【作者】 杨宇；

【导师】 许顶立；

【作者基本信息】 南方医科大学 ， 内科学（专业学位）， 2014， 博士

【摘要】 研究背景：经皮冠状动脉介入治疗(Percutaneous coronary intervention, PCI)是广泛用于恢复病变冠状动脉前向血流的主要方法,已成为治疗缺血性心脏病的基石。它可使狭窄或梗死相关动脉(Infarct-related artery, IRA)开通,使缺血心肌得到充分再灌注。但在临床工作中发现,急性心肌梗死(Acute myocardial infarction,AMI)患者PCI后虽然造影显示冠状动脉血管已开通,但仍有部分病例心肌组织无灌注或灌注不良,冠脉微循环的灌注不同,其近远期心血管事件发生率和死亡率也截然不同。因此越来越多的临床医生开始关注微循环的灌注。但是目前的技术尚无法在人体内直接观察冠脉微血管,冠脉微血管血流的测定也非常复杂,传统的无创性评估微循环的方法有：冠脉血流储备分数(coronary flow reserve, CFR)、对比增强心脏核磁共振(ceCMR)、冠脉造影及其血流影像判断、心肌对比心脏超声(MCE)及心电图等等。但以上方式对微循环的评估有一定的局限性,部分测量方式相对较复杂,对微循环评估只能进行定性评估,结果的分析主观因素影响较大,或是不能对微循环进行独立的评估。微循环阻力系数(index of microcirculatory resistance, IMR)是近年来在临床中使用的一种新的评价冠脉微循环状态的参数。与其他评估微循环系统的传统方法相比较,患者可在介入治疗术中测定,且检测操作相对简单,重复性好,能定量微循环阻力值,且测定时不受冠状动脉狭窄的影响。IMR测量的理论基础是根据Ohm’s定律,IMR被定义为心肌最大充血时,狭窄远端血管内压力除以转运时间的倒数,可简单表示为狭窄远端血管内压力乘以转运时间,即Pd·T,单位为mmHg·s或U。实际测量IMR需要使用镶嵌有压力/温度感受器的导丝,在冠状动脉介入操作中获得。近年研究发现,在STEMI患者PCI后,IMR值高的患者主要不良心脏事件的发生率明显增高。McGeoch等纳入57例STEMI患者,进行急诊PCI或补救PCI后测量IMR,然后分别在2天及3个月之后通过增强心脏核磁来评估有无微血管阻塞及左心室功能梗死程度情况研究发现,心肌梗死后有微血管阻塞表现的患者PCI后IMR值显著高于无微血管阻塞患者。Fearon等纳入253例STEMI患者进行研究,所有患者PCI术后进行IMR值测量,以IMR40.2为界值前瞻性预测主要终点事件为死亡或因心衰再次住院的发生率,结果表明与IMR<40.2相比,IMR>40.2组患者1年主要终点事件发生率更高。与PCI相关微循环灌注不良的冠脉血流的表现主要有冠脉慢血流(Slow Flow, SF)、无复流现象(No-reflow, NR)及血流相对正常。PCI相关的冠脉微循环障碍的病理机制目前尚无确定理论,但众多研究显示冠脉微循环障碍是多因素、多机制相互影响所致。血管内皮功能障碍及炎症反应均参与冠脉微循环障碍病理过程的发生发展。非对称性二甲基精氨酸(asymmetric dimethyl arginine, ADMA)是近年新发现的一种反映血管内皮损伤及功能障碍的分子标志物,是冠心病独立预测因子。它是内源性一氧化氮合酶竞争性抑制剂,可抑制一氧化氮合酶的活性,减少一氧化氮的合成,使内皮功能障碍。近年的研究表明内皮功能障碍与PCI相关并发症的发生密切相关,但目前大部分研究主要集中在ADMA对PCI术预后的预测价值,但ADMA是否参与PCI相关微循环灌注不良的病理过程目前尚不明确。高敏C-反应蛋白(hs-CRP)是急性炎症或损伤的标志物,也是冠心病患者危险评估因子和心血管事件的预测因子。研究发现,PCI显著增加急性冠脉综合征病人术后血清Hs-CRP水平,且冠状动脉病变越复杂,术后血清hs-CRP水平升高越明显,但hs-CRP在PCI相关微循环灌注不良发病机制中的作用目前尚不明确。目前冠脉微循环障碍方面的相关研究主要集中在PCI术对急性心肌梗塞患者的影响方面,但在稳定性心绞痛患者中,PCI术是否也会影响患者的冠脉微循环?术后IMR值不同的患者是否会有不同的预后?这些问题答案尚不明确。因此,本研究拟选择稳定性心绞痛患者行择期PCI术,通过比较PCI术前后微循环阻力系数值、hs-CRP及非对称性二甲基精氨酸等的变化,探讨PCI术对稳定性心绞痛患者冠脉微循环的影响及血清ADMA、hs-CRP在PCI相关冠脉微循环障碍中的作用及其可能机制。第一部分经皮冠状动脉介入治疗术对稳定性心绞痛患者冠脉微循环阻力的影响目的通过比较PCI术前后IMR的变化,初步探讨择期PCI术对稳定性心绞痛患者冠脉微循环的影响。方法选择35例2012年3月至2013年12月在广东医学院附属医院经药物优化治疗后仍有症状且罪犯血管为前降支近段或中段的稳定性心绞痛患者,所有患者均行PCI术。所有患者在术前均常规检测生化、肌红蛋白、CK-MB及超敏肌钙蛋白T,查心脏彩超；冠脉造影后检测前降支IMR；所有患者均于前降支置入药物涂层支架,PCI术后复测前降支IMR及肌红蛋白、CK-MB.超敏肌钙蛋白T,心脏彩超。术后随访6个月,观察主要不良心脏事件的发生情况。使用SPSS13.0软件(SPSS, Chicago, USA)对研究数据进行统计学分析。连续变量以均数±标准差(x±s)表示,计数变量以百分数表示。正态分布连续变量之间的比较使用t检验,其中探讨PCI术前后各临床指标比较时使用配对t检验,探讨糖尿病患者与非糖尿病患者、PCI相关性心肌梗死患者与非PCI相关性心肌梗死患者的临床指标比较时使用独立样本t检验方法；非正态分布连续性变量之间比较采用Mann-Whitney U检验。探讨IMR值与其他变量之间的关系采用Pearson直线相关及多元线性回归分析方法；分析相关系数r时,当r>0.8时称为高度相关,r<0.3时,称为低度相关,其它为中度相关。以双侧检验P<0.05为差异有统计学意义。结果1、PCI术后前降支的IMR值较术前增高,差异有统计学意义(P<0.05)。2、PCI术后CK-MB、肌红蛋白及超敏肌钙蛋白T均较PCI术前水平升高,差异有统计学意义(P<0.05)。其中PCI术后有5例患者出现了PCI相关性心肌梗死,1例患者出现冠脉无复流现象,无患者死亡。3、PCI术后BNP水平较术前高,差异有统计学意义(P<0.05)。LVEF值在PCI术后较术前降低,差异有统计学意义(P<0.05)。4、发生PCI相关性心肌梗死患者的术前后前降支IMR水平及HbAlc、术后超敏肌钙蛋白T、术前后CK-MB、术后肌红蛋白、术后BNP水平均较未发生PCI相关性心肌梗死患者高,差异有统计学意义(P<0.05);而发生PCI相关性心肌梗死患者的TG、术后FFR、术前及术后CFR水平均较未发生PCI相关性心肌梗死患者低,差异有统计学意义(P<0.05)。5、PCI术前后比较,糖尿病患者的IMR值均比非糖尿病患者的IMR高,差异有统计学意义(P<0.05)；糖尿病患者PCI术前后IMR的变化值(△IMR)比非糖尿病患者大,差异有统计学意义(P<0.05)。PCI术前后糖尿病患者的CFR、术前后CFR的变化值(△CFR)及术后LVEF值均较非糖尿病患者小,差异有统计学意义(P<0.05)。