An Exploration On Rules Of Treatment For Coronary Heart Disease Based On Syndrome Element-Fang Yuan By Data Mining And Network Pharmacology

Objective.Through data mining,we analyzed the clinical classical cases of coronary heart disease treated by Chinese medicine masters and national famous veteran Chinese medicine practitioners,and explored the relationship between " diagnostic information-evidence element-Fang Yuan" in the process of discriminating and using medicine.We use network pharmacology to establish the correspondence between "evidence element-Fang Yuan-target-disease",to investigate the biological basis of evidence element corresponding to Fang Yuan in the treatment of coronary heart disease,and to provide reference for evidence element-Fang Yuan diagnosis and medication use and informationization of Chinese medicine.MethodsExploring the evidence elements-Fang Yuan of coronary heart disease based on data mining:Searching the monographs and theses of three batches of national medical masters and four national old Chinese medicine experts’ academic experience succession instructors according to the search requirements.Inclusion of medical records suitable for study analysis according to the inclusion and exclusion criteria.The collected medical case data were normalized.Data analysis was performed using IBM SPSS Statistic 24.0.Exploring the biological basis of evidence elements based on network pharmacology:Obtain the evidence elements and formula elements of coronary heart disease through data mining,collect the modern medical symptoms mapped by Chinese medicine through SymMap,and analyze the relationship between the symptoms corresponding to different evidence elements.The chemical components of the formula elements corresponding to the evidence elements were retrieved through TCMSP and TCMID databases,and the targets were transformed into standard symbolic codes using Uniprot database.The disease genes were retrieved from OMIM,DisGeNET,GeneCards,DrugBank,GAD and TTD using the search term "coronary heart disease",and the targets related to coronary heart disease were obtained after de-duplication.GO function and KEGG pathway enrichment analysis were performed on the core targets of square elements to obtain the cellular components,molecular functions,biological processes and signaling pathways of each element.To analyze the differences and connections between the core targets and signaling pathways of different parties.Results Evidence-Fang Yuan data mining:according to the nadir criteria,a total of 555 coronary heart disease records were included in this study for analysis.The male to female gender ratio was 1.5:1;the average age was 58.7 for men and 57.6 for women,respectively,patients were mainly concentrated between 40 and 79 years old.After data normalization,a total of 71 symptom information was included in the statistics,among which 11 symptom information had a frequency≥10%,in descending order,502(90.45%)times of chest tightness,414(74.59%)times of chest pain,277(49.91%)times of palpitations,247(44.50%)times of shortness of breath,189(34.05%)times of weakness,130(23.42%)times,dizziness 115(20.00%)times,poor appetite 84(15.14%)times,sweating 80(10.36%)times,chilliness 70(12.61%)times,and panic 64(11.53%)times.After data normalization,a total of 25 tongue information were included in the statistics,including 13 tongue quality information and 12 tongue coating information.The frequency of tongue information≥10%,in descending order,was:red 321(57.84%)times,dark 256(56.13%)times,light 216(38.92%)times,purple 137(24.68%)times,and petechiae 58(10.45%)times.The frequency of tongue information was≥10%,from highest to lowest:white 362(65.23%)times,thin 236(42.52%)times,greasy 179(32.25%)times,little 78(14.05%)times,and yellow 70(12.61%)times.A total of 20 pulses were collected,9 of which were present≥10%of the time,in descending order of frequency:thin pulse 250(45.05%)times,string pulse 214(38.56%)times,sunken pulse 177(32.43%)times,slippery pulse 96(17.30%)times,and counted pulse 84(15.14%)times.The patient’s evidence was split,and a total of 18 evidence elements were counted.The pathogenic evidence elements with a cumulative frequency of≥10%were blood stasis 296(53.33%)times,yang deficiency 190(34.23%)times,phlegm 186(33.51%)times,yin deficiency 124(22.34%)times,qi stagnation 91(16.4%)times,fire(heat)77(13.87%)times,qi deficiency 77(13.87%)times,and blood deficiency 55(9.91%)times.The pathological evidence elements were heart 181(32.61%),kidney 60(10.18%)times,liver 56(10.09%)times,spleen 42(7.57%)times,lung 13(2.34%)times,stomach 8(1.44%)times,and gallbladder 5(0.90%)times.The four diagnostic information with frequencies≥10%were clustered,and the 30 four diagnostic information(symptoms11,pulse9,tongue 10)were divided into five categories,C1:pulse knot,pulse band,palpitation,panic,dizziness,sweating;C2:white tongue,pale tongue,thin tongue coating,sunken pulse,thin pulse,cold fear,shortness of breath,weakness,weak pulse;C3:chest