【作者】 李剑；

【导师】 沈节艳；

【作者基本信息】 上海交通大学 ， 内科学（心血管病）， 2017， 硕士

【摘要】 目的研究肝移植受者中心血管系统并发症的患病率、临床特征及其对预后的影响。分三部分进行阐述:1.晚期肝病患者的血流动力学特征及心脏改变;2.肝移植受者中门脉性肺动脉高压的患病率、临床特征及预后分析;3.乙肝后肝硬化肝移植受者中肝硬化心肌病的患病率、临床特征及预后分析。方法1.纳入上海仁济医院2012年1月至2015年6月期间接受原位肝移植的晚期肝病患者,按相同的年龄及性别比例选取同时期门诊进行体检的健康人群作为对照组。收集患者术前及对照组的心脏超声检查结果。2.纳入上海仁济医院2012年1月至2015年6月期间接受原位肝移植治疗的患者。依据2015年欧洲心脏病学会(ESC)/欧洲呼吸学会(ERS)发布的肺高压(pulmonary hypertension,PH)诊断指南,依据心脏超声三尖瓣返流速度(tricuspid regurgitation velocity,TRV)联合其他肺高压心超迹象诊断PH,排除其他病因,对于同时存在门脉高压、PH的患者诊断为门脉性肺动脉高压(portopulmonary hypertension,PoPH)。统计PoPH的患病率,分析其临床特征,随访所有患者并进行生存分析。3.纳入2014年5月至2016年4月期间接受原位肝移植的乙肝后肝硬化患者,排除患有其他已知心脏病的患者。收集患者术前心脏超声及心电图检查结果。根据2005年蒙特利尔世界消化学大会的专家共识,同时存在左心收缩或舒张功能不全的肝硬化患者诊断为肝硬化心肌病(cirrhotic cardiomyopathy,CCM),心电图提示QTc间期>440ms的患者诊断为QT间期延长。统计CCM及QTc间期延长的患病率,分析其临床特征,随访所有患者,复查心脏超声及心电图,并进行生存分析。结果1.共纳入223例晚期肝病患者及50例健康人群作为对照。与对照组相比,晚期肝病患者在年龄(p=0.14)及性别构成(p=0.79)上无统计学差异,但晚期肝病患者的收缩压(p=0.02)较低,心率(p=0.04)较快且EF(67.1±7.4 vs64.7±5.7,p=0.03)及CO(6.1±1.9 L/min vs 4.8±1 L/min,p<0.001)显著增加。心脏超声结果显示,与对照组相比,晚期肝病患者A峰速度(71.2±6.3 cm/s vs 62.5±5.4 cm/s,p=0.01)明显增加,而E峰速度(69.7±10.7cm/s vs 87.2±8.3cm/s,p=0.04)及E/A值(0.9±0.4vs 1.1±0.1,p=0.007)显著减小;心脏结构改变表现为主动脉根部内径(p<0.001)、左房内径(p<0.001)、室间隔厚度(p=0.02)、左室舒张末期内径(p<0.001)、左室后壁厚度(p=0.01)及肺动脉内径(p<0.001)增大明显。2.共纳入223例原位肝移植受者,平均年龄50.9±9岁,男性占76.2%,162例(72.6%)患者为乙肝感染。14例(6.3%)患者诊断为PoPH,所有患者在移植前后均未能接受肺血管扩张药物治疗。PoPH患者中女性比例较非PoPH患者高(50%比22%,p=0.03),且缺铁性贫血患者比例较高(43%比18%,p=0.03)。与非PoPH患者相比,PoPH患者的肝病病程(17.1±5.8年vs 12.1±7.3年,p=0.01)较长、Child-Pugh评分得分[9(6-11)vs 7(5-12),p=0.001]及MELD评分得分(19.4±7.3 vs 14±7.1,p=0.006)较高。多变量Logistic回归分析显示,女性患者(OR=3.76,p=0.04)、肝病病程(OR=1.1,p=0.02)、中度以上贫血(OR=4.27,p=0.02)及缺铁性贫血(OR=1.04,p=0.01)为PoPH的独立危险因素。肝移植术后平均随访26±13.5月,PoPH患者术后各阶段累计生存率明显低于非PoPH患者(术后6个月、1年、2年分别为64%vs 89%、50%vs85%、43%vs 82%,p<0.001,HR=16.7),术后中位生存时间仅为11.4个月。3.共纳入71例乙肝后肝硬化原位肝移植受者,平均年龄49.0±8.4岁,男性占83.1%。20例(28.2%)患者诊断为CCM,27例(38%)患者存在QTc间期延长。与QTc间期正常的患者相比,QTc间期延长患者其Child-Pugh评分得分[8(5-12)vs 6(5-10),p=0.003]、MELD评分得分(14.5±6.3 vs 10.5±4.5,p=0.006)较高。肝移植术后平均随访14±6.6月,与术前相比,患者的QTc间期显著缩短(394.8±21.0ms vs 432.0±18.8ms,p<0.001),CO(5.3±1.9L/min vs 6.6±2.3L/min,p=0.001)、心率(p=0.02)、E/e’(6.4±1.8 vs 7.4±3.4,p=0.03)及DT(172.6±39.7ms vs 187.3±39.0ms,p=0.04)显著降低;S波速度(11.8±2.6cm/s vs 10.6±1.8cm/s,p=0.004)、E峰速度(79±18.5cm/s vs71.1±11.0cm/s,p=0.01)及E/A值(1.2±0.3 vs 1.0±0.2,p=0.04)显著提高。生存分析显示,与QTc间期正常的患者相比,QTc间期延长患者术后各阶段累计生存率较低(6个月、1年、2年分别为74%vs 93%、68%vs 90%、61%vs90%,p=0.01,HR=4.11)。结论与正常人群相比,晚期肝病患者处于高动力循环状态,其心脏改变表现为左心增大,左室壁增厚明显。肝移植受者中,PoPH的患病率为6.3%。与非PoPH患者相比,PoPH患者中女性患者比例较高且患者肝病病情较重。女性患者、肝病病程长、中度以上贫血及缺铁性贫血会增加患PoPH的风险。未经肺血管靶向药物治疗的PoPH患者肝移植术后预后较差,术后中位生存时间仅为11.4个月。乙肝后肝硬化肝移植受者中,CCM及QTc间期延长较为常见,QTc间期延长患者肝病病情较重。肝移植术前存在QTc间期延长的患者术后预后不良。在肝移植术后平均随访14个月,患者心功能较术前明显改善,绝大部分术前QTc间期延长的患者QTc间期可恢复正常。更多还原

