缺血后适应对心肌微循环的影响及机制研究
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摘要
目的：建立兔心肌急性缺血再灌注模型，通过心肌声学造影来观察缺血后适应对心肌微循环的影响，同时探讨其作用机制。
方法：100只新西兰大白兔随机分为假手术(Sham)组、心肌梗死(AMI)组、缺血再灌注(I/R)组、缺血后适应(IPostC)组及缺血后适应+卟啉锌（Znpp）组五组，每组20只。假手术组为只开胸，在前降支下穿线不结扎而后关胸；心肌梗死组开胸结扎前降支后直接关胸；缺血再灌注组开胸结扎前降支1小时—再灌注2小时后关胸；缺血后适应组开胸结扎前降支1小时—再灌注30秒，再结扎30秒（重复4次），灌注2小时后关胸；缺血后适应+Znpp组在结扎前10分钟静脉给予Znpp0.2mg/kg推注，余步骤同IPostC组。术中持续心电监护，并分别于左前降支结扎前、结扎后10分钟和再灌注后2小时记录Ⅰ导联心电图。各组兔子于开胸前、结扎后3小时及实验后1周处死前经股静脉或颈内静脉抽取3ml血样，用EDTA-Na2抗凝剂1:9抗凝，室温3000转/分离心10分钟，获得贫含血小板的血清-20℃保存待用，测定血清肌钙蛋白I、高敏C-反应蛋白、超氧化物歧化酶（SOD）及丙二醛(MDA)浓度。饲养1周行心脏超声及左室心肌声学造影检查，取得图像后脱机应用EchoPAC-7超声图像工作站进行分析。在左室乳头肌水平短轴切面6个节段舒张期内选择感兴趣区域。以微气泡开始再灌注的第1帧为原点，绘制感兴趣区域心肌的时间-强度曲线。在微泡再填充的过程中，心肌视频强度(Y)的变化与造影剂再充填时间(t)之间的关系可以用Y=A×(1-e~(-Bt))来拟合, B为曲线上升的斜率，代表微气泡再充填平均速率即心肌血流速度,单位为S~(-1)；A为平台时期的视频强度，反映心肌血容量，单位为dB。A×B则代表感兴趣心肌内的绝对血流量，单位为dB×S~(-1)，感兴趣区容积相同时, A×B则可直接反映局部心肌血流灌注。一周后兔子经耳缘静脉缓慢推注3%戊巴比妥钠溶液麻醉后取心脏，分离出左心室心肌。5只心脏标本于冠脉穿线处下5mm剪取一小块左心室心肌行组织形态学检查并测定梗死面积。余15只心脏组织通过Western Blot检测Nrf2及HO-1蛋白表达。
结果：
1.各组兔子在体重和性别上无差异（P>0.05）。
2.血管结扎的四组心电图均可见Ⅰ导联ST段弓背上抬，结扎后3小时除心肌梗死组外心电图均可见ST段回落，其中回落>50%个数各组无显著性差异（P>0.05）。
3.血清肌钙蛋白I在结扎前各组无显著性差异，结扎的四组肌钙蛋白I高于假手术组，结扎四组中缺血后适应组肌钙蛋白I低于其余三组，有显著性差异（P<0.05），其优势保持到一周后。
4.血清高敏C-反应蛋白在结扎四组中结扎3小时后缺血后适应组浓度低于其余三组，有显著性差异（P<0.05），一周后无显著性差异(P>0.05)。
5.血清超氧化物歧化酶在结扎四组中结扎3小时后缺血后适应组及缺血后适应组+Znpp组浓度高于心肌梗死组及缺血再灌注组，有显著性差异（P<0.05），其优势保持到一周后。
6.血清丙二醛在结扎四组中结扎3小时后缺血后适应组丙二醛低于其余三组，有显著性差异（P<0.05），一周后无显著性差异(P>0.05)。
7.左室乳头肌短轴切面行心肌声学造影定量分析：假手术组前壁、前侧壁、下侧壁、下壁、后间隔及前间隔的心肌血容量（A值）、心肌血流速度（B值）及局部心肌血流灌注量（A×B值）无显著性差异(P<0.05)。结扎四组中前壁、前侧壁及前间隔A值、B值及A×B值均低于下侧壁、下壁及后间隔，有显著性差异(P<0.05)，前壁、前侧壁及前间隔A值、B值及A×B值两两比较无显著性差异（P>0.05），下侧壁、下壁及后间隔A值、B值及A×B值两两比较无显著性差异（P>0.05）。结扎四组中前壁、前侧壁及前间隔组间比较缺血后适应组A值、B值及A×B值均高于心肌梗死、缺血再灌注及缺血后适应+Znpp组，有显著性差异（P<0.05）；心肌梗死组A值、B值及AB值低于缺血后适应+Znpp组，有显著性差异(P<0.05)；心肌梗死组A值、B值及AB值低于缺血再灌注组，有显著性差异（P<0.05）；缺血再灌注组与缺血后适应+Znpp组比较A值、B值及AB值均无显著性差异(P>0.05)；缺血后适应组前壁、前侧壁及前间隔B值与假手术组比无显著性差异(P>0.05)。
8.左室乳头肌水平短轴切面心肌节段圆周应变峰值分析：缺血后适应组前壁、前侧壁及前间隔圆周应变峰值高于心肌梗死组、缺血再灌注组及缺血后适应+Znpp组，有显著性差异（P<0.05）。心肌梗死组、缺血再灌注组及缺血后适应+Znpp组之间前壁、前侧壁及前间隔圆周应变峰值无显著性差异(P>0.05)。
9.心肌梗死面积测定：结扎四组中缺血后适应组梗死面积小于其余三组，有显著性差异（P<0.05）。
10.光镜下检查结扎四组中缺血后适应组损伤轻于其余三组；正常心肌组织血管中未见造影剂储留及相关血栓形成。
11.心肌细胞核内Nrf2蛋白表达：假手术、心肌梗死组Nrf2表达明显低于缺血再灌注、缺血后适应及缺血后适应+Znpp组（P<0.05）；缺血后适应及缺血后适应+Znpp组Nrf2表达明显高于缺血再灌注组（P<0.05）；缺血后适应组与缺血后适应+Znpp组Nrf2表达明显无显著性差异(P>0.05)。
12.心肌细胞浆内HO-1蛋白表达：缺血后适应、缺血再灌注组HO-1蛋白表达明显高于假手术、心肌梗死及缺血后适应+Znpp组（P<0.05）；缺血后适应组HO-1蛋白表达明显高于缺血再灌注组（P<0.05）；假手术、心肌梗死及缺血后适应+Znpp组HO-1蛋白表达无显著性差异（P>0.05）。
