single-UIA patients harboring 414 stable UIAs and 78 unstable UIAs),the instability classifier performed well to evaluate the risk of UIA instability(AUC,0.89).Supplementation of OA and pharmacological inhibition of IL-1βand TNF-a could prevent intracranial aneurysms from rupturing in rat models.This study revealed the markers of UIA instability and provided a risk stratification model,which may guide treatment decision-making for UIAs.
作者
刘清源
李科
贺红卫
苗增利
崔宏图
吴俊
丁曙思
文铮
陈吉元
鲁晓杰
李江安
郑乐民
王硕
Qingyuan Liu;Ke Li;Hongwei He;Zengli Miao;Hongtu Cui;Jun Wu;Shusi Ding;Zheng Wen;Jiyuan Chen;Xiaojie Lu;Jiangan Li;Lemin Zheng;Shuo Wang(Department of Neurosurgery,Beijing Tiantan Hospital,China National Clinical Research Center for Neurological Diseases,Advanced Innovation Center for Human Brain Protection,Beijing Institute of Brain Disorders,The Capital Medical University,Beijing 100070,China;Department of Neurosurgery and Emergency Medicine,Jiangnan University Medical Center,Wuxi 214001,China;The Institute of Cardiovascular Sciences and Institute of Systems Biomedicine,School of Basic Medical Sciences,State Key Laboratory of Vascular Homeostasis and Remodeling,NHC Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides,Beijing Key Laboratory of Cardiovascular Receptors Research,Health Science Center,Peking University,Beijing 100191,China;Department of Cardiology and Institute of Vascular Medicine,Peking University Third Hospital,Beijing 100191,China;School of Basic Medical Sciences,Fujian Medical University,Fuzhou 350122,China)
基金
the Top Talent Support Program for Medical Experts Team and for Young and Middle-Aged People of Wuxi Health Committee(202109 and 202014)
the National Key R&D Program of China(2021YFC2501100 and 2020YFA0803700)
the National Natural Science Foundation of China(82071296,81801158,and 81970425)。