tightness,chest pain,dark tongue,purple tongue,astringent pulse,petechiae on the tongue;C4:greasy tongue coating,yellow tongue coating,poor appetite,insomnia;C5:red tongue,little tongue coating,stringent pulse,slippery pulse,and number of pulse.The public factor extraction was performed on 30 four diagnostic information,and the cumulative variance explained by 12 factors was 63.66%.They were FAC1:white tongue,pale tongue,dark tongue,purple tongue,petechiae on the tongue,and astringent pulse;FAC2:knotted pulse,substitution of pulse;FAC3:yellow tongue,pale tongue,red tongue;FAC4:thin tongue,little tongue;FAC5:greasy tongue,yellow tongue,little tongue;FAC6:stringent pulse,sunken pulse,and fear of cold;FAC7:chest tightness,chest pain;FAC 8:heart panic,palpitation.FAC9:pulse count,deficient pulse,shortness of breath,weakness;FAC10:slippery pulse,insomnia,poor appetite;FAC11:thin pulse,sweating;FAC 12:weakness,fear of cold,dizziness.After the evidence elements were determined,FAC1 was blood stasis,FAC2 was Qi deficiency and Yang deficiency,FAC3 was heat,FAC4 was Yin deficiency,FAC5 was phlegm-heat,FAC6 was Qi stagnation,FAC7 was Qi stagnation and blood stasis,FAC8 was blood deficiency,FAC9 was Qi deficiency,FAC10 was phlegm,FAC11 was Qi deficiency and Yang deficiency,and FAC 12 was Qi deficiency.There were 236 drugs related to the treatment of coronary heart disease,and 35 flavors were used more than 10%of the time cumulatively,in descending order of frequency:Salvia miltiorrhiza,Glycyrrhiza glabra,Poria cocos,Radix et Rhizoma ginseng,Radix et Rhizoma cinnamomi,Astragali,Rhizoma Chuanxiong,Psidium guajava,Radix Angelicae Sinensis,Radix Codonopsis pilosulae,etc.More than 30%of the patients used these herbs in the course of treatment.Frequency statistics were conducted on the efficacy of drugs and the four qi and five flavors.According to the efficacy 236 flavors of Chinese medicine can be divided into 16 categories,the cumulative frequency of use≥10%was 1855(25.52%)times for deficiency tonics,1170(16.10%)times for blood invigorating and stasis relieving medicines,719(9.89%)times for cough and phlegm relieving and asthma calming medicines;statistics were conducted for the four gases:3221(44.31%)times for warm medicines,2179(29.98%)times for cold medicines,167(2.30%)times,and 248(3.41%)times for hot drugs;there were 12 meridians involved in the drugs,and the meridians with a cumulative frequency of≥10%were:Foot Taiyin Spleen Meridian 3225(16.8%)times,Foot Turk’s Yin Liver Meridian 3148(16.4%)times,Hand Taiyin Lung Meridian 2994(15.60%)times,Hand Shao Yin Heart Meridian 2909(15.16%)times,Foot Yangming Stomach meridian 2440(12.72%)times.The drugs used more frequently than≥10%were clustered and analyzed,and the intercept was 25 when mainly clustered into 4 major categories,1 category:keel,oyster,peony,dioscorea,maitong,schisandra,princely ginseng,sour date;2 category:yujin,yanhuosuo,guajia,allium,danshen,chuanxiong,angelica,peach kernel,safflower,red peony,chai hu;3 category:calamus,huanglian,chenpi,half summer,poria,heliotrope,white atractylodes,bamboo rhizome;4 Category:Radix Codonopsis,Radix Astragali,Radix Ginseng,Radix et Rhizoma Glycyrrhizae,Radix Aconiti,Radix et Rhizoma Ginger,Radix Cinnamomum Cassiae,Radix Pulsatilla.Factor analysis was performed on 34 Chinese herbal medicines used≥10%(excluding Chen Pi),and 11 common factors were extracted,with an explained variance of 60%.11 factors were FAC1:Gui Zhi,Radix Astragali,Gan Jiang;FAC2:Danshen,Chuanxiong,Angelica,Safflower,Red Peony,Tao Ren;FAC3:Dragon Bone,Oyster;FAC4:Semen,Astragali,Citrus,Calamus,Huang Lian,Bamboo Roo.FAC5:Bamboo rhizome,Poria,Sempervivum,Atractylodes;FAC6:Medlar,Schisandra,Sour date palm,Prince’s ginseng;FAC7:Sempervisia,Guahua,Allium;FAC8:Yanhuo,Yujin;FAC9:Chaihu,Bai Shao;FAC10:Astragalus,Codonopsis,Prince’s ginseng;FAC11:Ginseng,Licorice.Biological basis of evidence elements:Evidence elements-fang yuan.Blood stasis:Yan Hu Suo,Yu Jin,Dan Shen,Chuan Xiong,Tao Ren,Hong Hua,Angelica Sinensis,Red Paeoniae,Pu Huang;Yang deficiency:Gui Zhi,Radix et Rhizoma,Gan Jiang;Yin deficiency:Di Huang,Mai Dong,Wu Wei Zi,Bai Shao,Sour Jujube;Yang hyperactivity:Dragon Bone,Oyster;Qi deficiency:Dang Shen,Huang Qi,Prince Ginseng,Ginseng,Licorice,Atractylodes;Phlegm:Semen,Zhu Ru,Chen Pi,Gua Pao,Fu Ling,Shi Calamus;Qi stagnation:Chai Hu,Citrus Aurantium,Allium;Heat.Huanglian.A total of 332 modern medical symptoms were retrieved by SymMap.There were 46 characteristic symptoms of blood stasis evidence,32 characteristic symptoms of phlegm evidence,26 characteristic symptoms of qi deficiency evidence,10 characteristic symptoms of yin deficiency evidence,7 characteristic symptoms of yang deficiency evidence,and only 1 characteristic symptom of qi stagnation evidence.There were 201 potential active ingredient compounds of blood stasis evidence element,48 of qi stagnation evidence element,47 of phlegm,30 of yang deficiency,149 of qi deficiency,30 of yin deficiency,and 14 of heat.The blood stasis