经导管肾脏去交感神经支配术对急性心肌梗死后左室重塑的影响

发布时间：2018-05-31 08:21

  本文选题：急性心肌梗死 + 左室重塑　； 参考：《北京协和医学院》2015年博士论文

【摘要】：第一部分球囊封堵再灌注法建立猪急性心肌梗死后左室重塑模型的研究背景：理想的可重复的大动物模型是支持心血管领域中研究的基础。猪由于其冠脉的解剖、直径和分布与人类相似,是建立急性心肌梗死模型较为理想的实验动物。心脏介入导管技术球囊封堵法较传统的开胸冠脉结扎具有麻醉时间短、动物创伤小、术后恢复快、冠脉内封堵再通模拟临床情况的优势,减少手术操作对交感系统的额外激活,并可避免结扎伴随冠脉走形的心脏交感神经导致的心脏去神经化,是适用于大动物心梗模型构建的方法。目的：采用介入导管技术球囊封堵前降支方法,建立猪的急性心肌梗死后左室重塑的动物模型。方法：12只中华小型猪(体重30±5kg)以球囊封堵前降支1.5小时的方法建立急性心肌梗死模型。于基线状态、建模后1.5小时、术后8周监测血流动力学改变,并行心脏超声对心室重塑现象进行形态学及功能学评定。监测血脑钠肽(BNP)水平。8周后处死动物,行HE染色、马宋染色、天狼星红染色观察心肌细胞坏死、肥大以及细胞外基质重塑情况。结果：4只动物在建模过程中死亡。8只动物活到实验终点。球囊封堵后,实验动物平均动脉压(131.3±28.54 vs.101.6±16.09,p=0.028)、左室收缩压(155.0±35.6 vs.129.63±21.70,p=0.043)、心排量(3.02±1.30 vs.2.14±0.85 L/min.m2, p=0.014).左室射血分数(73.65±8.55 vs.62.28±10.69,p=0.019)以及缩短分数(38.39±4.63 vs.32.88±5.46,p=0.045)显著降低,提示急性心肌缺血后实验动物心脏收缩功能下降。术后8周实验猪左室舒张末面积(9.24±2.58 vs.12.66±3.06,p=0.025)增大,心尖室壁厚度(1.25±0.20 vs.0.87±0.23,p=0.024)降低,提示心脏扩大,梗死区变薄。左室射血分数(73.65±8.55 vs.52.35±13.95,p=0.002),缩短分数(38.39±4.63 vs.32.90±8.82,p=0.037)降低,血浆BNP水平显著上升(119.48±66.17 vs.266.73±168.89,p=0.038),提示左室收缩功能降低。组织病理学检查提示心脏梗死区伸展、变薄和左室的整体扩展,非梗死区胶原纤维显著增多,符合心肌梗死后左室重塑表现。结论：球囊封堵前降支的方法成功建立了小型猪的急性心肌梗死模型。通过形态学、病理组织学以及血清学指标验证了心肌梗死后左室重塑的发生、发展情况。第二部分经导管肾脏去交感神经支配术对急性心肌梗死后左室重塑的影响背景：急性心肌梗死发生后,心脏和全身交感神经活性即刻升高并程持续性,在心肌梗死后心室重构及其向心衰发展的整个过程中发挥了关键作用。经导管去肾交感神经支配术(RDN)是近几年新兴的一种非外科手术方法,经股动脉途径将射频消融导管伸至肾动脉内,通过局部电频热能消除分布于肾动脉壁浆膜层浅表的肾脏交感神经纤维,从而显著降低肾脏以及全身交感神经活性。目的：对球囊封堵法建立的急性心肌梗死小型猪模型实施RDN,观察RDN对急性心肌梗死后左室重塑的影响。方法：12只中华小型猪(体重30±5kg)以球囊封堵前降支1.5小时的方法建立急性心肌梗死模型,再灌注2小时后行RDN,作为消融组。于基线状态、建模后1.5小时、RDN术后监测血流动力学改变,并行心脏超声对心室重塑现象进行形态学及功能学评定。监测血BNP水平。8周后处死动物,对肾动脉行HE染色、Mavot染色观察肾动脉和肾脏交感神经损伤情况。第一部分成功建模的小型猪作为对照组。结果：3只动物死于心梗建模过程中心室颤动,9只动物活到实验终点。8周后冠脉造影示血流通畅。施行RDN后,部分实验动物出现一过性肾动脉痉挛,动脉内注射硝酸甘油后缓解,未出现股动脉假性动脉瘤、血肿和肾动脉夹层等急性并发症。8周后复查肾动脉造影,1只动物出现单侧肾脏动脉狭窄引发单侧肾脏萎缩,其余8只实验动物示肾动脉通畅。对照组和消融组在基线和心梗建模后心脏彩超指标无显著区别。8周后,两组均发生了显著的左室重塑现象。消融组左室舒张末面积增加了37.6%(p=0.025),左室收缩末面积增大了84.7%(p0.001),心尖室壁厚度变薄了26.3%(p=0.030),左室射血分数降低了15.9%(p=0.017),心脏彩超各指标两组间均无显著差异,提示RDN并未改善急性心肌梗死左室重构情况。消融及对照组心梗建模8周后血浆BNP与基线相比,均显著上升(119.48±66.17 vs.266.73±168.89,p=0.038)和(141.53±97.44 vs.282.21±152.17,p=0.049),且两组间无显著差别。肾脏动脉Movat染色可见肾动脉壁中层局部坏死,蛋白多糖替代原有胶原蛋白,HE染色示交感神经不同程度坏死。结论：本研究证实在急性心肌梗死后急性期进行RDN并不会对血流动力学产生恶化影响,但未证实RDN可改善急性心肌梗死后左室重塑现象。通过病理组织学水平观察可证实通过现有器械和操作实施RDN可成功导致肾脏交感神经不同程度的消除。RDN导致的交感神经损伤处于坏死不同阶段,提示肾脏交感神经的损伤和修复可能是动态变化发展的。第三部分经导管肾脏去交感神经支配术对急性心肌梗死后交感神经系统和肾素血管紧张素醛固酮系统活性的影响目的：急性心肌梗死(acute myocardial infarction, AMI)发生后,全身性、局部性神经体液调节发生一系列的改变,其中交感神经系统(sympathetic nerve system, SNS)和肾素-血管紧张素-醛固酮系统(renin-angiotensin-aldosterone system, RAAS)过度激活在心肌梗死后心室重构及其向心衰发展的整个过程中起了关键作用。RDN对AMI后全身和肾脏局部SNS、RAAS活性影响尚不明确。目的：本研究将进一步探讨RDN对急性心肌梗死动物模型循环、肾脏和心脏SNS及RAAS活性的影响。方法：前两部分实验动物分别作为对照组和消融组。于基线状态和8周后静脉取血,于对照组动物基线状态、心梗后,消融组动物基线状态、心梗后、消融后肾静脉取血,术后8周处死动物,心脏梗死区和非梗死区、肾脏皮质取部分组织,分别测血和组织去甲肾上腺素(noradrenaline, NE)、肾上腺素(epinephrine, E)浓度,及血浆肾素活性(renin activity, PRA)、血管紧张素Ⅱ(angiotensin Ⅱ, AII)、醛固酮(aldosterone,Adl)浓度。结果：消融组和对照组在基线状态外周血、肾静脉血及肾脏皮质NE、E、PRA、AII、 Ald浓度均无显著性差异。8周后消融组外周血醛固酮显著低于对照组(0.08±0.03vs.0.19±0.5,p=0.001)；肾静脉血NE(0.38±0.11 vs.0.33±0.07, p=0.053)、 All (181.99±140.29 vs.45.81±17.74, p=0.102)均较基线出现下降趋势但未达到统计学差异,PRA(2.05±1.73vs.0.19±0.21, p=0.037)、 E(0.07±0.01 vs.0.05± 0.01, p=0.048)显著降低；心梗后肾静脉血RPA、AII升高,且在消融后降低。消融组和对照组小型猪8周后梗死区及非梗死区PRA±AII±Adl组间均无显著差异,肾脏皮质NE、E、PRA、AII、Ald浓度亦无显著差异。结论：肾静脉血生化指标在对RDN的反应上较外周血更为敏感。肾静脉血RAAS活性可能是作为判断即刻RDN成功的敏感指标。临床上仍需要简便有效的判断消融成功与否的检查手段。
