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兔非人工通气主动脉瓣上缩窄-松解模型的建立与评价.pdf

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第三军医大学硕士学位论文英文缩写一览表英文缩写 英文全称dp/dt max maximal rate of pmssure developmentdp/dt max maximal rate of pressure declineABAB8wABl6wAB24wBWDB8wEFExLVDdFSh/rHEHRIVSIⅣEDLVEDPLVESLVMILVPWLVSPLVWMFPFARAASaortic banding8 weeks after aortic banding1 6 weeks after aortic banding24 weeks after aortic bandingbody weight8 weeks after aortic debandingejection fractionexternal left ventricular diastolic diameterfractional shorteningthe ratio of diastolic wall thickness to radius ofthe LV cavityHaematoxylin Eosin staining‘heart rateinter ventricular septum at diastoleleft ventricular end.diastolic diameterleft ventricular end-diastolic pmssureleft ventricular endsystolic diameterleft ventricular mass indexleft ventricular wall posterior thickness at diastoleleft ventricular systolic pressureleft ventricular weightmyocardial fibrosisParaaldehyderenin··angiotensin·-aldosterone system中文全称等容收缩期左心室压力上升的最大速率等容舒张期左心室压力下降的最大速率升主动脉绑定升主动脉绑定后8周升主动脉绑定后16周升主动脉绑定后24周体质量升主动脉松解后8周射血分数左室舒张末外径左室短轴缩短率舒张期左室后壁厚度/左室腔的半径HE染色心率舒张期室间隔的厚度左室舒张末内径左室舒张末压左室收缩末内径左心室质量指数舒张期左室后壁的厚度左室收缩压左室质量心肌纤维化多聚甲醛肾素.血管紧张素.醛固酮系统第三军医大学硕士学位论文Characterization of a Rabbit Model to IndependentlyStudy Regression of Ventricular HypertrophyBackground and purposesAbstractLeft ventricular hypertrophyLVHis an adaptive response of the heart to an increasedworkload,caused by a variety of pathological changes,including hypertension and valvulardisease.However,if the pressure overload is severe and longstanding,the hypertrophicheart may progress to a pathological state.Although reversal of LVH occurs after aorticvalve replacement for aortic stenosis,Ikonomidis has revealed incomplete reversal ofpathophysiological changes,such as interstitial fibrosis,ventricular remodeling anddysfunction.Similar phenomenon,rio more than a 1 5%to 20%reduction in left ventricularLVmass,has also been observed after optimal blood pressure control in hypertensivepatients.The molecular mechanisms that underlie regression of LVH ale not yet completelyunderstood.An animal model of LVH regression is important to investigate both diseasemechanisms and potential therapies.Animals need undergo a thoracotomy in most ofstudies on LVH, and endotracheal intubation and mechanical ventilation are usuallyindispensable.However,several researchers have reported that experiment animals may bepredisposed to developing serious tracheal injury and clinically significant sequelae inassociation with endotracheal intubation.Examination