基于证候要素辨证治疗慢性心衰的临床疗效评价及代谢组学研究

发布时间：2018-04-30 09:24

  本文选题：代谢组学 + 慢性心力衰竭　； 参考：《北京中医药大学》2016年博士论文

【摘要】：目的1通过随机对照临床研究从宏观层面客观评价中药基于证候要素辨证治疗慢性心力衰竭的临床疗效。2构建基于血浆代谢组学的慢性心力衰竭三种证候的区分模式；通过代谢组学技术从微观层面评价中药基于证候要素辨证治疗慢性心力衰竭的整体疗效,并初步探讨益气活血中药治疗慢性心力衰竭气虚血瘀证的作用机制。方法1采用多中心、随机、对照的临床研究设计,对65例慢性心力衰竭气虚证、气虚血瘀证和气虚血瘀水饮证的患者进行疗效分析。将患者随机分为两组,即34例中药组(常规西药治疗+证候要素给药)和31例对照组(常规西药治疗)。分别于入组时、治疗28天后观测NT-proBNP值、射血分数、中医症状积分、慢性心衰生存质量量表和SF-36量表积分的变化。采用SPSS18.0统计软件进行分析。43例气虚血瘀证亚组的慢性心衰患者(中药组23例,对照组20例)也进行了疗效分析。2对128例慢性心衰患者和25例健康人'H-NMR谱血浆代谢物进行检测,采用MestReNoval 0.0.2软件对谱图进行处理,所产生的积分数据经归一化和中心化后以Excel格式存储,再进行PCA和PLS-DA模式识别分析；根据NMR图谱和PLS-DA模型中VIP值1代谢物的化学位移,结合Chenomx NMR Suite-8.12软件确定与疾病和证候相关的标志性代谢物；最后通过在线软件"MetaboAnalyst 3.1"进行标志性代谢物的代谢通路分析。3对临床研究部分的慢性心力衰竭患者中药治疗组(34例)和西药对照组(31例)治疗前后的血浆代谢物进行PLS-DA模式判别分析,从微观层面客观评价中药治疗慢性心力衰竭的整体疗效。4对临床研究部分气虚血瘀证亚组的慢性心力衰竭患者益气活血中药治疗组(23例)和西药对照组(20例)治疗前后的血浆代谢物进行PLS-DA模式判别分析,客观评价益气活血中药治疗慢性心力衰竭气虚血瘀证的疗效；通过对VIP值1代谢物的代谢通路分析,初步探讨了益气活血中药治疗慢性心力衰竭气虚血瘀证的作用机制。结果1随机对照临床研究1.1心功能分级疗效分析(1)心功能分级分布疗效比较：用药后28d,中药组和对照组比较,差异无统计学意义(P0.05)。(2)心功能分级改善等级比较：治疗后28d,两组患者心功能改善等级比较,差异无统计学意义(P0.05)。(3)气虚血瘀证亚组心功能疗效分析也没有统计学意义。1.2症状疗效分析(1)症状积分比较：中药组和对照组患者治疗28d后,症状积分及症状积分差值组间比较没有统计学差异(P0.05)；组内比较：两组患者治疗后的症状积分均较治疗前明显改善,差异有统计学意义(P0.05)。(2)症状有效率比较：中药组和对照组有效率分别为67.60%、51.60%,中药组有效率高于对照组,经卡方检验,差异无统计学意义(P0.05)。(3)气虚血瘀证亚组的症状疗效分析结果与此相同。1.3慢性心衰生存质量量表疗效分析(1)中药组和对照组患者治疗28d后,组间比较：量表总积分和六个维度的积分及积分差值的改善均无统计学意义(P0.05)；组内比较：两组治疗前后量表总积分和六个维度的积分的改善均有统计学意义(P0.05)。(2)气虚血瘀证亚组分析：气虚血瘀证中药组和对照组患者治疗28d后,组间比较：量表总积分和六个维度的积分及积分差值的改善均无统计学意义(P0.05)；组内比较：两组治疗前后量表总积分和生理机能、角色限制、活力、社会功能、医疗支持五个维度的积分的改善均有统计学意义(P0.05)。1.4 SF-36量表疗效分析(1)中药组和对照组患者治疗28d后,组间比较：HT健康变化和八个维度积分差值无统计学差异(P0.05)；组内比较：两组治疗后社会功能、HT健康变化积分较治疗前有统计学差异(P0.05),中药组治疗后生理机能、生理职能、躯体疼痛、一般健康、精力积分较治疗前有统计学差异(P0.05)。(2)气虚血瘀证亚组分析：气虚血瘀证中药组和对照组患者治疗28d后,组间比较：HT健康变化和八个维度积分及积分差值无统计学差异(P0.05)；组内比较：中药组治疗后生理机能、生理职能、躯体疼痛、一般健康、精力、社会功能积分较治疗前有统计学差异(P0.05)。1.5射血分数疗效分析(1)用药28d后,中药组和对照组组间EF值及EF值的差值的比较不具有统计学差异(P0.05)；两组治疗后与治疗前组内比较,EF值差异均无统计学意义(P0.05)。(2)气虚血瘀证亚组的射血分数疗效分析结果与此相同。(3)收缩性心力衰竭射血分数疗效分析：用药28d后,中药组和对照组的EF值及EF值的差值均没有统计学差异(P0.05)；中药组组内治疗后与治疗前比较,EF值差异有统计学意义(P0.05),对照组组内治疗后与治疗前比较,EF值差异无统计学意义(P0.05)。1.6NT-proBNP值疗效分析(1)用药28d后,中药组和对照组NT-proBNP值及NT-proBNP值的差值比较不具有统计学差异(P0.05)；两组治疗后与治疗前组内比较,NT-proBNP值差异均有统计学意义(P0.05)。(2)气虚血瘀证亚组分析：用药28d后,气虚血瘀证中药组和对照组的NT-proBNP值及NT-proBNP值的差值比较不具有统计学差异(P0.05)；中药组组内治疗后与治疗前比较,NT-proBNP值差异有统计学意义(P0.05),对照组组内治疗后与治疗前比较,NT-proBNP值差异无统计学意义(P0.05)。2代谢组学研究2.1慢性心力衰竭患者和健康对照组1H-NMR图谱血浆代谢物的主成分分析和偏最小二乘判别分析结果显示慢性心力衰竭患者和健康对照组可以得到很好的区分。进一步的VIP值分析确定了慢性心力衰竭与氨基酸代谢、糖代谢、三羧酸循环和脂质代谢等能量代谢紊乱相关的21个潜在代谢标志物及其相关代谢途径。2.2慢性心力衰竭三种证候的血浆代谢物PLS-DA模式识别结果显示慢性心力衰竭气虚证、气虚血瘀证、气虚血瘀水饮证之间不能得到很好的区分。这三种证候的两两判别分析结果显示慢性心力衰竭气虚血瘀证和气虚证、气虚血瘀证和气虚血瘀水饮证均不能得到有效的区分；而慢性心力衰竭气虚证与气虚血瘀水饮证能获得较好的区分。2.3慢性心力衰竭患者中药治疗组和西药对照组治疗前后的血浆代谢物的判别分析结果显示,在中药治疗组,慢性心衰患者经治疗后22个差异代谢物中5个代谢物水平恢复到与之对应的健康对照组水平,7个代谢物水平与治疗前比有统计学差异；在西药对照组,慢性心衰患者经治疗后21个差异代谢物中3个代谢物水平恢复到与之对应的健康对照组水平,1个代谢物水平与治疗前相比有统计学差异；单纯中药的干预作用体现在这两者对各异常代谢物的代谢途径调节的差异上。2.4慢性心力衰竭气虚血瘀证患者益气活血中药治疗组和西药对照组治疗前后的血浆代谢物的判别分析结果显示益气活血中药治疗组主要干预β-羟异丁酸、乳酸、甘氨酰脯氨酸、蛋氨酸、β-葡萄糖、α-葡萄糖、果糖、3-甲基组氨酸、苯丙氨酸这9个代谢物的通路；西药对照组主要干预乳酸、甘氨酰脯氨酸、β-葡萄糖、β-葡萄糖、苯丙氨酸这5个代谢物的通路；单纯益气活血中药的作用可能体现在干预β-羟异丁酸、蛋氨酸、果糖、3-甲基组氨酸这4个代谢物的通路上。结论1基于证候要素辨证运用中药治疗慢性心力衰竭,部分疗效指标组内治疗前后比较,差异有统计学意义；部分疗效指标组间比较,差异有统计学意义,提示基于证候要素辨证治疗慢性心力衰竭具有一定的临床疗效,并且适当延长临床观察周期后,中药的临床疗效可能会更加突出。2慢性心力衰竭代谢标志物与氨基酸代谢、糖代谢、三羧酸循环和脂质代谢等能量代谢紊乱相关,并且慢性心力衰竭气虚证与气虚血瘀水饮证能够得到区分,为疾病箱关证候的客观化和定量化研究提供了方向。3中药治疗慢性心力衰竭的临床疗效是通过调整其异常的代谢途径至正常状态来实现的,益气活血中药是通过对其中某些代谢通路的调节来发挥治疗作用的,为客观地评价中药治疗慢性心力衰竭的疗效和作用机制提供了一定的研究依据。