结论：
1.通过心肌声学造影定量分析的方法发现缺血后适应组无论在心肌血容量、心肌血流速度及局部心肌血流灌注量均高于其他结扎组，圆周应变峰值也高于其他结扎组，说明缺血后适应在改善心肌梗死心肌微循环的同时进一步改善了心脏的收缩功能。
2.试验各组行组织学检查，光镜下未发现造影剂潴留及相关血栓形成，证实心肌声学造影检查的安全可行性。
3.通过测定组织中Nrf2和HO-1浓度及血清SOD和MDA浓度的变化，证实了Nrf2和HO-1途径参与介导了缺血后适应对心肌梗死后心肌的保护作用。
Objective:
Establishment of rabbit acute myocardial ischemia-reperfusion model, by myocardialcontrast echocardiography to observe the effect of ischemic postconditioning onmyocardial microcirculation, and to explore its mechanism of action.
Methods:
100New Zealand white rabbits were randomly divided into sham operation group,myocardial infarction group, ischemia reperfusion group, ischemic postconditioning groupand ischemic postconditioning+Znpp group, with20rats in each group. Sham operationgroups only thoracotomy without ligation, threading and inserted in the left anteriordescendingartery(LAD); Acute myocardial infarction groups ligate LAD directly before chest closure;In reperfusion groups ligate LAD in1hours and reperfuse2hours before chest closure;Ischemic postconditioning groups ligate LAD for1hours and reperfusion for30seconds,was30seconds (4times),2hours of reperfusion before chest closure; Ischemicpostconditioning+Znpp groups ligate after ZnPP0.2mg/kg injection in10minutes, YuBuzhou with the IPostC group and another step is same as Ischemic postconditioninggroup. Continuous ECG is monitored during operation. And respectively we record ⅠleadECG before ligating LAD, after ligating LAD10minutes and2hours after reperfusion.Each rabbit collects3ml blood samples in open chest,3hours after ligation andexperiment after1weeks ago by femoral vein or jugular vein. We determinate theconcentration of serum troponin I, high sensitive C-reactive protein, SOD and MDA. After1weeks, rabbits were examinated by echocardiography and myocardial contrastechocardiography, were analyzed offline application by EchoPAC-7ultrasound imageworkstation and we obtain images. We isolate left ventricular myocardium after anesthesiarabbits by inject3%pentobarbital sodium solution through ear intravenous.5heartspecimens in coronary wear line under the5mm clipping a small piece of left ventricularmyocardial tissue morphological examination and determination of infarct size.15hearttissues determinate the Nrf2and HO-1protein concentration by means of Western Blot.
