冷血浆停搏液对幼兔缺血/再灌注损伤心肌心脏功能的影响及其机制的研究
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摘要
前言
心肌持续性缺血可导致组织损伤和细胞死亡,尽管早期再灌注对组织非常重要,但再灌注后血液循环中白细胞附壁、聚积、渗出血管而浸润心肌,导致心肌细胞坏死,加之补体激活以及活性氧的产生,致使缺血性心肌损伤更为严重,即缺血/再灌注损伤(MI/RI)。心脏直视手术时冠状动脉血运被阻断,心肌处于缺血乏氧状态;当手术结束心肌恢复正常血运时又导致心肌新的损伤——再灌注损伤。如何最大限度地减轻心肌MI/RI一直是临床至关重要的课题。
自1955年Melrose创用高钾停搏液以来,以高钾为主要成分的各种改良心肌保护液不断研制出来,明显改善了心肌保护的效果,提高了心脏手术的成功率。随着心脏外科技术的不断发展,先天性心脏病手术趋向幼龄化和复杂化。把适合于成熟心肌保护的停搏液直接应用于未成熟心肌保护是不合适的,缺乏理论和实验依据。近年来,未成熟心肌保护已成为心肌保护研究的热点之一。本研究中,由影像诊断和实验室基础研究两方面进行。首先应用高频超声检测幼兔的心功能的基本状态,以说明幼兔作为未成熟心肌的动物模型,其心肌的顺应性减低;然后采用幼兔离体缺血/再灌注心脏模型,测定其心肌的含水量以及心脏的冠脉储备功能;最后通过检测心肌细胞中TNF蛋白、TNF mRNA和Bcl-2蛋白表达的变化,以及心肌细胞凋亡情况,来探讨冷血浆停搏液对未成熟心肌的心脏功能的影响及其产生的机制,为冷血浆停搏液对未成熟心肌保护的临床研究提供实验依据和理论基础。
方法
论文一:
选择14～26日龄日本大耳白兔,体重350～580g,20只,雌雄不拘(清洁级,中国医科大学第二临床学院动物实验室提供)。腹腔内注射10%水合氯醛3ml/kg全身麻醉幼兔后,幼兔胸部备皮,仰卧位固定,对幼兔进行超声检查。于胸骨旁左心室长轴二维图像,在腱索水平将M型取样线垂直于室间隔和左心室后壁获得M型超声心动图,根据ASE推荐法测定舒张末期及收缩末期左心室内径(EDD、ESD)及室间隔(IVS)和后壁厚度(LVPW)。应用Teichholtz公式法计算左心室射血分数(EF%)及左心室短轴缩短率(FS%)。于心尖四腔观,将取样容积置于二尖瓣瓣尖获得二尖瓣多普勒血流流速曲线(E,A)并计算E/A;用DTI-PW测定二尖瓣前后叶瓣环运动速度,获得二尖瓣瓣环舒张早期速度(Ea)和舒张晚期速度(Aa)并计算Ea/Aa。于心尖五腔心切面将取样容积放在二尖瓣与左室流出道之间描记多普勒频谱图,测量射血时间(ET),二尖瓣口血流A峰终止处至下一心动周期二尖瓣口血流E峰开始处的时间间隔(a),a-ET=等容收缩时间(ICT)+等容舒张时间(IRT),利用公式Tei=(ICT+IRT)/ET=(a-ET)/ET计算出Tei指数。
论文二:
离体心脏制备与标本收集:腹腔注射10%水合氯醛3ml/kg,耳缘静脉注入肝素150U/kg抗凝,正中开胸摘取心脏,立即浸入4℃的盐水中,主动脉插管,连接Langendorff灌注装置,用37℃的K-H液灌注,灌注压为60cm H_2O(5.88kPa),灌注10分钟后收集10分钟的冠脉流出液。正常对照组立即终止灌注,取右室心肌作检测用。P组和B组降温同时开始分别灌注冷血浆停搏液或冷血停搏液(4℃)15ml/kg,灌注压为60cm H_2O(5.88kPa)。低温(10℃)停搏30分钟后,开始复温并再灌注37℃K-H液,10分钟后收集冠脉流出液,实验结束时取右室心肌作检测用。测定灌注停搏液至心脏机械停搏时间、心脏停搏前、后工作心的复跳时间、心率、冠脉流量、心肌含水量。
论文三:
采用免疫组化、原位杂交、TUNEL法和RT-PCR方法检测心肌组织中TNF蛋白、TNF mRNA和Bcl-2蛋白表达及细胞凋亡发生情况。按照试剂盒说明书步骤操作。
结果
论文一
1、M型超声检测的心功能指标:左心室射血分数正常值72.2±3.5%,短轴缩短率正常值37.5±3.0%。
2、多普勒超声检测的心功能指标:二尖瓣血流频谱舒张早期峰值流速58.5±6.4cm/s,舒张晚期峰值流速72.6±5.7cm/s,二者之比0.81±0.07;二尖瓣环舒张早期速度6.8±1.5cm/s,舒张晚期速度8.5±2.3cm/s,二者之比0.84±0.24;Tei指数0.31±0.05。
论文二
1、灌注冷血浆停搏液和冷血停搏液至心脏机械停搏时间分别为40.5±2.2秒和80.0±2.0秒,差异显著(P＜0.01)。
2、P组复跳时间、心率、冠脉流量和心肌含水量分别为46.4±8.7秒、142.4±22.7 bpm、12.3±2.4 ml/min和73%±5%,B组为88.6±10.2秒、122.8±14.7 bpm、6.4±2.2ml/min和82%±14%,差异显著(P＜0.05):P组与B组复跳后心率恢复率及冠脉流量的恢复率比较,均具有显著差异(P＜0.05)。