[Abstract]:Objective 1 to evaluate the clinical efficacy of traditional Chinese medicine based on syndrome differentiation in the treatment of chronic heart failure from the macro level by randomized controlled clinical study.2 construction of three syndromes of chronic heart failure based on plasma metabonomics and the evaluation of TCM based on syndrome differentiation treatment based on metabonomics. The overall effect of chronic heart failure and preliminary discussion on the mechanism of qi deficiency and blood stasis syndrome of chronic heart failure treated by Yiqi Huoxue Chinese medicine. Method 1 the clinical research and design of multi center, random and controlled clinical study were adopted to analyze the curative effect of 65 cases of qi deficiency syndrome of chronic heart failure, Qi deficiency and blood stasis syndrome and Qi deficiency blood stasis water syndrome. It was divided into two groups: 34 cases of traditional Chinese medicine (conventional western medicine + syndrome factors) and 31 cases of control group (conventional Western Medicine). At the time of entering the group, the NT-proBNP value, the ejection fraction, the TCM symptom score, the quality of life quality scale of chronic heart failure and the change of the SF-36 scale were observed respectively. The SPSS18.0 statistics software was used to analyze the.43 case gas. The chronic heart failure patients (23 cases of Chinese medicine group and 20 cases of control group) were also analyzed by.2. The plasma metabolites of'H-NMR spectrum in 128 cases of chronic heart failure and 25 healthy people were detected by MestReNoval 0.0.2 software, and the product data were stored in Excel format after normalization and centralization. PCA and PLS-DA pattern recognition analysis; the chemical shift of the VIP value 1 metabolites in the NMR atlas and PLS-DA model and the Chenomx NMR Suite-8.12 software to determine the marker metabolites associated with the disease and syndrome; finally, the metabolic pathway analysis of the marker metabolites by the online software "MetaboAnalyst 3.1" is used for the clinical study of the clinical research. PLS-DA model discriminant analysis of plasma metabolites before and after treatment in some patients with chronic heart failure (34 cases) and Western medicine control group (31 cases), the overall efficacy of traditional Chinese medicine in the treatment of chronic heart failure was objectively evaluated from the microcosmic level and.4 was used to promote qi and activating blood circulation in the chronic heart failure patients of qi deficiency and blood stasis syndrome subgroup. The plasma metabolites of the Chinese medicine treatment group (23 cases) and the western medicine control group (20 cases) were analyzed by PLS-DA pattern discriminant analysis. The effect of Yiqi Huoxue Chinese medicine on Qi deficiency and blood stasis syndrome of chronic heart failure was objectively evaluated. Through the analysis of metabolic pathway of VIP value 1 metabolites, the treatment of qi deficiency of chronic heart failure by Yiqi Huoxue Chinese medicine was preliminarily discussed. The effect mechanism of blood stasis