糖尿病患者术后超敏肌钙蛋白T、肌红蛋白、CK-MB及BNP水平均比非糖尿病患者高,差异有统计学意义(P<0.05)。6、PCI术前后前降支IMR值均与糖化血红蛋白、术后CK-MB、术后肌红蛋白、前降支狭窄程度及术后BNP水平呈中度正相关(P<0.05)；与术前后CFR及术前LVEF呈中度负相关(P<0.05)。PCI术后前降支IMR值与相关指标建立的多元线性回归方程是：(PCI术后前降支IMR值)=-21.468+2.897*(糖化血红蛋白)-1.321*(术后CFR)+0.393*(前降支狭窄程度)+39.915*(术后超敏肌钙蛋白)。7、随访期间无患者出现主要不良心脏事件。结论对于稳定性心绞痛患者,PCI术可使其术后即时冠脉微循环阻力明显增加；合并糖尿病的患者PCI术后即时冠脉微循环阻力增加更明显；基础冠脉微循环阻力高者,PCI术后更容易发生PCI相关性心肌梗死。第二部分经皮冠状动脉介入治疗术对稳定性心绞痛患者血清不对称二甲基精氨酸及高敏C-反应蛋白的影响目的通过比较PCI术前后血清ADMA及hs-CRP水平的变化,初步探讨血清ADMA及hs-CRP在PCI相关冠脉微循环障碍的病理过程中的作用及其可能机制方法入选患者及标准见本研究第一部分。所有35例患者于PCI术前1小时及术后24小时抽血行hs-CIRP及ADMA检测；用ELISA法检测血清中的ADMA水平。PCI术前后均检测前降支IMR。术后随访6个月。使用SPSS13.0软件(SPSS, Chicago, USA)对研究数据进行统计学分析。连续变量以均数±标准差(x±s)表示。正态分布连续变量之间的比较使用t检验,其中PCI术前后血清ADMA与hs-CRP值的比较时使用配对t检验；糖尿病患者与非糖尿病患者、PCI相关性心肌梗死患者与非PCI相关性心肌梗死患者的临床指标比较时使用独立样本t检验方法。非正态分布连续性变量之间比较采用Mann-Whitney U检验,探讨血清ADMA与hs-CRP水平与其他变量之间的关系采用Pearson直线相关及多元线性回归分析方法；分析相关系数r时,当r>0.8时称为高度相关,r<0.3时,称为低度相关,其它为中度相关。以双侧检验P<0.05为差异有统计学意义。结果1、PCI术后患者血清ADMA水平较PCI术前降低,差异有统计学意义(P<0.05); PCI术后患者血清hs-CRP水平较PCI术前升高,差异有统计学意义(P<0.05)。2、PCI术后血清ADMA水平与术后CK-MB、肌红蛋白、BNP呈中度正相关(P<0.05)；与术后FFR呈中度负相关(P<0.05)；与术前后IMR值无相关(P>0.05)。3、PCI术后hs-CRP水平与术前后IMR值、术后CK-MB、术前ADMA呈中度正相关(P<0.05);与术后CFR呈中度负相关(P<0.05)。术后hs-CRP与其他相关指标建立的多元线性回归方程式是：(术后hs-CRP)=9.814+0.118*(前降支术后IMR)-0.112*(术前FFR)。4、糖尿病与非糖尿病患者比较,PCI术前后患者血清ADMA、△ADMA、△hs-CRP及术后hs-CRP水平差异均无统计学意义(P>0.05)；而糖尿病患者术前hs-CRP水平较非糖尿病患者高,差异有统计学意义(P<0.05)。5、发生PCI相关性心肌梗死与未发生PCI相关性心肌梗死患者比较,术前后ADMA、术后hs-CRP值差异无统计学意义(P>0.05); PCI相关性心肌梗死患者术后ADMA水平较未发生PCI相关性心肌梗死患者高,差异有统计学意义(P<0.05)。PCI相关性心肌梗死患者术前后ADMA比较差异无统计学意义(P>0.05)；无PCI相关性心肌梗死患者术前ADMA水平较术后高,差异有统计学意义(P<0.05)。PCI相关性心肌梗死患者术前hs-CRP水平较无PCI相关性心肌梗死患者高,差异有统计学意义(P<0.05)。6、随访期间无患者出现主要不良心脏事件。结论对于稳定性心绞痛患者,ADMA不是一个反映PCI术后冠脉微循环内皮功能障碍的敏感指标；PCI术后ADMA水平下降的原因可能得益于狭窄血管供血的改善,从而使血管内皮功能获益；基础hs-CRP水平高者,PCI术后更容易出现PCI相关性心肌梗死；hs-CRP是反映PCI术后冠脉微循环障碍的一个敏感指标。更多还原

【Abstract】 Background:Percutaneous coronary intervention (PCI) is a widely used method which can restore coronary artery blood flow. It has become the cornerstone treatment for ischemic heart disease. Although coronary angiography indicates that the coronary artery has been reopened, the myocardial tissue continues to prime weak or no perfusion of the coronary microcirculation after PCI in some acute myocardial infarction (AMI) patients. Altered perfusion in the coronary microcirculation indicates poorer prognosis with respect to cardiovascular events and mortality. Therefore, many clinicians have begun to focus on the perfusion of the coronary microcirculation.However, the current technology can not directly observe in humans coronary microvascular. Traditional noninvasive assessment of microcirculation methods including coronary flow reserve (CFR), contrast-enhanced cardiac magnetic resonance (ceCMR), coronary angiography and flow imaging to determine myocardial contrast echocardiography (MCE) and ECG ect. However, these methods for assessment of the microcirculation has some limitations, such as some relatively complex measurement, only qualitative assessment of the microcirculation, the results of the analysis of