论文三
1、在无缺血/再灌注的未成熟心肌组织中没有TNF蛋白和TNF mRNA表达,染色呈阴性;但是,在经历缺血/再灌注的实验组,心肌组织中TNF蛋白和TNFmRNA表达明显,P组染色呈弱阳性或阳性,而B组呈强阳性或阳性。
2、在无缺血/再灌注的对照组心肌组织中没有看到凋亡细胞;在经历缺血/再灌注的实验组,出现少量心肌细胞凋亡。
3、缺血/再灌注损伤可以使心肌组织中Bcl-2 mRNA表达减弱;对照组心肌组织中Bcl-2蛋白相对含量为0.921±0.015,P组为0.712±0.021,B组为0.504±0.028,差异显著(P＜0.01或P＜0.05)。
结论
1、幼兔的心功能示心肌顺应性低,舒张功能减低,收缩功能正常。
2、冷血浆停搏液具有可使幼兔心脏快速停搏于舒张期的作用。
3、与冷血停搏液相比,冷血浆停搏液可明显提高幼兔心率及冠脉流量的恢复率,减轻心肌水肿。
4、在缺血/再灌注过程中,冷血浆停搏液能抑制TNF蛋白和TNF mRNA在心肌内的表达,上调Bcl-2蛋白在心肌内的表达,从而抑制或延缓未成熟心肌细胞凋亡的发生。
Preface
Persistent myocardial ischemia is known to result in cell injury and death. Reperfusion is very important for myocardium,but attachment of leukocyte-endothelial cell,aggregation of platelet-leukocyte and transendothelial leukocyte migration can result in cell death after reperfusion of ischemia myocardium,in addition to activation of complement and production of active oxygen free radicals also leads to severer myocardial damage,namely myocardial ischemia reperfusion injury.During the open heart operation,the coronary flow is blocked,which leads myocardium to be ischemic and hypoxemic.By the end of the operation,the coronary flow is recovered which leads to new myocardial injury,namely reperfusion injury.It is a key task in the field of cardiac surgery how to reduce myocardial ischemia reperfusion injury.
The modified hyperpotassium cardioplegia was developed since Melrose created the hyperpotassic cardioplegia in 1955,which improved the effect of myocardial protection and decreased operative mortality.It is out of place or lacks sound academic and experimental basis to protect the immature myocardium using the cardioplegia suitable to mature myocardium.Recently the research on immature myocardial protection is being as a hotspot in myocardial protection.In this study,to investigate the protective mechanism of cold plasma cardioplegia on immature myocardium,we measured myocardial tumor necrosis factor(TNF) mRNA,Bcl-2 protein and cardiomyocyte apoptosis.
