CYP2C19基因多态性与颅内动脉瘤支架置入术后临床预后的相关性分析研究

发布时间：2018-05-09 04:19

本文选题：颅内动脉瘤 + 支架　；参考：《首都医科大学》2017年博士论文

【摘要】：背景:颅内动脉瘤作为一种危害人类生命健康的严重脑血管出血性疾病,许多年来关于其最优化治疗方式的选择一直饱受争议且得不到定论。尽管随着医疗材料技术的进步,颅内支架系统目前已广泛应用于多种类型的复杂颅内动脉瘤(如宽颈、夹层、梭型动脉瘤等),众多患者得到了较为积极的治疗。但是,支架的致血栓特性也限制了应用。现阶段,口服双重抗血小板药物,尤其是氯吡格雷的广泛应用,使得支架内血栓形成的概率大大的降低,缓解了很多患者的病痛之苦。然而,有相当数量的患者在服用标准剂量抗血小板药物——氯吡格雷后,仍旧出现心脑血管意外事件(主要为缺血性事件)的发生,这种情况通常被认为产生了“氯吡格雷抵抗”。目前,已有研究证实基因表达水平(主要有CYP2C19多态性等)为影响氯吡格雷抵抗与否的一项非常重要的因素。但是,其在颅内动脉瘤支架治疗及预后检测方面的相关性研究仍然相对缺乏。目的:本次研究旨在探索CYP2C19基因多态性与颅内动脉瘤支架置入术后临床预后及抗血小板药物疗效之间的相关性。方法:前瞻性登记入组于2014年9月至2015年10月期间,在首都医科大学附属北京天坛医院神经介入科住院,并且接受颅内支架系统置入治疗的颅内动脉瘤患者,并且详细记录了所有入组患者的临床资料、影像学信息及预后随访资料等数据。提取所有入组患者的静脉血液样本,并对标本进行CYP2C19基因多态性检测;对所有入组的患者分别于抗血小板药物服用前、手术前、术后或随访期间,采用血栓弹力图(thrombelastography,TEG)技术对血小板功能进行检测,并且根据检测结果评估抗血小板药物(尤其是氯吡格雷)的疗效。所有患者均于手术后48h内接受核磁共振弥散加权成像(MRI-DWI)及灌注加权成像(MRI-PWI)检查,以观察和鉴别是否有新发或急性颅内梗塞灶。制订临床终点事件为颅内缺血性事件或全身出血性事件,并对所有入组患者进行术后为期3个月的临床随访,详细记录随访期间入组患者的m RS评分、预后及各个临床终点事件的发生情况。对所得数据进行统计学检测,分析CYP2C19基因多态性、血小板功能检测结果与颅内动脉瘤支架置入术后临床结局的相关性。结果:共计215例颅内动脉瘤患者于首都医科大学附属北京天坛医院神经介入科接受颅内支架系统置入治疗,并登记入组于数据库中。其中,男性患者有86例(40.0%),女性患者有129例(60.0%),入组患者年龄范围为18岁至79岁,平均年龄为52.3±10.2岁。本次研究共计使用275个颅内各类型支架治疗243个颅内动脉瘤,包括170个前循环动脉瘤及73个后循环动脉瘤。经过术后即刻脑血管造影检查,在215例动脉瘤患者中,有171例(79.5%)得到了完全栓塞;有25例(11.6%)为近全栓塞;有19例(8.9%)为部分栓塞或仅是支架覆盖动脉瘤。在215例入组病例中,广泛代谢组(extensive metabolizers,EM,CYP2C19*1/*1基因型)病例有76(35.3%)例;中间代谢组(intermediate metabolizers,IM,CYP2C19*1/*2,*1/*3基因型)有108(50.3%)例;缓慢代谢组(poor metabolizers,PM,CYP2C19*2/*2,*2/*3,*3/*3基因型)有31(14.4%)例。在总计215例入组病例中,有68例(31.6%)病例通过血栓弹力图被检测到存在氯吡格雷药物抵抗;有69例患者(32.1%,69/215)在术后及随访期间经检查发现与支架释放部位相关的颅内缺血性并发症;有20例患者(9.3%,20/215)经检查发现出现颅内或全身系统的出血性并发症。将EM组患者分别与IM组患者及PM组患者进行统计学对比,可以发现,EM组患者发生术后颅内缺血性事件的概率明显低于IM组患者(p=0.02)和PM组患者(p=0.027)。通过单因素及多因素回归分析发现,CYP2C19慢代谢等位基因(*2、*3)携带与否(p=0.032,OR=2.07,95%CI=1.063-4.030)及服药后出现氯吡格雷抵抗情况(p=0.047,OR=0.534,95%CI=0.287-0.993)可有较高几率伴随颅内动脉瘤支架置入术后颅内缺血性并发症的发生;而未携带CYP2C19慢代谢等位基因可以伴随颅内及全身系统出血性事件的发生(p=0.002,OR=0.205,95%CI=0.075-0.557);后循环动脉瘤(p=0.038,OR=3.856,95%CI=1.076-13.822)、颅内动脉瘤破裂史(p=0.001,OR=0.078,95%CI=0.019-0.329)、携带2个CYP2C19慢代谢等位基因即PM组(p=0.001,OR=9.058,95%CI=2.366-34.682)与较差的临床预后具有明显的统计学相关性。结论:CYP2C19基因多态性可以影响接受颅内支架系统置入的颅内动脉瘤患者口服抗血小板药物氯吡格雷的疗效,这可能会在一定程度上导致一些出血性或缺血性并发症的发生;并且CYP2C19基因多态性可以作为颅内动脉瘤支架置入术后缺血性及出血性临床终点事件的风险预测因素。
[Abstract]:Background: intracranial aneurysm is a serious cerebral vascular hemorrhagic disease which endangers human life and health. The selection of optimal treatment methods has been disputed for many years. Although with the progress of medical materials technology, the intracranial stent system has been widely used in many types of complex intracranial aneurysms. Many patients have been treated more actively, such as wide neck, interlayer and spindle aneurysm. However, the thrombus characteristics of the scaffold are also limited. At this stage, the extensive use of oral antiplatelet drugs, especially clopidogrel, makes the probability of thrombosis in the stent greatly reduced and alleviates the pain of many patients. However, a considerable number of patients, after taking the standard dose antiplatelet drug - clopidogrel, still have the occurrence of cardiac and cerebrovascular accidents (mainly ischemic events), which are usually considered to produce "clopidogrel resistance". Currently, the level of gene expression (mainly CYP2C19 polymorphism, etc.) has been confirmed. It is a very important factor affecting the resistance of clopidogrel. However, the correlation of the correlation between the stent therapy and the prognosis of intracranial aneurysms is still relatively lack. Objective: This study aims to explore the relationship between CYP2C19 gene polymorphism and the clinical prognosis of intracranial aneurysm after stent implantation and the effect of antiplatelet drugs. Methods: the prospective registration group was hospitalized in the Neurointerventional Department of Beijing Tiantan Hospital, Capital Medical University, from September 2014 to October 2015, and received intracranial aneurysm patients treated with intracranial stent system, and the clinical data, imaging information and prognosis of all the patients were recorded in detail. The venous blood samples of