| STUDY 1: Evidence Analysis of Nourishing Yin in Treating Heart Failure with Normal Ejection FractionOBJECTIVE To evaluate the efficacy and safety of accessing nourishing Yin treatment in patients with heart failure with normal ejection fraction(HFNEF),GRADE classification were used to classify the evidence result from the Meta-analysis.METHODS We systematically searched China National Knowledge Infrastructure(CNKI),Chinese Scitech Journal Full-text Database(VIP),Wanfang Database,Chinese Biomedical Literature Database(CBM),Embase Database,Pub Med Database,The Cochrane Library Database and OVID database for randomized controlled trials(RCTs)accessing nourishing Yin treatment in patients with HFNEF from the time of the establishment of the database to December 2019.The "Cochrane Intervention System Evaluation Manual" assessment was used to assess the risk of bias in the included RCTs;The Rev Man5.3 software was used to conduct a meta-analysis to evaluate its efficacy and safety.The GRADE grading system was used to evacuate the quality of evidence.RESULTS We included data from 24 RCTs.The results of efficacy analysis and evidence rating were as follows.1 Efficacy 1.1 Patient rehospitalization rate and mortality was reduced(within 6 months after discharge)Compared with routine western medicine treatment,the treatment of HFNEF by nourishing Yin significantly reduced the rate of rehospitalization within 6 months after discharge [RR=0.5,95%CI(0.31,0.82),P=0.006],its evidence level was a medium quality;the treatment of HFNEF by nourishing Yin reduced the mortality within 6 months after discharge [RR=0.3,95%CI(0.08,1.07),P=0.06],but the result was not significant,and the evidence was of medium quality.1.2 BNP and NT-pro BNP level was reduced Compared with routine western medicine treatment,the therapy of HFNEF by nourishing Yin significantly reduced the BNP level of patients [SMD=-1.39,95%CI(-2.09,-0.68),P=0.0001],the evidence was of moderate quality;It significantly reduced patients' NT-pro BNP level [SMD=-0.33,95%CI(-0.55,-0.11),P=0.004],the evidence was of high quality.1.3 Related indexes of cardiac ultrasound were improved.Compared with routine western medicine treatment,the treatment of HFNEF by nourishing Yin significantly increased the early diastolic peak flow rate E peak [MD = 13.02,95% CI(7.10,18.95),P <0.0001],the evidence was of moderate quality;it significantly reduced the patient's late diastolic peak flow velocity peak A [MD=-7.97,95%CI(-13.33,-2.61),P=0.004],the evidence was of medium quality;significantly increased the patient's E/A ratio [MD = 0.17,95%CI(0.09,0.25),P<0.0001];it significantly reduced the patient's rapid left ventricular filling phase transmittal valve blood flow rate peak/early diastolic mitral valve annulus level myocardial velocity peak(E/e')Ratio [MD=-2.12,95%CI(-3.23,-1.02),P=0.0002],the evidence was of medium quality;it significantly improved the patient's left ventricular ejection fraction(LVEF)[MD= 2.52,95%CI(0.59,4.44),P=0.01],the evidence was of moderate quality;significantly reduced the patient's left ventricular isovolumic relaxation time(IVRT)[MD=-1.82,95%CI(-2.88,-0.75),P<0.0008 ],the evidence was of low quality.1.4 6-minute walking distance was increased(6Minutes Walking Distance,6MWD)Compared with routine western medicine treatment,the treatment of HFNEF by nourishing Yin significantly increased the 6-minute walking distance of patients [RR=55.80,95%CI(44.38,67.22),P<0.00001],its evidence was of moderate quality.1.5 Lee's heart failure score was lowered.Compared with routine western medicine treatment,the treatment of HFNEF by nourishing Yin method significantly reduced Lee's heart failure score [MD=-0.71,95%CI(-1.34,-0.08),P=0.03],its evidence was of extremely low quality.1.6 Improve the quality of life of patients with heart failure Compared with routine western medicine