| Purpose: To analyze and summarize the syndrome elements,syndrome characteristics and syndrome evolution law of coronary heart disease complicated with heart failure in different stages through the clinical experts questionnaire in multi-center and with large sample in China;Using network meta-analysis to explore the clinical effective traditional Chinese medicine treatment of coronary heart disease complicated with heart failure;Using the method of network pharmacology,the effective components of each traditional Chinese medicines in the basic prescription "Shenqi Gualou Xiebai Banxia Decoction" used by Professor Zhang Mingxue and the disease targets of coronary heart disease complicated with heart failurewere clarified,and the main targets and pathways screened out were predicted and analyzed,in order to provide reference for the clinical diagnosis mind-set of "syndrome type-treatment principle-prescription and medication" of coronary heart disease complicated with heart failure.Material and method:1.Based on the survey results of a large sample clinical expert questionnaire(Clinical Expert Questionnaire on Syndrome Factors,Syndrome Characteristics and Evolution Law of Syndrome and Pathogenesis of Coronary Heart Disease Complicated with Other Diseases(Coronary Heart Disease Complicated with Heart Failure))distributed to many centers and regions in China(covering Northeast China,Northwest China,North China,Southeast China,Southwest China and South China),exploratory factor analysis(factor analysis ? principal component analysis ? syndrome group)was selected as a statistical method to obtain TCM syndrome elements in each stage.According to syndrome combination rules,the syndrome types and characteristics in each stage of coronary heart disease complicated with heart failure were determined,and the evolution laws of syndrome in each stage were summarized.2.With "Chinese medicine therapy,traditional Chinese medicine therapy,combination of Chinese and Western medicine,coronary heart disease complicated with heart failure,coronary heart disease complicated with heart failure" as the theme words,CNKI,CBM,Wanfang and VIP databases were searched by combining theme words with free words.The search time ranged from self-built database to 2020,and the documents meeting the standards of admission and exclusion were included,and the duplicate documents were eliminated.After reading the abstract and the full text,the final included literatures were selected for follow-up network Meta-analysis,so as to obtain the clinical effective treatment methods commonly used in treating coronary heart disease complicated with heart failure by traditional Chinese medicine and the curative effect difference between them.3.The active components of each traditional Chinese medicine in the prescription of "Panax quinquefolium-Astragalus membranaceus-Trichosanthes kirilowii-Allium macrostemon-Pinellia ternate" were searched and screened through the database of TCMSP and Uniprot by means of network pharmacological analysis method,and the key action targets were screened by means of Cytoscape software.Genecards,OMIM,Digsee,TTD and Drugbank databases were used to screen the related targets of coronary heart disease complicated with heart failure.Introducing the intersection target of the above two into String database for PPI analysis to construct protein interaction network.The hub genes were obtained by using the plug-in of Cytohubba in Cytoscape,and KEGG pathway analysis and GO enrichment analysis were carried out in Metascape database to explore the possible biological functions and pathways of potential targets,so as to obtain the key active molecules and potential molecular mechanism of "American ginseng-Astragalus membranaceus-Fructus Trichosanthis-Allium macrostemon-Pinellia ternate" prescription in treating coronary heart disease complicated with heart failure.Finally,using Auto Dock Tools 1.5.6 software,performed the molecular docking of the main active components of the drug with the selected targets.Results:1.Through exploratory factor analysis of four stages of coronary heart disease complicated with heart failure,the syndrome elements of each stage were obtained,and the syndrome types and characteristics of each stage were obtained as follows according to the principle of syndrome combination:(1)stage A included two TCM syndrome types: deficiency of heart-spleen deficiency,syndrome of Qixu Chongni.(2)stage B included five TCM syndrome types: deficiency of deficiency of both qi and yin,deficiency of qi-deficiency and blood-stasis,syndrome of liver-spleen disharmony,syndrome of dampness and stagnation of qi,syndrome of(Kidney)Yang deficiency causing water-rheum collecting internally.(3)stage C included four TCM syndrome types: syndrome of deficiency of Zongqi,syndrome of Yinting Zuluo,syndrome of Shenxu Shuifan,syndrome of Hanyin Zuluo;(4)stage D included two TCM syndrome types: syndrome of Chuantuo Wangyang,syndrome of Shuiqi Lingxin.In each stage,qi deficiency and yang deficiency run through all the time,and phlegm retention and blood stasis are important syndrome elements that affect the prognosis of the disease.The evolution rules of syndromes in different stages of coronary heart disease complicated with heart failure are as follows:(1)Entering pre-heart failure stage: there is no obvious abnormality in the initial cardiac function of patients,and there are no symptoms and signs of heart failure.Most of the diseases are mainly qi deficiency,which may affect the functions of heart,liver and spleen due to diet,addiction to tobacco and alcohol,or cold,fatigue,anxiety and anger,thus entering the pre-heart failure stage.However,the condition at this stage is mild and easy to recover.