| Objective1 To evaluate the clinical efficacy of Traditional Chinese Medicine in the treatment of chronic heart failure from a macro level according to syndrome elements with randomized controlled clinical study objectively.2 To construct classificatory model of three syndromes of chronic heart failure based on plasma metabolomics, to evaluate the overall efficacy of Traditional Chinese Medicine in the treatment of chronic heart failure from a micro level according to syndrome elements with metabolomics technology, and to explore the mechanism of yiqihuoxue Chinese medicine in the treatment of chronic heart failure with qi-deficiency and blood-stasis syndrome.Methods1 A multi-center, randomized study was designed in this study, and the efficacy of 65 patients of chronic heart failure with qi deficiency syndrome, qi-deficiency and blood-stasis syndrome, qi-deficiency, blood-stasis and morbid-fluid syndrome was analyzed. Patients were randomly divided into two groups, the treatment group (conventional western medicine+ Chinese herbal medicine according to syndrome elements) and the control group (conventional western medicine). We observed NT-proBNP, LVEF, TCM symptom score, scale for evaluating the quality of life in CHF with TCM and western medicine and SF-36 questionnaire condensed condition at baseline and 28 days. SPSS 18.0 statistical software was used in the data analysis. The subgroup of 43 patients with qi-deficiency and blood-stasis syndrome (treatment group 23 cases,20 cases in the control group) also conducted efficacy analysis.2 Tests on plasma metabolites of 1H-NMR spectrum were conducted on 128 patients with chronic heart failure and 25 healthy controls. The data generated from the’H-NMR spectrum which was processed by software MestReNoval0.0.2 was normalized and standardized by centralization, and then was further converted into Excel format for PCA and PLS-DA pattern recognition. According to’H-NMR spectrum and chemical shift of VIP> 1 and by using the software of Chenomx NMR Suite-8.12, metabolites associated with disease and syndromes in the spectrum were determined. Further, metabolic pathways of those metabolites were analyzed by using the online software "MetaboAnalyst 3.1".3 Changes in metabolites of the treatment group and the control group were analyzed by PLS-DA pattern recognition so as to evaluate the overall efficacy of Traditional Chinese Medicine in the treatment of chronic heart failure from a micro level.4 The subgroup of patients with qi-deficiency and blood-stasis syndrome was also conducted with PLS-DA pattern recognition. The mechanism of yiqihuoxue Chinese medicine in the treatment of chronic heart failure with qi-deficiency and blood-stasis syndrome was explored through metabolic pathways analysis of metabolites of VIP> 1.Results1 Randomized controlled clinical trial1.1 The efficacy analysis of NYHA functional classification(1) Comparison of the efficacy of NYHA functional classification distribution:The NYHA functional classification distribution in the treatment group was similar to the control group (P>0.05); (2) Comparison of the improved level of NYHA functional classification:There was no significant difference between the treatment group and the control group after treatment (P>0.05); (3) The efficacy of NYHA functional classification in the subgroup between the treatment group and the control group also had no significant difference.1.2 The efficacy analysis of symptoms(1) The score of symptoms:the score of symptoms had no statistical disparity between the treatment group and the control group after 28 days’treatment(P>0.05), and there was a remarkable difference within each group compared to pre-treatment at the end points (P<0.05); (2) Effective rate of symptoms:The effective rate of the treatment group was higher than the control group, but there was no statistical significance between two groups(P>0.05);(3) No difference showed in the subgroup analysis(P>0.05).1.3 The efficacy analysis of scale for evaluating the quality of life in CHF with TCM and western medicine(1) There was no statistically difference on the total score of the scale and the score of the six dimensions between the treatment group and the control group after the treatment (P>0.05), while there was a remarkable difference on the total score of the scale and the score of the six dimensions within each group (P<0.05); (2) Analysis of subgroup:there was no statistical significance on the total score of the scale and the score of the six dimensions between the treatment group and the control group after the treatment (P>0.05), while there was a statistical significance on the total score of the scale and the score of the five dimensions within each group (P<0.05).1.4 The efficacy analysis of SF-36 questionnaire condensed condition(1) There was no statistically significance on the score of the health change and the score of the eight dimensions between the treatment group and the control group after the treatment (P>0.05), while there was a statistical difference on the score of the social ability and health change within each group (P<0.05), and compared to pre-treatment at the end points there was a statistical difference on the score of the physical function, physical ability, body pain, general health, energy