急性肺血栓栓塞症继发慢性血栓栓塞性肺动脉高压的临床及基础研究
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摘要
目的：1.观察急性肺血栓栓塞症(PTE)患者正规抗凝治疗后3个月慢性血栓栓塞性肺动脉高压(CTEPH)的发生率,并分析其危险因素及预后；2.观察急性PTE患者长期随访的生存情况及CTEPH发生率并分析CTEPH的危险因素；3.观察是否能够成功制备日本大耳白兔两次PTE模型并观察两次PTE后兔体内纤溶系统的变化。
内容及方法：1.我们入选了104例急性PTE患者,根据临床表现,进行Wells评分及改良Geneva评分。2.测量患者的血气分析、心肌损伤标志物(CK-MB)、D-二聚体等；根据心电图计算心电图评分；心脏超声测量各房室大小,并根据三尖瓣返流评估肺动脉收缩压(PASP)；根据CT肺血管造影(CTPA)结果,计算Qanadli栓塞指数及Mastora栓塞指数。3.根据患者病情给予溶栓+抗凝治疗或单纯抗凝治疗,定期复查心脏超声、CTPA。通过电话及门诊进行随访,评估患者的WHO心功能分级；记录死亡、再入院等主要不良事件的时间及原因。4.采用日本大耳白兔为实验对象,通过颈静脉途径,应用介入导管技术制作两次PTE模型,经4F猪尾导管测定肺动脉压力。5.通过ELISA方法测定血浆中D-二聚体、t-PA与PAI-1的浓度；HE染色了解肺动脉的变化；免疫组织化学方法显示肺动脉内t-PA与PAI-1的表达；RT-PCR测定包括栓塞肺动脉在内的肺组织中t-PA与PAI-1 mRNA的表达。
结果：1.104例急性PTE患者中7例患者失访,住院期间死亡2例,出院后2个月死亡1例,共有94例患者达到3个月随访终点,19例诊断CTEPH,发生率为20.2%(19/94)。2. CTEPH患者预后较差,死亡率明显高于非CTEPH患者。62个月CTEPH患者生存率为53.5%,非CTEPH患者为97.8%,二者之间差异有统计学意义(P<0.001)。3.男性、初始PASP^再发PTE、右房大小、右室大小、CK-MB、D-二聚体以及Wells评分在CTEPH患者与非CTEPH患者中差异均有统计学意义(P<0.05)。二分类Logistic回归分析显示,再发PTE、男性和初始PASP是三个月时CTEPH的影响因素,再发PTE可以使CTEPH发生率增加1335倍,男性使CTEPH发生率增加35倍,初始PASP每升高20mmHg, CTEPH发生率增加16倍左右。4.长期随访发现,3个月随访诊断CTEPH的部分患者PASP逐渐回落至正常范围。因此,长期随访CTEPH发生率为14.4%(14/97)。5.初始PASP、再发PTE、右房大小、右室大小以及CK-MB在长期随访的CTEPH患者与非CTEPH患者中差异有统计学意义(P<0.05)。二分类Logistic回归分析显示,初始肺动脉压力和CK-MB是CTEPH发生的危险因素(P<0.05)。初始肺动脉压力每升高20mmHg,可以使CTEPH发生率增加5.0倍；CK-MB增高使CTEPH发生率增加8.3倍左右。6.本研究中以日本大耳白兔为研究对象,成功制备了两次PTE动物模型,并通过4F猪尾导管监测了肺动脉压力的变化,为多次PTE制备兔CTEPH模型提供了可能。7.ELISA结果显示,造模后D-二聚体
过性增高,但很快恢复正常。t-PA出现一过性降低后逐渐增高,PAI-1则逐步下降,但造模后1周均恢复正常；免疫组织化学显示,1次PTE组肺动脉内膜PAI-1表达下降,两次PTE组表达进一步下降。1次PTE组、两次PTE组t-PA表达较对照组增强；3组实验兔肺组织中的t-PAmRNA表达未见明显不同。但PAI-1mRNA表达一次PTE组有所降低,两次PTE组进一步降低。
结论：1.急性PTE患者经过3个月正规抗凝治疗后CTEPH的发生率为20.2%。CTEPH患者预后较差,生存时间短,死亡率明显高于非CTEPH患者。2.再发PTE、男性和初始PASP升高是3个月时发生CTEPH的危险因素。3.长期随访发现,3个月随访诊断CTEPH的部分患者PASP逐渐回落至正常范围,CTEPH发生率降至14.4%(14/97)。4.初始PASP以及心肌损伤标记物升高是长期随访CTEPH发生的危险因素。5.采用介入导管手段成功制备了两次PTE的动物模型。6.两次PTE后,实验兔表现为机体纤溶系统平衡,栓塞局部纤溶活性亢进。
Objective:1. To document the incidence of CTEPH after acute PTE despite 3 months of therapeutic anticoagulation and evaluate risk factors for CTEPH and prognosis of CTEPH.2. To estimate the mortality of acute PTE and the cumulative incidence of CTPH after long-term follow up and evaluate risk factors for CTEPH after long-term follow up.3. To document if we can make the rabbits model of CTEPH after twice acute PTE and investigate the change of t-PA and PAI-1 in rabbits model of twice acute PTE.