Methods
Part one:
Twenty healthy infant rabbits(age 14—26 days) weighting 350—580g were used in this study.The animal was placed in the left side position after anesthetized. Two-dimensional images and M-mode tracings were recorded from the long-axis view at the papillary muscle level.LV end-diastolic diameter(EDD),diastolic interventricular septum and pssterior wall thickness(ⅣSd,LVPWd) ejection fraction (EF),fraction shortening(FS) were measured and calculated,averaging 3 cardiac cycles. Mitral valve orifice flow velocity was recorded by Doppler flow imaging from the apical four-chamber view.Peak early velocity(E) and late filling wave(A) were measured.DTI was applied in the pulsed wave Doppler mode to allow for a spectral display of the mitral annulus velocities at its septal and lateral corners.
Part two:
Preparation for the isolated heart and Collection of samples:.After anesthesia by injection intramuscularly and heparinization by heparin-sodium 150 u/kg intravenously, the infant rabbits heart were excised rapidly,rinsed thoroughly in chilled 4℃saline and then suspended on a cannula,and the perfused retrogradely in the isolated Langendroff model with 37℃oxygenated K-H buffer solution at a constant pressure of 60 cm H_2O for 10 minutes and 10 minutes coronary outflow solution was collected. Four control ones were stopped perfusion.After that,the isolated heart was s cooled down to 10℃,and 4℃cardioplegia(cold blood or plasma cardioplegia) was perfused at 15 ml/kg.After 30 minutes of hypothermic arrest,it is rewarmed and the K-H solution was perfused again.After 10 minutes equilibration,the time from the beginning of perfusion to heart beating and heart rate was recorded,10 minutes coronary outflow solution was collected.The rebeating time of arrested heart,heart rate, coronary outflow and myocardial water content in group P and in group B were respectively measured.
Part three:
We used immunohistochemical study to visualize the presence of TNF,in situ hybridization to visualize the presence and localization of TNF,TUNEL to observe apoptosis,reverse transcription-polymerase chain reaction(RT-PCR) to detect mRNA of Bcl-2.
Results
1.The values of EF,FS,E,A,E/A,Ea,Aa,Ea/Aa and Tei index respectively were 72.2±3.5%,37.5±3.0%,58.5±6.4cm/s,72.6±5.7cm/s,0.81±0.07,6.8±1.5cm/s, 8.5±2.3cm/s,0.84±0.24,0.31±0.05.
2.The time arrested heart by the cold plasma cardioplegia or cold blood was respectively 40.5±2.2 sec or 80.0±2.0 sec,significant difference(P＜0.05 ).
3.The rebeating time of arrested heart,heart rate,coronary outflow and myocardial water content in group P were respectively 46.4±8.7 sec,142.4±22.7bpm, 12.3±2.4 ml/min and 73%±5%,but in group B they were respectively 88.6±10.2sec, 122.8±14.7bpm,6.4±2.2 ml/min and 82%±14%.There was significant difference between group P and group B(P＜0.05).
4.Immunostaining of TNF protein was not detected in the hearts without I/R injury.There was more obvious immunostaining in group B than in group P in the hearts undergoing I/R.The expression of TNF mRNA was not detected in the hearts without I/R injury.In situ hybridization of TNF was localized to cardiac myocytes.
5.Apoptosis in cardiomyocytes was not observed by TUNEL in the control hearts. In contrast,there were a few apoptosis cardiomyocytes observed by TUNEL after I/R, and TUNEL staining was positive in these cells.
6.Bcl-2 mRNA relative content in cardiomyocytes in control group,group P and group B were respectively 0.921±0.015,0.712±0.021 and 0.504±0.028,with significant difference(P＜0.01 or P＜0.05).
Conclusions
1.Left ventricular function could be evaluated in infant rabbit using High-frequency Echocardiography.Left ventricular diastolic function was abnormal, but systolic function was normal in infant rabbit.
2.Cold plasma cardioplegia could arrest promptly beating heart at diastole.
3.Cold plasma cardioplegia was able to increase recovery of coronary outflow and heart rate and to decrease myocardial edema after I/R.
4.Cold plasma cardioplegia could restrain TNF expression in cardiomyocyte,and enhance Bcl-2 mRNA expression,which restrains apoptosis.