of both progression and regression ofLVH in rabbits without endotracheal intubation and mechanical ventilation has notpreviously been reported but.is the subject of this study.Ultimately,this model willfacilitate focused study of the mechanisms involved with LVH progression and regression.s1.The experimental animals were randomized 3 times in turn and assigned to 5groupssham-operated groupsham group,8 weeks of aoaic bandingABgroupAB8wgroup,1 6 weeks of AB groupAB 1 6w group,24 weeks of AB groupAB24w group,2第三军医大学硕士学位论文early debandingDBgroup8 weeks of AB followed by 8 weeks of DB,late DB group1 6 weeks ofAB followed by 8 weeks of DB.2.Without endotracheal intubation and mechanical ventilation,a median sternotomywas pered。To avoid injury the parietal pleura,the median incision Was made exactlyalong the midline of the sternum.Ascending aortic diameter was reduced 50-5 8%above theaortic valve,which leads to an approximate 75%reduction in crosssectional area.Thesham-operated rabbits underwent the same procedures without actual ligation of the aorta.The animals of early DB group and late DB group were subjected to the second operationfor removing ligation 8 weeks or 1 6 weeks after the initial banding surgery,respectively.3.Transthoracic echocardiography Was pered before surgery and 2,4,8,10,12,l 6,1 8,20 and 24 weeks after surgery for animals subjected to AB and 2,4,and 8 weeks foranimals subjected to DB.4.Hemodynamic assessment Was examined for each group at the last time point.5.At the time of death,body weights and LV weights were obtained after rabbits weresacrificed.And the samples of left ventricular myocardium were obtained for H.E童orMasson’S trichrome staining and electron microscopic observation.Results ’1.The model of promoting LVH regression in rabbits Was successfully developedwithout the need for endotracheal intubation and mechanical ventilation.The mortality rateWas lOW.2.There Was significant difference in LVDD,LVSD,IVS,LVPW,LVMI and FSbetween AB24w group and sham group since 4 weeks after ABP0.05.There wasno significant difference in heart rate among the groups over the study period.3.Compared with sham group.LV systolic arterial anddp/dt max were markedly3第三军医大学硕士学位论文elevated in AB8w,ABl6w and AB24w groupP0.05,各组实验兔的心率没有显著差异。3.AB8w组、ABl6w组及AB24w组与sham组相比,dp/dt max有显著差异P0.01。ABl6w组、AB24w组与sham组相比,.dp/dt max有显著差异PO.01。AB8wDB8w组与ABl6w组相比,ABl6wDB8w组与AB24w及sham组相比,dp/dt max、。dp/dt max均有有显著差异PO.01。AB8wDB8w组与ABl6wDB8w组比较,.dp/dtmax有显著差异PO.01,说明缩窄时间的长短对缩窄解除术后心脏舒张功能的恢复有重要影响。4.AB8w组、ABl6w组及AB24w组的左室质量及左室质量/体质量均较假手术组明显增大PO.01。