发布时间:2020年03月26日 16:30:09 来源:振东健康网
李雪杰,陈晖
(首都医科大学附属北京友谊医院心内科,北京100050)
中图分类号:R541.6;R459.9文献标识码:A
文章编号:1006-2084(2019)04-0637-05
【摘 要】:纤维蛋白原是主要的血浆蛋白凝血因子,除参与凝血外,在局部和全身炎症中也有一定的作用,是多种炎性疾病治疗干预的新靶标。纤维蛋白原也是多种心血管疾病的独立预测因子,其与缺血性心脏病、冠心病、心律失常、心力衰竭、糖尿病、高脂血症等的相关性已被众多研究所证实,也可用于评估心血管疾病的发生风险,对于预防心血管疾病有重要意义。除此之外,纤维蛋白原也与心血管疾病危险因素相关。深入研究纤维蛋白原在心血管疾病中的预测作用,可能有助于改善患者的生存质量,减轻社会负担。
【关键词】:纤维蛋白原;心血管疾病;缺血性心脏病;心律失常;心力衰竭
Clinical Research Progress in Relationship between Fibrinogen and Cardiovascular Diseases
LI Xuejie,CHEN Hui.
(Department of Cardiology,Beijing Friendship Hospital,Capital Medical University,Beijing 100050,China)
【Abstract】:Fibrinogen is the major plasma protein coagulation factor. In addition to participating in blood coagulation,fibrinogen also plays a role in local and systemic inflammation,which is a new target for therapeutic intervention in a variety of inflammatory diseases. Fibrinogen is also an independent predictor of various cardiovascular diseases,and its correlation with ischemic heart disease,coronary heart disease,arrhythmia,heart failure,diabetes,hyperlipidemia,etc. has been confirmed by many research institutions. It can be used to assess cardiovascular risk to prevent cardiovascular diseases. In addition,fibrinogen is also associated with cardiovascular risk factors. An in-depth study of the predictive role of fibrinogen in cardiovascular diseases may help improve the quality of life of the patients and reduce the social burden.
【Key words】Fibrinogen; Cardiovascular diseases; Ischemic heart diseases; Arrhythmia; Heart failure
纤维蛋白原(fibrinogen,Fib)是由肝脏合成和分泌的由三对不相同的多肽链组成的糖蛋白,参与了血栓形成。除在凝血瀑布中发挥作用外,Fib在心血管疾病、自身免疫和炎性疾病(如类风湿关节炎、血管炎、炎症性肠病、多发性硬化症、慢性阻塞性肺疾病、肾脏疾病、移植后器官衰竭)[1]以及某些癌症[2]中还可作为一种促炎因子存在。已有研究表明,Fib可通过配体-受体相互作用与炎性细胞结合,干扰免疫炎性应答[2]。此配体-受体相互作用的机制不同于参与凝血级联反应的机制。Fib不仅刺激血管生成,还能促进成纤维细胞分裂[3],在人类疾病中扮演着多种角色。研究表明,Fib的水平不仅与缺血性心脏病、心房颤动[4-5]、心源性猝死[6]等心血管疾病的临床诊断和预后相关,还与心血管疾病的危险因素(如糖尿病、高脂血症等)存在相关性[7-9]。Meade[4]研究显示,Fib的水平与冠状动脉疾病的严重程度相关,高Fib水平是血栓形成的有力证据。众所周知,血浆胆固醇水平与缺血性心脏病存在显著相关性,一项前瞻性研究显示,Fib水平与缺血性心脏病的发病率存在独立相关性[10]。Fib水平还与心肌梗死、脑血管疾病以及下肢动脉疾病中缺血发作、复发及进展相关[11]。高Fib水平通过影响血液黏度、血小板聚集性以及凝血初始时产生的纤维蛋白量等诱发缺血性心脏病。标准化Fib的测量方法有利于评估心血管疾病风险,现就Fib与心血管疾病的相关性研究进展进行综述。