[Abstract]:The first part is the study of the model of left ventricular remodeling after acute myocardial infarction in pigs. The ideal and repeatable large animal model is the basis for supporting the research in the cardiovascular field. The pig's coronary anatomy, diameter and distribution are similar to humans. It is an ideal experimental movement for the establishment of acute myocardial infarction model. Transcatheter closure of cardiac catheterization has a shorter anesthesia time, less trauma, faster recovery after operation, and an internal closure of the coronary artery, which reduces the additional activation of the sympathetic system, and avoids the ligation of the heart caused by the coronary artery form of the heart. Denervation is a suitable method for the construction of large animal myocardial infarction model. Objective: to establish an animal model of left ventricular remodeling after acute myocardial infarction in pigs by interventional catheter technique. Methods: 12 small Chinese miniature pigs (weight 30 5kg) were established for 1.5 hours of anterior descending branch with balloon occlusion for 1.5 hours. At baseline, 1.5 hours after modeling, the hemodynamic changes were monitored at 8 weeks after the operation. The morphological and functional assessment of ventricular remodeling was performed by echocardiography. The blood brain natriuretic peptide (BNP) level was monitored after.8 weeks. HE staining, Ma song staining, Sirius red staining and Sirius red staining were used to observe the necrosis, hypertrophy and extracellular matrix weight. Results: 4 animals died in the modeling process of.8 animals to live to the end of the experiment. After balloon occlusion, the average arterial pressure (131.3 + 28.54 vs.101.6 + 16.09, p=0.028), left ventricular systolic pressure (155 + 35.6 vs.129.63 + 21.70, p=0.043), cardiac displacement (3.02 + 1.30 vs.2.14 + 0.85 L/min.m2, p=0.014). Left ventricular ejection fraction (73.65 +) The 8.55 vs.62.28 + 10.69, p=0.019) and the shortened fraction (38.39 + 4.63 vs.32.88 + 5.46, p=0.045) decreased significantly, suggesting that the cardiac contractile function of the experimental animals decreased after acute myocardial ischemia. The left ventricular end diastolic area (9.24 + 2.58 vs.12.66 + 3.06, p=0.025) increased and the thickness of the apical ventricular wall (1.25 + 0.20 vs.0.87 + 0.23, p=0.024) decreased in the 8 weeks after the operation. The infarct area was enlarged and the infarct area was thinner. The left ventricular ejection fraction (73.65 + 8.55 vs.52.35 + 13.95, p=0.002), the shortened fraction (38.39 + 4.63 vs.32.90 + 8.82, p=0.037) decreased, and the plasma BNP level increased significantly (119.48 + 66.17 vs.266.73 + 168.89, p=0.038), suggesting that the left ventricular systolic function decreased. Histopathological examination suggested the extension of the infarct area. Thinning and overall expansion of the left ventricle increased significantly in the non infarct area collagen fibers, which conformed to the left ventricular remodeling after myocardial infarction. Conclusion: the anterior descending branch of the balloon was successfully established in a miniature pig model of acute myocardial infarction. By morphology, histopathology and serological indications, the left ventricular remodeling after myocardial infarction was verified. Development. The influence of the second part of the transcatheter renal innervation on left ventricular