【作者】 任培华；

【导师】 冼绍祥；

【作者基本信息】 广州中医药大学 ， 中医内科学， 2010， 博士

【摘要】 一、文献研究本研究在参考国内外文献,了解慢性心力衰竭研究现状基础上,推本溯源,掌握从《黄帝内经》到唐宋元明清时期及现代各医家对心衰病的病因病机及治疗方法的认识,研究了近年来中、西医治疗慢性心力衰竭的方法和成果,为临床和实验研究打下了坚实的理论基础。二、临床研究1.目的客观评价养心康片治疗慢性心力衰竭的临床疗效和安全性,为养心康片获国家批准生产上市提供理论依据。2.方法以目前公认的慢性心力衰竭治疗方案为对照,开展前瞻性、随机、双盲、多中心对照的临床研究,将纳入病例随机分为对照组和治疗组,对照组给予基础治疗加养心康片模拟片,治疗组给予基础治疗加养心康片,每次3片,每天3次,疗程4周。观察治疗前后心衰患者的心功能、中医证候和明尼苏达生存质量量表的变化。3.结果(1)心功能疗效比较,治疗组总有效率为83.5%,对照组总有效率为71.3%,两组的疗效差别有统计学意义(P<0.05)。(2)中医证候疗效比较,治疗组总有效率为88.7%,对照组总有效率为77.7%,两组的疗效差别有统计学意义(P<0.05)。(3)两组治疗前后气喘、畏寒肢冷、面浮肢肿和咳嗽咯痰的症状积分比较,治疗后两组的气喘等症状积分都有了明显降低,与治疗前比较,其差别有统计学意义(P<0.01)。治疗组症状积分降低更为明显,治疗后两组的变化值比较差别有统计学意义(P<0.05)。(4)明尼苏达量表总维度积分和体力维度积分的比较,治疗后两组均有明显的降低,与治疗前比较,其差别有统计学意义(P<0.01)。治疗组积分下降的幅度大于对照组,治疗后两组及两组的变化值比较差别有统计学意义(P<0.01或P<0.05)。4.结论(1)养心康片可以改善慢性心力衰竭患者的心功能,减轻临床症状,是治疗慢性心力衰竭的有效药物。(2)养心康片可以改善慢性心力衰竭患者的中医证候,尤其是在改善心衰患者的气喘、畏寒肢冷、面浮肢肿和咳嗽咯痰方面疗效突出。(3)养心康片可以增加慢性心力衰竭患者的活动耐量,改善慢性心力衰竭患者的生存质量。(4)养心康片有良好的安全性和依从性。三、实验研究1.目的观察养心康片对心衰模型兔心脏结构和功能的保护作用及对神经-内分泌系统、炎症因子和血管内皮功能的影响,以及养心康片对心衰模型兔的抗氧化作用,深入探讨养心康片治疗心力衰竭的作用机制,评价养心康在防止心衰动物模型的心室重构和改善心脏收缩同步性方面的疗效。2.方法应用结扎兔冠状动脉的方法建立兔心梗后心力衰竭的动物模型,将实验动物分成空白对照组、实验对照组、卡托普利组、养心康片低剂量组、养心康片中剂量组和养心康片高剂量组,分别给予相应的处理措施,连续4周。观察养心康片对心衰模型兔超声心动图、B型尿钠肽(BNP)、心肌肌钙蛋白工(cTnI)、白细胞介素-6(IL-6)、肿瘤坏死因子-α(TNF-α)和心肌超微结构等的影响。3.结果(1)用药后实验对照组的室间隔(IVS)最薄,空白对照组IVS最厚,其差别有统计学意义(P<0.01)。实验对照组的LVEDd最大,与中剂量组和高剂量组比较,其间差别有统计学意义(P<0.05)。(2)用药后,实验对照组的LVEF值最低,与中剂量组和高剂量组比较,其间的差别有统计学意义(P<0.01)。(3)各组间BNP、cTNI比较,实验对照组的值最高,与其他各组比,其间的差别有统计学意义(P<0.05或P<0.01)。(4)各组间AngⅡ比较,实验对照组的AngⅡ值最高,与其他各组比其间的差别有统计学意义(P<0.05或P<0.01)。(5)各组间TNF-α比较,空白对照组TNF-α的值最低,与高剂量组相比,TNF-α的差别无统计学意义(P>0.05)。实验对照组TNF-α值最高,与其他各组比较,其间差别有统计学意义(P<0.05或P<0.01)。(6)各组间ET-1比较,实验对照组的ET-1值最高,与其他各组比较,其间的差别有统计学意义(P<0.01)(7)各组间IL-6比较,实验对照组IL-6值最高,与其他各组比较,其间差别有统计学意义(P<0.01)。(8)各组间MDA比较,实验对照组的MDA最高,与其他各组比较差别有统计学意义(P<0.01)。各组间SOD比较,实验对照组SOD的值最低,与空白对照组、中剂量组和高剂量组比较,其间差别有统计学意义(P<0.05或P<0.01)。(9)各组间凋亡指数的比较,空白对照组的凋亡指数最小,实验对照组的凋亡指数最大,各组间比较,其差别均有统计学意义(P<0.05或P<0.01)。(10)用药后,实验对照组的Tvr-SD最高,空白对照组的Tvr-SD最低,与其他各组比较,其间差别有统计学意义(P<0.05或P<0.01)。(11)电镜结果显示高剂量组肌小节可见,肌原纤维排列整齐,肌节结构基本清楚,肌丝尚完整,明暗带结构较清晰,可见Z线、M线。线粒体及肌浆网,数量增多,结构正常。嵴结构基本清楚。细胞核核膜清楚,染色质分布基本正常。而实验对照组的肌小节变形,肌丝断裂,排列紊乱,肌膜水肿。线粒体增多,嵴消失,内质网扩张,部分肌细胞崩解,明暗带结构模糊,Z线增粗,M线不清晰。细胞核核膜部分溶解、消失,边缘欠规则,染色质分布异常。4.结论：(1)结扎兔冠状动脉可以复制心梗后心衰模型,操作步骤相对简单,成功率较高。(2)养心康片可以提高心衰模型兔的心功能,降低血清BNP、cTnI水平。(3)养心康片可以防止心衰模型兔的室间隔变薄,减少其舒张末容积,降低心脏指数,改善心脏的超微结构,有防止心衰模型兔心室重构的作用。(4)养心康片可以降低心衰模型兔的血清AngⅡ的水平,可以阻断其神经-内分泌系统的激活。(5)养心康可以降低心衰模型兔血清的TNF-α、IL-6水平,表明养心康片具有抗炎症因子的作用。(6)养心康片可以降低心衰模型兔血清的ET-1水平,有改善血管内皮功能的作用。(7)养心康片可以降低心衰模型兔血清的MDA水平,升高血清的SOD水平,表明养心康片具有抗氧化作用。(8)养心康片可以减少心衰模型兔心肌细胞的凋亡。(9)养心康具有改善心衰模型兔心脏收缩同步性的作用。更多还原

【Abstract】 Part one Literature ResearchThis research based on referring to domestic and international literature and observing the current research situation of chronic heart failure (CHF) and mastered the cognition of etiology, pathogenesis, treatment of CHF from the period of Huangdineijing to tang, song, yuan, ming, qing dynasty and the clinical experience of modern traditional Chinese physician. We also summarized the research method and achievements of TCM and western medicine in treating CHF for the past few years and provided solid theory support for clinical and experimental study.Part two Clinical Research1.ObjectiveTo objectively evaluate clinical effect and safety on treatment of CHF using yangxinkang tablet and to provide the theoretical basis for yangxinkang tablet being approved by the State for production and sale.2. MethodTaking the currently accepted treatment of CHF as a control, We carried out a prospective, randomized, double-blind, multi-center controlled clinical study. Cases included in this study were randomly divided into control group and treatment group. Cases of control group received basic therapy plus analog Yangxinkang tablet, and cases of treatment group received basic therapy plus Yangxinkang tablet,3 tablets each time,3 times each day, for 4 weeks. We observed the changes in cardiac function, TCM Syndroms, and Minnesota Satisfaction Questionnaire Scales of patients