1 Fib与冠心病的相关性
急性心肌梗死与Fib的水平具有相关性,但对稳定型冠心病患者12个月的随访中未发现Fib水平与疾病预后存在关联[12],其原因主要是心肌坏死的急性期反应会导致各种急性期蛋白发生改变。多项研究发现,Fib升高的幅度与冠状动脉粥样硬化的程度和风险之间存在关联[13-15]。目前公认急性冠状动脉综合征与复杂的凝血系统紊乱相关[16-17]。有研究采用Gensini评分评估418例35岁以下男性急性心肌梗死患者冠状动脉狭窄的程度,结果显示冠状动脉狭窄组和高Gensini评分组Fib的水平较冠状动脉非狭窄组和低Gensini评分组明显升高,提示血浆Fib的水平与冠状动脉狭窄的存在以及严重程度显著相关[18]。多项研究应用Syntax评分评估了冠心病患者冠状动脉狭窄程度,并对冠心病的发病率进行了多因素回归分析,结果显示Fib是冠心病的独立预测因子[19-23]。
DeSutter等[24]在血管成形术后1个月,应用单光子发射计算机化断层显像技术测量患者心肌梗死面积,与入院时应用Aldrich评分测得的心肌梗死面积进行比较发现,患者入院时Fib的水平与心肌梗死面积存在相关性,且独立于入院时疼痛持续时间及C反应蛋白(C-reactiveprotein,CRP)水平。Peng等[25]对3020例冠心病患者进行平均(27.2±13.1)个月的随访,以稳定型心绞痛、不稳定型心绞痛、急性心肌梗死及死亡为终点事件,结果显示不同亚型冠心病患者的Fib水平与预后存在相关性。
Ang等[26]应用VerifyNow测定氯吡格雷预处理后血小板的反应情况发现,无论血小板反应情况如何,高水平的Fib与择期经皮冠状动脉介入治疗(percutaneouscoronaryintervention,PCI)后缺血性心肌损伤风险独立相关,且在无全身炎症的情况下(CRP<5mg/L),Fib的作用最为突出。Mahmud等[27]对332例行PCI的患者进行12个月的随访,结果表明,Fib水平的升高与主要不良心血管事件(majoradversecardiacevents,MACE)的发生存在相关性。临床病例对照分析发现,血清Fib水平升高、急性冠状动脉综合征表现以及支架总长度更长与PCI后6个月的MACE存在独立相关性,低Fib水平与PCI后出血事件无关[28]。对上述332例行PCI的患者进行2年的随访,结果显示,Fib水平升高、急性冠状动脉综合征PCI指征、置入支架总长度、裸金属支架或小直径支架的使用与PCI术后MACE独立相关[29]。
2 Fib与心力衰竭的相关性
近期对4个纵向社区的基础队列(心血管健康研究、弗雷明汉心脏研究、动脉粥样硬化多民族研究和肾脏及血管终末期疾病预防研究)进行研究,研究者对参与者进行平均12年的随访,结果表明,心力衰竭患者Fib的水平与无心力衰竭患者显著不同,但在射血分数保留型和下降型心力衰竭中差异无统计学意义[30]。Yan等[31]对1096例未诊断为心血管疾病且无症状的患者进行心功能评估,同时检测其CRP、N端脑钠肽前体以及Fib的水平,结果发现,Fib水平的升高与心肌收缩功能受损独立相关,研究提示炎症、促凝血作用以及高Fib血症在初发心肌收缩功能障碍中有一定作用。
Wannamethee等[32]对3366例60~79岁无心力衰竭、心肌梗死、静脉血栓形成及未服用华法林的男性进行平均13年的随访,随访期间共发生203起心力衰竭事件。该前瞻性研究发现,凝血活性与心力衰竭的发展无关,D-二聚体、血管性血友病因子与N端脑钠肽前体显著相关,提示凝血活性增加与心脏压力有关;心力衰竭患者凝血功能增强部分可能是神经激素活化所致;Fib与心力衰竭事件相关,但在校正年龄后,Fib与N端脑钠肽前体无相关性。Mongirdiene和Kubilius[33]对138例慢性心力衰竭患者进行观察随访,结果显示,体育锻炼后可增加患者的运动负荷水平,患者Fib的水平会随体育锻炼的增加而降低。Eisen等[34]对2945例无心力衰竭的冠心病患者进行平均7.9年的随访发现,CRP、Fib以及白细胞水平与稳定型冠心病患者心力衰竭的发生率独立相关。临床研究显示,在未患缺血性心脏病的患者中,血浆Fib水平升高、促血栓状态形成与左心室舒张功能障碍会增加患舒张性心力衰竭的风险[35]。
在心力衰竭患者中,促炎标志物的水平与疾病严重程度及预后显著相关,运动训练可降低健康人和心力衰竭患者促炎细胞因子和其他促炎标志物的循环水平[36]。最近有荟萃分析研究,有氧训练和阻力训练对心力衰竭患者循环中炎性标志物(肿瘤坏死因子α、白细胞介素6、CRP、Fib、可溶性细胞间黏附分子、可溶性血管黏附分子等)水平的影响,结果显示,炎性标志物并无明显变化[37]。
