肺动脉高压患者右心功能与预后的评价

【作者】 杨涛；

【导师】 何建国；

【作者基本信息】 北京协和医学院 ， 内科学， 2014， 博士

【摘要】 第一部分：超声心动图评价肺动脉高压患者右心功能与心脏磁共振和右心导管测值的对比研究(PLos one.2013;8(8):e71276)目的：本研究通过分析超声心动图检测的右心功能指标与心脏磁共振检测的右心室射血分数和右心导管检测的血流动力学指标的相关性,探讨超声心动图指标在评价动脉性肺动脉高压患者右心功能的作用。方法：于2010年10月至2012年4月,前瞻性入选在阜外心血管病医院首次诊断为动脉性肺动脉高压的住院患者30例,包括特发性肺动脉高压24例,结缔组织病相关性肺动脉高压5例,遗传性肺动脉高压1例。所有入选患者于一周内完成右心导管、超声心动图和心脏磁共振检查。超声心动图检测指标包括：三尖瓣环收缩期位移幅度(tricuspid annular plane systolic excursion, TAPSE)、三尖瓣环收缩期峰值运动速度(tricuspid annular plane systolic velocity, S’)、右心室面积变化分数(right ventricular fractional area changes, RVFAC)、三尖瓣环等容收缩期加速度(isovolumic contraction acceleration, IVA)、右心室做功指数(right ventricular myocardial performance index, RVMPI)和右心室与左心室横径之比(ratio of right ventricular end-diastolic transverse diameter to left ventricular end-diastolic transverse diameter, RVETD/LVETD)。分析超声心动图检测的右心功能指标与心脏核磁共振检测的右心室射血分数及右心导管检测的血流动力学指标的相关性。结果：1.超声心动图检测的右心功能指标与心脏磁共振检测的右心室射血分数的相关性为：TAPSE (r=0.440, P=0.015), S’(r=0.444, P=0.016), IVA (r=0.600, P=0.001)、RVFAC (r=0.416, P=0.022)、RVETD/LVETD (r=-0.649, P<0.001)均与心脏磁共振检测的右心室射血分数的相关性均具有统计学意义,而RVMPI与心脏磁共振检测的右心室射血分数的相关性无统计学意义(r=-0.027,P=0.888)。在校正右房平均压、肺动脉平均压和肺血管阻力后,只有IVA和RVETD/LVETD可以独立反映右心室射血分数。2.超声心动图检测的右心功能指标与右心导管检测的血流动力学指标的相关性为：TAPSE(r=-0.615, P<0.001)、S’(r=-0.557, P=0.002)、RVFAC (r=-0.454, P=0.012和RVETD/LVETD (r=0.543, P=0.002)与肺血管阻力的相关性均具有统计学意义；TAPSE (r=-0.378, P=0.039)、RVFAC(r=-0.369,p=0.0045)和RVMPI (r=-0.367, P=0.046)与肺动脉平均压的相关性具有统计学意义；TAPSE (r=-0.403, P=0.027)、IVA (r=-0.408, P=0.025)和RVETD/LVETD (r-0.395, P=0.031)与右房平均压的相关性具有统计学意义。结论：IVA和RVETD/LVETD可以独立反映右心室射血分数；TAPSE、S’、RVFAC和RVETD/LVETD也可以反映肺血管阻力。第二部分：PET技术评价肺动脉高压患者右心功能的研究(Clin Nucl Med.2014,39(5)：426-430)目的：本研究应用正电子发射断层显像技术(positron emission tomography, PET)检测肺动脉高压患者空腹和糖负荷状态下心室18F-氟脱氧葡萄糖(18F-fluorodeoxy-glycose, FDG)标准摄取值,分析心室葡萄糖摄取指标与心脏磁共振检测的右心室射血分数及右心导管检测的血流动力学指标的相关性,探讨这些指标在评价肺动脉高压患者右心功能中的价值。方法：于2010年10月至2012年4月,前瞻性入选在阜外心血管病医院首次诊断为肺动脉高压的住院患者38例,包括特发性肺动脉高压21例,先天性心脏病相关性肺动脉高压修补术后5例,结缔组织病相关性肺动脉高压6例,遗传性毛细血管增多症相关性肺动脉高压1例,遗传性肺动脉高压1例和慢性血栓栓塞性肺动脉高压4例。所有入选患者均于1周内完成右心导管、PET和心脏磁共振检查。检测患者空腹和糖负荷状态下心室FDG标准摄取值(standard uptake value, SUV),并校正部分容积效应,计算右心室与左心室SUV之比(SUV-R/L)。分析葡萄糖摄取指标与心脏磁共振检测的右心室射血分数(right ventricular ejection fraction, RVEF)和右心导管检测的血流动力学指标的相关性。结果：糖负荷状态下患者右心室FDG标准摄取值(SUV-R)和左心室FDG标准摄取值(SUV-L)均高于空腹状态(1.43±0.79vs.1.09±0.37),差异具有统计学意义(P=0.005)。患者空腹和糖负荷状态下,SUV-R和SUV-R/L与心脏磁共振检测的RVEF均呈显著负相关(空腹状态：r=-0.341,P=0.036和r=-0.345,P=0.034；糖负荷状态：r=-0.362,P=0.028和r=-0.512,P=0.001)。患者空腹和糖负荷状态下,SUV-R和SUV-R/L与肺血管阻力均呈显著正相关(空腹状态：r=0.627,P<0.001和r=0.576,P<0.001；糖负荷状态：r=0.392,P=0.016和r=0.615,P<0.001)。但在校正年龄、体重指数、性别和血流动力学指标后只有SUV-R/L能够独立反映RVEF (P=0.048)。结论：肺动脉高压患者右心室与左心室葡萄糖摄取量之比可以反映肺动脉高压患者的右心功能,在糖负荷状态下较空腹状态下意义更大。第三部分：血浆CXCL10、CXCL12和CXCL16评价特发性肺动脉高压患者右心功能的研究(Heart&Lung.已接收)目的：对比研究特发性肺动脉高压患者和正常对照组血浆CXC-趋化因子配体10(CXC-Chemokine Ligand10,CXCL10)、CXCL12和CXCL16水平,探讨这三项生物学标记物在评价特发性肺动脉高压患者右心功能中的价值。方法：于2010年10月至2012年7月,前瞻性入选在阜外心血管病医院首次诊断为特发性肺动脉高压的住院患者61例和性别、年龄匹配的正常对照组20例。采集患者和正常对照组外周静脉血标本,离心处理后用酶联免疫吸附测定法检测血浆CXCL10、CXCL12和CXCL16水平。所有患者均行超声心动图和右心导管检查,其中29例患者行心脏磁共振检查。血标本采集、超声心动图、右心导管和心脏磁共振检查于一周内完成。分析患者血浆生物学标记物水平与影像学技术检测右心功能指标及右心导管检测血流动力学指标的相关性。结果：特发性肺动脉高压患者血浆CXCL10、CXCL12和CXCL16水平高于正常对照组,差异有统计学意义(202.79±104.58pg/ml vs.103.56±65.00pg/ml,P<0.001；2656.55±459.52pg/ml vs.2323.02±400.87pg/ml,p=-0.004和2.83±0.62ng/ml vs.2.28±0.47ng/ml,P=0.001).