本文選題：代謝組學(xué) + 慢性心力衰竭��； 參考：《北京中醫(yī)藥大學(xué)》2016年博士論文

【摘要】：目的1通過隨機(jī)對照臨床研究從宏觀層面客觀評價中藥基于證候要素辨證治療慢性心力衰竭的臨床療效。2構(gòu)建基于血漿代謝組學(xué)的慢性心力衰竭三種證候的區(qū)分模式；通過代謝組學(xué)技術(shù)從微觀層面評價中藥基于證候要素辨證治療慢性心力衰竭的整體療效,并初步探討益氣活血中藥治療慢性心力衰竭氣虛血瘀證的作用機(jī)制。方法1采用多中心、隨機(jī)、對照的臨床研究設(shè)計,對65例慢性心力衰竭氣虛證、氣虛血瘀證和氣虛血瘀水飲證的患者進(jìn)行療效分析。將患者隨機(jī)分為兩組,即34例中藥組(常規(guī)西藥治療+證候要素給藥)和31例對照組(常規(guī)西藥治療)。分別于入組時、治療28天后觀測NT-proBNP值、射血分?jǐn)?shù)、中醫(yī)癥狀積分、慢性心衰生存質(zhì)量量表和SF-36量表積分的變化。采用SPSS18.0統(tǒng)計軟件進(jìn)行分析。43例氣虛血瘀證亞組的慢性心衰患者(中藥組23例,對照組20例)也進(jìn)行了療效分析。2對128例慢性心衰患者和25例健康人'H-NMR譜血漿代謝物進(jìn)行檢測,采用MestReNoval 0.0.2軟件對譜圖進(jìn)行處理,所產(chǎn)生的積分?jǐn)?shù)據(jù)經(jīng)歸一化和中心化后以Excel格式存儲,再進(jìn)行PCA和PLS-DA模式識別分析；根據(jù)NMR圖譜和PLS-DA模型中VIP值1代謝物的化學(xué)位移,結(jié)合Chenomx NMR Suite-8.12軟件確定與疾病和證候相關(guān)的標(biāo)志性代謝物；最后通過在線軟件"MetaboAnalyst 3.1"進(jìn)行標(biāo)志性代謝物的代謝通路分析。3對臨床研究部分的慢性心力衰竭患者中藥治療組(34例)和西藥對照組(31例)治療前后的血漿代謝物進(jìn)行PLS-DA模式判別分析,從微觀層面客觀評價中藥治療慢性心力衰竭的整體療效。4對臨床研究部分氣虛血瘀證亞組的慢性心力衰竭患者益氣活血中藥治療組(23例)和西藥對照組(20例)治療前后的血漿代謝物進(jìn)行PLS-DA模式判別分析,客觀評價益氣活血中藥治療慢性心力衰竭氣虛血瘀證的療效；通過對VIP值1代謝物的代謝通路分析,初步探討了益氣活血中藥治療慢性心力衰竭氣虛血瘀證的作用機(jī)制。結(jié)果1隨機(jī)對照臨床研究1.1心功能分級療效分析(1)心功能分級分布療效比較：用藥后28d,中藥組和對照組比較,差異無統(tǒng)計學(xué)意義(P0.05)。(2)心功能分級改善等級比較：治療后28d,兩組患者心功能改善等級比較,差異無統(tǒng)計學(xué)意義(P0.05)。(3)氣虛血瘀證亞組心功能療效分析也沒有統(tǒng)計學(xué)意義。1.2癥狀療效分析(1)癥狀積分比較：中藥組和對照組患者治療28d后,癥狀積分及癥狀積分差值組間比較沒有統(tǒng)計學(xué)差異(P0.05)；組內(nèi)比較：兩組患者治療后的癥狀積分均較治療前明顯改善,差異有統(tǒng)計學(xué)意義(P0.05)。(2)癥狀有效率比較：中藥組和對照組有效率分別為67.60%、51.60%,中藥組有效率高于對照組,經(jīng)卡方檢驗,差異無統(tǒng)計學(xué)意義(P0.05)。