(2)From pre-heart failure stage to pre-clinical stage: If the patient is not intervened in the pre-heart failure stage,or if the patient is not far away from the risk factors,the disease may progress,and gradually develop deficiency in origin and excess in superficislity.Patients will suffer from deficiency of qi and blood,and the heart structure will change.Qi deficiency involves yin and yang,and there are solid evils such as water dampness and blood stasis,which are superimposed on the original qi deficiency and qi stagnation,making Yuan Yang in the kidney gradually weak,and aggravating the deficiency of heart and yang,thus showing the syndrome of deficiency of both qi and yin,qi deficiency and blood stasis,dampness blocking qi stagnation,and(kidney)yang deficiency stopping water.At this stage,although the symptoms increase and the viscera function is extensive,the disease is not serious,and proper intervention can still prevent the disease from progressing in time;(3)Pre-clinical stage-clinical stage: On the basis of pre-clinical stage,if patients do not pay attention to it because they have no obvious symptoms of coronary heart disease or heart failure and do not intervene,the original phlegm-drinking,water-dampness,qi stagnation and blood stasis can quickly consume the qi and blood of the five internal organs through their interaction,hindering the metabolism of water,the transportation and transformation of Shui Gu and the operation of qi-qi,and the pathogenesis tends to be complicated.When entering the clinical stage of coronary heart disease complicated with heart failure,the symptoms of deficiency of qi,stagnation of phlegm and blood stasis,deficiency of both yin and yang can be seen,and the symptoms of deficiency of Zongqi,Yinting Zuluo,Shenxu Shuifan,Hanyin Zuluo develop.Then the disease will develop to a critical situation.(4)Clinical stage-terminal stage: This stage is the most severe or critical stage of disease development,in which the patient's quality of life is extremely poor,the disease is severe,or the symptoms such as lethargy are shallow coma.At this stage,the heart structure and function of the patients are seriously damaged,which may be progressively aggravated,and multiple organs are involved in.Therefore,the symptoms of organ failure and even shock can be seen,and the disease is serious and difficult to turn.2.A total of 61 RCT studies were included in the network Meta-analysis,with a total sample size of 5827 cases,involving six traditional Chinese medicine treatments: Yiqi+nourishing yin,Yiqi+free urination,Yiqi+promoting blood circulation,Yiqi+warming yang+free urination,Yiqi+warming yang,and Yiqi+tongmai.The results of Meta meta-analysis showed that:(1)In terms of total effective rate and left ventricular ejection fraction,the best treatment plan is to Yiqi +warming yang+ free urination+conventional treatment.Combined with the exploratory factor analysis results in the first paper,it can be seen that for the patients in the middle and later stages of this disease,if they have the symptoms of decreased left ventricular ejection fraction,or symptoms such as chest stuffiness,palpitation,asthma,peripheral edema,etc.,the method of invigorating qi,warming yang to promote diuresis can be used,which is helpful to improve the ejection fraction and clinical symptoms of patients;(2)For the improvement of left ventricular diastolic diameter,left ventricular systolic diameter and NT-pro BNP,Yiqi+nourishing yin+routine therapy is the best treatment.Combined with the exploratory factor analysis results of the first paper,it can be seen that the deficiency of both qi and yin in coronary heart disease complicated with heart failure is more common in preclinical stage,such as yin deficiency of liver and kidney,blood deficiency of heart and liver,etc.Therefore,the method of invigorating qi and nourishing yin can be used for such patients,which can not only invigorate qi and nourish yin,reduce plasma NT-pro BNP level to improve cardiac function and reduce ventricular volume,but also prevent the disease from progressing to the next stage and the emergence of yin and yang deficiency;(3)Yiqi+Tongmai+conventional therapy can optimally increase the patient's six-minute walking distance.Combined with the exploratory factor analysis results of the first paper,it can be seen that the syndromes targeted by this therapy can correspond to the syndrome of qi deficiency and blood stasis,dampness blocking qi stagnation,(kidney)yang deficiency stopping water in pre-clinical stage of coronary heart disease complicated with heart failure,syndrome of Yinting Zuluo,Shenxu Shuifan,Hanyin Zuluo in clinical stage,and syndrome of Shuiqi Lingxin in the end stage.At this time,the method of Yiqi+Tongmai can correct the phenomenon of qi deficiency,eliminate blood stasis and phlegm retention,restore qi and blood flow,improve the patient's exercise tolerance and improve their quality of life.The Meta-analysis results obtained above were all statistically significant,and accord with the prediction order of mesh meta-analysis,and the results were reliable.3.The results of network pharmacological analysis showed that there were 10 key proteins in the prescription of "Panax quinquefolium-Astragalus membranaceus-Trichosanthes kirilowii-Pinellia ternata",which were quercetin,?