with heart failure before and after treatment.3. Result(1) comparison of curative effect on cardiac function:the total effective rate was 83.5% in the treatment group and 71.3% in the control group, and there was a statistically significant difference in efficacy between the two groups (P<0.05)(2) comparison of curative effect on TCM Syndroms:the total effective rate was 88.7% in the treatment group and 77.7% in the control group, and there was a statistically significant difference in efficacy between the two groups (P<0.05)(3) comparison of symptoms scores of gasp, fear of cold and cold in the extremities, swollen of face and limbs, cough and expectoration:after treatment, symptom scores of two groups had a significantly lower, and comparing with before treatment, the difference was statistically significant (P<0.01).Symptom scores in treatment group decreased more significantly, and there were statistically significant differences in the change value between the two groups (P<0.05)(4) comparison of total dimension scores and physical dimension scores of Minnesota Satisfaction Questionnaire Scale:after treatment, scores of two groups had a significantly lower, and comparing with before treatment, the difference was statistically significant (P<0.01). Scores of treatment group decreased more significantly than that of control group, and there were statistically significant difference in scores after treatment and in the change value between the two groups (P<0.01 or P<0.05)4. Conclusion(1) Yangxinkang tablet can improve cardiac function and relieve clinical symptoms of patients with CHF, so it is an effective drug for treating CHF.(2) Yangxinkang tablet can improve TCM syndrome of patients with CHF, and especially in the improvement of gasp, fear of cold and cold in the extremities, swollen of face and limbs, cough and expectoration is highly effective.(3) Yangxinkang tablet can increase exercise tolerance in patients with CHF, and improve the life quality of patients with CHF.(4) Yangxinkang tablet possess good security and compliance.Part three Experimental Research1. ObjectiveObserved the protective effect of yangxinkang tablet for heart structure and function of rabbit model with CHF and it’s influence on neuroendocrine system, inflammation factor, endothelial function and antioxidation. In-depth investigated the mechanism of action of Yangxinkang tablets in the treatment of heart failure. Evaluated effect in preventing ventricular remodeling and systolic asynchronous of animal model of heart failure by Yangxinkang tablet.2. MethodMaking heart failure animal model by blocking rabbit left anterior descending coronary artery. The experimental animals were divided into control group, experimental control group, captopril group, Yangxinkang tablet low dose group, Yangxinkang tablet middle dose group and Yangxinkang tablet high dose group, and were given appropriate treatment measures for 4 weeks. Investgated the effects of yangxinkang tablet on echocardiography, B-type natriuretic peptide (BNP), Cardiac troponin I (cTnⅠ), Interleukin-6 (IL-6) Tumor necrosis factor-α(TNF-α) and myocardial ultrastructure,etc. of rabbit model with heart failure.3. Result(1) After treatment, the interventricular septum (IVS) of experimental control group was thinnest, the interventricular septum (IVS) of control group was thickest, the difference between them was statistically significant (P< 0.01). The LVEDd of experimental control group was maximum, compared with that of middle dose group and high dose group, the difference among them were statistically significant(P<0.05).(2) After treatment, the LVEF of experimental control group was lowest, compared with that of middle dose group and high dose group, the differences among them were statistically significant(P<0.01).(3) Comparison of BNP and cTNI in each groups, the experimental control group is highest, compared with other groups, the differences among them were statistically significant(P<0.05 or P<0.01).