subjective factors greater, or not to conduct an independent assessment of the microcirculation.Index of microcirculatory resistancet (IMR) is a new parameter to evaluate the coronary microcirculation in recent years. Compared with other traditional methods, it can be measured in interventional therapy and quantitatively microcirculation resistance value when measured against the impact of coronary artery stenosis. The detection of IMR is relatively simple and reproducible. The theoretical basis of IMR is Ohm’s laws, in which IMR is defined as the maximum congestive heart when under pressure divided by the reciprocal of the narrow distal vessel transit time, transit time can be expressed simply multiply within a narrow distal vessel pressure. IMR is obtained by the actual measurement set with pressure/temperature sensors in the guide wire in coronary interventional procedures.Recent studies have found that in STEMI patients post PCI, higher IMR values were associated with high incidence of major adverse cardiac events. McGeoch selected57cases of patients with STEMI, and measured the IMR value after primary PCI or rescue PCI, then assessed the presence or absence of left ventricular function and the degree of microvascular obstruction case with enhanced cardiac magnetic resonance imaging after two days and three months. study found IMR values after PCI in patients with microvascular obstruction were significantly higher than in patients without microvascular obstruction. Yong found that in253STEMI patients after PCI, those with IMR value>40.2were associated with higher primary endpoint events (death or rehospitalization for heart failure) than those with IMR value<40.2.The clinical manifestations of coronary microcirculation dysfunction after PCI including coronary slow flow (SF) and no-reflow phenomenon (NR). The mechanisms of PCI-related coronary microcirculation dysfunction remain unclear. However, numerous studies have shown that multiple factors are involved in the mechanisms of PCI-related coronary microcirculation dysfunction.In addition, some studies also showed that endothelial dysfunction and inflammation were involved in the development of coronary microcirculation pathological process. Asymmetric dimethyl arginine (ADMA) is a new molecular marker which can reflect endothelial dysfunction, and it is an independent predictor of coronary heart disease. Recent studies indicated that endothelial dysfunction was closely related with the occurrence of complications associated with PCI. However, most of these studies focused on the prognostic value of ADMA for PCI. But ADMA is involved in the pathological process of microcirculation PCI-related adverse unclear. Numerous studies indicated that PCI significantly increased the serum hs-CRP levels in ACS patients, and the levels of serum hs-CRP were positively correlated with the complexity of coronary lesions. But the role of hs-CRP in PCI-related adverse microcirculatory perfusion is unclear.Part one. The impact of PCI on coronary microcirculation resistance in stable