心肌持续性缺血可导致组织损伤和细胞死亡,尽管早期再灌注对组织非常重要,但再灌注后血液循环中白细胞附壁、聚积、渗出血管而浸润心肌,导致心肌细胞坏死,加之补体激活以及活性氧的产生,致使缺血性心肌损伤更为严重,即缺血/再灌注损伤(MI/RI)。心脏直视手术时冠状动脉血运被阻断,心肌处于缺血乏氧状态;当手术结束心肌恢复正常血运时又导致心肌新的损伤——再灌注损伤。如何最大限度地减轻心肌MI/RI一直是临床至关重要的课题。
自1955年Melrose创用高钾停搏液以来,以高钾为主要成分的各种改良心肌保护液不断研制出来,明显改善了心肌保护的效果,提高了心脏手术的成功率。随着心脏外科技术的不断发展,先天性心脏病手术趋向幼龄化和复杂化。把适合于成熟心肌保护的停搏液直接应用于未成熟心肌保护是不合适的,缺乏理论和实验依据。近年来,未成熟心肌保护已成为心肌保护研究的热点之一。本研究中,由影像诊断和实验室基础研究两方面进行。首先应用高频超声检测幼兔的心功能的基本状态,以说明幼兔作为未成熟心肌的动物模型,其心肌的顺应性减低;然后采用幼兔离体缺血/再灌注心脏模型,测定其心肌的含水量以及心脏的冠脉储备功能;最后通过检测心肌细胞中TNF蛋白、TNF mRNA和Bcl-2蛋白表达的变化,以及心肌细胞凋亡情况,来探讨冷血浆停搏液对未成熟心肌的心脏功能的影响及其产生的机制,为冷血浆停搏液对未成熟心肌保护的临床研究提供实验依据和理论基础。
方法
论文一:
选择14～26日龄日本大耳白兔,体重350～580g,20只,雌雄不拘(清洁级,中国医科大学第二临床学院动物实验室提供)。腹腔内注射10%水合氯醛3ml/kg全身麻醉幼兔后,幼兔胸部备皮,仰卧位固定,对幼兔进行超声检查。于胸骨旁左心室长轴二维图像,在腱索水平将M型取样线垂直于室间隔和左心室后壁获得M型超声心动图,根据ASE推荐法测定舒张末期及收缩末期左心室内径(EDD、ESD)及室间隔(IVS)和后壁厚度(LVPW)。应用Teichholtz公式法计算左心室射血分数(EF%)及左心室短轴缩短率(FS%)。于心尖四腔观,将取样容积置于二尖瓣瓣尖获得二尖瓣多普勒血流流速曲线(E,A)并计算E/A;用DTI-PW测定二尖瓣前后叶瓣环运动速度,获得二尖瓣瓣环舒张早期速度(Ea)和舒张晚期速度(Aa)并计算Ea/Aa。于心尖五腔心切面将取样容积放在二尖瓣与左室流出道之间描记多普勒频谱图,测量射血时间(ET),二尖瓣口血流A峰终止处至下一心动周期二尖瓣口血流E峰开始处的时间间隔(a),a-ET=等容收缩时间(ICT)+等容舒张时间(IRT),利用公式Tei=(ICT+IRT)/ET=(a-ET)/ET计算出Tei指数。
论文二:
离体心脏制备与标本收集:腹腔注射10%水合氯醛3ml/kg,耳缘静脉注入肝素150U/kg抗凝,正中开胸摘取心脏,立即浸入4℃的盐水中,主动脉插管,连接Langendorff灌注装置,用37℃的K-H液灌注,灌注压为60cm H_2O(5.88kPa),灌注10分钟后收集10分钟的冠脉流出液。正常对照组立即终止灌注,取右室心肌作检测用。P组和B组降温同时开始分别灌注冷血浆停搏液或冷血停搏液(4℃)15ml/kg,灌注压为60cm H_2O(5.88kPa)。低温(10℃)停搏30分钟后,开始复温并再灌注37℃K-H液,10分钟后收集冠脉流出液,实验结束时取右室心肌作检测用。测定灌注停搏液至心脏机械停搏时间、心脏停搏前、后工作心的复跳时间、心率、冠脉流量、心肌含水量。
论文三:
采用免疫组化、原位杂交、TUNEL法和RT-PCR方法检测心肌组织中TNF蛋白、TNF mRNA和Bcl-2蛋白表达及细胞凋亡发生情况。按照试剂盒说明书步骤操作。
结果
论文一
1、M型超声检测的心功能指标:左心室射血分数正常值72.2±3.5%,短轴缩短率正常值37.5±3.0%。
2、多普勒超声检测的心功能指标:二尖瓣血流频谱舒张早期峰值流速58.5±6.4cm/s,舒张晚期峰值流速72.6±5.7cm/s,二者之比0.81±0.07;二尖瓣环舒张早期速度6.8±1.5cm/s,舒张晚期速度8.5±2.3cm/s,二者之比0.84±0.24;Tei指数0.31±0.05。
论文二
1、灌注冷血浆停搏液和冷血停搏液至心脏机械停搏时间分别为40.5±2.2秒和80.0±2.0秒,差异显著(P＜0.01)。
2、P组复跳时间、心率、冠脉流量和心肌含水量分别为46.4±8.7秒、142.4±22.7 bpm、12.3±2.4 ml/min和73%±5%,B组为88.6±10.2秒、122.8±14.7 bpm、6.4±2.2ml/min和82%±14%,差异显著(P＜0.05):P组与B组复跳后心率恢复率及冠脉流量的恢复率比较,均具有显著差异(P＜0.05)。
