The Potential Biological Basis Of HTN-HFpEF,and Syndrome,Treatment Law And Pharmacological Mechanism Of Herbs Were Studies Based On Systems Biology

Objective:Ejection fraction preserved heart failure(HFpEF)is a complex systemic disease,and its pathological mechanism is easily affected by concomitant diseases.HFpEF patients are often accompanied by hypertension(HTN),and there is a significant difference between HTN-HFpEF patients and unclassified heart failure(HF)patients,leading to the inability of previously effective strategies in HF treatment to be successfully applied to HTN-HFpEF patients.Myocardial tissue dysfunction plays an important role in the progression of HTN-HFpEF disease,and the interaction between myocardial tissue,adipose tissue,and cerebral arterial tissue reflects the complexity of the pathological mechanism of HTN-HFpEF.The theory of Systems biology is consistent with the holistic view of the theory of traditional Chinese medicine.The Systems biology method is used to analyze the differences between the syndrome types,etiology and pathogenesis of HF patients and HTN HFpEF patients.The pathological mechanism of HTN HFpEF disease progression and the pathological mechanism of HTN HFpEF multiple tissue dysfunction can better explain the potential biological basis of HTN HFpEF.Traditional Chinese medicine has achieved good results in the treatment of HTN-HFpEF,and analyzing the TCM syndrome differentiation and mechanism of action of HTN-HFpEF is an urgent problem to be solved.The theory of "meridian tropism of traditional Chinese medicine" is combined with Systems biology methods to analyze the biological basis of the theory of "meridian tropism of traditional Chinese medicine" and provide an effective tool for analyzing the intervention of traditional Chinese medicine in multiple tissue dysfunction.By combining clinical prescription data with the biological basis of the "Chinese medicine meridian tropism" theory,we can effectively analyze the patterns and mechanisms of traditional Chinese medicine treatment.Methods:1.Potential biological basis of HTN-HFpEF1.1 Heterogeneity between HF and HTN-HFpEF: Collect symptom data from HF patients and HTN-HFpEF patients.Combining T-Random Neighborhood Embedding(t-SNE)with Cluster Analysis to Explore the Syndrome Types of HF and HF-HFpEF.Combining typical symptoms of different subtypes with 7 machine learning algorithms to construct recognition models for different syndrome types.1.2 Pathological mechanism of HTN HFpEF disease progression: Proteomics was used to detect the changes of myocardial Histone protein expression in salt sensitive(DS)rats during HTN and HTN HFpEF periods,obtain HTN and HTN HFpEF related proteins,construct HTN and HTN HFpEF disease networks,and identify their neutron modules.Through enrichment analysis of overlapping modules in the HTN and HTN-HFpEF disease networks,we aim to elucidate the pathological mechanisms of disease progression in HTN-HFpEF.1.3Pathological Mechanism of Multitissue Dysfunction in HTN-HFpEF: We propose a multi-level comparative framework based on differentially expressed genes(DEGs)and differentially expressed gene pairs(DCGs)to study the common and specific pathological features between cardiac tissue,adipose tissue,and cerebral arterial tissue,in order to obtain the pathological mechanism of HTN-HFpEF multi-tissue function.2.Prescription rules and pharmacological mechanism2.1 The potential biological basis of the "Traditional Chinese Medicine Meridian" theory: obtaining protein tissue relationships from Tissue Enrich,GIANT,HURI,and LoCOPDB.High quality protein tissue relationships were screened through tissue specific biological processes(BP),"GOSemsim",error rate,Jaccard index,meridian theory,and HIT 2.0.Construct an integrated molecular network framework using three heterogeneous data types: traditional Chinese medicine target,protein tissue,and protein BP.2.2 Study on medication patterns and potential pharmacological mechanisms of different subtypes of HTN-HFpEF patients: Traditional Chinese Medicine Inheritance Assistance Platform V3.0was used to analyze the frequency,efficacy,taste,meridian distribution,and prescription patterns of drugs prescribed for different subtypes of HTN-HFpEF patients.In addition,the potential pharmacological mechanisms of representative core prescriptions were analyzed based on the relationship between traditional Chinese medicine protein BP tissue.Results:1.Potential biological basis of HTN-HFpEF1.1 Heterogeneity of HF and HTN-HFpEF: From the clinical symptom data of 6617 HF heart failure patients,a total of 6 syndrome types were identified,including heart and kidney yang deficiency syndrome,yang qi deficiency detachment syndrome,phlegm yin obstruction lung syndrome,liver fire inflammation syndrome,lung qi deficiency syndrome,and qi yin deficiency syndrome.The main syndrome types of HTN-HFpEF are phlegm heat stagnation in the lungs with yin and yang deficiency,qi deficiency and blood stasis with heart and kidney yang deficiency,and blood stasis drink cessation.Finally,effective recognition models for different syndrome types were trained using XGBoost,Light GBM,Random Forest,Ada