Methods:1. We enrolled 104 patients with CT angiography-proven PTE and calculated Wells score and revised Geneva score according to clinic symptoms.2. Recorded blood lab data (blood gas analysis, CK-MB, D-dimer and so on), Calculated the ECG score according to 12-lead ECG. PASP was estimated from the Doppler-estimated tricuspid valve regurgitant. Evaluated Qanadli obstruction index and Mastora obstruction index correlated with CTPA.3. Patients were treated with thrombolysis plus anticoagulation or anticoagulation only. Patients were followed up by telephone or clinic visit to assess the WHO cardiac functional grade. Echocardiography doppler and CTPA were performed regularly. The times and reasons of death and readmission were recorded during study period.4. Rabbits model of twice acute PTE was established by injection of auto-blood clots through 4F catheter by jugular vein. Monitored PASP by 4F pigtail catheter.5. The plasma levels of D-dimer, t-PA and PAI-1 was measured by ELISA. Observed pulmonary artery changes by HE stain. The expressions of t-PA and PAI-1 in pulmonary arterys were assessed by immunohistochemistry. The expressions of mRNA of t-PA and PAI-1 were assessed by RT-PCR.
Results:1. Of the104 patients, seven patients were lost, two patients died during hospitalization, one died after hospital discharge but before follow up. Thus 94 patients were followed up on three months end point.19 patients were diagnosised CTEPH and the ratio of CTEPH was 20.2%(19/94).2. The mortality of CTEPH was higher than that of non-CTEPH after long-term follow up. The survival rate of 62 months was significantly different between two groups(53.5%vs 97.8%, P＜0.001).3. Gender, baseline PASP, recurrent PTE, diameter of right atrium, diameter of right ventricular, CK-MB, D-dimer and Wells scores were significantly different between CTEPH and non-CTEPH(P<0.05). Recurrent PTE (odds ratio,1335.4), male(odds ratio,35.2), higher baseline PASP (odds ratio,15.9 per 20mmHg increment) were risk factors for three months CTEPH.4. A few patients'PASP was decreased to normal after long-term anticoagulation therapy who were diagnosised CTEPH on three months. So the ratio of CTEPH after long-term follow up was down to 14.4%(14/97). 5. Baseline PASP, recurrent PTE, diameter of right atrium, diameter of right ventricular and CK-MB were significantly different between long-term CTEPH and non-CTEPH(P<0.05). Higher CK-MB (odds ratio,8.3), baseline pulmonary artery pressure(odds ratio,5.0 per 20mmHg increment)were risk factors for long-term CTEPH.6. Rabbits model of twice acute PTE was established by injection of auto-blood clots. Pulmonary artery pressure was monitored by 4F pigtail catheter. This method could help us to establish rabbits'CTEPH model after many times'PTE in future.7. The plasma level of D-dimer was increased transiently after injection of auto-blood clots. That of t-PA was decreased transiently then increased step by step. That of PAI-1 was decreased gradually in two hours after injection of auto-blood clots. The plasma levels of t-PA and PAI-1 were normal at one week after injection of auto-blood clots. The expression of PAI-1 in pulmonary arterys of one time PTE was decreased compared with that of control by immunohistochemistry. That of twice PTE was decreased further. The expression of t-PA in pulmonary arterys of one time and twice PTE was increased compared with that of control. The expressions of t-PA mRNA in pulmonary sample were not significantly different among three groups. The expressions of PAI-1 mRNA of one time PTE was decreased compared with that of control. That of twice PTE was decreased further.
Conclusion:1. The ratio of CTEPH was 20.2% after acute PTE despite 3 months of therapeutic anticoagulation. The mortality of CTEPH was higher and the survival rate of CTEPH until 62 months was lower than that of non-CTEPH.2. Recurrent PTE, male and baseline PASP were the risk factors of 3 months CTPH.3. The ratio of CTEPH after long-term follow up was down to 14.4% because some patients'PASP was decreased to normal who were diagnosised CTEPH on 3 months.4. Higher CK-MB, higher baseline PASP increased the risk of long-term CTPH.5. Rabbits model of twice acute PTE was established by 4F catheter though jugular vein.6. The fibrolysis system of rabbits was returned to balance at one week after twice PTE. But that of pulmonary arterys with thrombus was more active.
