压力负荷诱导的舒张性心力衰竭动物模型建立与倍他乐克干预治疗

发布时间：2018-06-24 02:02

本文选题：舒张性心力衰竭 + 兔　；参考：《中国人民解放军军医进修学院》2007年硕士论文

【摘要】： 背景：舒张性心力衰竭(DHF)是一组具有充血性心力衰竭(CHF)表现、以射血分数(EF)正常而舒张功能受损为特点的临床症候群。临床上有25～40％的CHF患者属DHF。但是目前尚缺乏一种有效的DHF模型，且EF并不是评价收缩功能的敏感指标。大规模临床试验证实β受体阻滞剂可降低CHF死亡率，但对DHF动物的治疗研究还鲜有报道。本研究通过缩窄新西兰兔腹主动脉，采用超声心动图和血流动力学全面评价心脏舒缩功能，并结合病理学、神经内分泌和肾功能改变，探索压力负荷诱导的DHF模型建立方法。同时在疾病早期用倍他乐克干预，观察其对DHF的治疗作用。方法：1)雄性新西兰兔75只随机分为假手术组(n=15)、手术1组(n=45)和手术2组(n=15)。手术1组在右侧肾动脉分支上方1cm处行腹主动脉缩窄术(外径缩窄35～40％)；手术2组在同一部位将外径缩窄50～60％。术后观察5周。术前和处死时用左心导管测定血流动力学。术前、术后2周、4周和5周行超声心动图检查。每次超声检查后6h内从耳中央动脉取血并分离血清。血流动力学指标有左室收缩压(LVSP)、左室舒张未压(LVEDP)、压力最大上升速率(+dp/dt_(max))、压力最大下降速率(-dp/dt_(min))和松弛时间常数(τ)。用二维超声测量左房容积(LAV)；M超测量室间隔厚度(IVSD)、左室后壁厚度(LVPWD)、左室舒张末容积(LVEDV)、左室收缩末容积(LVESV)、EF及舒张早期左室内血流播散速度(Vp)；脉冲多普勒检测二尖瓣血流舒张早期峰速度(E)、舒张晚期峰速度(A)、、肺静脉血流心房收缩期峰速度(PVa)和a峰持续时间(PVaD)；组织多普勒检测二尖瓣环收缩期峰值运动速度(Sm)和舒张早期峰值运动速度(Em)，并计算E/Em和E/Vp。用酶联免疫吸附法检测血清与心肌血管紧张素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)浓度，并将NT-proBNP与EF、Sm、Em、E/Em和E/Vp行相关分析。尿素酶法检测血清尿素氮(BUN)和肌酐(Cr)变化。2)雄性新西兰兔30只随机分为假手术组(n=6)、手术组(n=12)和手术治疗组(n=12)。手术方法同手术1组，手术治疗组从术后第1天起应用倍他乐克(25mg，2/日)治疗，观察4周，检测指标同前。3)SPSS13.0统计分析，P＜0.05为有显著差异。结果：1)手术1组有22只兔术后26～30天出现精神萎靡、食欲不振、呼吸困难等心衰表现，手术2组有6只兔术后6～10天因急性肺水肿死亡。2)手术1组兔术后2周出现IVSD、LVPWD增加(P＜0.000)和LAV、LVEDV扩大(P＜0.01)；Sm(P＜0.05)、Em(P＜0.05)、Vp(P＜0.000)均降低，E/Em(P＜0.01)、E/Vp(P＜0.05)增加。术后4～5周上述指标变化更加明显，而EF无改变。LVEDP和τ值也显著增高(P＜0.000)，-dp/dt_(min)下降明显(P＜0.01)。血清和心肌AngⅡ、ET-1、NE、NT-proBNP(P＜0.000，P＜0.01)及BUN与Cr(P＜0.000)水平均升高。3)手术2组LAV(P＜0.000)、LVEDV(P＜0.05)、LVESV(P＜0.000)扩大明显，Sm(P＜0.000)、Em(P＜0.01)、Vp(P＜0.000)、E/Em(P＜0.05)和E/Vp(P＜0.01)显著改变，EF降至50％以下(P＜0.000)。LVEDP、τ、-dp/dt_(max)和+dp/dt_(min)也存在明显变化(P＜0.000)。血清和心肌各项指标变化更加明显。4)NT-proBNP与Sm、Em、E/Em和E/Vp均显著相关(P＜0.000)，而与EF相关性差(r=-0.395)。5)倍他乐克治疗组仅1只兔出现心衰表现，，其余兔的精神饮食活动情况尚可。与手术组相比，手术治疗组兔LVEDP(P＜0.000)、τ(P＜0.000)、LAV(P＜0.01)、IVSD(P＜0.05)、Em(P＜0.05)和E/Em(P＜0.05)均明显改善；血清AngⅡ、ET-1(P＜0.01)和血清与心肌NE、NT-proBNP(P＜0.01，P＜0.05)显著降低；BUN、Cr无变化。结论：1)通过缩窄新西兰兔肾动脉分支上方的腹主动脉(外径缩窄35～40％)，26～30天可出现心衰表现，-dp/dt_(min)、Vp和Em显著降低，LVEDP、τ、E/Em和E/Vp明显增高而EF正常，可以作为人类高血压病导致的DHF动物模型；2)缩窄兔腹主动脉后出现Sm降低，提示收缩功能损伤可能也参与DHF的发病过程；3)循环和心肌局部神经内分泌系统激活可能是导致DHF的重要机制；4)NT-proBNP与Sm、Em、E/Em和E/Vp显著相关，与EF相关性差；5)倍他乐克可有效减轻DHF兔的心室肥厚、心腔扩大和舒缩功能损伤，抑制神经内分泌系统激活。
[Abstract]:Background: diastolic heart failure (DHF) is a group of clinical syndromes with congestive heart failure (CHF) manifestations, characterized by normal EF and impaired diastolic function. 25 to 40% of CHF patients are clinically DHF. but there is a lack of an effective DHF model, and EF is not a sensitive index for evaluating contractile function. The clinical trial verified that beta blockers can reduce the mortality of CHF, but there are few reports on the treatment of DHF animals. By narrowing the abdominal aorta of New Zealand rabbits, echocardiography and hemodynamics were used to evaluate the cardiac systolic and systolic function, and to explore the pressure load induction combined with pathology, neuroendocrine and renal function changes. To establish a DHF model, and to observe the therapeutic effect of Betaloc on DHF in the early stage of the disease.
Methods: 1) 75 male New Zealand rabbits were randomly divided into sham operation group (n=15), operation 1 groups (n=45) and operation 2 group (n=15). The 1 group underwent abdominal aorta coarctation (35 to 40%) at the right part of the right branch of the right renal artery (35 to 40%), and 2 groups narrowed the outer diameter for 5 weeks after 50 to 60%. in the same site. Left cardiac catheterization was used before and when the operation was executed. Hemodynamics was measured. Echocardiography was performed 2 weeks, 4 and 5 weeks after operation. Blood and serum were removed from the central ear artery in 6h after each ultrasound examination. The hemodynamic indexes were left ventricular systolic pressure (LVSP), left ventricular diastolic Unpressure (LVEDP), maximum pressure rise rate (+dp/dt_ (max)), and the maximum pressure drop