本文選題：急性心肌梗死 + 左室重塑　； 參考：《北京協和醫(yī)學院》2015年博士論文

【摘要】：第一部分球囊封堵再灌注法建立豬急性心肌梗死后左室重塑模型的研究背景：理想的可重復的大動物模型是支持心血管領域中研究的基礎。豬由于其冠脈的解剖、直徑和分布與人類相似,是建立急性心肌梗死模型較為理想的實驗動物。心臟介入導管技術球囊封堵法較傳統的開胸冠脈結扎具有麻醉時間短、動物創(chuàng)傷小、術后恢復快、冠脈內封堵再通模擬臨床情況的優(yōu)勢,減少手術操作對交感系統的額外激活,并可避免結扎伴隨冠脈走形的心臟交感神經導致的心臟去神經化,是適用于大動物心梗模型構建的方法。目的：采用介入導管技術球囊封堵前降支方法,建立豬的急性心肌梗死后左室重塑的動物模型。方法：12只中華小型豬(體重30±5kg)以球囊封堵前降支1.5小時的方法建立急性心肌梗死模型。于基線狀態(tài)、建模后1.5小時、術后8周監(jiān)測血流動力學改變,并行心臟超聲對心室重塑現象進行形態(tài)學及功能學評定。監(jiān)測血腦鈉肽(BNP)水平。8周后處死動物,行HE染色、馬宋染色、天狼星紅染色觀察心肌細胞壞死、肥大以及細胞外基質重塑情況。結果：4只動物在建模過程中死亡。8只動物活到實驗終點。球囊封堵后,實驗動物平均動脈壓(131.3±28.54 vs.101.6±16.09,p=0.028)、左室收縮壓(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).左室射血分數(73.65±8.55 vs.62.28±10.69,p=0.019)以及縮短分數(38.39±4.63 vs.32.88±5.46,p=0.045)顯著降低,提示急性心肌缺血后實驗動物心臟收縮功能下降。術后8周實驗豬左室舒張末面積(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,提示心臟擴大,梗死區(qū)變薄。左室射血分數(73.65±8.55 vs.52.35±13.95,p=0.002),縮短分數(38.39±4.63 vs.32.90±8.82,p=0.037)降低,血漿BNP水平顯著上升(119.48±66.17 vs.266.73±168.89,p=0.038),提示左室收縮功能降低。組織病理學檢查提示心臟梗死區(qū)伸展、變薄和左室的整體擴展,非梗死區(qū)膠原纖維顯著增多,符合心肌梗死后左室重塑表現。結論：球囊封堵前降支的方法成功建立了小型豬的急性心肌梗死模型。通過形態(tài)學、病理組織學以及血清學指標驗證了心肌梗死后左室重塑的發(fā)生、發(fā)展情況。第二部分經導管腎臟去交感神經支配術對急性心肌梗死后左室重塑的影響背景：急性心肌梗死發(fā)生后,心臟和全身交感神經活性即刻升高并程持續(xù)性,在心肌梗死后心室重構及其向心衰發(fā)展的整個過程中發(fā)揮了關鍵作用。經導管去腎交感神經支配術(RDN)是近幾年新興的一種非外科手術方法,經股動脈途徑將射頻消融導管伸至腎動脈內,通過局部電頻熱能消除分布于腎動脈壁漿膜層淺表的腎臟交感神經纖維,從而顯著降低腎臟以及全身交感神經活性。目的：對球囊封堵法建立的急性心肌梗死小型豬模型實施RDN,觀察RDN對急性心肌梗死后左室重塑的影響。方法：12只中華小型豬(體重30±5kg)以球囊封堵前降支1.5小時的方法建立急性心肌梗死模型,再灌注2小時后行RDN,作為消融組。于基線狀態(tài)、建模后1.5小時、RDN術后監(jiān)測血流動力學改變,并行心臟超聲對心室重塑現象進行形態(tài)學及功能學評定。監(jiān)測血BNP水平。8周后處死動物,對腎動脈行HE染色、Mavot染色觀察腎動脈和腎臟交感神經損傷情況。第一部分成功建模的小型豬作為對照組。結果：3只動物死于心梗建模過程中心室顫動,9只動物活到實驗終點。8周后冠脈造影示血流通暢。施行RDN后,部分實驗動物出現一過性腎動脈痙攣,動脈內注射硝酸甘油后緩解,未出現股動脈假性動脈瘤、血腫和腎動脈夾層等急性并發(fā)癥。8周后復查腎動脈造影,1只動物出現單側腎臟動脈狹窄引發(fā)單側腎臟萎縮,其余8只實驗動物示腎動脈通暢。