in the treatment group (P<0.05). (2) Analysis of subgroup:there was no statistical difference on the score of the health change and the score of the eight dimensions between the treatment group and the control group after the treatment (P>0.05), while there was a statistically significance on the score of the physical function, physical ability, body pain, general health, energy, social ability in the treatment group compared to pre-treatment at the end points (P<0.05).1.5 The efficacy analysis of left ventricular ejection fraction(1) Left ventricular ejection fraction (LVEF) had no statistical disparity between the treatment group and the control group after treatment(P>0.05), the same result was showed in each group compared to pre-treatment at the end points (P>0.05); (2) The result of subgroup analysis showed no difference(P>0.05); (3) Analysis of systolic heart failure:LVEF in the treatment group was similar to the control group after 28 days’treatment(P>0.05), the same result was showed in the control group compared to pre-treatment at the end points (P>0.05), while there was a statistical significance on LVEF in the treatment group(P<0.05).1.6 The efficacy analysis of NT-proBNP(1) NT-proBNP had no statistical significance between the treatment group and the control group after treatment(P>0.05), while there was a remarkable difference on NT-proBNP within each group(P<0.05); (2) Analysis of subgroup:there was no statistically significance on NT-proBNP between two groups after treatment(P>0.05), the same result was showed in the control group compared to pre-treatment at the end points (P>0.05), while there was a statistical significance on NT-proBNP in the treatment group.2 Metabolomics research2.1 PCA and PLS-DA pattern recognition were used to analyze the metabolites of 1H-NMR spectrum between the patients with chronic heart failure and healthy controls, and the result showed that the CHF patients and the healthy controls can be well distinguished. We confirmed 21 metabolic markers and metabolic pathways of these metabolites according to the VIP score. Those markers which can distinguish CHF patients from the healthy controls were associated with energy metabolism, include amino acid metabolism, glucose metabolism, citric acid cycle, lipid metabolism.2.2 PLS-DA model in plasma metabolomics of patients of chronic heart failure with three syndromes showed that there was no clear separation of the three syndromes. The result of multiple comparison showed that the qi deficiency syndrome and the qi-deficiency and blood-stasis syndrome can not be well distinguished, and the same result was showed in the qi-deficiency, blood-stasis and morbid-fluid syndrome and qi-deficiency and blood-stasis syndrome, while the qi deficiency syndrome and qi-deficiency, blood-stasis and morbid-fluid syndrome can be separated clearly.2.3 After the combined treatment,5 out of 22 different metabolites of the CHF patients returned back to healthy levels of the healthy controls, and 7 out of these 22 metabolites had statistical significance compared to pre-treatment in the treatment group. In the control group received Western treatment,3 out of 21 different metabolites of the CHF patients returned back to healthy levels of the healthy controls, and 1 out of these 21 metabolites had statistical significance compared to pre-treatment. Therefore, it implied that Chinese medicine’s intervention effects might be found at the difference between these two treatments.2.4 Analysis of the subgroup of qi-deficiency and blood-stasis syndrome:Combined treatment took effects by regulating the pathways of 9 metabolites, namely 3-Hydroxyisobutyrate, Lactate, Glycylproline, Methionine, p-Glucose, a-Glucose, Fructose,3-Methylhistidine, Phenylalanine; Western medicine intervened 5 metabolites’pathways:Lactate, Glycylprolinec, β-Glucose, a-Glucose, Phenylalanine. Therefore, it implied that yiqihuoxue Chinese medicine’s intervention effects might be found at 4 metabolites’pathways: 3-Hydroxyisobutyrate, Methionine, Fructose,3-Methylhistidine.Conclusion1 The clinical efficacy analysis showed that some efficacy endpoint has statistically significance between two groups, while some efficacy endpoint has statistical difference within each group. It implies that the treatment of chronic heart failure with Traditional Chinese Medicine according to syndrome elements has certain clinical efficacy which may become more prominent if clinical observation period can be extended appropriately.2 The metabolic markers which can distinguish CHF patients from the healthy controls were associated with energy metabolism, include amino acid metabolism, glucose metabolism, citric acid cycle and lipid metabolism. The qi deficiency syndrome and qi-deficiency, blood-stasis and morbid-fluid syndrome of CHF can be separated clearly. It provides a direction for the quantitative and objective research of the diseases and related symptoms.3 Traditional Chinese Medicine can adjust metabolic pathway of CHF patients to a normal state, and yiqihuoxue Chinese medicine might be functioning by regulating pathways of some of the aforementioned metabolites. This study provides an objective and scientific evaluation on efficacy of TCM in treating CHF.
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