syndrome. Results 1 randomized controlled clinical study of 1.1 cardiac function classification effect analysis (1) cardiac function classification distribution effect comparison: after 28d, Chinese medicine group and the control group, the difference was not statistically significant (P0.05). (2) the classification of cardiac function improvement grade comparison: after the treatment of 28d, the two groups of heart function improvement grade comparison, the difference was no Statistical significance (P0.05). (3) the analysis of cardiac function in the sub group of qi deficiency and blood stasis syndrome was also not statistically significant for the analysis of.1.2 symptoms (1) the symptom integral comparison: after the treatment of 28d in the traditional Chinese medicine group and the control group, there was no statistical difference between the symptom integral and the difference of symptom integral groups (P0.05); in the group comparison, the symptoms after the treatment of the two groups were compared. The scores were significantly improved than before the treatment (P0.05). (2) the efficiency of the symptoms was compared: the effective rate of the Chinese medicine group and the control group was 67.60%, 51.60%, the effective rate of the Chinese medicine group was higher than that of the control group. The difference was not statistically significant (P0.05) by the chi square test (3) the results of the analysis of the symptoms of the symptoms of the Qi deficiency and blood stasis syndrome were the same as that of the same.1.3. Analysis of the quality of heart failure quality of life (1) after the treatment of 28d in the traditional Chinese medicine group and the control group, there was no significant difference between the group and the six dimensions of integral and integral difference (P0.05). In group comparison, the improvement of total integral and six dimensions of the two groups before and after treatment were statistically significant (P0.05 (2) analysis of qi deficiency and blood stasis syndrome subgroup: after the treatment of 28d in the Chinese medicine group and the control group of qi deficiency and blood stasis syndrome, there was no significant difference between the group and the six dimensions of integral and integral difference (P0.05); in the group, the total integral and physiological function, the role limitation, the vitality, the social function, and the medical treatment of the two groups before and after the treatment were compared. The improvement of the integration of five dimensions was statistically significant (P0.05).1.4 SF-36 scale effect analysis (1) after the treatment of 28d in the traditional Chinese medicine group and the control group, there was no statistical difference between the HT health changes and the eight dimension integral difference (P0.05). In the group comparison, the social function of the two groups after treatment, the integral of HT health changes were compared with those before the treatment. There were statistical differences (P0.05). The physiological function, physiological function, somatic pain, general health and energy integral after treatment were statistically different (P0.05). (2) the analysis of qi deficiency and blood stasis syndrome subgroup: after the treatment