對照組和消融組在基線和心梗建模后心臟彩超指標無顯著區(qū)別。8周后,兩組均發(fā)生了顯著的左室重塑現象。消融組左室舒張末面積增加了37.6%(p=0.025),左室收縮末面積增大了84.7%(p0.001),心尖室壁厚度變薄了26.3%(p=0.030),左室射血分數降低了15.9%(p=0.017),心臟彩超各指標兩組間均無顯著差異,提示RDN并未改善急性心肌梗死左室重構情況。消融及對照組心梗建模8周后血漿BNP與基線相比,均顯著上升(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),且兩組間無顯著差別。腎臟動脈Movat染色可見腎動脈壁中層局部壞死,蛋白多糖替代原有膠原蛋白,HE染色示交感神經不同程度壞死。結論：本研究證實在急性心肌梗死后急性期進行RDN并不會對血流動力學產生惡化影響,但未證實RDN可改善急性心肌梗死后左室重塑現象。通過病理組織學水平觀察可證實通過現有器械和操作實施RDN可成功導致腎臟交感神經不同程度的消除。RDN導致的交感神經損傷處于壞死不同階段,提示腎臟交感神經的損傷和修復可能是動態(tài)變化發(fā)展的。第三部分經導管腎臟去交感神經支配術對急性心肌梗死后交感神經系統和腎素血管緊張素醛固酮系統活性的影響目的：急性心肌梗死(acute myocardial infarction, AMI)發(fā)生后,全身性、局部性神經體液調節(jié)發(fā)生一系列的改變,其中交感神經系統(sympathetic nerve system, SNS)和腎素-血管緊張素-醛固酮系統(renin-angiotensin-aldosterone system, RAAS)過度激活在心肌梗死后心室重構及其向心衰發(fā)展的整個過程中起了關鍵作用。RDN對AMI后全身和腎臟局部SNS、RAAS活性影響尚不明確。目的：本研究將進一步探討RDN對急性心肌梗死動物模型循環(huán)、腎臟和心臟SNS及RAAS活性的影響。方法：前兩部分實驗動物分別作為對照組和消融組。于基線狀態(tài)和8周后靜脈取血,于對照組動物基線狀態(tài)、心梗后,消融組動物基線狀態(tài)、心梗后、消融后腎靜脈取血,術后8周處死動物,心臟梗死區(qū)和非梗死區(qū)、腎臟皮質取部分組織,分別測血和組織去甲腎上腺素(noradrenaline, NE)、腎上腺素(epinephrine, E)濃度,及血漿腎素活性(renin activity, PRA)、血管緊張素Ⅱ(angiotensin Ⅱ, AII)、醛固酮(aldosterone,Adl)濃度。結果：消融組和對照組在基線狀態(tài)外周血、腎靜脈血及腎臟皮質NE、E、PRA、AII、 Ald濃度均無顯著性差異。8周后消融組外周血醛固酮顯著低于對照組(0.08±0.03vs.0.19±0.5,p=0.001)；腎靜脈血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)均較基線出現下降趨勢但未達到統計學差異,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)顯著降低；心梗后腎靜脈血RPA、AII升高,且在消融后降低。消融組和對照組小型豬8周后梗死區(qū)及非梗死區(qū)PRA±AII±Adl組間均無顯著差異,腎臟皮質NE、E、PRA、AII、Ald濃度亦無顯著差異。結論：腎靜脈血生化指標在對RDN的反應上較外周血更為敏感。腎靜脈血RAAS活性可能是作為判斷即刻RDN成功的敏感指標。臨床上仍需要簡便有效的判斷消融成功與否的檢查手段。
[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.
【學位授予單位】：北京協和醫(yī)學院
【學位級別】：博士
【學位授予年份】：2015
【分類號】：R542.22
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本文編號：1958949