内容及方法：1.我们入选了104例急性PTE患者,根据临床表现,进行Wells评分及改良Geneva评分。2.测量患者的血气分析、心肌损伤标志物(CK-MB)、D-二聚体等；根据心电图计算心电图评分；心脏超声测量各房室大小,并根据三尖瓣返流评估肺动脉收缩压(PASP)；根据CT肺血管造影(CTPA)结果,计算Qanadli栓塞指数及Mastora栓塞指数。3.根据患者病情给予溶栓+抗凝治疗或单纯抗凝治疗,定期复查心脏超声、CTPA。通过电话及门诊进行随访,评估患者的WHO心功能分级；记录死亡、再入院等主要不良事件的时间及原因。4.采用日本大耳白兔为实验对象,通过颈静脉途径,应用介入导管技术制作两次PTE模型,经4F猪尾导管测定肺动脉压力。5.通过ELISA方法测定血浆中D-二聚体、t-PA与PAI-1的浓度；HE染色了解肺动脉的变化；免疫组织化学方法显示肺动脉内t-PA与PAI-1的表达；RT-PCR测定包括栓塞肺动脉在内的肺组织中t-PA与PAI-1 mRNA的表达。
结果：1.104例急性PTE患者中7例患者失访,住院期间死亡2例,出院后2个月死亡1例,共有94例患者达到3个月随访终点,19例诊断CTEPH,发生率为20.2%(19/94)。2. CTEPH患者预后较差,死亡率明显高于非CTEPH患者。62个月CTEPH患者生存率为53.5%,非CTEPH患者为97.8%,二者之间差异有统计学意义(P<0.001)。3.男性、初始PASP^再发PTE、右房大小、右室大小、CK-MB、D-二聚体以及Wells评分在CTEPH患者与非CTEPH患者中差异均有统计学意义(P<0.05)。二分类Logistic回归分析显示,再发PTE、男性和初始PASP是三个月时CTEPH的影响因素,再发PTE可以使CTEPH发生率增加1335倍,男性使CTEPH发生率增加35倍,初始PASP每升高20mmHg, CTEPH发生率增加16倍左右。4.长期随访发现,3个月随访诊断CTEPH的部分患者PASP逐渐回落至正常范围。因此,长期随访CTEPH发生率为14.4%(14/97)。5.初始PASP、再发PTE、右房大小、右室大小以及CK-MB在长期随访的CTEPH患者与非CTEPH患者中差异有统计学意义(P<0.05)。二分类Logistic回归分析显示,初始肺动脉压力和CK-MB是CTEPH发生的危险因素(P<0.05)。初始肺动脉压力每升高20mmHg,可以使CTEPH发生率增加5.0倍；CK-MB增高使CTEPH发生率增加8.3倍左右。6.本研究中以日本大耳白兔为研究对象,成功制备了两次PTE动物模型,并通过4F猪尾导管监测了肺动脉压力的变化,为多次PTE制备兔CTEPH模型提供了可能。7.ELISA结果显示,造模后D-二聚体
过性增高,但很快恢复正常。t-PA出现一过性降低后逐渐增高,PAI-1则逐步下降,但造模后1周均恢复正常；免疫组织化学显示,1次PTE组肺动脉内膜PAI-1表达下降,两次PTE组表达进一步下降。1次PTE组、两次PTE组t-PA表达较对照组增强；3组实验兔肺组织中的t-PAmRNA表达未见明显不同。但PAI-1mRNA表达一次PTE组有所降低,两次PTE组进一步降低。
结论：1.急性PTE患者经过3个月正规抗凝治疗后CTEPH的发生率为20.2%。CTEPH患者预后较差,生存时间短,死亡率明显高于非CTEPH患者。2.再发PTE、男性和初始PASP升高是3个月时发生CTEPH的危险因素。3.长期随访发现,3个月随访诊断CTEPH的部分患者PASP逐渐回落至正常范围,CTEPH发生率降至14.4%(14/97)。4.初始PASP以及心肌损伤标记物升高是长期随访CTEPH发生的危险因素。5.采用介入导管手段成功制备了两次PTE的动物模型。6.两次PTE后,实验兔表现为机体纤溶系统平衡,栓塞局部纤溶活性亢进。
Objective:1. To document the incidence of CTEPH after acute PTE despite 3 months of therapeutic anticoagulation and evaluate risk factors for CTEPH and prognosis of CTEPH.2. To estimate the mortality of acute PTE and the cumulative incidence of CTPH after long-term follow up and evaluate risk factors for CTEPH after long-term follow up.3. To document if we can make the rabbits model of CTEPH after twice acute PTE and investigate the change of t-PA and PAI-1 in rabbits model of twice acute PTE.