Results:
1. The rabbit is no difference in body weight and sex (P>0.05)
2. Four groups of ECG vascular ligation were seen in lead ST segment arch lift，3hoursof ECG of four groups were observed after ligation of ST segment drop, there was nosignificant difference about>50%ST segment drop in each group (P>0.05)
3. The value of serum cardiac troponin I in before the ligation groups had no significantdifference between the four groups of troponin I, was higher than that in shamoperation group, ischemia group after ligation four adaptation of cardiac troponin Ilower than the other three groups, there were significant differences (P<0.05), itsadvantage into a week later.
4. Serum high sensitivity C-reactive protein in ligation group ischemia postconditioninggroup concentration lower than the other three groups, there was significant difference(P<0.05), no significant difference (P>0.05) after a week.
5. Serum superoxide dismutase to concentration of ischemia postconditioning group andischemia postconditioning+Znpp group was higher than ischemia reperfusion group,myocardial infarction group in ligation group after3hours of ischemia,there was asignificant difference (P<0.05), its advantage into a week later.
6. Serum levels of malondialdehyde in ligation group, postconditioning group ofmalondialdehyde was lower than the other three groups, there was significantdifference (P<0.05), there was no significant difference after a week(P>0.05).
7. Analysis of left ventricular short axis view by myocardial contrast echocardiography quantitative: The front wall, anterolateral wall, anterior septal, underside wall, inferiorwall and inferior septum, posterior septal A value, B value and AB value were nosignificant difference(P<0.05). The front wall, anterolateral wall, anterior septal andunderside wall, inferior wall and inferior septum, posterior septal A value, B value andA×B values were significantly different in four ligation groups(P<0.05). The frontwall, anterolateral wall, anterior septal comparison ischemic postconditioning groupand myocardial infarction, ischemic reperfusion and ischemic postconditioning+ZnppA value, B value and A×B value were significantly different in four ligation groups.(P<0.05)
8. Analysis of left ventricular short axis view of myocardial segment of circumferentialstrain：Ischemic postconditioning group front wall, anterolateral wall and anteriorseptum circumferential strain peak value was higher than that of myocardial infarctiongroup, ischemia reperfusion group and ischemic postconditioning+Znpp groups, therewas significant difference(P<0.05). Myocardial infarction group, ischemia reperfusiongroup and ischemic postconditioning+Znpp, the circumferential strain of front wall,anterolateral wall and anterior septum were no significant difference (P>0.05).
9. The area of myocardial infarction: infarction area of ischemic postconditioning groupis less than the other three groups in four ligation ischemia group, there weresignificant differences (P<0.05).
10. Light microscopic examination was performed in four groups. Damage of ischemicpostconditioning group was lighter than other three groups; Leave no thrombus andcontrast agent storage vessels in normal myocardial tissue.
11. Expression of Nrf2protein of myocardial cells: Sham operation group, myocardialinfarction, expression of Nrf2was significantly lower than that in ischemia reperfusion,ischemic postconditioning and ischemic postconditioning+Znpp (P<0.05); Ischemicpostconditioning and ischemic postconditioning+Znpp Nrf2expression wassignificantly higher than that in ischemia reperfusion group (P<0.05); Ischemicpostconditioning and ischemic postconditioning+Znpp Nrf2expression had no differences(P>0.05).
12. HO-1protein expression in cardiac myocytes: HO-2protein expression of ischemicpostconditioning group, ischemia reperfusion group was significantly higher than shamoperation, myocardial infarction and ischemic postconditioning group+Znpp (P<0.05);HO-2protein expression of ischemic postconditioning group was significantly higherthan ischemia reperfusion group (P<0.05); Expression of HO-1protein in ischemicpostconditioning group+Znpp group had no significant difference to myocardialinfarction group and sham operation(P>0.05).