患者组血浆CXCL10、CXCL12和CXCL16水平均与N-末端B型脑钠肽原(r=0.452,P<0.001；r=-0.458,p=0.001和r=-0.590,P=0.001)、三尖瓣环收缩期位移幅度(r=0.364,P<0.001;r=-0.479,P<0.001和r=-0.569,P=0.017)和右心室射血分数(r=0.300,p=-0.026;r=0.280,p=-0.029和r=-0.507,P=0.003)呈显著正相关。血浆CXCL10和CXCL12水平与mRAP呈正相关(r=0.387,p=0.004和r=0.255,p=0.049)。但CXCL16水平与血流动力学指标的相关性均无统计学意义。三项生物学标记物水平与肺血管阻力和mPAP的相关性也无统计学意义。结论：特发性肺动脉高压患者血浆CXCL10.CXCL12和CXCL16水平较正常人升高,并可以反映患者的右心功能。第四部分：红细胞分布宽度评价艾森曼格综合症患者预后的研究(Clin Chem Lab Med.2014,52(5):743-750)目的：本研究旨在探讨红细胞分布宽度在预测艾森曼格综合征患者生存中的意义。方法：回顾性分析于2005年1月至2009年10月首次诊断为艾森曼格综合症住院患者的临床资料,自2009年10月开始,每6个月±2周对患者随访一次,随访方式包括电话、信函、门诊和住院,随访终点为全因死亡,随访信息由专门设计的网络数据库记录。随访截止时间为2012年12月31日,生存时间定义为行右心导管的时间到死亡或随访结束的时间。用ROC曲线分析产生红细胞分布宽度预测患者死亡的界值,应用Kaplan-Meier曲线描述红细胞分布宽度高于界值的患者和低于界值的患者的生存,用Log-Rank方法比较两组患者之间生存是否存在统计学差异。用多因素COX风险比例模型分析影响艾森曼格综合征患者生存的因素。结果：本研究共纳入艾森曼格综合征患者109例,中位随访时间为4.2年(3.7-5.0年),在此期间21例(19.3%)患者死亡。患者基线红细胞分布宽度与肺动脉平均压(r=0.271,P=0.004)和全肺阻力(r=0.465,P<0.001)呈显著正相关,与混合静脉血氧饱和度(r=-0.286,P=0.003)和体动脉血氧饱和度(r=-0.423,P<0.001)呈显著负相关。该组艾森曼格综合征患者的1年、3年和5年的生存率分别为94%,87%和78%。Kaplan-Meier生存分析显示基线红细胞分布宽度大于或等于13.9%的患者的生存率较红细胞分布宽度小于13.9%的患者更低,Log-rank检验差异具有统计学意义(P=0.001)。多因素Cox回归分析显示红细胞分布宽度为艾森曼格综合征患者生存的独立预测因子,风险比为1.162(95%可信区间：1.036-1.302；P=0.010)。结论：基线红细胞分布宽度与艾森曼格综合征患者的血流动力学指标相关,是艾森曼格综合征患者生存的独立预测因子。更多还原

【Abstract】 Part I:Echocardiographic Parameters in Patients with Pulmonary Arterial Hypertension:Correlations with Right Ventricular Ejection Fraction Derived From Cardiac Magnetic Resonance and HemodynamicsPurpose:To analyze the correlations between the echocardiographic parameters and RVEF as well as hemodynamics, in order to systematically elucidate the role of these parameters to assess the right ventricular function in patients with pulmonary arterial hypertension.Methods:Thirty patients were enrolled prospectively including24with idiopathic PAH,5with PAH associated with connective tissue diseases and1with hereditary PAH. Right heart catheterization, echocardiography and cardiac magnetic resonance (CMR) were performed within1week interval. The echocardiographic parameters measured included: tricuspid annular plane systolic excursion (TAPSE), tricuspid annular plane systolic velocity (S’), right ventricular fractional area changes,(RVFAC), isovolumic contraction acceleration (IVA), right ventricular myocardial performance index,(RVMPI) and ratio of right ventricular end-diastolic transverse diameter to left ventricular end-diastolic transverse diameter (RVETD/LVETD). The correlations between echocardiographic parameters and right ventricular ejection fraction (RVEF) derived from CMR as well as hemodynamics were analyzed.Results:All echocardiographic parameters except RVMPI correlated significantly with RVEF (TAPSE,r=0.440, P=0.015; S’,r=0.444, P=0.016; IVA,r=0.600, P=0.001; RVFAC, r=0.416, P=0.022; RVETD/LVETD, r=-0.649, P<0.001; RVMPI,r=-0.027, P=0.888). After adjusted for mean right atrial pressure, mean pulmonary arterial pressure and pulmonary vascular resistance (PVR), only IVA and RVETD/LVETD could independently predict RVEF. Four echocardiographic parameters displayed significant correlations with PVR (TAPSE, r=-0,615, P<0.001; S’,r=-0.557, P=0.002; RVFAC, r=-0.454, P=0.012; RVETD/LVETD, r=0.543, P=0.002). Moreover, TAPSE (r=-0.403, P=0.027), IVA (r=-0.408, P=0.025) and RVETD/LVETD (r=0.395, P=0.031) had significant relationships