论文三
1、在无缺血/再灌注的未成熟心肌组织中没有TNF蛋白和TNF mRNA表达,染色呈阴性;但是,在经历缺血/再灌注的实验组,心肌组织中TNF蛋白和TNFmRNA表达明显,P组染色呈弱阳性或阳性,而B组呈强阳性或阳性。
2、在无缺血/再灌注的对照组心肌组织中没有看到凋亡细胞;在经历缺血/再灌注的实验组,出现少量心肌细胞凋亡。
3、缺血/再灌注损伤可以使心肌组织中Bcl-2 mRNA表达减弱;对照组心肌组织中Bcl-2蛋白相对含量为0.921±0.015,P组为0.712±0.021,B组为0.504±0.028,差异显著(P＜0.01或P＜0.05)。
结论
1、幼兔的心功能示心肌顺应性低,舒张功能减低,收缩功能正常。
2、冷血浆停搏液具有可使幼兔心脏快速停搏于舒张期的作用。
3、与冷血停搏液相比,冷血浆停搏液可明显提高幼兔心率及冠脉流量的恢复率,减轻心肌水肿。
4、在缺血/再灌注过程中,冷血浆停搏液能抑制TNF蛋白和TNF mRNA在心肌内的表达,上调Bcl-2蛋白在心肌内的表达,从而抑制或延缓未成熟心肌细胞凋亡的发生。
Preface
Persistent myocardial ischemia is known to result in cell injury and death. Reperfusion is very important for myocardium,but attachment of leukocyte-endothelial cell,aggregation of platelet-leukocyte and transendothelial leukocyte migration can result in cell death after reperfusion of ischemia myocardium,in addition to activation of complement and production of active oxygen free radicals also leads to severer myocardial damage,namely myocardial ischemia reperfusion injury.During the open heart operation,the coronary flow is blocked,which leads myocardium to be ischemic and hypoxemic.By the end of the operation,the coronary flow is recovered which leads to new myocardial injury,namely reperfusion injury.It is a key task in the field of cardiac surgery how to reduce myocardial ischemia reperfusion injury.
The modified hyperpotassium cardioplegia was developed since Melrose created the hyperpotassic cardioplegia in 1955,which improved the effect of myocardial protection and decreased operative mortality.It is out of place or lacks sound academic and experimental basis to protect the immature myocardium using the cardioplegia suitable to mature myocardium.Recently the research on immature myocardial protection is being as a hotspot in myocardial protection.In this study,to investigate the protective mechanism of cold plasma cardioplegia on immature myocardium,we measured myocardial tumor necrosis factor(TNF) mRNA,Bcl-2 protein and cardiomyocyte apoptosis.