Boost,logistic,GNB,and CNB methods.1.2 Pathological mechanism of HTN HFpEF disease progression: immune reaction,energy metabolism,inflammatory reaction and Post-translational modification play an important role in HTN HFpEF;Myocardial contraction,energy metabolism,apoptosis,and oxidative stress are typical pathological mechanisms of HTN.The biological connections between HTN and HTN-HFpEF are mainly classified into myocardial contraction,energy metabolism,cell apoptosis,oxidative stress,immune response,and myocardial hypertrophy.1.3Pathological mechanism of multiple tissue dysfunction in HTN-HFpEF: Cell cycle and immune response are common pathological mechanisms in cardiac tissue,adipose tissue,and cerebral arterial tissue;Hemostasis,G protein coupled receptor(GPCR)ligands and other biological processes occur in heart tissue and adipose tissue;Inflammation and myocardial hypertrophy are closely related to cardiac tissue dysfunction;Cell adhesion regulation and peptide response are specific pathological mechanisms in adipose tissue;And gene expression(transcription)is closely related to abnormal brain arterial tissue function.2.Prescription rules and pharmacological mechanism2.1 Biological basis of the theory of "Chinese herbal meridian tropism" : Tissue Enrich performed well in different evaluations.In addition,the accuracy of the predicted traditional Chinese medicine protein tissue relationship was evaluated through HIT 2.0 and meridian theory.By integrating SymMap,Tissue Enrich,and traditional Chinese medicine BP connections,69881 traditional Chinese medicine protein BP tissue relationships were obtained.The clinical data and the case of Sanqi further confirm the reliability of the traditional Chinese medicine protein BP tissue relationship.2.2 Study on the medication patterns and potential pharmacological mechanisms of different subtypes of HTN-HFpEF patients: The drugs in the prescription of HTN-HFpEF subtype 1 patients mostly belong to the categories of tonifying deficiency,resolving phlegm,relieving cough,and asthma,as well as promoting blood circulation and resolving blood stasis.Traditional Chinese medicine for tonifying deficiency,promoting blood circulation and resolving stasis,clearing heat,promoting water and dampness,and relieving external symptoms are typical types of drugs in the prescription of HTN-HFpEF subtype 2 patients.The maximum occurrence frequency of tonifying drugs in the prescription of HTN-HFpEF subtype 3patients is 279 times.Licorice,Platycodon grandiflorum,bitter almond,Ophiopogon japonicus,and Scutellaria baicalensis are representative core formulas for HTN-HFpEF subtype 1.Their potential pharmacological mechanisms are related to regulating biological processes such as myocardial contraction,hypertrophy,hemodynamics,tissue regeneration,and lipid metabolism.Peach kernel,safflower,angelica,red peony root and Chuanxiong are representative core prescriptions of HTN-HFpEF subtype 2.Their potential pharmacological mechanism is closely related to regulating metabolism,Thyroid hormones production,transport and related downstream pathway functions.The three representative core prescriptions of HTN-HFpEF subtype are licorice,poria cocos,astragalus,chuanxiong and codonopsis pilosula.Its pharmacological mechanism is related to regulating the contraction of the heart and other muscle tissues,improving hemodynamics and affecting the functions of Thyroid hormones and adrenal hormone related pathways.Conclusion:1.This study analyzed the clinical syndrome types of HF and HTN-HFpEF,effectively resolving the heterogeneity between HTN and HTN-HFpEF.Compared with HF,patients with HTN-HFpEF often exhibit coexistence of multiple syndromes,mixed deficiency and excess,and multiple organ damage,and HTN-HFpEF has more severe water intake and blood stasis.2.The pathological mechanisms related to myocardial contraction,energy metabolism,cell apoptosis,oxidative stress,immune response,and myocardial hypertrophy are closely related to the progression of HTN-HFpEF disease.3.The interaction between cardiac tissue and adipose tissue exacerbates inflammation and damages myocardial contractile function.The interaction between cardiac tissue,cerebral arterial tissue,and adipose tissue promotes the activation of systemic chronic inflammation and dysfunction of proteasomes,promoting the progression of HTN-HFpEF disease.4.By integrating SymMap,Tissue Enrich,and traditional Chinese medicine BP connections,69881 traditional Chinese medicine protein BP tissue relationships were obtained,elucidating the biological basis of the "Chinese medicine meridian tropism" theory.5.The prescription of HTN-HFpEF subtype 1 is mainly based on the lung meridian,which includes the spleen meridian,stomach meridian,heart meridian,and liver meridian;In the prescription of HTN-HFpEF subtype 2,the five flavors of traditional Chinese medicine are mainly pungent,sweet,and bitter;The prescription of HTN-HFpEF subtype 3often includes sweet and bitter medicines,which are often classified as liver,heart,spleen,and lung meridians.Finally,representative core prescriptions for each subtype were screened and their potential pharmacological mechanisms were predicted.