with mRAP. TAPSE, RVFAC and RVMPI showed significant correlations with mPAP (r=-0.378,P=0.039; r=-0.369, P=0.045; r=0.367, P=0.046).Conclusions:The echocardiographic parameters IVA and RVETD/LVETD can reflect RVEF independently regardless of hemodynamics in patients with PAH. In addition, TAPSE, S’, RVFAC and RVETD/LVETD can also reflect PVR in PAH patients. Part II:Significance of PET in evaluating right ventricular function in patients with Pulmonary HypertensionPurpose:This study was designed to measure18F-fluorodeoxyglycose (FDG) uptake of ventricles in patients with pulmonary hypertension by positron emission tomography (PET) in fasting and glucose loading conditions, and to investigate the correlations between FDG uptake parameters and right ventricular function as well as hemodynamics.Methods:Thirty eight patients were included prospectively idiopathic pulmonary arterial hypertension21patients, congenital heart disease associated pulmonary arterial hypertension after repair surgery5patients, pulmonary hypertension associated with connective tissue diseases6patients, pulmonary hypertension with hereditary haemorrhagic telangiectasia1patient, hereditary pulmonary hypertension1patient and chronic thromboembolic pulmonary hypertension4patients. All patients erolled underwent FDG PET imaging in fasting and glucose loading conditions. The FDG standardized uptake value (SUV) corrected for partial volume effect in both right ventricle (RV) and left ventricle (LV) were measured, in addition, the ratio of RV to LV SUV (SUV-R/L) was calculated. Right heart catheterization and cardiac magnetic resonance (CMR) were performed in all patients within1week. The correlations between FDG uptake parameters and right ventricular function as well as hemodynamics were analyzed.Results:SUV of RV (SUV-R) and SUV of LV (SUV-L) were significantly higher in glucose loading than in fasting condition. SUV-R and SUV-R/L in fasting condition showed significant relations with RV ejection fraction (RVEF) derived from CMR (r=-0.341, P=0.036and r=-0.345, P=0.034), and in glucose loading condition (r=-0.362, P=0.028and r=-0.512, P=0.001). In fasting condition, SUV-R and SUV-R/L showed significantly positive correlations with pulmonary vascular resistance (PVR)(r=0.627, P<0.001and r=0.576, P<0.001) as well as in glucose loading condition (r=0.392, P=0.016and r=0.615, P<0.001). Only SUV-R/L in glucose loading condition could independently predict RVEF after adjusted for age, body mass index, gender, mean right atrial pressure, mean pulmonary arterial pressure and PVR (P=0.048).Conclusions:The glucose uptake of right ventricle increases with right ventricular function decrease in PH patients, which is more significant in glucose loading than in fasting condition. Part Ⅲ:Increased Levels of Plasma CXC-Chemokine Ligand10,12and16are associated with Right Ventricular Function in Patients with Idiopathic Pulmonary Arterial HypertensionPurpose:To investigate the significance of plasma CXC-Chemokine Ligand10(CXCL10), CXC-Chemokine Ligand12(CXCL12) and CXC-Chemokine Ligand16(CXCL16) for assessing right ventricular function in patients with idiopathic pulmonary arterial hypertension (IPAH).Methods:Sixty one patients with IPAH from Pulmonary Vascular Diseases Center of Fu Wai hospital