Conclusion:
1. Through the quantitative myocardial contrast echocardiography analysis showed thatischemic preconditioning can improve the myocardial infarction myocardialmicrocirculation.
2. Myocardial contrast echocardiography examination is safe and feasible.
3. The Nrf2and HO-1pathways are involved in mediating ischemic postconditioning onmyocardial protection after myocardial infarction.
方法：100只新西兰大白兔随机分为假手术(Sham)组、心肌梗死(AMI)组、缺血再灌注(I/R)组、缺血后适应(IPostC)组及缺血后适应+卟啉锌（Znpp）组五组，每组20只。假手术组为只开胸，在前降支下穿线不结扎而后关胸；心肌梗死组开胸结扎前降支后直接关胸；缺血再灌注组开胸结扎前降支1小时—再灌注2小时后关胸；缺血后适应组开胸结扎前降支1小时—再灌注30秒，再结扎30秒（重复4次），灌注2小时后关胸；缺血后适应+Znpp组在结扎前10分钟静脉给予Znpp0.2mg/kg推注，余步骤同IPostC组。术中持续心电监护，并分别于左前降支结扎前、结扎后10分钟和再灌注后2小时记录Ⅰ导联心电图。各组兔子于开胸前、结扎后3小时及实验后1周处死前经股静脉或颈内静脉抽取3ml血样，用EDTA-Na2抗凝剂1:9抗凝，室温3000转/分离心10分钟，获得贫含血小板的血清-20℃保存待用，测定血清肌钙蛋白I、高敏C-反应蛋白、超氧化物歧化酶（SOD）及丙二醛(MDA)浓度。饲养1周行心脏超声及左室心肌声学造影检查，取得图像后脱机应用EchoPAC-7超声图像工作站进行分析。在左室乳头肌水平短轴切面6个节段舒张期内选择感兴趣区域。以微气泡开始再灌注的第1帧为原点，绘制感兴趣区域心肌的时间-强度曲线。在微泡再填充的过程中，心肌视频强度(Y)的变化与造影剂再充填时间(t)之间的关系可以用Y=A×(1-e~(-Bt))来拟合, B为曲线上升的斜率，代表微气泡再充填平均速率即心肌血流速度,单位为S~(-1)；A为平台时期的视频强度，反映心肌血容量，单位为dB。A×B则代表感兴趣心肌内的绝对血流量，单位为dB×S~(-1)，感兴趣区容积相同时, A×B则可直接反映局部心肌血流灌注。一周后兔子经耳缘静脉缓慢推注3%戊巴比妥钠溶液麻醉后取心脏，分离出左心室心肌。5只心脏标本于冠脉穿线处下5mm剪取一小块左心室心肌行组织形态学检查并测定梗死面积。余15只心脏组织通过Western Blot检测Nrf2及HO-1蛋白表达。
结果：
1.各组兔子在体重和性别上无差异（P>0.05）。
2.血管结扎的四组心电图均可见Ⅰ导联ST段弓背上抬，结扎后3小时除心肌梗死组外心电图均可见ST段回落，其中回落>50%个数各组无显著性差异（P>0.05）。
3.血清肌钙蛋白I在结扎前各组无显著性差异，结扎的四组肌钙蛋白I高于假手术组，结扎四组中缺血后适应组肌钙蛋白I低于其余三组，有显著性差异（P<0.05），其优势保持到一周后。
4.血清高敏C-反应蛋白在结扎四组中结扎3小时后缺血后适应组浓度低于其余三组，有显著性差异（P<0.05），一周后无显著性差异(P>0.05)。
5.血清超氧化物歧化酶在结扎四组中结扎3小时后缺血后适应组及缺血后适应组+Znpp组浓度高于心肌梗死组及缺血再灌注组，有显著性差异（P<0.05），其优势保持到一周后。
6.血清丙二醛在结扎四组中结扎3小时后缺血后适应组丙二醛低于其余三组，有显著性差异（P<0.05），一周后无显著性差异(P>0.05)。
7.左室乳头肌短轴切面行心肌声学造影定量分析：假手术组前壁、前侧壁、下侧壁、下壁、后间隔及前间隔的心肌血容量（A值）、心肌血流速度（B值）及局部心肌血流灌注量（A×B值）无显著性差异(P<0.05)。结扎四组中前壁、前侧壁及前间隔A值、B值及A×B值均低于下侧壁、下壁及后间隔，有显著性差异(P<0.05)，前壁、前侧壁及前间隔A值、B值及A×B值两两比较无显著性差异（P>0.05），下侧壁、下壁及后间隔A值、B值及A×B值两两比较无显著性差异（P>0.05）。结扎四组中前壁、前侧壁及前间隔组间比较缺血后适应组A值、B值及A×B值均高于心肌梗死、缺血再灌注及缺血后适应+Znpp组，有显著性差异（P<0.05）；心肌梗死组A值、B值及AB值低于缺血后适应+Znpp组，有显著性差异(P<0.05)；心肌梗死组A值、B值及AB值低于缺血再灌注组，有显著性差异（P<0.05）；缺血再灌注组与缺血后适应+Znpp组比较A值、B值及AB值均无显著性差异(P>0.05)；缺血后适应组前壁、前侧壁及前间隔B值与假手术组比无显著性差异(P>0.05)。
8.左室乳头肌水平短轴切面心肌节段圆周应变峰值分析：缺血后适应组前壁、前侧壁及前间隔圆周应变峰值高于心肌梗死组、缺血再灌注组及缺血后适应+Znpp组，有显著性差异（P<0.05）。心肌梗死组、缺血再灌注组及缺血后适应+Znpp组之间前壁、前侧壁及前间隔圆周应变峰值无显著性差异(P>0.05)。
9.心肌梗死面积测定：结扎四组中缺血后适应组梗死面积小于其余三组，有显著性差异（P<0.05）。
10.光镜下检查结扎四组中缺血后适应组损伤轻于其余三组；正常心肌组织血管中未见造影剂储留及相关血栓形成。
11.心肌细胞核内Nrf2蛋白表达：假手术、心肌梗死组Nrf2表达明显低于缺血再灌注、缺血后适应及缺血后适应+Znpp组（P<0.05）；缺血后适应及缺血后适应+Znpp组Nrf2表达明显高于缺血再灌注组（P<0.05）；缺血后适应组与缺血后适应+Znpp组Nrf2表达明显无显著性差异(P>0.05)。