of 28d in Qi deficiency and blood stasis syndrome group and the control group, the health changes of HT and the integral and integral difference of the eight dimensions were compared. No statistical difference (P0.05), group comparison: the physiological function, physiological function, somatic pain, general health, energy and social function score of the Chinese medicine group were statistically different from before treatment (P0.05).1.5 ejection fraction effect analysis (1) after the use of 28d, the difference between the EF value and the EF value of the Chinese medicine group and the control group was not statistically poor. Difference (P0.05); there was no significant difference in EF between the two groups after treatment and in the pre treatment group (P0.05). (2) the results of the ejection fraction of the Qi deficiency and blood stasis syndrome group were the same. (3) the effect analysis of the ejection fraction of the systolic heart failure: after the use of 28d, there was no statistical difference between the EF value and the EF value of the Chinese medicine group and the control group (P 0.05): compared with before treatment, the difference of EF value was statistically significant (P0.05). There was no statistically significant difference in EF value (P0.05).1.6NT-proBNP value analysis (1) after treatment in the control group (P0.05).1.6NT-proBNP value (28d), the difference between the NT-proBNP value and NT-proBNP value of the Chinese medicine group and the control group was not statistically different (the difference of the value of NT-proBNP and NT-proBNP). P0.05); two groups after treatment and before treatment group, NT-proBNP value difference was statistically significant (P0.05). (2) Qi deficiency and blood stasis syndrome subgroup analysis: after the use of 28d, Qi deficiency and blood stasis syndrome of Chinese medicine group and the control group NT-proBNP value and NT-proBNP value difference is not statistically different (P0.05); Chinese medicine group in the group after treatment and before treatment before treatment The difference in NT-proBNP value was statistically significant (P0.05). There was no significant difference in NT-proBNP value (P0.05) in the control group after treatment (P0.05).2 metabolic group study 2.1 chronic heart failure patients and healthy control group with 1H-NMR map plasma metabolites principal component analysis and partial least squares discriminant analysis results showed chronic heart failure Exhaustive patients and healthy controls can be distinguished. Further VIP analysis determines 21 potential metabolic markers related to energy metabolism disorders such as chronic heart failure and amino acid metabolism, glucose metabolism, three carboxylic acid cycle and lipid metabolism, and the plasma metabolite PL of three syndromes of chronic heart failure in.2.2 S-DA pattern recognition results show that chronic heart failure Qi deficiency syndrome, Qi deficiency and blood stasis syndrome, Qi deficiency and blood stasis water drinking syndrome can not be distinguished well. The 22 discriminant analysis results of these three syndromes show that qi deficiency and blood stasis syndrome and Qi deficiency syndrome of chronic heart failure, Qi deficiency and blood stasis syndrome and Qi