(3)氣虛血瘀證亞組的癥狀療效分析結(jié)果與此相同。1.3慢性心衰生存質(zhì)量量表療效分析(1)中藥組和對照組患者治療28d后,組間比較：量表總積分和六個維度的積分及積分差值的改善均無統(tǒng)計學(xué)意義(P0.05)；組內(nèi)比較：兩組治療前后量表總積分和六個維度的積分的改善均有統(tǒng)計學(xué)意義(P0.05)。(2)氣虛血瘀證亞組分析：氣虛血瘀證中藥組和對照組患者治療28d后,組間比較：量表總積分和六個維度的積分及積分差值的改善均無統(tǒng)計學(xué)意義(P0.05)；組內(nèi)比較：兩組治療前后量表總積分和生理機(jī)能、角色限制、活力、社會功能、醫(yī)療支持五個維度的積分的改善均有統(tǒng)計學(xué)意義(P0.05)。1.4 SF-36量表療效分析(1)中藥組和對照組患者治療28d后,組間比較：HT健康變化和八個維度積分差值無統(tǒng)計學(xué)差異(P0.05)；組內(nèi)比較：兩組治療后社會功能、HT健康變化積分較治療前有統(tǒng)計學(xué)差異(P0.05),中藥組治療后生理機(jī)能、生理職能、軀體疼痛、一般健康、精力積分較治療前有統(tǒng)計學(xué)差異(P0.05)。(2)氣虛血瘀證亞組分析：氣虛血瘀證中藥組和對照組患者治療28d后,組間比較：HT健康變化和八個維度積分及積分差值無統(tǒng)計學(xué)差異(P0.05)；組內(nèi)比較：中藥組治療后生理機(jī)能、生理職能、軀體疼痛、一般健康、精力、社會功能積分較治療前有統(tǒng)計學(xué)差異(P0.05)。1.5射血分?jǐn)?shù)療效分析(1)用藥28d后,中藥組和對照組組間EF值及EF值的差值的比較不具有統(tǒng)計學(xué)差異(P0.05)；兩組治療后與治療前組內(nèi)比較,EF值差異均無統(tǒng)計學(xué)意義(P0.05)。(2)氣虛血瘀證亞組的射血分?jǐn)?shù)療效分析結(jié)果與此相同。(3)收縮性心力衰竭射血分?jǐn)?shù)療效分析：用藥28d后,中藥組和對照組的EF值及EF值的差值均沒有統(tǒng)計學(xué)差異(P0.05)；中藥組組內(nèi)治療后與治療前比較,EF值差異有統(tǒng)計學(xué)意義(P0.05),對照組組內(nèi)治療后與治療前比較,EF值差異無統(tǒng)計學(xué)意義(P0.05)。1.6NT-proBNP值療效分析(1)用藥28d后,中藥組和對照組NT-proBNP值及NT-proBNP值的差值比較不具有統(tǒng)計學(xué)差異(P0.05)；兩組治療后與治療前組內(nèi)比較,NT-proBNP值差異均有統(tǒng)計學(xué)意義(P0.05)。(2)氣虛血瘀證亞組分析：用藥28d后,氣虛血瘀證中藥組和對照組的NT-proBNP值及NT-proBNP值的差值比較不具有統(tǒng)計學(xué)差異(P0.05)；中藥組組內(nèi)治療后與治療前比較,NT-proBNP值差異有統(tǒng)計學(xué)意義(P0.05),對照組組內(nèi)治療后與治療前比較,NT-proBNP值差異無統(tǒng)計學(xué)意義(P0.05)。2代謝組學(xué)研究2.1慢性心力衰竭患者和健康對照組1H-NMR圖譜血漿代謝物的主成分分析和偏最小二乘判別分析結(jié)果顯示慢性心力衰竭患者和健康對照組可以得到很好的區(qū)分。