12.心肌细胞浆内HO-1蛋白表达：缺血后适应、缺血再灌注组HO-1蛋白表达明显高于假手术、心肌梗死及缺血后适应+Znpp组（P<0.05）；缺血后适应组HO-1蛋白表达明显高于缺血再灌注组（P<0.05）；假手术、心肌梗死及缺血后适应+Znpp组HO-1蛋白表达无显著性差异（P>0.05）。
结论：
1.通过心肌声学造影定量分析的方法发现缺血后适应组无论在心肌血容量、心肌血流速度及局部心肌血流灌注量均高于其他结扎组，圆周应变峰值也高于其他结扎组，说明缺血后适应在改善心肌梗死心肌微循环的同时进一步改善了心脏的收缩功能。
2.试验各组行组织学检查，光镜下未发现造影剂潴留及相关血栓形成，证实心肌声学造影检查的安全可行性。
3.通过测定组织中Nrf2和HO-1浓度及血清SOD和MDA浓度的变化，证实了Nrf2和HO-1途径参与介导了缺血后适应对心肌梗死后心肌的保护作用。
Objective:
Establishment of rabbit acute myocardial ischemia-reperfusion model, by myocardialcontrast echocardiography to observe the effect of ischemic postconditioning onmyocardial microcirculation, and to explore its mechanism of action.
Methods:
100New Zealand white rabbits were randomly divided into sham operation group,myocardial infarction group, ischemia reperfusion group, ischemic postconditioning groupand ischemic postconditioning+Znpp group, with20rats in each group. Sham operationgroups only thoracotomy without ligation, threading and inserted in the left anteriordescendingartery(LAD); Acute myocardial infarction groups ligate LAD directly before chest closure;In reperfusion groups ligate LAD in1hours and reperfuse2hours before chest closure;Ischemic postconditioning groups ligate LAD for1hours and reperfusion for30seconds,was30seconds (4times),2hours of reperfusion before chest closure; Ischemicpostconditioning+Znpp groups ligate after ZnPP0.2mg/kg injection in10minutes, YuBuzhou with the IPostC group and another step is same as Ischemic postconditioninggroup. Continuous ECG is monitored during operation. And respectively we record ⅠleadECG before ligating LAD, after ligating LAD10minutes and2hours after reperfusion.Each rabbit collects3ml blood samples in open chest,3hours after ligation andexperiment after1weeks ago by femoral vein or jugular vein. We determinate theconcentration of serum troponin I, high sensitive C-reactive protein, SOD and MDA. After1weeks, rabbits were examinated by echocardiography and myocardial contrastechocardiography, were analyzed offline application by EchoPAC-7ultrasound imageworkstation and we obtain images. We isolate left ventricular myocardium after anesthesiarabbits by inject3%pentobarbital sodium solution through ear intravenous.5heartspecimens in coronary wear line under the5mm clipping a small piece of left ventricularmyocardial tissue morphological examination and determination of infarct size.15hearttissues determinate the Nrf2and HO-1protein concentration by means of Western Blot.
