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冠心病患者介入治疗前后胎盘生长因子水平的变化及临床意义
Changes of Serum Placental Growth Factor Levels during Percutaneous Coronary Intervention and Clinical Significance
【作者】 李勇；
【导师】 李拥军；
【作者基本信息】 河北医科大学 ， 内科学， 2008， 硕士
【摘要】 目的:冠心病(coronary heart disease,CHD)已成为世界范围内严重危害人类健康的常见疾病,其发病率和病死率呈逐年升高趋势。虽然目前对冠心病患者采取了积极的抗凝、溶栓、介入及外科手术治疗,但仍有不少患者发生严重的心血管事件而危及生命,因此,积极寻求早期预测并干预心血管事件发生的方法显得尤为重要。大量研究表明炎症在冠心病发生、发展过程中起着重要作用。激活的炎症反应可导致冠状动脉粥样硬化不稳定斑块破裂,继发血小板聚集、血栓形成造成冠状动脉的急性狭窄或闭塞,从而引起心血管事件的发生,一些炎症生物标记成为冠心病患者危险预后的预测指标。近来研究发现胎盘生长因子(placental growth factor, PlGF)具有促炎作用,其能促进单核细胞聚集,巨噬细胞浸润,激发斑块内炎症,导致斑块破裂,可作为冠心病患者不良预后预测的生物标志,但其在冠心病介入方面的研究以及对冠心病患者介入治疗后临床预后的影响目前报道较少。本实验主要通过观察冠心病患者介入治疗(percutaneous coronary intervention, PCI)前后胎盘生长因子、高敏C-反应蛋白(high sensitivity C-reactive protein ,hs-CRP)水平变化趋势以及两者之间的相关性,并跟踪随访6个月,观察主要心血管事件(major adverse cardiac events,MACE)发生情况与PlGF水平变化的关系,探讨PlGF对冠心病患者介入治疗后近期预后的影响,为临床早期预防术后心血管事件的发生提供理论依据。方法:冠心病组为河北医科大学第二医院住院的冠心病患者110例,所有患者均为首次接受介入治疗(PTCA和支架植入)。其中男性76例,女性34例,年龄35-74岁,平均(56.0±8.79)岁。根据冠状动脉造影结果分为单支病变组43例,双支病变组39例,三支病变组28例。所有研究对象均除外有恶性肿瘤、心脏瓣膜病、急性或慢性感染、近期创伤或手术、结缔组织疾病、血液系统疾病和左室射血分数小于40%。对照组为30例健康体检者,并经常规12导联心电图、运动心电图、ECT或冠状动脉造影检查除外冠心病。其中男性21例,女性9例,年龄35-62岁,平均(53.9±7.12)岁,年龄、性别与冠心病组差异无统计学意义。冠心病组分别于介入治疗前1天,术后1天、3天、5天抽取肘静脉血4ml。对照组抽取肘静脉血4ml一次(其测定值作为正常对照)。应用离心机,转速3000r/min,离心15分钟,留取血清,置于Eppendorf管中-80℃冰箱内保存,待测定。血清胎盘生长因子采用酶联免疫吸附测定法(enzyme-linked immunosorbent assay,ELISA)测定;高敏-C反应蛋白采用超离子免疫透射比浊法(immunoturbidimetric assay, ITA)测定。观察冠心病患者介入治疗前后胎盘生长因子、高敏C-反应蛋白的水平变化以及它们之间的相关性。并跟踪随访6个月,观察心血管事件发生情况,探讨胎盘生长因子对冠心病患者介入治疗后近期预后的影响。结果:(1)冠心病组与对照组术前各指标水平比较:冠心病患者血清PlGF、hs-CRP水平分别为(13.06±4.05)pg/ml、(5.50±2.78)mg/L ,明显高于健康对照组(9.67±2.55)pg/ml、(3.54±1.01)mg/L,两组之间差异有统计学意义(p<0.01)。(2)单支病变组、双支病变组和三支病变组术前各指标水平比较:单支病变组术前PlGF、hs-CRP水平分别为(11.83±3.95)pg/ml、(4.42±1.95)mg/L,低于双支病变组(12.93±4.28)pg/ml、(5.25±1.96)mg/L和三支病变组(15.11±3.07)pg/ml、(5.82±1.77)mg/L,三组之间差异有统计学意义(P<0.05)。(3)冠心病组手术前后各指标水平变化:冠心病患者PCI术后1天PlGF水平较术前升高(14.49±3.42比13.06±4.05, P<0.01),术后3天明显升高达到峰值(16.44±3.25比13.06±4.05, P< 0.01),术后5天下降至正常左右。hs-CRP术后1天明显高于术前且达到峰值(8.17±1.88比5.50±2.78,P<0.01),术后3天开始下降(6.64±2.34比5.50±2.78,P<0.01),术后5天恢复正常左右。在单支病变组、双支病变组和三支病变组上述指标变化趋势相同。(4)PlGF与hs-CRP相关性:PCI手术前、后血清PlGF峰值水平与hs-CRP峰值水平呈显著正相关(术前r = 0.816, P=0.001;术后r = 0.216, P=0.023)。(5)随访结果:随访期间无1例失访,再发心绞痛14例,其中1例再次接受PCI治疗。14例心血管事件中,单支病变组5例,双支病变组5例,三支病变组4例。发生MACE的患者PCI术前和术后PlGF水平峰值较未发生MACE者明显升高(P<0.01)。(6)对主要影响术后预后的因素进行Logistic回归分析,结果显示,LDL(OR=1.944, 95%可信区间1.044, 5.265,P=0.016)、PlGF(OR=4.839, 95%可信区间1.262,10.092,P=0.022)、hs-CRP(OR=3.464, 95%可信区间1.609,5.905,P=0.038)和支架长度(OR=1.250, 95%可信区间1.165, 10.454,P=0.026)是冠心病患者PCI术后发生心血管事件的独立相关危险因素。结论:(1)冠心病患者术前血清PlGF、hs-CRP水平明显高于健康对照组。PlGF、hs-CRP水平与冠状动脉病变程度有关,随着病变程度的增加,PlGF、hs-CRP水平升高,单支病变组低于双支和三支病变组。提示PlGF、hs-CRP参与了冠心病的发生、发展。(2)单支病变、双支病变与三支病变三组患者PCI术后1天PlGF水平较术前均有显著升高,术后3天达到高峰,术后5天下降。(3)术前、后血清PlGF峰值水平与hs-CRP峰值水平呈显著正相关,提示PlGF和hs-CRP之间相互作用,参与了冠心病术前和术后炎症反应。(4)术前和术后血清PlGF峰值水平与心血管事件相关,术前和术后PlGF水平升高是冠心病患者介入治疗后发生心血管事件的独立危险因素。
【Abstract】 Objective:Coronary heart disease（CHD） has become one of the common diseases which affects human health seriously in the whole world. The rate of morbidity and mortality increases steadily year by year. Although we took active measures, including anticoagulant,thrombolysis,intervention and surgery, but some patients still suffered from serious cardiovascular events. So it is important for seeking methods of predicting and interventing cardiovascular events early. Many research revealed that inflammation plays an important role in the occurrence and development of coronary heart disease. Activated inflammatory