无症状性舒张功能不全动物模型的建立及倍他乐克对其治疗的探讨

发布时间：2018-05-13 22:22

本文选题：无症状舒张功能不全 + 压力超负荷　；参考：《中国人民解放军军医进修学院》2007年硕士论文

【摘要】： 目的：无症状舒张功能不全(Asymptomatic Diastolic Dysfunciton，ADD)是指舒张功能异常、射血分数正常，不伴有心衰的症状和体征。ADD患者由于无明显症状，因此临床上往往忽视这部分患者，相关研究和报道也较少。故本研究通过新西兰兔腹主动脉缩窄术，模拟人类高血压诱导的ADD的病理生理特点，建立人类高血压诱导的ADD的动物模型，采用超声心动图、血流动力学、血清和心肌局部神经内分泌水平、组织形态学等多项指标综合评价模型的病理生理特点。并在术后第二日给予倍他乐克，观察其治疗效果。方法：健康雄性新西兰兔47只，随机分为假手术组(n=15)、手术组(n=32)。手术组在双侧肾动脉分支下方1cm处行腹主动脉缩窄术(外径缩窄35～40％)；假手术组作为正常对照组。术后观察兔精神状态、饮食、活动、体重等指标变化。分别于术前和处死前行血流动力学检查检测心脏功能的变化，于术前、术后2周、4周、8周行超声心动图检查动态监测心脏结构和功能的变化。酶联免疫吸附法(Elisa)检测各个阶段血清(0、2、4、8周)和心肌中血管紧张素Ⅱ(AngⅡ)、内皮素-1(ET-1)、去甲肾上腺素(NE)和脑型利尿钠肽前体氨基端肽(NT-proBNP)和尿素酶法检测血清尿素氮(BuN)和肌酐(Cr)变化。HE染色观察心肌形态学改变。其中超声检查包括M超测量左室室壁厚度、左室内径，用2切面改良Simpson法测量左室容积、左室射血分数(LVEF)；用脉冲多普勒测量二尖瓣血流频谱E峰、A峰、E峰减速时间(decelerating time，DT)、A峰持续时间(A duration，AD)，右上肺静脉收缩期S波(PVs)、肺静脉舒张期D波(PVd)、左房收缩逆向a波时间(PVa duration，，PVaD)；用彩色M型获取舒张早期左室内血流播散速度(early diastolic flow propagation velocity，Vp)；用组织多普勒(tissue Doppler imaging，TDI)在二尖瓣环室间隔、侧壁、下壁、前壁4处测量心肌长轴方向的收缩期峰速(Sm)、舒张早期峰速(Em)、舒张晚期峰速(Am)和等容舒张时间(isovolumic relaxation time，IVRT)等值，计算E／Em、E／Vp等参数。血流动力学检查包括左室收缩压(LVSP)、左室舒张末压(LVEDP)、压力最大上升速率(+dp／dt_(max))、压力最大下降速率(-dp／dt_(max))、等容舒张期松弛时间常数(τ)等指标变化。2)将NT-proBNP与EF、Vp、sm、Em、E／Em和E／Vp行相关分析。3)雄性新西兰兔24只随机分为假手术组(n=8)、ADD组(n=8)和ADD+药物治疗组(n=8)。药物治疗组于术后第二日给予倍他乐克(25mg，2／日)，观察8周，检测指标同前。结果：1)术后7～8周，部分手术组兔出现食欲不振和活动量减少，但均未出现呼吸困难、肺Up音等明显心衰的症状；而假手术组兔未出现任何临床症状和体征。2)与假手术组相比，术后2周IVSD、LVPWD、LVmass增加(P＜0.000)；4周时肥厚增加更加明显，Em降低(P＜0.05)、E／Vp增加(P＜0.05)；8周时LAV、LVEDD、LVEDV增加(P＜0.05)；Sm(P＜0.01)、Em(P＜0.01)、Vp(P＜0.000)均降低，E／Em(P＜0.05)、E／Vp(P＜0.000)增加。而EF始终保持正常。血流动力学检查测定LVEDP增高(P＜0.01)，τ值延长(P＜0.01)。病理检查提示心肌细胞肥大。8周时血清AngⅡ、ET-1、NE、NT-proBNP水平均显著升高(P＜0.000)，心肌AngⅡ(P＜0.000)、ET-1(P＜0.05)、NE和NT-proBNP(P＜0.01)也升高。3)NT-proBNP与Sm、Em、E／Em和E／Vp均显著相关，而与EF相关性差。4)倍他乐克治疗组LVEDP(P＜0.000)、τ(P＜0.05)、IVSD(P＜0.05)、Em(P＜0.05)和E／Vp(P＜0.05)等均明显改善；血清AngⅡ(P＜0.01)、ET-1(P＜0.05)、NE和NT-proBNP(P＜0.05)也显著降低。心肌中AngⅡ、ET-1、NE和NT-proBNP均下降(P＜0.05)。结论：1)通过缩窄新西兰兔肾下腹主动脉(缩窄比例为35％～40％)，8周时舒张功能受损、射血分数正常而且无明显心衰症状。观察16周后超声和血流动力学指标均未发生明显变化，说明该模型具有一定的稳定性，或许可以作为人类高血压诱导的ADD的动物模型。2)进一步通过TDI技术检查发现，ADD以舒张功能受损为主，同时也伴有收缩功能的轻度损伤。3)血清和心肌中AngⅡ、ET-1、NE和NT-proBNP均升高，可能参与了舒张功能的损伤。4)NT-proBNP与反映左室舒张功能的Em、E／Em、E／Vp也存在良好的相关性，是检出舒张功能早期损伤的敏感指标。5)倍他乐克可逆转左室肥厚，改善血流动力学和左室舒张功能。6)倍他乐克可降低血清和心肌组织中AngⅡ、ET-1、NE和NT-proBNP水平。
[Abstract]:Objective: asymptomatic diastolic dysfunction (Asymptomatic Diastolic Dysfunciton, ADD) refers to abnormal diastolic function, normal ejection fraction, asymptomatic symptoms and signs of heart failure without symptoms and signs of.ADD patients. Therefore, this part of the patients is often neglected in clinical and less related studies and reports. Pulse constriction, which simulates the pathophysiological characteristics of ADD induced by human hypertension, establishes an animal model of ADD induced by human hypertension. It uses echocardiography, hemodynamics, serum and myocardial local neuroendocrine levels, histomorphology and other indicators to evaluate the pathophysiology of the model and give times more than second days after operation. He Lok, to observe the effect of his treatment.
Methods: 47 healthy male New Zealand rabbits were randomly divided into sham operation group (n=15) and operation group (n=32). Abdominal aorta coarctation (35 to 40%) was performed at 1cm below the bilateral renal artery branch (35 to 40%), and the sham operation group was used as a normal control group. The changes of cardiac function were detected by hemodynamic examination before operation. The changes of cardiac structure and function were monitored dynamically by echocardiography at 2 weeks, 4 weeks and 8 weeks after operation. Enzyme linked immunosorbent assay (Elisa) was used to detect serum (0,2,4,8 weeks) and myocardial angiotensin II (Ang II), endothelin -1 (ET-1), norepinephrine (N). E) and the changes of serum urea nitrogen (BuN) and creatinine (Cr) and serum urea nitrogen (BuN) and creatinine (Cr) changes with brain type diuretic natriuretic peptide (NT-proBNP) and serum urease assay. The echocardiographic examination included M ultra measurement of left ventricular wall thickness, left ventricular diameter, left ventricular volume, left ventricular ejection fraction (LVEF) with 2 cut surface improved Simpson method, and pulse multiple. E peak, A peak, E peak deceleration time (decelerating time, DT), A peak duration (A duration, AD), S wave (PVs) in the right upper pulmonary vein (PVs), pulmonary venous systolic time, and left atrial systolic time were used to measure the velocity of early diastolic blood flow in the left chamber. C flow propagation velocity, Vp); the systolic peak velocity (Sm), early diastolic velocity (Em), late diastolic peak velocity (Em), late diastolic peak velocity (Am) and equal volume diastolic time were measured by tissue Doppler (tissue Doppler imaging, TDI) at the mitral annular space, lateral wall, lower wall, and anterior wall at 4 places. Vp and other parameters. The hemodynamic examination included left ventricular systolic pressure (LVSP), left ventricular end diastolic pressure (LVEDP), maximum pressure rise rate (+dp / dt_ (max)), maximum pressure drop rate (-dp / dt_ (max)), equal volume relaxation time constant (tau) and other indexes changed.2) 24 rabbits were randomly divided into the sham operation group (n=8), the ADD group (n=8) and the ADD+ drug treatment group (n=8). The drug treatment group was given Betaloc (25mg, 2 / day) on the second day after the operation and was observed for 8 weeks.
Results: 1) 1) 7~8 weeks after the operation, there was no appetite and less activity in the rabbits in the operation group, but there was no symptom of dyspnea, lung Up sound and other symptoms of heart failure, while the rabbits in the sham operation group had no clinical symptoms and signs.2), compared with the sham operation group, 2 weeks after the operation, IVSD, LVPWD, LVmass increased (P < 0), and the hypertrophy increased more clearly at 4 weeks. Em decreased (P < 0.05), E / Vp increased (P < 0.05); LAV, LVEDD, LVEDV increased at 8 weeks (P < 0.05); Sm (P < 0.01), Em (0) decreased. Serum Ang II, ET-1, NE, NT-proBNP water increased significantly at.8 weeks (P < 0), Ang II (P < 0), ET-1 (P < 0.05), NE and NT-proBNP (< 0.01). P < 0.05) and E / Vp (P < 0.05) were significantly improved, and serum Ang II (P < 0.01), ET-1 (P < 0.05), NE and NT-proBNP (P < 0.05) were also significantly reduced.
Conclusion: 1) by narrowing the lower abdominal aorta of New Zealand rabbits (the proportion of coarctation is 35% to 40%), the function of Shi Shuzhang is damaged in 8 weeks, the ejection fraction is normal and there is no obvious heart failure symptoms. There is no obvious change in the ultrasonic and hemodynamic indexes after 16 weeks, which indicates that the model has a certain stability and may be used as human hypertension. The induced ADD animal model.2) further through the TDI technique examination, it was found that ADD was mainly diastolic dysfunction, accompanied by a mild injury of.3) in.3) serum and Ang II, ET-1, NE and NT-proBNP in the myocardium, and may be involved in the diastolic function of.4) NT-proBNP and the left ventricular diastolic function. In good correlation,.5 is a sensitive indicator of early diastolic dysfunction. Betaloc can reverse left ventricular hypertrophy, improve hemodynamics and left ventricular diastolic function.6) Betaloc can reduce the level of Ang II, ET-1, NE and NT-proBNP in serum and myocardial tissue.

【学位授予单位】：中国人民解放军军医进修学院
【学位级别】：硕士
【学位授予年份】：2007
【分类号】：R-332;R96

【参考文献】