| Background:With advances in the treatment of coronary heart disease,valvular heart disease,and cardiomyopathy,the population of people living with heart disease is gradually expanding,making Chronic Heart Failure(CHF)one of the most important cardiovascular diseases in the 21st century.Systematic assessment of the clinical characteristics and co-morbidities of CHF and evaluation of the extent of the disease to guide clinical practice are important tools to slow down the progression of the disease,improve quality of life,increase survival rates and reduce the burden of medical care.As the most energy consuming organ in the human body,the heart must produce sufficient adenosine triphosphate(ATP)to supply the heart to do its work.The process of myocardial energy metabolism is divided into three main stages,namely substrate utilization,oxidative phosphorylation and ATP transport.Under normal conditions,sugars,fats and proteins can be used as substrates for cardiac energy metabolism.60%-90%of energy is provided by fatty acid β-oxidation,glucose oxidative phosphorylation can provide about 40%of ATP,and glycolysis can provide a very small amount of energy.Under pathological conditions,myocardial energy metabolism is disturbed and ATP supply is inadequate,leading to cardiac dysfunction and ultimately CHF,while myocardial energy dysregulation further leads to the progression of CHF.Altered energy metabolism and cardiac insufficiency interact,and altered metabolic pathways usually take precedence over structural changes in the heart,which to some extent suggests that metabolic reprogramming is an early event in the pathogenesis of CHF.N-terminal brain natriuretic peptide precursor(NT-Pro BNP)has a high sensitivity and specificity and can effectively respond to the level of cardiac function.Mitochondria are the main site of fatty acid and glucose metabolism,and normal mitochondrial function is the basis for normal energy metabolism in cardiomyocytes.In a healthy state,mitochondria are in a dynamic equilibrium of splitting and fusion regulated by fusion proteins,and normal kinetic homeostasis can maintain the morphological distribution of mitochondria and promote the regulation of cellular metabolism.Mitochondria are not only a major source of energy,but also regulate redox reactions,maintain calcium homeostasis,and control lipid synthesis,thus ensuring normal cardiac energy metabolism.In the course of altered cardiac energy metabolism,fatty acid oxidation gradually decreases and the overall dependence of glucose metabolism increases.The shift in uptake of metabolic substrates,altered kinetics(splitting,fusion),and increased reactive oxygen species(ROS)levels are distinctive features of CHF mitochondria.The deficiency of fusion-related proteins leads to changes in mitochondrial morphology and fusion balance,and changes in mitochondrial fusion protein 2(Mitofusinl2,Mfn2),a mitochondrial fusion protein,can reflect changes in cardiac energy metabolism.The nature of CHF always belongs to the deficiency of the essence,the deficiency of qi and blood,yin and yang,phlegm,blood stasis and water retention.Among them,the deficiency of the essence is mainly qi deficiency,which is the initial factor of the disease,leading the whole disease process and determining the prognosis of the disease.Qi-yin deficiency and Yang-qi deficiency are two common TCM syndromes of CHF,and their symptoms are quite different.Abnormal metabolism is a high risk factor for cardiovascular disease,and disorders of myocardial energy metabolism can affect the course of CHF.Metabolomic studies can elucidate the changes in energy metabolism during the development of CHF.Therefore,exploring the relationship between CHF and metabolic abnormalities can help reduce the incidence of CHF,slow down the disease process and reduce the medical burden.Based on the above studies,a untargeted metabolomics approach was used to explore the relationship between different TCM syndromes of CHF and different degrees of the disease,providing new ideas and methods for the prevention,assessment,and treatment of CHF.Objective:By examining the differences in serum metabolomics between the typical symptoms of CHF in TCM and different degrees of CHF,respectively,we searched for the correlation between differential metabolites and CHF,and explored biomarkers that may be clinically significant,in order to be able to detect the effects of metabolic processes at an early stage,to provide a basis for assessing CHF disease and early intervention in TCM,and to improve the quality of life and survival rate of CHF patients.Methods:In this study,the patients in general department and cardiovascular department of Guang ’anmen Hospital,Chinese Academy of Chinese Medical Sciences from July 2021 to November 2021 were collected,and the inclusion and exclusion criteria were established.According to the value of NT-Pro BNP,the included patients were divided into two groups,that is,the mildly elevated group(125<NT-Pro BNP≤900 pg/ml)and the moderately elevated group(NT-Pro BNP>900 pg/ml).All data were analyzed using SPSS 24.0,and P<0.05 was used as the basis for determining statistically significant differences;Untargeted metabonomics was used to compare different TCM syndromes(Qi-yin deficiency and Yang-qi deficiency)and different degrees of CHF(non-heart failure