angina patientsObject To study the impact of elective PCI on coronary microcirculation in patients with stable angina by comparing the values of IMR before and after PCI.Method A total of35patients were enrolled in this study. They were diagnosed coronary heart disease with stable angina and subsequently undergone PCI from March2012to December2013in Affiliated Hospital of Guangdong Medical College. The preoperative biochemical, myoglobin, CK-MB, hypersensitive troponin T, and echocardiography were routine checked, and the IMR values of the left anterior descending artery before PCI were detected in all patients and retested after PCI. All patients were followed up for6months. Datas were statistically analyzed with SPSS13.0software (SPSS, Chicago, USA). Continuous variables were expressed as mean±standard deviation (x±s), and count variables were expressed as a percentage. Comparison between continuous variables were used the normal t test, when comparison various clinical indicators before and after PCI were used paired t test, and when comparison clinical indicators between diabetic and non-diabetic patients, PCI-related myocardial infarction and non-PCI-related myocardial infarction patients were used independent sample t test method; Mann-Whitney U test was used to compare between non-normally distributed continuous variables. Exploring the relationship between IMR values and other variables were used Pearson linear correlation analysis. When analyzing the correlation coefficient r, r>0.8was called highly correlated, and r<0.3was called low correlation, the other for moderate correlation. With two-tailed P<0.05was considered statistically significant.Result1. The postoperative values of IMR of left anterior descending artery were significantly increased in comparisons with the preoperative levels (P<0.05).2. The levels of postoperative values of CK-MB, myoglobin and high-sensitivity troponin T sensitive were significantly higher than the preoperative levels (P<0.01). There were five patients suffered from PCI-related myocardial infarction after PCI, and one patient arose coronary no-re flow phenomenon, and no patients died.3. The postoperative values of BNP were significantly increased compared with the preoperative levels (P<0.05). Consistently, the postoperative values of LVEF were significantly decreased compared with the preoperative levels (P<0.05).4. The values of HbAlc, postoperative high-sensitivity troponin T, preoperative CK-MB, postoperative CK-MB, preoperative myoglobin, postoperative myoglobin, postoperative BNP, preoperative BNP, preoperative and postoperative left anterior descending artery IMR in patients with PCI-related myocardial infarction were all significantly higher than those in patients without PCI-related myocardial infarction (P<0.05), whereas the value of TG, postoperative FFR, preoperative and preoperative CFR in patients with PCI-related myocardial infarction were markedly lower than those in patients without PCI-related myocardial infarction patients (P<0.05).5. The values of HbAlc, postoperative