all the patients were extracted and the CYP2C19 gene polymorphisms were detected. The platelet function was detected by thrombelastography (TEG) technique before and after the operation, before the operation, and during the follow-up period. The results were evaluated for antiplatelet drugs (especially clopidogrel). All patients received NMR diffusion weighted imaging (MRI-DWI) and perfusion weighted imaging (MRI-PWI) within 48h after surgery to observe and identify new or acute intracranial infarction. Clinical endpoints were developed for intracranial ischemic events or systemic hemorrhage. All the patients were followed up for 3 months. The m RS score, prognosis and the occurrence of various clinical endpoints were recorded during the follow-up period. The data were statistically tested, the CYP2C19 gene polymorphism, the blood plate function test and the intracranial aneurysm stent implantation were analyzed. Results: a total of 215 cases of intracranial aneurysms were implanted in the Neurointerventional Department of the Beijing Tiantan Hospital of Capital Medical University, which were treated with intracranial stent system and registered in the database. Among them, 86 cases (40%) were male patients and 129 cases (60%) in female patients. The age range of the patients in the group was 18 to 79. The average age was 52.3 + 10.2 years. A total of 275 intracranial stents were used to treat 243 intracranial aneurysms, including 170 anterior circulation aneurysms and 73 posterior circulating aneurysms. After immediate cerebral angiography after operation, 171 cases (79.5%) were completely embolized in 215 patients with aneurysm; 25 (11.6%) were nearly complete. Embolization; 19 cases (8.9%) were partially embolized or only stent covered aneurysms. Among the 215 cases, 76 (35.3%) cases were in the extensive metabolizers, EM, CYP2C19*1/*1 genotype, 108 (50.3%) in the intermediate metabolism group (intermediate metabolizers, IM, CYP2C19*1/*2, *1/*3 genotype); the slow metabolism group (poor metabolize) There were 31 (14.4%) cases of RS, PM, CYP2C19*2/*2, *2/*3, *3/*3 genotypes. In a total of 215 cases, 68 (31.6%) cases were detected with clopidogrel resistance through a thrombus map; 69 patients (32.1%, 69/215) were examined after and followed up for intracranial ischemic complications associated with the release site of the stent; 20 Patients (9.3%, 20/215) were found to have intracranial or systemic hemorrhagic complications after examination. Compared with group EM and group PM, the probability of intracranial ischemic events in group EM patients was significantly lower than that of group IM (p=0.02) and PM group (p=0.027). By single factor and more, the patients in group EM were found to be more likely to have hemorrhagic complications. Factor regression analysis found that the CYP2C19 slow metabolic allele (*2, *3) carrying or not (p=0.032, OR=2.07,95%CI=1.063-4.030) and the presence of clopidogrel (p=0.047, OR=0.534,95%CI=0.287-0.993) after taking the drug (p=0.047, OR=0.534,95%CI=0.287-0.993) could have a higher risk of intracranial ischemic complications following the stent placement of intracranial aneurysm, but not CYP2C19 slow. Metabolic alleles can be associated with intracranial and systemic hemorrhagic events (p=0.002, OR=0.205,95%CI=0.075-0.557); posterior circulating aneurysm (p=0.038, OR=3.856,95%CI=1.076-13.822), intracranial aneurysm rupture history (p=0.001, OR=0.078,95%CI=0.019-0.329), and PM group (p=0.001, OR=9.058,95%CI=) carrying 2 CYP2C19 slow metabolic alleles. 2.366-34.682) has a significant statistical correlation with poor clinical prognosis. Conclusion: CYP2C19 gene polymorphism may affect the efficacy of oral antiplatelet drug clopidogrel in intracranial aneurysm patients receiving intracranial stent implantation, which may cause some hemorrhagic or ischemic complications to a certain extent. The CYP2C19 gene polymorphism can be used as a predictor of ischemic and hemorrhagic clinical endpoint events after stent placement for intracranial aneurysms.

【学位授予单位】：首都医科大学
【学位级别】：博士
【学位授予年份】：2017
【分类号】：R743.3

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