升主动脉缩窄解除术后,增加的LVW逐渐恢复。AB8wDB8w组与ABl6w组相比、ABl6wDB8w组与AB24w相比,LVW及LVW/BW都有显著差异。ABSwDB8w组与ABl6wDB8w组相比,LVW有显著差异P0.01。5.sham组心肌纤维排列正常,间质无明显增生,无血管扩张及血管壁增厚等表现。AB8w组、ABl6w组及AB24w组心肌纤维走行紊乱,心肌细胞肥大,分支增多,间质胶原纤维显著增生。升主动脉松解术后,实验兔的心肌细胞肥大明显减轻,增生的间质胶原纤维明显减少,AB8wDB8w组的恢复程度较ABl6wDB8w组更加明显。提示缩窄时间的长短对缩窄解除术后心脏结构的恢复也有重要影响,早期解除压力负荷可以更好地逆转心肌纤维化。6.与sham组比较,升主动脉缩窄组兔的透射电镜表现有如下特征①肌原纤维排6第三军医大学硕士学位论文列紊乱,肌节结构模糊;②闰盘结构不连续、模糊;③肌浆网肿胀、破裂;④核周空泡形成;⑤线粒体数量明显增多。结论在非人工通气的条件下,采用升主动脉缩窄的方法可成功建立稳定的兔主动脉瓣上缩窄一松解模型。该模型避免了气管插管及机械通气的损伤和并发症,操作简单、效果明显、重复性好,为心肌肥厚和心肌纤维化逆转的研究提供了良好的平台,从而有助于促进高血压和主动脉瓣狭窄等左室肥厚相关疾病的进一步研究。关键词左心室肥大;升主动脉缩窄;非人工通气;动物模型;兔7_i赫;第三军医大学硕士学位论文免非人工通气主动脉瓣上缩窄一松解模型的建立及评价幸._上.-JL一月IJ 吾左室肥厚多见于压力负荷长期增加的疾病,如高血压、主动脉瓣狭窄等,它是心脏的一种代偿反应,主要表现为心肌细胞肥大、间质细胞增生、间质胶原沉积、心脏重量增加等。该代偿反应在初期往往是有益的,可以维持正常的室壁张力,但是长期的左室肥厚会显著增加心衰和猝死的发生率川。从形态而言,心肌重量的增加有生理性和病理性之分【21。生理性肥厚时,左室充盈率增加,心率缓慢,左室容积增加,每搏量增加,但是,射血分数、冠脉储备保持正常或轻度增加,无心肌纤维化,心肌异位起搏少见;病理性肥厚有向心性肥厚和离心性肥大两种。向心性肥厚是指心脏重量增加、室壁肥厚、室腔容积稍大或正常,而室壁厚度和室腔直径比值大于正常。离心性肥大是指心脏重量增加,室腔扩大,室壁稍厚,而室壁和室腔直径之比值等于或小于正常。高血压引起的左室肥厚多是向心性肥厚,左室质量和相对室壁厚度均增加,而离心性肥大多出现在充血性心力衰竭时,左室重量增加,相对室壁厚度正常,此时心室腔扩大,左心功能明显受影响。离心性肥大也可由向心性肥厚转变而来。左室肥厚与心脏舒张、收缩功能下降、冠脉储量减少、心律失常及心脏自主神经活性的变化密切相关,是心血管意外发生的重要预测指标,故逆转左室肥厚是高血压等疾病治疗的最终目标。合并左室肥厚的病人发生死亡和其他并发症的风险增加了24倍,与年龄、性别和其他危险因素无关【3,4】。许多实验和观察研究证明,肥厚反应减弱可以保护心脏功能,改善生存率15,6】。目前,对压力超负荷心肌肥厚和心肌纤维化的研究,主要集中在心肌肥厚和心肌纤维化的形成原因、机制,以及干预压力超负荷的结果等r卜11l,鲜有对去压力超负荷后心肌肥厚和心肌纤维化转归的研究,左室肥厚逆转的分子机制尚不清楚。然而,在心脏外科领域,去压力超负荷病理生理过程较常见。Kingsbu巧等【12J认为,慢性主动脉瓣狭窄瓣膜置换手术,是临床上典型的去压力超负荷病理生理过程。心脏瓣膜置换术是治疗瓣膜疾病的主要手段,尽管瓣膜置换手术后早期死亡率不断降低,血流动力学得到改善,但并没有达到预期的临床目的,特别是部分主动脉瓣狭窄为主’基金项目重庆市科委自然科学基金2009BB50258第三军医大学硕士学位论文的瓣膜疾病,手术后心脏舒张功能恢复不佳,影响手术的中、远期疗效【l 31,具体原因不明,推测可能与心肌纤维化恢复不良有关。我们的研究也发现,瓣膜置换手术后左心室舒张功能恢复不完善,特别是主动脉瓣狭窄为主的患者更明显,病理研究发现主动脉瓣狭窄为主的联合瓣膜病患者心肌纤维化程度尤其严重【l 41。逆转或减轻已形成心肌纤维化,改善异常左心室僵硬度,是提高瓣膜置换手术后中、远期心脏功能急需解决的主要问题。研究去压力负荷后心肌纤维化的变化和机制,不仅能拓宽我们对心肌肥厚、心肌纤维化的认识,为促进心肌肥厚、心肌纤维化逆转提供新的治疗手段,对主动脉瓣狭窄等瓣膜置换手术后心肌纤维化转归的认识和干预也有非常重要的理论价值和实际意义【11,12,15l。但由于去压力超负荷的模型难于建立,关于去压力超负荷后心肌纤维化转归特征的研究较少116】。新近,Stansfield等通过主动脉弓部缩窄建成左心室压力超负荷模型,对肥厚左心室全基因组的研究显示,与对照组相比,压力性心肌肥厚发展过程中有288个基因表达不同,而在压力性心肌肥厚逆转过程中有265个基因不同,压力性心肌肥厚发展过程中和逆转过程中仅有23个基因表达相同,提示压力性心肌肥厚发展和逆转过程各有特剧15】。我们推测在不同时间段解除压力超负荷,心肌纤维化亦可能有不同的转归特征。一理想的压力超负荷左室肥厚模型对心肌肥厚和心肌纤维化的研究是非常重要的,也是非常必要的。目前,人们经常用自发高血压、腹主动脉缩窄或一侧肾动脉夹闭的方法来获得压力超负荷动物模型。通常认为近心端主动脉缩窄是更理想的实验性压力超负荷左室肥厚模型,最近,有采用主动脉弓部缩窄或升主动脉缩窄建成压力超负荷左室肥厚模型的报道,但均较少,而且现有报道的胸主动脉缩窄动物模型,都需要气管插管,呼吸机辅助呼吸,增加了实验条件和技术难度,增加了操作环节,也更容易导致气管损伤和并发症【7,11,15,17】。基于此,我们设想创建非人工通气兔主动脉瓣上缩窄.松解模型,期望建成接近临床,稳定性、重复性好的压力超负荷性心肌肥厚、心肌纤维化动物模型,探寻模型建立的可行性以及相关条件,为进一步研究心肌肥厚和心肌纤维化提供更优良的动物模型,并初步研究不同时相点去压力超负荷后心功能恢复、心肌纤维化逆转的特征,从而为心肌纤维化逆转的研究提供基础。9
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