rate (-dp/dt_ (min)) He Song. Relaxation time constant (tau). Measurement of left atrial volume (LAV) with two-dimensional ultrasound; M super measurement of ventricular septum thickness (IVSD), left ventricular posterior wall thickness (LVPWD), left ventricular end diastolic volume (LVEDV), left ventricular end systolic volume (LVESV), EF and early diastolic flow velocity (Vp) in left chamber; pulse Doppler detection of early diastolic peak velocity (E) and late relaxation of mitral valve flow (E), and late relaxation Peak velocity (A), atrial systolic peak velocity (PVa) and a peak duration (PVaD) of pulmonary venous blood flow; tissue Doppler detected peak systolic velocity (Sm) and early diastolic peak velocity (Em) in the mitral annulus, and determined the serum and myocardial angiotensin II (Ang II) and endothelin -1 (ET-) by enzyme linked immunosorbent assay (E/Em and E/Vp.). 1) the concentration of norepinephrine (NE) and brain type natriuretic peptide amino end peptide (NT-proBNP), and the correlation analysis between NT-proBNP and EF, Sm, Em, E/Em and E/Vp. The Urease method was used to detect the serum urea nitrogen (BUN) and creatinine (Cr) change.2). 30 male New Zealand rabbits were randomly divided into sham operation group (n=6), operation group and surgical treatment group. In the 1 groups, the treatment group was treated with betaloc (25mg, 2/ day) from first days after the operation, and observed for 4 weeks, and the test index was same as the former.3) SPSS13.0 statistical analysis. There were significant differences in P < 0.05.
Results: 1) in the 1 groups, there were 22 rabbits in the operation, 26~30 days after the operation of 22 rabbits, which showed mental malaise, poor appetite, dyspnea and other heart failure. The 2 group had 6 rabbits who died of acute pulmonary edema on 6~10 days after the operation in the 2 group, and the operation of 1 rabbits appeared at 2 weeks after the operation. LVPWD increased (P < 0) and LAV, LVEDV enlarged (P < 0.01); Sm (P < 0.05), Em (P < 0.05), Vp (Vp < 0) were all. Decrease, E/Em (P < 0.01), E/Vp (P < 0.05) increased. The changes of the above indexes were more obvious after 4~5 weeks, while EF without change of.LVEDP and tau increased significantly (P < 0), -dp/dt_ (min) decreased significantly (P < 0.01). 0), LVEDV (P < 0.05), LVESV (P < 0) expanded obviously, Sm (P < 0), Em (P < 0.01), Vp (P < 0), E/Em (P < 0.05) and P < 0.01). Both E/Em and E/Vp were significantly correlated (P < 0), but with EF correlation (r=-0.395).5), only 1 rabbits in the treatment group had heart failure, and the rest of the rabbits were still in the mental diet. Compared with the operation group, the operation group had LVEDP (P < 0), tau (P < 0), LAV (P < 0.05), IVSD (0.05) and 0.05 < 0.05). Improvement: serum Ang II, ET-1 (P < 0.01), serum and myocardial NE, NT-proBNP (P < 0.01, P < 0.05) significantly decreased; BUN and Cr did not change.
Conclusion: 1) by narrowing the abdominal aorta above the renal artery branch of New Zealand rabbits (the outer diameter narrowed from 35 to 40%), the expression of heart failure could appear on 26~30 days. -dp/dt_ (min), Vp and Em were significantly reduced, LVEDP, tau, E/Em and E/Vp were significantly increased and EF normal, and can be used as the DHF animal model caused by human hypertension; 2) Sm descending after the abdominal aorta of narrowing rabbit. Low, suggesting that contractile dysfunction may also participate in the pathogenesis of DHF; 3) circulation and activation of local neuroendocrine system may be an important mechanism for DHF; 4) NT-proBNP is significantly related to Sm, Em, E/Em and E/Vp, and is poor with EF; 5) Betaloc can effectively reduce ventricular hypertrophy, dilation of heart cavity and impairment of systolic function in DHF rabbits, Inhibition of the activation of the neuroendocrine system.
【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;R541.6

【引证文献】