remodeling after acute myocardial infarction: after acute myocardial infarction, the sympathetic activity of the heart and the whole body increases immediately and has a continuous course. It plays a key role in the whole process of ventricular remodeling and the development of heart failure after myocardial infarction. The transcatheter renal sympathetic innervation (RDN) is a new nonsurgical method in recent years. The radiofrequency catheter is extended through the femoral artery to the renal artery, and the local electrical heat energy is used to eliminate the renal sympathetic nerve fiber distributed in the superficial serous layer of the renal artery wall, and the renal and systemic sympathetic activity is significantly reduced. Objective: To observe the effect of RDN on left ventricular remodeling after acute myocardial infarction (RDN), a miniature pig model of acute myocardial infarction established by balloon occlusion. Methods: an acute myocardial infarction model was established in 12 small Chinese pigs (weight 30 + 5kg) for 1.5 hours before the balloon was blocked, and RDN was performed after 2 hours of reperfusion as the ablation group. Line state, 1.5 hours after modeling, the hemodynamic changes were monitored after RDN, and the morphological and functional assessment of ventricular remodeling was carried out in parallel with echocardiography. The blood BNP level was monitored after.8 weeks. The renal artery was stained with HE, and the renal artery and renal sympathetic nerve injury was observed by Mavot staining. The first part of the successful modeling of miniature pigs As a control group. Results: 3 animals died of myocardial infarction modeling process center ventricular fibrillation, 9 animals survived to the end of the experiment.8 weeks after the coronary angiography showed a smooth circulation of blood. After RDN, some experimental animals had an excessive renal artery spasm, intra-arterial injection of nitroglycerin, and no femoral artery pseudoaneurysm, hematoma, and dissection of the renal artery. Renal arteriography after.8 weeks after acute complications, unilateral renal atrophy was caused by unilateral renal artery stenosis in 1 animals. The remaining 8 experimental animals showed renal artery patency. In the control group and the ablation group, there was no significant difference between the baseline and myocardial infarction models after the modeling of cardiac color Doppler echocardiography after.8 weeks. The two groups had significant left ventricular remodeling. The left group left the left ventricle. The area of the end of Shi Shuzhang increased by 37.6% (p=0.025), the area of left ventricular end contraction increased by 84.7% (p0.001), the thickness of the apical ventricular wall thinned by 26.3% (p=0.030), the left ventricular ejection fraction decreased by 15.9% (p=0.017), and there was no significant difference between the two groups of cardiac color Doppler indexes, suggesting that RDN did not improve the left ventricular remodeling in the acute myocardial infarction. The ablation and the control group heart were not improved. After 8 weeks of stem modeling, the plasma BNP was significantly increased (119.48 + 66.17 vs.266.73 + 168.89, p=0.038) and (141.53 + 97.44 vs.282.21 + 152.17, p=0.049), and there was no significant difference between the two groups. The renal artery Movat staining showed the partial