response cause rupture of unstable atherosclerotic plaque, with consequent platelet aggregation and thrombosis, acute coronary artery stenosis or occlusion, by which leading to the cardiovascular events. Previous researches have demonstrated that some inflammatory biomarkers could regarded as a risk factor in predicting cardiac events in patients with coronary heart disease. Recent investigations have shown that placental growth factor（ PlGF）, as a proinflammatory factor, promotes monocyte recruitment,macrophage infiltration and triggers intraplaque inflammation, thereby resulting in unstable atherosclerotic plaque progression and plaque rupture. It serves as an independent biomarker of adverse outcome in patients with coronary heart disease. But there is little research about PlGF in patients with coronary heart disease during percutaneous coronary intervension （PCI）. And the effect of placental growth factor on clinical prognosis in PCI patients has been researched less. In this experiment, we observed changes of serum PlGF and high-sensitive C reactive protein （hs-CRP） levels before and after PCI. In the same time, the correlation between PlGF and hs- CRP were studied. The postoperative follow-up was 6 months, relationship between serum PlGF levels and incidence of cardiovascular events were observed. Throughout these, we evaluate the short-term predictive value of placental growth factor and provide theoretical evidence for preventing the occurrence of acute cardiac events.Methods: 110 patients with coronary heart disease （ CHD ）, who came from the inpatients of 2th hospital affiliated with the HEBEI Medical University. All patients were firstly treated by percutaneous coronary intervention （PCI）. 76 males and 34 females, with average age of 56.0±8.79 years. The patients were divided into three groups by the results of coronary angiography: single vessel lesion group （43 cases ）, double vessel lesion group （39 cases）, three vessle lesion group （ 28 cases）. All subjects had excluded: malignant tumors; valvular heart disease; acute or chronic infection; recent trauma or surgery; connective tissue diseases; hematologic diseases; left ventricular ejection fraction<40%. Another 30 healthy people were in control group （ 21 males and 9 females ）, with average age of 53.9±7.12 years. They were eliminated coronary heart disease by routine 12 lead ECG,exercise ECG,Emission Computed Tomography （ ECT ） or coronary angiography. There was no statistical difference in age and sex between all CHD and control group. Four mls of ulnar venous blood were withdrawn from CHD group before PCI and on the first, third, 5 th days after PCI respectively. In the control group, blood specimens were taken from vein only once（measurement served as normal control）. Then all samples were poured into tube, using centrifugal machine, 3000r/min, centrifuging 15min, and the serum in Eppendorf was preserved in -80℃refrigerator. Serum PlGF were detected by enzyme-linked immuneosorbent assay （ ELISA ）, while the levels of hs-CRP were detected by immunoturbidimetric assay （ITA）. The serum level of PlGF and hs-CRP were observed before and after PCI.. The relationship between PlGF and hs-CRP was analyzed. The postoperative follow-up was 6 months, cardiovascular events was observed. Throughout these, we study the short-term prognostic value of PlGF on outcomes of patients with coronary heart disease.Results: （1）Comparison of indexes before PCI between CHD group and normal control group: Serum levels of PlGF and hs-CRP in patients with CHD [（13.06±4.05 ） pg/ml ,（5.50±2.78）mg/L)] were significantly higher than those in healthy control group[（9.67±2.55）pg/ml,（3.54±1.01）mg/L （p<0.01）].