Results:
1. The rabbit is no difference in body weight and sex (P>0.05)
2. Four groups of ECG vascular ligation were seen in lead ST segment arch lift，3hoursof ECG of four groups were observed after ligation of ST segment drop, there was nosignificant difference about>50%ST segment drop in each group (P>0.05)
3. The value of serum cardiac troponin I in before the ligation groups had no significantdifference between the four groups of troponin I, was higher than that in shamoperation group, ischemia group after ligation four adaptation of cardiac troponin Ilower than the other three groups, there were significant differences (P<0.05), itsadvantage into a week later.
4. Serum high sensitivity C-reactive protein in ligation group ischemia postconditioninggroup concentration lower than the other three groups, there was significant difference(P<0.05), no significant difference (P>0.05) after a week.
5. Serum superoxide dismutase to concentration of ischemia postconditioning group andischemia postconditioning+Znpp group was higher than ischemia reperfusion group,myocardial infarction group in ligation group after3hours of ischemia,there was asignificant difference (P<0.05), its advantage into a week later.
6. Serum levels of malondialdehyde in ligation group, postconditioning group ofmalondialdehyde was lower than the other three groups, there was significantdifference (P<0.05), there was no significant difference after a week(P>0.05).
7. Analysis of left ventricular short axis view by myocardial contrast echocardiography quantitative: The front wall, anterolateral wall, anterior septal, underside wall, inferiorwall and inferior septum, posterior septal A value, B value and AB value were nosignificant difference(P<0.05). The front wall, anterolateral wall, anterior septal andunderside wall, inferior wall and inferior septum, posterior septal A value, B value andA×B values were significantly different in four ligation groups(P<0.05). The frontwall, anterolateral wall, anterior septal comparison ischemic postconditioning groupand myocardial infarction, ischemic reperfusion and ischemic postconditioning+ZnppA value, B value and A×B value were significantly different in four ligation groups.(P<0.05)
8. Analysis of left ventricular short axis view of myocardial segment of circumferentialstrain：Ischemic postconditioning group front wall, anterolateral wall and anteriorseptum circumferential strain peak value was higher than that of myocardial infarctiongroup, ischemia reperfusion group and ischemic postconditioning+Znpp groups, therewas significant difference(P<0.05). Myocardial infarction group, ischemia reperfusiongroup and ischemic postconditioning+Znpp, the circumferential strain of front wall,anterolateral wall and anterior septum were no significant difference (P>0.05).
9. The area of myocardial infarction: infarction area of ischemic postconditioning groupis less than the other three groups in four ligation ischemia group, there weresignificant differences (P<0.05).
10. Light microscopic examination was performed in four groups. Damage of ischemicpostconditioning group was lighter than other three groups; Leave no thrombus andcontrast agent storage vessels in normal myocardial tissue.
11. Expression of Nrf2protein of myocardial cells: Sham operation group, myocardialinfarction, expression of Nrf2was significantly lower than that in ischemia reperfusion,ischemic postconditioning and ischemic postconditioning+Znpp (P<0.05); Ischemicpostconditioning and ischemic postconditioning+Znpp Nrf2expression wassignificantly higher than that in ischemia reperfusion group (P<0.05); Ischemicpostconditioning and ischemic postconditioning+Znpp Nrf2expression had no differences(P>0.05).
12. HO-1protein expression in cardiac myocytes: HO-2protein expression of ischemicpostconditioning group, ischemia reperfusion group was significantly higher than shamoperation, myocardial infarction and ischemic postconditioning group+Znpp (P<0.05);HO-2protein expression of ischemic postconditioning group was significantly higherthan ischemia reperfusion group (P<0.05); Expression of HO-1protein in ischemicpostconditioning group+Znpp group had no significant difference to myocardialinfarction group and sham operation(P>0.05).