Methods
Part one:
Twenty healthy infant rabbits(age 14—26 days) weighting 350—580g were used in this study.The animal was placed in the left side position after anesthetized. Two-dimensional images and M-mode tracings were recorded from the long-axis view at the papillary muscle level.LV end-diastolic diameter(EDD),diastolic interventricular septum and pssterior wall thickness(ⅣSd,LVPWd) ejection fraction (EF),fraction shortening(FS) were measured and calculated,averaging 3 cardiac cycles. Mitral valve orifice flow velocity was recorded by Doppler flow imaging from the apical four-chamber view.Peak early velocity(E) and late filling wave(A) were measured.DTI was applied in the pulsed wave Doppler mode to allow for a spectral display of the mitral annulus velocities at its septal and lateral corners.
Part two:
Preparation for the isolated heart and Collection of samples:.After anesthesia by injection intramuscularly and heparinization by heparin-sodium 150 u/kg intravenously, the infant rabbits heart were excised rapidly,rinsed thoroughly in chilled 4℃saline and then suspended on a cannula,and the perfused retrogradely in the isolated Langendroff model with 37℃oxygenated K-H buffer solution at a constant pressure of 60 cm H_2O for 10 minutes and 10 minutes coronary outflow solution was collected. Four control ones were stopped perfusion.After that,the isolated heart was s cooled down to 10℃,and 4℃cardioplegia(cold blood or plasma cardioplegia) was perfused at 15 ml/kg.After 30 minutes of hypothermic arrest,it is rewarmed and the K-H solution was perfused again.After 10 minutes equilibration,the time from the beginning of perfusion to heart beating and heart rate was recorded,10 minutes coronary outflow solution was collected.The rebeating time of arrested heart,heart rate, coronary outflow and myocardial water content in group P and in group B were respectively measured.
Part three:
We used immunohistochemical study to visualize the presence of TNF,in situ hybridization to visualize the presence and localization of TNF,TUNEL to observe apoptosis,reverse transcription-polymerase chain reaction(RT-PCR) to detect mRNA of Bcl-2.
Results
1.The values of EF,FS,E,A,E/A,Ea,Aa,Ea/Aa and Tei index respectively were 72.2±3.5%,37.5±3.0%,58.5±6.4cm/s,72.6±5.7cm/s,0.81±0.07,6.8±1.5cm/s, 8.5±2.3cm/s,0.84±0.24,0.31±0.05.
2.The time arrested heart by the cold plasma cardioplegia or cold blood was respectively 40.5±2.2 sec or 80.0±2.0 sec,significant difference(P＜0.05 ).
3.The rebeating time of arrested heart,heart rate,coronary outflow and myocardial water content in group P were respectively 46.4±8.7 sec,142.4±22.7bpm, 12.3±2.4 ml/min and 73%±5%,but in group B they were respectively 88.6±10.2sec, 122.8±14.7bpm,6.4±2.2 ml/min and 82%±14%.There was significant difference between group P and group B(P＜0.05).
4.Immunostaining of TNF protein was not detected in the hearts without I/R injury.There was more obvious immunostaining in group B than in group P in the hearts undergoing I/R.The expression of TNF mRNA was not detected in the hearts without I/R injury.In situ hybridization of TNF was localized to cardiac myocytes.
5.Apoptosis in cardiomyocytes was not observed by TUNEL in the control hearts. In contrast,there were a few apoptosis cardiomyocytes observed by TUNEL after I/R, and TUNEL staining was positive in these cells.
6.Bcl-2 mRNA relative content in cardiomyocytes in control group,group P and group B were respectively 0.921±0.015,0.712±0.021 and 0.504±0.028,with significant difference(P＜0.01 or P＜0.05).
Conclusions
1.Left ventricular function could be evaluated in infant rabbit using High-frequency Echocardiography.Left ventricular diastolic function was abnormal, but systolic function was normal in infant rabbit.
2.Cold plasma cardioplegia could arrest promptly beating heart at diastole.
3.Cold plasma cardioplegia was able to increase recovery of coronary outflow and heart rate and to decrease myocardial edema after I/R.
4.Cold plasma cardioplegia could restrain TNF expression in cardiomyocyte,and enhance Bcl-2 mRNA expression,which restrains apoptosis.
引文
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