treatment,the treatment of HFNEF by nourishing Yin significantly reduced the Minnesota Heart Failure Quality of Life Score [RR=-3.35,95%CI(-0.53,-1.66),P<0.0001],its evidence was of low quality.1.7 Heart function was improved Compared with routine western medicine treatment,the treatment of HFNEF by nourishing Yin significantly improved patients' heart function by the assessment of the improvement rate of NYHA score[RR=1.22,95%CI(1.03,1.34),P<0.0001],its evidence was of moderate quality.1.8 TCM syndrome points were lowered.Compared with routine western medicine treatment,the treatment of HFNEF by nourishing Yin significantly lowered the TCM syndrome score [MD=-3.52,95%CI(-4.40,-2.64),P=0.00001],the evidence was of low quality.2.Safety 13 articles did not mention adverse effect(AE),8 trials reported that no AE was occurred,only 3 of them reported AEs that occurred during the trial(Including 1 case of angina pectoris,1 case of palpitation,3 cases of dizziness,1 case of transient ischemic attack,1 case of hepatic function impairment,1 case of renal function damagement,1 case of acute gastroenteritis,1 case of abdominal distension,3 cases of cold),No adverse reactions that are absolutely related to the tested Chinese medicines have been reported.CONCLUSION Compared to routine western medicine treatment,the treatment of HFNEF by nourishing Yin reduced the mortality and rehospitalization rate within 6 months after discharge,lowered BNP and NT-pro BNP level,upgraded E peak,reduced A peak,increased E/A ratio,reduced E/e' ratio,increased LVEF,decreased IVRT level,increased patients' 6MWD,lowered Lee's heart failure score,improved the quality of life of patients with heart failure,repaired heart function,reduced TCM syndrome score,etc.But the clinical efficacy GRADE scores ranged from high to low which indicated that the evidence was still insufficient even though the safety is good.STUDY 2: Network Pharmacology-Based Study on the Molecular Biological Mechanism of Action for Compound Yangyin Shuxin Decoction in the treatment of HFNEFOBJECTIVE Yangyin Shuxin Decoction(YYSXF)was conducted based on Professor Mao Jingyuan's experience in treating HFNEF and was used for clinical treatment of HFNEF in our hospital.The purpose of this study was to identify the major active compounds from YYSXF and to investigate its mechanisms in the treatment of HFNEF via drug target biological network pharmacology construction and prediction.METHODS Constituents of YYSXF(Cornus,Ophiopogon,Polygonatum,Salvia Miltiorrhiza,Fructus Trichocarpa,Citrus aurantium,Coptis,Pinellia,Earthworm and Soft-shell Turtle)were retrieved from Traditional Chinese Medicine Systems Pharmacology(TCMSP),an Encyclopedia of Traditional Chinese Medicine(ETCM)and Traditional Chinese Medicine Integrated Database(TCMID).Disease targets were collected in Gene Cards database and Therapeutic Target Database(TTD).Wayne analysis tool was used to take the intersection of screened out YYSXF-HFNEF Targets.“Ingredients-protein targets-pathway” networks were constructed using Cytoscape 3.7.2,from which we screened out the effective components of the herbs in YYSXF for treating HFNEF.STRING database were used to construct a protein interaction(Protein-Protein Interaction,PPI)network of YYSXF-HFNEF.The PPI network was imported into Cytoscape 3.7.2 for topological attribute analysis with the degree value(Degree Centrality,DC)as the standard,from which we preliminary screened the core target of YYSXF for treating HFNEF.Gene Ontology(GO)enrichment analysis including biological process(BP),molecular function(MF)and cells components(CC)and Kyoto Encyclopedia of Genes and Genomes(KEGG)biological signaling pathway enrichment analysis were also performed to investigate by using Bioconductor tool for analysis.Finally,we used Cytoscape 3.7.2 software to construct a target-signal pathway network and