Conclusion:
1. Through the quantitative myocardial contrast echocardiography analysis showed thatischemic preconditioning can improve the myocardial infarction myocardialmicrocirculation.
2. Myocardial contrast echocardiography examination is safe and feasible.
3. The Nrf2and HO-1pathways are involved in mediating ischemic postconditioning onmyocardial protection after myocardial infarction.
引文
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[1] Camici PG, Crea F. Coronary microvascular dysfunction. N Engl J Med,2007,356(8):830-40.
[2] Kaufmann PA, Camici PG. Myocardial blood flow measurement by PET: technicalaspects and clinical applications. J Nucl Med,2005,46(1):75-88.
[3]唐红,解俊敏.心肌声学造影的临床应用进展.中国医疗器械信息,2006,(02):10-12.
[4] Schartl M, Fritzsch T, Friedmann W, et al.[Quantification of myocardial perfusiondefects using2-dimensional contrast echocardiography]. Z Kardiol,1984,73(9):560-7.
[5] Martin RP. Myocardial contrast echocardiography: a light in the (heart of) darkness. JAm Coll Cardiol,1989,13(4):857-9.
[6] Meza MF, Mobarek S, Sonnemaker R, et al. Myocardial contrast echocardiography inhuman beings: correlation of resting perfusion defects to sestamibi single photonemission computed tomography. Am Heart J,1996,132(3):528-35.
[7] Marwick TH, Brunken R, Meland N, et al. Accuracy and feasibility of contrastechocardiography for detection of perfusion defects in routine practice: comparisonwith wall motion and technetium-99m sestamibi single-photon emission computedtomography. The Nycomed NC100100Investigators. J Am Coll Cardiol,1998,32(5):1260-9.
[8] Swinburn JM, Lahiri A, Senior R. Intravenous myocardial contrast echocardiographypredicts recovery of dysynergic myocardium early after acute myocardial infarction.J Am Coll Cardiol,2001,38(1):19-25.
[9] Vogel R, Indermuhle A, Reinhardt J, et al. The quantification of absolute myocardialperfusion in humans by contrast echocardiography: algorithm and validation. J AmColl Cardiol,2005,45(5):754-62.
[10] Agati L, Tonti G, Galiuto L, et al. Quantification methods in contrastechocardiography. Eur J Echocardiogr,2005,6Suppl2:S14-20.
[11] Galiuto L, Garramone B, Scara A, et al. The extent of microvascular damage duringmyocardial contrast echocardiography is superior to other known indexes ofpost-infarct reperfusion in predicting left ventricular remodeling: results of themulticenter AMICI study. J Am Coll Cardiol,2008,51(5):552-9.
[12] Hayat SA, Senior R. Myocardial contrast echocardiography in ST elevationmyocardial infarction: ready for prime time. Eur Heart J,2008,29(3):299-314.
[13] Wei K, Jayaweera AR, Firoozan S, et al. Quantification of myocardial blood flowwith ultrasound-induced destruction of microbubbles administered as a constantvenous infusion. Circulation,1998,97(5):473-83.
[14] Masugata H, Lafitte S, Peters B, et al. Comparison of real-time and intermittenttriggered myocardial contrast echocardiography for quantification of coronarystenosis severity and transmural perfusion gradient. Circulation,2001,104(13):1550-6.
[15]李传亭,刘玉清.缺血性心脏病CT_MRI心肌灌注技术的应用进展.医学影像学杂志,2003,13(4):282-284.
[16] Cuocolo A, Acampa W, Imbriaco M, et al. The many ways to myocardial perfusionimaging. Q J Nucl Med Mol Imaging,2005,49(1):4-18.
[17] Iglesias-Garriz I, Fernandez-Vazquez F, Perez A, et al. Preinfarction angina limitsmyocardial infarction size in nondiabetic patients treated with primary coronaryangioplasty. Chest,2005,127(4):1116-21.
[18] Skyschally A, Leineweber K, Gres P, et al. Coronary microembolization. Basic ResCardiol,2006,101(5):373-82.
[19] Canton M, Skyschally A, Menabo R, et al. Oxidative modification of tropomyosinand myocardial dysfunction following coronary microembolization. Eur Heart J,2006,27(7):875-81.