necrosis of the middle layer of the renal artery wall, the proteoglycan was replaced by the original collagen, and the HE staining showed the different sympathetic nerves. Conclusion: This study confirmed that RDN did not affect the hemodynamics in acute myocardial infarction after acute myocardial infarction, but it was not confirmed that RDN could improve the left ventricular remodeling after acute myocardial infarction. Through the histopathological level, the existing instruments and the operation of RDN could be proved to lead to the renal sympathetic nerve. Different degrees of.RDN induced sympathetic nerve injury at different stages of necrosis, suggesting that the injury and repair of the renal sympathetic nerve may be dynamic. The effect of the third part of the catheterization on the sympathetic nervous system and the activity of renin angiotensin aldosterone system after acute myocardial infarction Objective: after the occurrence of acute myocardial infarction (AMI), a series of changes in the systemic and local neurohumoral regulation have occurred, in which the sympathetic nervous system (sympathetic nerve system, SNS) and the renin angiotensin aldosterone system (renin-angiotensin-aldosterone system, RAAS) are excessively activated in myocardial infarction The effect of.RDN on SNS and RAAS activity in the whole body and kidney after AMI is not clear. Objective: This study will further explore the effect of RDN on the animal model cycle of acute myocardial infarction, the SNS and RAAS viability of the kidney and heart. Methods: the first two parts of the experimental animals were divided. Do not act as the control group and the ablation group. In the baseline state and 8 weeks after the baseline, the baseline state of the animals in the control group, the baseline state of the ablation group, the renal vein after the myocardial infarction, the blood after the ablation, 8 weeks after the ablation, the infarct area and the non infarct area, and the renal cortex, the blood and tissue norepinephrine respectively (Nora Drenaline, NE), concentration of adrenaline (epinephrine, E), and plasma renin activity (renin activity, PRA), angiotensin II (angiotensin II, AII), aldosterone (aldosterone, Adl) concentration. The peripheral blood aldosterone in the post ablation group was significantly lower than that in the control group (0.08 + 0.03vs.0.19 + 0.5, p=0.001), NE (0.38 + 0.11 vs.0.33 + 0.07, p=0.053) and All (181.99 + 140.29 vs.45.81 + 17.74, p=0.102) in the renal vein were lower than the baseline but did not reach the statistical difference, PRA (2.05 + 1.73vs.0.19 + 0.21, p=0.037), E (0.07 + 0.01) The renal vein blood RPA, AII increased after myocardial infarction and decreased after ablation. There was no significant difference between the infarct area and the non infarct area PRA + AII + Adl group after 8 weeks. Conclusion: the renal cortex NE, E, PRA, AII, Ald concentration also had no significant difference. Conclusion: the renal venous blood biochemical indexes were compared with the response to RDN. Peripheral blood is more sensitive. RAAS activity in renal venous blood may be a sensitive indicator of the success of immediate RDN. It still needs a simple and effective method to judge whether the ablation is successful or not.
【学位授予单位】：北京协和医学院
【学位级别】：博士
【学位授予年份】：2015
【分类号】：R542.22
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