concentrated the network according to BC value to pinch the most core target based on signal pathway.RESULTS 1.Screening of active compounds in YYSXF A total of 771 active compounds were obtained by searching relevant databases,of which 226 were from cornus,202 were from Salvia miltiorrhiza,116 were from Pinellia ternata,80 were from Gualou peel,and 50 were from Ophiopogon,48 from Coptis,38 from Polygonatum,5 from Citrus aurantium,3 from soft-shell turtle,3 from earthworm.2.Screening of targets related to HFNEF According to the established search strategy,a total of 5,567 related targets of HFNEF were retrieved.After integrating and deleting the duplicated genes,3763 disease-related targets were finally screened.3.Potential targets of YYSXF for treating HFNEF.Through Wayne intersection analysis,a total of 259 targets were obtained.4.The network of YYSXF Recipe-active ingredients-target The analyze was conducted by Cytoscape 3.7.2 software.The average degree value of various compounds in YYSXF was 9.326389.Most of the active ingredients isolated from YYSXF included quercetin(from Coptis),adenine nucleoside(from Ophiopogon japonicus),Luteolin(from Salvia miltiorrhiza),oleanolic acid(from Ophiopogon japonicus),tanshinone II A(from Salvia miltiorrhiza),naringenin(from Fructus Aurantii),nobiletin(from Fructus Aurantii),baicalein(from Pinellia and Polygonatum),?-sitosterol(from Pinellia,Polygonatum,Cornus),isocryptanone(from Salvia miltiorrhiza).The compounds mentioned above were important pharmacological components of YYSXF for treating HFNEF.5.PPI network analysis The STRING database platform was used to construct a protein interaction network of the extracted 259 common targets.A total of 259 nodes and 4590 edges were obtained.The average node degree value was 35.6,P<1.0e-16.We imported the PPI network into the Cytoscape3.7.2 for topological analysis.Finally,34 core targets were obtained.6.GO biological function annotation and KEGG pathway enrichment analysis for targets 113 target genes of the drug active ingredient-cancer intersection were introduced into Bioconductor bioinformatics data processing tools.,A total of 1730 BP,65 MF and 32 CC were obtained.KEGG biological signal pathway enrichment analysis: With the help of the enrichplot program package in R software,a total of 154 biological signaling pathways with significant enrichment of targets were obtained.KEGG network analysis: According to the degree value and centrality value,10 major targets namely mitogen-activated protein kinase 1(MAPK1),mitogen-activated Protein kinase 3(MAPK3),V-Rel reticuloendotheliosis virus oncogene homolog A(,RELA),serine/threonine kinase 1(AKT1),mitogen-activated protein kinase 14(MAPK14),mitogen-activated protein kinase 8(MAPK8),AP-1 transcription factor subunit(JUN),AP-1 transcription factor subunit(FOS),interleukin-6(IL-6),tumor necrosis factor(TNF)were obtained.These target genes mainly affected substances or signaling pathways,including phosphatidylinositol 3-kinase-Serine/threonine kinase(PI3K-Akt)signaling pathway,mitogen-activated protein kinase(MAPK)signaling pathway,diabetes complications related glycosyls Advanced Glycation End products-Receptor for Advanced Glycation End products(AGE-RAGE)signaling pathway,Hypoxia Inducible Factor-1(HIF-1)signaling pathway,Tumor Narcotic Factor(TNF)signaling pathway,Interleukin-17(IL-17)signaling pathway.CONCLUSION This study was based on pharmacological networks results for the prediction of the multiconstituent,multitarget,and multi-pathway mechanisms of YYSXF,which might be a promising potential therapeutic and prevention candidate for the treatment of HFNEF.However,based on computer data mining and analysis,this study still needs to be further verified by in vivo/in vitro experiments,and the safety of YYSXF needs to be evaluated... |
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