[20] van 'HAW, Liem A, de Boer MJ, et al. Clinical value of12-lead electrocardiogramafter successful reperfusion therapy for acute myocardial infarction. ZwolleMyocardial infarction Study Group. Lancet,1997,350(9078):615-9.
[21] Kosuge M, Kimura K, Ishikawa T, et al. Reliability of resolution of ST-segmentelevation after coronary reperfusion in predicting myocardial salvage in anterior wallacute myocardial infarction. Am J Cardiol,2002,90(3):227-32.
[22] Giugliano RP, Sabatine MS, Gibson CM, et al. Combined assessment of thrombolysisin myocardial infarction flow grade, myocardial perfusion grade, and ST-segmentresolution to evaluate epicardial and myocardial reperfusion. Am J Cardiol,2004,93(11):1362-7, A5-6.
[23] Thiele H, Scholz M, Engelmann L, et al. ST-segment recovery and prognosis inpatients with ST-elevation myocardial infarction reperfused by prehospitalcombination fibrinolysis, prehospital initiated facilitated percutaneous coronaryintervention, or primary percutaneous coronary intervention. Am J Cardiol,2006,98(9):1132-9.
[1] Kobayashi A, Ohta T, Yamamoto M. Unique function of the Nrf2-Keap1pathwayin the inducible expression of antioxidant and detoxifying enzymes. MethodsEnzymol,2004,378:273-86.
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[17] Lakkisto P, Palojoki E, Backlund T, et al. Expression of heme oxygenase-1inresponse to myocardial infarction in rats. J Mol Cell Cardiol,2002,34(10):1357-65.
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[19] Brouard S, Otterbein LE, Anrather J, et al. Carbon monoxide generated by hemeoxygenase1suppresses endothelial cell apoptosis. J Exp Med,2000,192(7):1015-26.
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[21] Pachori AS, Melo LG, Zhang L, et al. Chronic recurrent myocardial ischemic injuryis significantly attenuated by pre-emptive adeno-associated virus hemeoxygenase-1gene delivery. J Am Coll Cardiol,2006,47(3):635-43.
[22] Busserolles J, Megias J, Terencio MC, et al. Heme oxygenase-1inhibits apoptosisin Caco-2cells via activation of Akt pathway. Int J Biochem Cell Biol,2006,38(9):1510-7.
[23] Pachori AS, Smith A, McDonald P, et al. Heme-oxygenase-1-induced protectionagainst hypoxia/reoxygenation is dependent on biliverdin reductase and itsinteraction with PI3K/Akt pathway. J Mol Cell Cardiol,2007,43(5):580-92.
[24]何作云,罗惠兰,杨胜利.血红素加氧酶系统对ox-LDL介导的血管平滑肌细胞增殖的影响及其机制.中国微循环,2004,(02):72-74+82.
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[49] Yu R, Chen C, Mo YY, et al. Activation of mitogen-activated protein kinasepathways induces antioxidant response element-mediated gene expression via aNrf2-dependent mechanism. J Biol Chem,2000,275(51):39907-13.
[50] Zipper LM, Mulcahy RT. Inhibition of ERK and p38MAP kinases inhibits bindingof Nrf2and induction of GCS genes. Biochem Biophys Res Commun,2000,278(2):484-92.
[51] Reichard JF, Petersen DR. Involvement of phosphatidylinositol3-kinase andextracellular-regulated kinase in hepatic stellate cell antioxidant response andmyofibroblastic transdifferentiation. Arch Biochem Biophys,2006,446(2):111-8.
[52] Kobayashi A, Kang MI, Okawa H, et al. Oxidative stress sensor Keap1functions asan adaptor for Cul3-based E3ligase to regulate proteasomal degradation of Nrf2.Mol Cell Biol,2004,24(16):7130-9.
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[43] Abraham NG, Kappas A. Pharmacological and clinical aspects of heme oxygenase.Pharmacol Rev,2008,60(1):79-127.
[44] Murphy BJ, Laderoute KR, Short SM, et al. The identification of heme oxygenaseas a major hypoxic stress protein in Chinese hamster ovary cells. Br J Cancer,1991,64(1):69-73.
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[61]何作云,罗惠兰,杨胜利.血红素加氧酶系统对ox-LDL介导的血管平滑肌细胞增殖的影响及其机制.中国微循环,2004,(02):72-74+82.
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[1] Camici PG, Crea F. Coronary microvascular dysfunction. N Engl J Med,2007,356(8):830-40.
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