evidence elements corresponded to 303 targets,254 Qi stagnation evidence elements,178 phlegm,63 Yang deficiency,274 Qi deficiency,113 Yin deficiency,and 38 heat.Treatment of coronary heart disease had 201 potential active ingredients of blood stasis evidence elements,of which 174(86.57%)were unique to blood stasis evidence elements,87.92%(131/149)of qi deficiency evidence elements were unique to qi deficiency evidence elements,75%(36/48)of qi stagnation evidence elements,70.21%(33/47)of phlegm evidence elements,60%(18/30)of yin deficiency evidence elements,and 86.67%(18/30)of yang deficiency evidence elements.86.67%(26/30),and 57.14%(8/14)were unique to evidence of heat.There were four active ingredients present only in evidence element Yin deficiency and blood stasis,heat and blood stasis,and phlegm and blood stasis,and three active ingredients present only between phlegm and blood stasis evidence.A total of 9,278 targets related to coronary heart disease were retrieved.There were 92 genes overlapping blood stasis formula elements and coronary heart disease,of which 49(53.26%)genes were only present in blood stasis evidence elements;45.71%(32/70)of qi deficiency formula elements,30.00%(9/30)of phlegm formula elements,10.81%(4/37)of qi stagnation formula elements,20%(5/25)of yin deficiency formula elements,and 30.44%(7/23)of yang deficiency formula elements were only present in each evidence element formula element.Results of GO enrichment analysis.The results of GO analysis of different formulae showed that in the biological process analysis,heat formulae were enriched in dopamine transport;qi deficiency formulae were enriched in inflammatory response regulation,cellular response to peptides,reactive oxygen species metabolism,protein secretion regulation;yin deficiency formulae were enriched in alcohol metabolism,radiation response;yang deficiency formulae were mainly enriched in the inverse regulation of stimulus source,organic cyclic compound catabolic process,steroid metabolism The blood stasis formula is mainly enriched in the regulation of inflammatory response,cell proliferation,response to nutrients;the qi stagnation formula is mainly enriched in the biological processes such as cell aging,pain sensation,response to ethanol;the molecular functions involved in the regulation of the yin deficiency formula are cannabinoid receptor activity,allyl alcohol dehydrogenase activity;the qi deficiency formula is mainly The phlegm formula is involved in the regulation of heme binding and tetrapyrrole binding;the yang deficiency formula is involved in the regulation of nuclear receptor activity and ligand-activated transcription factor activity;the qi deficiency formula is involved in the regulation of RNA polymerase Ⅱ-specific DNA-binding transcription factor binding and DNA-binding transcription factor binding;the blood stasis formula mainly regulates steroid The blood stasis formula element mainly regulates steroid binding,transcriptional co-regulator binding,nuclear receptor activity,and ligandactivated transcription factor activity;the heat formula element targets only four genes,and no molecular functional analysis results were available.KEGG analysis results:a total of 5 had good pathway enrichment.Among them,heat square element was mainly enriched in cocaine addiction and amphetamine addiction.Qi deficiency was mainly enriched in chemoattractant-receptor activation,insulin resistance,prolactin signaling pathway,EGFR tyrosine kinase inhibitor resistance,AGE-RAGE signaling pathway,HIF-1 signaling pathway;Qi stagnation square element was mainly enriched in cancer signaling pathway;blood stasis square element was mainly enriched in neuroactive ligand-receptor interaction,chemoattractant-receptor activation,lipid and atherosclerosis,IL-17 signaling pathway,5-hydroxytryptaminergic synapse,and AGE-RAGE signaling pathway;phlegm formula elements were mainly enriched in steroid hormone biosynthesis and ovarian steroidogenesis.Conclusion The main pathogenesis of coronary heart disease is deficiency,and the core four diagnostic information obtained from data mining can explain more than 60%of the evidence,which belong to 8 pathogenic evidence elements.35 core drugs can be divided into 8 formula elements according to the evidence elements,which can explain more than 60%of the prescriptions for evidence.There are differences in the active substances,corresponding symptoms,cellular components,molecular functions,biological processes and major enriched signaling pathways among the formula elements of different pathological elements of coronary heart disease.The active ingredients of the formulae of different evidence elements are diverse,and different active ingredients can have therapeutic effects on the same targets,or act on multiple signaling pathways to treat coronary heart disease.The combination of formulae for the treatment of coronary heart disease can be regarded as the superposition of multiple targets and pathways for better therapeutic effect.