進(jìn)一步的VIP值分析確定了慢性心力衰竭與氨基酸代謝、糖代謝、三羧酸循環(huán)和脂質(zhì)代謝等能量代謝紊亂相關(guān)的21個潛在代謝標(biāo)志物及其相關(guān)代謝途徑。2.2慢性心力衰竭三種證候的血漿代謝物PLS-DA模式識別結(jié)果顯示慢性心力衰竭氣虛證、氣虛血瘀證、氣虛血瘀水飲證之間不能得到很好的區(qū)分。這三種證候的兩兩判別分析結(jié)果顯示慢性心力衰竭氣虛血瘀證和氣虛證、氣虛血瘀證和氣虛血瘀水飲證均不能得到有效的區(qū)分；而慢性心力衰竭氣虛證與氣虛血瘀水飲證能獲得較好的區(qū)分。2.3慢性心力衰竭患者中藥治療組和西藥對照組治療前后的血漿代謝物的判別分析結(jié)果顯示,在中藥治療組,慢性心衰患者經(jīng)治療后22個差異代謝物中5個代謝物水平恢復(fù)到與之對應(yīng)的健康對照組水平,7個代謝物水平與治療前比有統(tǒng)計學(xué)差異；在西藥對照組,慢性心衰患者經(jīng)治療后21個差異代謝物中3個代謝物水平恢復(fù)到與之對應(yīng)的健康對照組水平,1個代謝物水平與治療前相比有統(tǒng)計學(xué)差異；單純中藥的干預(yù)作用體現(xiàn)在這兩者對各異常代謝物的代謝途徑調(diào)節(jié)的差異上。2.4慢性心力衰竭氣虛血瘀證患者益氣活血中藥治療組和西藥對照組治療前后的血漿代謝物的判別分析結(jié)果顯示益氣活血中藥治療組主要干預(yù)β-羥異丁酸、乳酸、甘氨酰脯氨酸、蛋氨酸、β-葡萄糖、α-葡萄糖、果糖、3-甲基組氨酸、苯丙氨酸這9個代謝物的通路；西藥對照組主要干預(yù)乳酸、甘氨酰脯氨酸、β-葡萄糖、β-葡萄糖、苯丙氨酸這5個代謝物的通路；單純益氣活血中藥的作用可能體現(xiàn)在干預(yù)β-羥異丁酸、蛋氨酸、果糖、3-甲基組氨酸這4個代謝物的通路上。結(jié)論1基于證候要素辨證運用中藥治療慢性心力衰竭,部分療效指標(biāo)組內(nèi)治療前后比較,差異有統(tǒng)計學(xué)意義；部分療效指標(biāo)組間比較,差異有統(tǒng)計學(xué)意義,提示基于證候要素辨證治療慢性心力衰竭具有一定的臨床療效,并且適當(dāng)延長臨床觀察周期后,中藥的臨床療效可能會更加突出。2慢性心力衰竭代謝標(biāo)志物與氨基酸代謝、糖代謝、三羧酸循環(huán)和脂質(zhì)代謝等能量代謝紊亂相關(guān),并且慢性心力衰竭氣虛證與氣虛血瘀水飲證能夠得到區(qū)分,為疾病箱關(guān)證候的客觀化和定量化研究提供了方向。3中藥治療慢性心力衰竭的臨床療效是通過調(diào)整其異常的代謝途徑至正常狀態(tài)來實現(xiàn)的,益氣活血中藥是通過對其中某些代謝通路的調(diào)節(jié)來發(fā)揮治療作用的,為客觀地評價中藥治療慢性心力衰竭的療效和作用機(jī)制提供了一定的研究依據(jù)。
[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.

【學(xué)位授予單位】：北京中醫(yī)藥大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2016
【分類號】：R259
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本文編號：1823994