【Abstract】 Objective To investigate the prevalence,clinical characteristics and the prognosis of cardiovascular complications in liver transplant recipients.The main contents of this study include the following three parts: 1.hemodynamic characteristics and cardiac alterations of patients with advanced liver disease;2.prevalence,clinical characteristics and prognosis of portopulmonary hypertension(Po PH)in liver transplant recipients;3.prevalence,clinical characteristics and prognosis of cirrhotic cardiomyopathy(CCM)in liver transplant recipients with HBV-related cirrhosis.Methods 1.Patients with advanced liver disease who received orthotopic liver transplantation(OLT)were included,from January 2012 to June 2015.Healthy examiners with same age and gender ratio were selected as normal control group at the same period.The echocardiographic results of patients and healthy examiners were recorded.2.Patients who received OLT were included in this study from January 2012 to June 2015.According to the 2015 ESC/ERS guidelines for the diagnosis of pulmonary hypertension(PH),tricuspid regurgitation velocity(TRV)and other echocardiographic PH signs were used for the diagnosis of PH.Patients with portal hypertension and without other known causes of PH were diagnosed as Po PH.Clinical characteristics and prognosis of Po PH patients were compared with those of non-Po PH patients.3.Patients with HBV-related cirrhosis without other known cardiac disease who underwent OLT from May 2014 to April 2016 were included.Patients’ echocardiographic and ECG results were recorded.According to the expert consensus of 2005 World Congress of Gastroenterology at Montreal,patients with systolic or diastolic dysfunction were diagnosed as cirrhotic cardiomyopathy(CCM),and patients with QTc>440ms were diagnosed as QTc interval prolongation.The prevalence,clinical characteristics and prognosis of patients with CCM or QTc interval prolongation were investigated.Results 1.A total of 223 patients with advanced liver disease and 50 healthy examiners(control group)were included.There were no significant difference in age(p=0.14)and gender ratio(p=0.79)between patients and control group.Compared with control group,patients with advanced liver disease had lower systolic blood pressure(p=0.02),higher heart rate(p=0.14),increased EF(67.1±7.4 vs 64.7±5.7,p=0.03)and CO(6.1±1.9 L/min vs 4.8±1 L/min,p<0.001).Echocardiography results showed that compared with control group,patients with advanced liver disease had higher A velocity(71.2±6.3 cm/s vs 62.5±5.4 cm/s,p=0.01),lower E velocity(69.7±10.7 cm/s vs 87.2±8.3 cm/s,p=0.04)and E/A ratio(0.9 ± 0.4 vs 1.1 ± 0.1,p=0.007);they also had significantly increased aortic root inside diameter(p<0.001),left atrial diameter(p<0.001),interventricular septal thickness(p=0.02),left ventricular end-diastolic diameter(p<0.001),left ventricular posterior wall thickness(p=0.01)and pulmonary artery diameter(p<0.001).2.A total of 223 middle aged(50.9±9 years-old),mostly male(76.2%)patients were included,162 patients(72.6%)with HBV infection.14 patients(6.3%)were diagnosed with Po PH and none of them was treated with vasodilators before or after OLT.Compared with non-Po