Methods:1. We enrolled 104 patients with CT angiography-proven PTE and calculated Wells score and revised Geneva score according to clinic symptoms.2. Recorded blood lab data (blood gas analysis, CK-MB, D-dimer and so on), Calculated the ECG score according to 12-lead ECG. PASP was estimated from the Doppler-estimated tricuspid valve regurgitant. Evaluated Qanadli obstruction index and Mastora obstruction index correlated with CTPA.3. Patients were treated with thrombolysis plus anticoagulation or anticoagulation only. Patients were followed up by telephone or clinic visit to assess the WHO cardiac functional grade. Echocardiography doppler and CTPA were performed regularly. The times and reasons of death and readmission were recorded during study period.4. Rabbits model of twice acute PTE was established by injection of auto-blood clots through 4F catheter by jugular vein. Monitored PASP by 4F pigtail catheter.5. The plasma levels of D-dimer, t-PA and PAI-1 was measured by ELISA. Observed pulmonary artery changes by HE stain. The expressions of t-PA and PAI-1 in pulmonary arterys were assessed by immunohistochemistry. The expressions of mRNA of t-PA and PAI-1 were assessed by RT-PCR.
Results:1. Of the104 patients, seven patients were lost, two patients died during hospitalization, one died after hospital discharge but before follow up. Thus 94 patients were followed up on three months end point.19 patients were diagnosised CTEPH and the ratio of CTEPH was 20.2%(19/94).2. The mortality of CTEPH was higher than that of non-CTEPH after long-term follow up. The survival rate of 62 months was significantly different between two groups(53.5%vs 97.8%, P＜0.001).3. Gender, baseline PASP, recurrent PTE, diameter of right atrium, diameter of right ventricular, CK-MB, D-dimer and Wells scores were significantly different between CTEPH and non-CTEPH(P<0.05). Recurrent PTE (odds ratio,1335.4), male(odds ratio,35.2), higher baseline PASP (odds ratio,15.9 per 20mmHg increment) were risk factors for three months CTEPH.4. A few patients'PASP was decreased to normal after long-term anticoagulation therapy who were diagnosised CTEPH on three months. So the ratio of CTEPH after long-term follow up was down to 14.4%(14/97). 5. Baseline PASP, recurrent PTE, diameter of right atrium, diameter of right ventricular and CK-MB were significantly different between long-term CTEPH and non-CTEPH(P<0.05). Higher CK-MB (odds ratio,8.3), baseline pulmonary artery pressure(odds ratio,5.0 per 20mmHg increment)were risk factors for long-term CTEPH.6. Rabbits model of twice acute PTE was established by injection of auto-blood clots. Pulmonary artery pressure was monitored by 4F pigtail catheter. This method could help us to establish rabbits'CTEPH model after many times'PTE in future.7. The plasma level of D-dimer was increased transiently after injection of auto-blood clots. That of t-PA was decreased transiently then increased step by step. That of PAI-1 was decreased gradually in two hours after injection of auto-blood clots. The plasma levels of t-PA and PAI-1 were normal at one week after injection of auto-blood clots. The expression of PAI-1 in pulmonary arterys of one time PTE was decreased compared with that of control by immunohistochemistry. That of twice PTE was decreased further. The expression of t-PA in pulmonary arterys of one time and twice PTE was increased compared with that of control. The expressions of t-PA mRNA in pulmonary sample were not significantly different among three groups. The expressions of PAI-1 mRNA of one time PTE was decreased compared with that of control. That of twice PTE was decreased further.
Conclusion:1. The ratio of CTEPH was 20.2% after acute PTE despite 3 months of therapeutic anticoagulation. The mortality of CTEPH was higher and the survival rate of CTEPH until 62 months was lower than that of non-CTEPH.2. Recurrent PTE, male and baseline PASP were the risk factors of 3 months CTPH.3. The ratio of CTEPH after long-term follow up was down to 14.4% because some patients'PASP was decreased to normal who were diagnosised CTEPH on 3 months.4. Higher CK-MB, higher baseline PASP increased the risk of long-term CTPH.5. Rabbits model of twice acute PTE was established by 4F catheter though jugular vein.6. The fibrolysis system of rabbits was returned to balance at one week after twice PTE. But that of pulmonary arterys with thrombus was more active.
引文
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