high-sensitivity troponin T, postoperative myoglobin, postoperative CK-MB and postoperative BNP in diabetics were higher than in non-diabetic patients (P<0.01). The IMR values were significantly higher in diabetics than non-diabetic patients before and after PCI (P<0.01). The changes in perioperative values of IMR changing in diabetic patients (AIMR) was greater than in non-diabetic patients (P<0.05). The changes in values of preoperative and preoperative CFR, CFR perioperative (ACFR), postoperative LVEF in diabetic patients were markedly lower than in non-diabetic patients (P<0.01).6. The preoperative and preoperative IMR values of Anterior descending artery were positively correlated with the levels of HbAlc, postoperative CK-MB, postoperative myoglobin, postoperative anterior descending artery stenosis and postoperative BNP (P<0.05), and were negatively correlated with the values of the preoperative and preoperative CFR, preoperative LVEF (P<0.05). The preoperative IMR values were highly positive correlated with postoperative IMR values in patients (P<0.05).Conclusion PCI therapy promotes coronary microcirculation resistancet The increased levels of microcirculation resistance are greater in diabetic patients after PCI than those in non-diabetic patients. The elevated level of baseline coronary microcirculation resistance is associated with increased occurrence of PCI-related myocardial infarction in patients with stable angina. Part two The impact of PCI on serum levels of asymmetric dimethyl arginine and high-sensitivity C-reactive protein in patients with stable anginaObjective To study the impact of elective PCI on coronary microcirculation endothelial function and inflammatory in stable angina patients by comparing the levels of Serum ADMA and hs-CRP before PCI and after PCI.Methods Standards for selected patients are the same as the first part of this study. All patients were phlebotomized to detect the levels of hs-CRP and ADMA in one hour before PCI and24hours after PCI. And the serum level of ADMA was detected with ELISA. The FFR, CFR and IMR values of the anterior descending artery were detected before and after PCI in all patients.Study datas were statistically analyzed with SPSS13.0software (SPSS, Chicago, USA). Continuous variables were expressed as mean±standard deviation (x±s), and count variables were expressed as a percentage. Comparison between continuous variables were used the normal t test, when comparison the values of serum ADMA and hs-CRP before and after PCI were used paired t test, and when comparison the values of serum ADMA and hs-CRP between diabetic and non-diabetic patients, PCI-related myocardial infarction and non-PCI-related myocardial infarction patients were used independent sample t test method; Mann-Whitney U test was used to compare between non-normally distributed continuous variables. Exploring the relationship between the values of serum ADMA and hs-CRP with other variables were used Pearson linear correlation analysis. When analyzing the correlation coefficient r, r>0.8was