between October2010and July2012were enrolled prospectively. Peripheral venous blood samples were collected from61patients with IPAH and20healthy volunteers. Plasma levels of all three biomarkers CXCL10, CXCL12and CXCL16were measured by enzyme-linked immunosorbent assay. Echocardiography and right heart catheterization were performed in all patients, while cardiac magnetic resonance was performed in29patients. Echocardiography, cardiac magnetic resonance, RHC and blood samples collection were conducted in three-day interval. The Spearman correlation test was performed to assess correlations between levels of biomarkers and right functional parameters.Results:Plasma CXCL10, CXCL12and CXCL16concentrations were increased significantly in IPAH patients compared with controls (202.79±104.58pg/ml vs103.56±65.00pg/ml, P<0.001;2656.55±459.52pg/ml vs.2323.02±400.87pg/ml, P=0.004和2.83±0.62ng/ml vs2.28±0.47ng/ml, P=0.001). CXCL10, CXCL12and CXCL16correlated significantly with NT-proBNP (r=0.452, P<0.001;r=0.364, P<0.001and r=0.300, P=0.026), TAPSE derived from echocardiography (r=-0.458, P=0.001; r=-0.479, P<0.001and r=-0.302, P=0.026) and RVEF derived from cardiac magnetic resonance (r=-0.590, P=0.001;r=-0.569, P=0.017and r=-0.507, P=0.003).Conclusions:Increased levels of CXCL10, CXCL12and CXCL16can reflect right ventricular dysfunction in patients with IPAH. Part Ⅳ:Red Blood Cell Distribution Width Predicts Survival in Patients with Eisenmenger SyndromePurpose:This study aimed to investigate the significance of RDW for predicting survival in patients with Eisenmenger syndrome (ES).Methods:We retrospectively reviewed the clinical records and collected baseline data for patients newly diagnosed with ES in our hospital between January2005and October2009. Follow-up data were collected periodically using a specifically designed network database until December31,2012. The end point was all-cause death. A receiver operating characteristic (ROC) curve was generated to identify the optimal cutoff value of RDW for predicting survival. Survival curves were calculated using the Kaplan-Meier method and compared using log-rank tests. Univariate Cox regression analyses were performed to identify variables related to survival. All variables with a P value<0.05were tested in a forward stepwise multivariate Cox proportional hazards model, and hazard ratios with95%confidence intervals (CI) were expressed.Results:A total of109patients with ES were included in the study. Twenty-one patients (19.3%) died during a median follow-up period of4.2years (interquartile range3.7-5.0years). Baseline RDW was significantly correlated with mixed venous oxygen saturation (r=-0.286, P=0.003), arterial oxygen saturation (r=-0.423, P<0.001), mean pulmonary arterial pressure (r=0.271, P=0.004) and total pulmonary resistance (r=0.465, P<0.001). The1-,3-and5-year survival rates for all109patients were94%,87%and78%, respectively. Kaplan-Meier analysis showed that patients with RDW>13.9%had a lower survival rate than patients with RDW<13.9%(P=0.001). Multivariate Cox regression analysis showed that RDW was an independent prognostic marker in ES, with a hazard ratio of1.162(95%CI1.036-1.302; P=0.010).Conclusions:Baseline RDW correlates with hemodynamics and is an independent prognostic marker in ES.更多还原