3 Fib与心律失常的相关性
在心律失常方面,作为凝血和促炎因子的Fib与心房颤动的相关性研究的较为深入。对心房颤动相关卒中风险的评估目前主要基于临床风险评分,如CHADS2(充血性心力衰竭、高血压、年龄≥75岁,糖尿病、卒中/短暂性脑缺血发作/血栓史)评分和CHA2DS2-VASc[充血性心力衰竭、高血压、年龄≥75岁、糖尿病、卒中/短暂性脑缺血发作/血栓史、血管病变、年龄65~75岁、性别(女性)]评分,但这些评分仅可对个体患者的风险进行适度区分。血液中的某些生物学标志物可能有助于评估心房颤动患者的卒中结局和死亡风险。心房颤动时肌钙蛋白、利尿钠肽、凝血相关指标等生物学标志物可以显著改善风险分层,而心房颤动患者的肾功能、凝血相关指标以及炎性标志物等可作为改善心房颤动临床风险评估的新手段[8]。Erdogan等[38]发现,高心室率的非瓣膜性心房颤动患者血浆Fib的水平较心室率正常的非瓣膜性心房颤动患者升高。
有学者认为,循环中较高的Fib水平是由心房颤动本身引起的[39],也有学者认为这是多项传统危险因素与心血管疾病并存共同作用导致的[5]。Fu等[39]研究了90例特发性心房颤动患者,其中60例为独立性心房颤动,通过酶联免疫吸附法检测血浆可溶性P选择素的水平,通过测色法测量血浆Fib的水平,根据性别、年龄以及风险因素匹配出正常对照组。结果发现,与正常对照组相比,特发性心房颤动患者可溶性P选择素和Fib的水平较高,提示特发性心房颤动和独立心房颤动患者的血小板活化和凝血发生异常改变,支持心房颤动本身促进高凝的观点。Mukamal等[40]发现,较高水平的Fib和较低水平的白蛋白与心房颤动风险升高相关,为炎症促进心房颤动这一假设提供了证据。在分析凝血的研究中,血浆达比加群浓度与凝血酶时间具有相关性,Fib水平的改变可以解释凝血酶时间的改变,血浆Fib水平可用于反映受药物影响的凝血酶时间中达比加群残留的血药浓度[41]。Weymann等[42]对凝血、纤维蛋白溶解以及内皮标志物在心房颤动、中风及血栓栓塞患者中的预测作用进行了研究,Fib水平升高与心房颤动的发生率相关,与窦性心律组相比,心房颤动组中凝血酶原片段1、凝血酶原片段2、凝血酶-抗凝血酶复合物以及抗凝血酶Ⅲ的水平也显著升高,D-二聚体的水平与心房颤动患者血栓栓塞的发生密切相关,而Fib、凝血酶原片段1和凝血酶原片段2与之无关。现有数据表明,Fib与心源性猝死有一定的独立相关性[6],但需要进一步的研究来证明血浆Fib水平在预防心源性猝死中的作用。
4 Fib与心血管疾病危险因素的相关性
动脉硬化狭窄程度可预测心血管事件,炎症改变在大动脉硬化中起主要作用。在患代谢综合征、糖尿病、外周动脉疾病、风湿性疾病、肾脏疾病以及先兆子痫或绝经后人群中,动脉硬化严重程度与炎性标志物(如白细胞计数、中性粒细胞/淋巴细胞比率、黏附分子、Fib、CRP、微RNA以及环氧合酶2等)存在显著相关性[43]。Ang等[44]的前瞻性研究纳入了需要使用氯吡格雷治疗的心血管疾病患者(每日75mg,持续7d或招募前24h负荷600mg),随访发现,存在糖尿病和体质指数升高(≥25kg/m2)的患者,血浆Fib水平的升高(≥3750mg/L)与心血管疾病患者中氯吡格雷的血小板抑制率降低有关。血液中的Fib会增加血小板与腺苷二磷酸结合时的细胞脱粒反应,因此Fib所涉及的心血管疾病风险可能是通过增加血小板的反应实现的[45]。有学者研究了PCI前糖尿病和高Fib水平与氯吡格雷血小板抑制率的相关性,结果显示,糖尿病和高Fib与氯吡格雷血小板抑制率存在相关性,并与PCI后MACE存在相关性;PCI后,无论是否存在糖尿病,高Fib水平都与氯吡格雷血小板抑制率存在独立相关性[9]。Hosomi等[11]进行了一项针对非心源性缺血性卒中患者的随机、多中心、非盲、盲法终点平行组研究,随访(4.9±1.4)年发现,在Ⅱ型高脂蛋白血症患者中,Fib水平的增加可能与特定脂蛋白(如三酰甘油、高密度脂蛋白)血清水平的改变有关。
5 小结
在健康成人中,血浆Fib的水平与冠心病、脑卒中和其他血管病死率以及非血管性死亡风险之间存在中等强度的相关性[24]。随着年龄的增长,Fib的水平呈现升高的趋势,这可能与Fib在不同年龄段人群的合成代谢速度不同有关。目前对Fib的研究已深入到基因水平,结合新的测序技术,对几个或多个候选基因进行大规模并行测序,从全基因组关联研究确定的那些蛋白质组学分析中寻找临床上同质群体中的生物学标志物,排除其中与增加的混杂性共存疾病相关的结合蛋白,可能为阐明血浆Fib基因结构的完整性开辟新途径。未来心血管疾病的治疗可针对抑制促炎机制展开。作为预防心血管疾病的发生,评估疾病风险及临床预后的指标,Fib可实现患者生存质量的提高及社会疾病负担的减轻。
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