PH patients,Po PH patients had higher proportion of female(50% vs 22%,p=0.03)and iron-deficiency anemia(43% vs 18%,p=0.03);longer duration of liver disease(17.1±5.8 years vs 12.1±7.3 years,p=0.01),higher Child-Pugh score [9(6-11)vs 7(5-12),p=0.001] and MELD score(19.4 ±7.3 vs 14 ±7.1,p=0.006).Multivariate Logistic regression analysis showed that female(OR=3.76,p=0.04),duration of liver disease(OR=1.10,p=0.02),middle or severe anemia(OR=4.27,p=0.02)and iron-deficiency anemia(OR=1.04,p=0.01)were independent risk factors of Po PH.After OLT,patients were followed up for 26±13.5 months.Compared with non-Po PH patients,Po PH patients had a significantly lower cumulative survival rate(6 months,1 year,2 year survival rates were 64% vs 89%,50% vs 85%,43% vs 82%,respectively,p<0.001,HR 16.7),and the median survival time after surgery was 11.4 months.3.A total of 71 middle aged(49.0±8.4 years),mostly male(83.1%)patients with HBV-related cirrhosis were included.CCM was diagnosed in 20 patients(28.2%),and 27 patients(38%)had QTc interval prolongation.Compared with patients with normal QTc interval,patients with QTc interval prolongation had significantly increased Child-Pugh score [8(5-12)vs 6(5-10),p=0.003] and MELD score(14.5±6.3 vs 10.5±4.5,p=0.006).Patients were followed up for 14±6.6 months.Compared with preoperative values,at the end of follow up,patients’ QTc interval(394.8±21.0ms vs 432.0±18.8ms,p<0.001),CO (5.3±1.9L/min vs 6.6±2.3L/min,p=0.001),heart rate(p=0.02),E/e’ ratio(6.4±1.8 vs 7.4±3.4,p=0.03)and DT(172.6±39.7ms vs 187.3±39.0 ms,p=0.04)were significantly decreased;S velocity(11.8±2.6cm/s vs 10.6±1.8cm/s,p=0.004),E velocity(79±18.5cm/s vs 71.1±11.0cm/s,p=0.01)and E/A ratio(1.2±0.3 vs 1.0±0.2,p=0.04)were significantly increased.Survival curve analysis showed a lower cumulative survival rate in patients with prolonged QTc interval(6 months,1 year,2 year survival rates were 74% vs 93%,68% vs 90%,61% vs 90%,p=0.01,HR 4.11).Conclusion Compared with healthy people,patients with advanced liver disease had hyperdynamic state with left ventricular diamter and left ventricular wall thickness increased.The prevalence of Po PH was 6.3% in OLT recipients.Compared with non-Po PH patients,Po PH patients had a higher proportion of female and more serious liver disease.Female,longer duration of liver disease,middle or severe anemia and iron-deficiency anemia increased the risk of Po PH.The prognosis of Po PH patients without vasodilators therapy was poor after OLT,and the median survival time after surgery was only 11.4 months.CCM and QTc interval prolongation occurred frequently in liver transplant recipients with HBV-related cirrhosis.Compared with normal QTc interval patients,patients with QTc interval prolongation had more serious liver disease and poor prognosis.At the end of 14 months’ follow up period,patients’ cardiac function were significantly improved,and almost all patients’ QTc interval returned to normal.更多还原