(4) Comparison of AngⅡin each groups, the experimental control group was highest, compared with other groups, the differences among them were statistically significant(P<0.05 or P<0.01).(5) Comparison of TNF-αin each groups, the control group was lowest, compared with high dose group, the difference between them was not statistically significant(P>0.05). the experimental control group was highest, compared with other groups, the differences among them were statistically significant(P<0.05或P<0.01). (6) Comparison of ET-1 in each groups, the experimental control group was highest, compared with other groups, the differences among them were statistically significant(P<0.01).(7) Comparison of IL-6 in each groups, the experimental control group was highest, compared with other groups, the differences among them were statistically significant(P<0.01).(8) Comparison of MDA in each groups, the experimental control group was highest, compared with other groups, the differences among them were statistically significant(P<0.01). Comparison of SOD in each groups, the experimental control group is lowest, compared with control group, middle dose group and high dose group, the differences among them were statistically significant(P<0.01).(9) Comparison of apoptosis index in each groups, the control group was lowest, the experimental control group was highest, compared with each groups, the differences among them were statistically significant (P<0.05 or P<0.01)(10) After treatment, the Tvr-SD of experimental control group was highest, the Tvr-SD of control group was lowest, compared with other groups, the differences among them were statistically significant (P<0.05 or P<0.01)(11) Results of transmission electron microscopy:in the high dose group, sarcomere can be found, myofibrils aligned regularly, Sarcomere structure was basically clear, myofilament were still intact, isotropic and anisotropic band structure were also clear, Z and M line can also be found. The number of mitochondria and sarcoplasmic reticulum increased, the structure of them were normal. The structure of crista and the nuclear membrane were clearly. The distribution of chromatin was basically normal. But in the experimental control group, the sarcomere was deformed, myofilament was fractured and disordered, sarcolemma was edema, the number of mitochondria increased, crista disappeared, endoplasmic reticulum distended, part of the muscle cell disintegrated, isotropic and anisotropic band structure were illegible, Z line was thickened, M line was illegible. The nuclear membrane were partly dissolved and disappeared, the edge of the nuclear membrane was irregular. The distribution of chromatin was abnormal.4. Conclusion(1) Blocking rabbit left anterior descending coronary artery can make heart failure animal model, and it’s operating procedures was relatively simple and Success rate was higher.(2) Yangxinkang tablet can improve cardiac function of rabbit model with heart failure and reduce serum BNP, cTnⅠlevels.(3)Yangxinkang tablet can prevent IVS of rabbit model with heart failure thinning, reduce the diastolic volume and cardiac index, improve the heart ultrastructure, and prevent ventricular remodeling in rabbit model with heart failure.(4) Yangxinkang tablet can reduce serum AngⅡlevels of rabbit model with heart failure, and block the nerve-endocrine system’s activation.(5) Yangxinkang tablet can reduce serum TNF-α、IL-6 levels of rabbit model with heart failure and be against inflammation factors.(6) Yangxinkang tablet can reduce serum ET-1 levels of rabbit model with heart failure, improve endothelial function.(7) Yangxinkang tablet can reduce serum MDA levels and elevate serum SOD levels of rabbit model with heart failure, and it is with antioxidant effect.(8) Yangxinkang tablet can reduce apoptosis of myocardial of rabbit model with heart failure.(9) Yangxinkang tablet can improve systolic synchronous of rabbit model with heart failure.更多还原