deficiency blood stasis water drinking syndrome can not be effectively distinguished; slow Qi deficiency syndrome of heart failure and Qi deficiency and blood stasis water drinking syndrome can obtain a better distinction between.2.3 and Western medicine control group before and after treatment. The results show that the 5 metabolites of the 22 different metabolites of chronic heart failure patients recovered to the same time after treatment. In the corresponding healthy control group, the level of the 7 metabolites was significantly different from that before the treatment. In the western medicine control group, the level of 3 metabolites in the 21 different metabolites of the chronic heart failure patients recovered to the corresponding level of the healthy control group, and the 1 metabolites were statistically different from those before treatment; the pure Chinese medicine was dry. The preconditioning is reflected in the difference of metabolic pathways between the two abnormal metabolites in.2.4 patients with Qi deficiency and blood stasis syndrome of chronic heart failure. The results of the discriminant analysis of plasma metabolites in the treatment group of Yiqi Huoxue Chinese medicine and the western medicine control group before and after treatment show that the treatment group of Yiqi Huoxue Chinese medicine is mainly interfered with beta hydroxyisobutyric acid, lactic acid, glyamyl Proline, methionine, beta glucose, alpha glucose, fructose, 3- methyl histidine, phenylalanine, the pathway of the 9 metabolites; the western medicine control group mainly intervened the 5 pathways of lactate, glycine proline, beta glucose, beta glucose, phenylalanine, and the effect of single pure qi invigorating Chinese medicine may be reflected in the intervention of beta hydroxyisobutyric acid. The 4 metabolites of methionine, fructose and 3- methyl histidine were on the path. Conclusion 1 based on syndrome differentiation and TCM treatment of chronic heart failure based on syndrome differentiation, the difference is statistically significant before and after treatment in part of the therapeutic target group; the difference is statistically significant between the groups of some therapeutic targets, suggesting that syndrome differentiation based on syndrome factors is slow. The clinical efficacy of heart failure has a certain clinical effect, and after the clinical observation period is extended properly, the clinical efficacy of Chinese medicine may be more prominent in the metabolic markers of.2 chronic heart failure and the metabolic disorders of amino acids, sugar metabolism, three carboxylic acid circulation and lipid metabolism, and chronic heart failure Qi deficiency syndrome and Qi deficiency and blood stasis water. Drinking syndrome can be distinguished, and the objective and quantitative study of the syndrome of the disease box provides the direction of direction.3 in the treatment of chronic heart failure by adjusting its abnormal metabolic pathway to the normal state. The evaluation of the curative effect and mechanism of traditional Chinese medicine on chronic heart failure provides a certain basis for research.

【学位授予单位】：北京中医药大学
【学位级别】：博士
【学位授予年份】：2016
【分类号】：R259
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本文编号：1823994