-sitosterol,1,7-dihydroxy-3,9-dimethoxypterocene,7-O-methylisomucronulatol,formononetin,Baicalin,baicalein,naringenin,stigmasterol and cavendine.These may be the main active ingredients in the prescription for treating coronary heart disease complicated with heart failure.The PPI protein interaction network was constructed based on 182 common target genes,and the top 10 core key targets were selected,which were AKT1,TP53,JUN,STAT3,BCL2L1,CDKN1 A,CDK2,IL10,CCND1,MYC,etc.Enrichment analysis of KEGG pathway suggests that apoptosis and AGE-RAGE signaling pathway are very likely to be the key signaling pathways in the treatment of coronary heart disease complicated with heart failure.The results of GO enrichment analysis showed that the molecular biological functions involved in drugs mainly included regulating kinase activity and interfering ligand-receptor binding;The results of cell composition suggested that cell membrane,endoplasmic reticulum and mitochondria were the core target tissue distribution and subcellular distribution areas;In the biological process,the prescription mainly affected the human body's response to toxic substances,inorganic substances,lipids and lipopolysaccharide,and played a certain role in the process of active oxygen metabolism,and could affect the biological processes such as cell proliferation and apoptosis.The results of molecular docking showed that the drug active ingredients had better binding activity with target receptor protein,and the binding effect of MMP9 with formononetin was the best,followed by MMP9 with kaempferol,MAPK8 with ?-sitosterol,MMP9 with ?-sitosterol,VEGFA with formononetin.Conclusion:1.Based on the results of exploratory factor analysis and principal component analysis,it can be seen that the pathogenesis of coronary heart disease complicated with heart failure is complex and there are many syndromes,so it is necessary to grasp the key syndromes based on different stages of the disease for intervention.At the initial stage of the disease,the condition was shallow,especially qi deficiency.However,with the progress of the disease,the syndrome of phlegm,water and blood stasis gradually occurred,which was difficult to change.Pre-heart failure stage and pre-clinical stage are the key stages of this disease.In this stage,the symptoms of patients are not obvious,or there may be non-heart disease syndromes.However,if the key syndrome elements and syndrome characteristics can be grasped in the high-risk groups at this stage during clinical treatment,the disease development can be restrained before the pathogenesis is formed,and patients can recover well,thus delaying the disease progress and effectively improving the prognosis and quality of life.2.According to the results of network Meta-analysis,the methods of invigorating qi,warming yang and promoting diuresis,supplementing qi and nourishing yin,and invigorating qi and dredging pulse are all commonly used in clinic,but each of the three methods has its own emphasis.Based on the exploratory factor analysis results of the questionnaire in paper 1,it can be seen that the Yiqi+warming yang+free urination method is suitable for patients in the middle and late stage of this disease,and the symptoms include decreased left ventricular ejection fraction,or symptoms such as chest stuffiness,palpitation,asthma,peripheral edema,etc.Yiqi Tongmai method is suitable for coronary heart disease complicated with heart failure at the pre-clinical stage and the end stage.It can be seen that the patient's exercise tolerance is decreased,or the symptoms of qi deficiency and phlegm and blood stasis are blocked;The method of Yiqi+nourishing yin is mostly used in the pre-clinical stage of coronary heart disease complicated with heart failure,and the condition at this stage is mild.Intervention at this time can significantly improve the prognosis of patients and delay the disease progress.Therefore,for patients with this disease who have developed into structural heart disease but have no obvious symptoms of heart failure in clinic or whose condition is in chronic remission stage,the method of Yiqi+nourishing yin should be used according to the syndrome of deficiency of both qi and yin,so as to effectively grasp the best treatment opportunities.3.Based on the results of network pharmacology,the basic prescription "American ginseng-Astragalus membranaceus-Trichosanthes kirilowii-Allium macrostemon-Pinellia ternate" used by my tutor in clinical treatment of coronary heart disease complicated with heart failure with deficiency of both qi and yin has the characteristics of multi-component,multi-target and multi-channel,which can effectively improve patients' symptoms,resist oxidative stress,inhibit inflammatory reaction,regulate blood lipid,improve heart function and prevent myocardial and histocyte damage.It can reduce myocardial cell loss by interfering with apoptosis pathway,and delay the process of myocardial fibrosis by blocking AGE-RAGE pathway.Therefore,this prescription can effectively reverse ventricular remodeling,correct ventricular compensatory enlargement,restore myocardial compliance,reduce stiffness,and prevent the disease from progressing to the next stage,which can be used as a good foundation for the critical transition stage of coronary heart disease complicated with heart failure.In addition,when using this prescription for clinical treatment,we should also pay attention to the proper administration of Chinese medicines for promoting blood circulation and eliminating phlegm according to the symptoms of patients,so as to alleviate the symptoms of light phlegm and blood stasis in patients and support the contribution of this prescription to delay the disease progress. |
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