called highly correlated, and r<0.3was called low correlation, the other for moderate correlation. With two-tailed P<0.05was considered statistically significant.Result1. The postoperative levels of ADMA was significantly lower than the preoperative levels (P<0.05), whereas the postoperative levels of hs-CRP was markedly higher than the preoperative levels (P<0.05).2. The levels of preoperative ADMA were positively correlated with CH, LDL, left anterior descending artery stenosis and postoperative hs-CRP (P<0.05), and were negatively correlated with the value of preoperative and postoperative FFR (P<0.05). The levels of postoperative ADMA were positively correlated with postoperative CK-MB, postoperative myoglobin and postoperative BNP (P<0.05); and were negatively correlated with the value of postoperative FFR in patients (P<0.05).3. The levels of preoperative hs-CRP were positively correlated with the levels of HbAlc, LDL, preoperative high-sensitivity troponin T, left anterior descending artery stenosis, postoperative BNP, postoperative and preoperative IMR (P<0.05), and were negatively correlated with the values of preoperative FFR, preoperative CFR, preoperative LVEF, postoperative FFR, postoperative CFR and postoperative LVEF (P<0.05), and were highly correlation with postoperative hs-CRP (P<0.05). In addition, the levels of postoperative hs-CRP were positively correlated with HbAlc, LDL, left anterior descending artery stenosis, postoperative CK-MB, preoperative ADMA, preoperative and postoperative IMR (P<0.05), and were negatively correlated with the value of preoperative FFR, preoperative LVEF, preoperative and postoperative CFR (P<0.05).4. There were no significant difference in the levels of preoperative and postoperative serum AMDA and postoperative hs-CRP between diabetes patients and non-diabetes patients (P>0.05). The preoperative hs-CRP levels in diabetes patients were higher than those in non-diabetic patients (P<0.05).5. There were no significant difference on the levels of preoperative and postoperative ADMA and postoperative hs-CRP between patients with and without PCI-related myocardial infarction (P>0.05). The levels of postoperative ADMA in PCI-related myocardial infarction patients were higher than those in patients without PCI-related myocardial infarction (P<0.05). The preoperative hs-CRP levels in PCI-related myocardial infarction patients were higher than those in patients without PCI-related myocardial infarction patients (P<0.05).Conclusion ADMA could not be as an indicator for assessing the state of the coronary microcirculation endothelial function in patients with stable angina. The decrease of postoperative serum ADMA levels may be due to the improvement of endothelial function which benefited from the blood supply to the stenotic lesions. The elevated base line hs-CRP level is associated with the increased occurrence of PCI-related myocardial infarction in patients with stable angina during PCI. Hs-CRP could be as an indicator for assessing the state of the coronary microcirculation.更多还原