（2）Comparison of indexes before PCI among single vessel group,double vessel group and three vessle group: The serum PlGF and hs-CRP levels in single vessel group were significantly lower than those in double-vessel group （[11.83±3.95）pg/ml vs（12.93±4.28）pg/ml（;4.42±1.95） mg/L vs（5.25±1.96）mg/L]. The serum PlGF and hs-CRP levels in double-vessel group were significantly lower than those in three vessle group[（12.93±4.28）pg/ml vs （15.11±3.07）pg/ml;（5.25±1.96）mg/Lvs（5.82±1.77）mg/L].（3）Changes of serum PlGF,hs-CRP levels before and after PCI: Serum PlGF levels of CHD patients on the first day after PCI were elevated as compared with those before PCI （ 14.49±3.42vs 13.06±4.05, P<0.01）, obviously reached up peak on the 3rd day（16.44±3.25 vs 13.06±4.05, P< 0.01） and declined on the 5th day after PCI. Serum hs-CRP levels on the first day after PCI were elevated as compared with those before PCI, reaching up peak(8.17±1.88 vs 5.50±2.78,P<0.01. On the 3rd day after PCI, serum hs-CRP levels declined（6.64±2.34 vs 5.50±2.78,P<0.01）and returned to normal levels or so on the 5th day. The trend are same in single vessel group,double vessel group and three vessle group.（4） Correlation between PlGF and hs-CRP: The peak of serum PlGF levels before and after PCI was positively correlated with that of hs-CRP （r=0.816,P=0.001;r=0.216,P=0.023 respectively）. （5） The follow-up results: No one case were out of followed . During the follow-up period, angina pectoris recurred in 14 cases, of which 1 received the treatment of PCI again. All of the cases, 5 with one vessel lesion, 5 with double lesion and 4 with triple lesion. The peak of serum PlGF levels were significantly higher before and after PCI in patients with cadiac events than those in patients without cardiac events（P<0.01）.（6） The results of logistic regression revealed that LDL[odds ratio（OR）1.944; 95%confidence interval （CI） 1.044 to 5.265; P<0.05], PlGF [odds ratio（OR）4.839; 95%confidence interval （CI） 1.262 to 10.092; P<0.05], hs-CRP[odds ratio（OR）3.464; 95%confidence interval （CI） 1.609 to 5.905; P<0.05] and length of stent [odds ratio（OR）=1.250, 95%confidence interval （CI） 1.165, 10.454, P=0.026 ) might be powerful predictor of cardiovascular events after PCI in CHD patients.Conclusion: 1 The serum levels of PlGF and hs-CRP in patients with CAD were significantly higher than those in healthy control group. The level of serum PlGF is related with severity of coronary artery lesion. Serum PlGF and hs-CRP levels increases with the increasing of the degree of coronary artery lesion. Serum PlGF levels in patients with one vessel lesion were significantly lower than those with double lesion and triple lesion. The levels of serum PlGF are highest in three vessle group.These results indicate that PlGF and hs-CRP maybe take part in the occurrence and development of coronary heart disease. 2 Serum PlGF levels in 3 groups after PCI were elevated as compared with those before PCI, obviously reached up peak on the 3rd day after PCI and declined on the 5th day. 3 The peak of serum PlGF level before and after PCI was positively correlated with that of hs-CRP. 4 The peak of serum PlGF before and after PCI is related with cardiovascular events. Elevation of serum placental growth factor levels before PCI could be regarded as an independent risk factor in predicting cardiovascular events in patients with coronary heart disease.