group,mildly elevated group and moderately elevated group).Orthogonal partial least squares discriminant analysis(OPLS-DA)was used to analyze the differential metabolites,and metabolites with VIP>1.0 and P<0.05 were selected as differential metabolites and enriched by KEGG pathway.Results:1 Comparison of clinical information in the non-heart failure group,mildly elevated group and moderately elevated groupA total of 90 subjects were included in this study,including 30 in the non-heart failure group,30 in the mildly elevated group and 30 in the moderately elevated group.After statistical analysis,the results showed that there were no statistical differences between the three groups in terms of gender,white blood cells,platelets,blood potassium,blood sodium,blood chloride,glutamic-oxaloacetic transaminase,total bilirubin,total cholesterol,high-density lipoprotein,low-density lipoprotein,Mfn2,and age,erythrocytes,hemoglobin,creatinine,urea,triglycerides and LVEF were statistically significant.2 Metabolomic differences between the non-heart failure group,Qi-yin deficiency group and Yang-qi deficiency group2.1 Results of metabolite differences between the non-heart failure group and the Qi-yin deficiency groupThe results showed that the main differential metabolites between the non-heart failure group and the Qi-yin deficiency were hydroxy acids and their derivatives,fatty acyl groups,organic oxygen compounds,and glycerophospholipids.The main differential metabolites were enriched in ether lipid metabolism,glutathione metabolism,metabolic pathways and other pathways.2.2 Results of metabolite differences between the non-heart failure group and the Yang-qi deficiency groupThe main metabolites that differed between the non-heart failure group and the Yang-qi deficiency group were hydroxy acids and their derivatives,isoprenoid lipids,fatty acyl groups,mainly enriched in amino acid biosynthesis,lysine biosynthesis,amino acid-tRNA biosynthesis,protein digestion and absorption,2-oxocarboxylic acid metabolism,β-alanine metabolism,alkaloid biosynthesis from histidine and purine,histidine metabolism,sphingolipid metabolism,starch and sucrose metabolism,carbohydrate digestion and absorption,and other pathways.2.3 Results of metabolite differences between the Qi-yin deficiency group and the Yang-qi deficiency groupThe differential metabolites between the two main syndromes of CHF include hydroxy acids and their derivatives,glycerides,steroids and steroid derivatives.The differential metabolites between the Qi-yin deficiency group and the Yang-qi deficiency group were enriched in the pathways of biosynthesis of class II polyketide products,biosynthesis of tetracycline,cholesterol metabolism,fat digestion and absorption,and steroid biosynthesis.3 Metabolomic differences between the non-heart failure group,mildly elevated group and moderately elevated group3.1 Metabolomic differences between the non-heart failure group and the mildly elevated groupThe main metabolites that were found to be different between the non-heart failure group and the mildly elevated group were steroids and steroid derivatives,hydroxy acids and their derivatives,and isoprenoid lipids,and the different metabolites were concentrated in the metabolic pathways such as tyrosine metabolism and the interconversion of pentose and glucuronide.3.2 Metabolomic differences between the non-heart failure group and the moderately elevated groupThe main differential metabolites between the non-heart failure group and the moderately elevated group were isoprenoid lipids,organic oxygen compounds,hydroxy acids and their derivatives,steroids and steroid derivatives,fatty acyl groups,and glycerophospholipids,whose lipid species were elevated compared to the results of the non-heart failure group and the mildly elevated group.The differential metabolites were enriched in metabolic pathways such as phosphatidylinositol signaling system,glutathione metabolism,biosynthesis of phenylalanine,tyrosine and tryptophan,fructose and mannose metabolism,and arachidonic acid metabolism.3.3 Metabolomic differences between the mildly elevated and moderately elevated groupsThe metabolites that differed between the mildly elevated and moderately elevated groups were mainly isoprenoid lipids,organic oxygen compounds,hydroxy acids and their derivatives,steroids and steroid derivatives.The differential metabolites were enriched in metabolic pathways such as biosynthesis of histidine and purine-derived alkaloids,fructose and mannose metabolism,arachidonic acid metabolism,and linolenic acid metabolism.Conclusion:1 Significant correlation between age,erythrocytes,hemoglobin,creatinine,urea,triglycerides,albumin,and LVEF with CHF.2 The differential metabolites in the non-heart failure group,the Qi-yin deficiency group and the Yang-qi deficiency group were mainly concentrated in amino acids and lipid compounds,and the differential metabolites were mainly enriched in amino acid metabolism,lipid and sugar metabolic.3 Metabolomic findings in the non-heart failure and NT-Pro BNP elevation groups suggested that the differential metabolites in the three groups were mainly amino acid classes and lipid compounds,with the differential metabolites mainly enriched in lipid,glycan and amino acid metabolic pathways. |
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