| Purpose: Diuretic resistance in heart failure is the inability of a patient to achieve the therapeutic goal of improving congestion and effusion despite the use of adequate diuretics.Once diuretic resistance has occurred,the patient enters a refractory stage of heart failure with a very poor prognosis.In this study,we screened for differential metabolites between diuretic resistance and non-diuretic resistance based on untargeted metabolomics,and identified biomarkers for the development of diuretic resistance to provide new ideas for early clinical diagnosis.We analyzed the distribution patterns of the four TCM diagnoses and evidence elements in the occurrence of diuretic resistance,and explored the independent influencing factors of the combination of laboratory indicators and the four TCM diagnoses,in order to deepen the understanding of the TCM evidence patterns and the essence of diuretic resistance.Methods:1.Metabolomic study of diuretic-resistant patients with chronic heart failure Patients with heart failure attending the First Affiliated Hospital of Hunan University of Traditional Chinese Medicine and the Eighth Hospital of Changsha City between December 2021 and December 2022 were collected.Inclusion and exclusion criteria were established,and patients were divided into two groups,diuretic-resistant and non-diuretic-resistant,according to the presence or absence of diuretic resistance.Case data were collected from subjects within 24 hours of admission and serum samples were collected from patients in both groups.All data were analysed using SPSS 26.0 and P<0.05 was used as the basis for statistical significance.Nontargeted metabolomics techniques were used to compare the diuretic-resistant and non-diureticresistant groups.Orthogonal partial least squares discriminant analysis(OPLS-DA)was applied for differential metabolite analysis,and metabolites with a threshold of VIP>1.0 and P<0.05 were selected as differential metabolites and subjected to KEGG pathway enrichment analysis to find potential differential metabolites.2.Study of TCM evidence in diuretic-resistant patients with chronic heart failure Based on the first part,20 cases were added to each group by screening according to the inclusion and exclusion criteria,collecting information from the patients’ TCM four diagnosis data and extracting the disease location and nature according to the evidence extraction criteria for both groups.All data were analysed using SPSS 26.0 and differences were considered statistically significant at P<0.05.The extracted evidence was analysed by clustering,and the kinship between the evidence elements was studied using R-type cluster analysis.Risk factors for the development of diuretic resistance in patients with chronic heart failure were analysed using multifactorial logistic regression.Results:1.Metabolomic study of patients with diuretic resistance in chronic heart failure(1)Comparison of demographic data: There was no statistical difference between the diureticresistant and non-diuretic-resistant groups in terms of gender and age(P > 0.05).(2)Comparison of vital signs: There was no statistical difference between the two groups in respiration,pulse,systolic blood pressure,diastolic blood pressure,heart rate and body temperature(P>0.05).(3)Comparison of clinical data: There were statistically significant differences between the two groups in terms of duration of illness,coronary heart disease,diabetes mellitus and NTpro BNP comparison(P<0.05),and the duration of illness,prevalence of coronary heart disease,diabetes mellitus and NT-pro BNP values were significantly higher in diuretic-resistant patients than in non-diuretic-resistant patients.There were no statistical differences in cardiomyopathy,atrial fibrillation,history of cardiac surgery,hypertension,history of smoking,history of alcohol consumption,BMI,or New York cardiac function class(P>0.05).(4)There were 192 major differential metabolites in the two groups: 164 up-regulated differential metabolites and 28 down-regulated differential metabolites.(5)The two differential metabolome groups were mainly enriched in transactive ligandreceptor interactions,amino acid biosynthesis,central carbon metabolism in cancer,γ-aminobutyric acid(GABA),a-alanine,aspartate and glutamate metabolism,protein digestion and uptake,biosynthesis of plant secondary metabolites,tyrosine metabolism,β-alanine metabolism,phenylalanine metabolism,aminoacyl-t RNA biosynthesis and ABC transporters,glycine and serine and threonine metabolic pathways.2.Study of Chinese medical evidence in diuretic-resistant patients with chronic heart failure(1)Comparison of the four diagnostic data between the two groups: there were statistical differences between the two groups in abdominal distension,oedema,chest pain,low volume of urine,pale and fatty tongue,petechiae on the tongue,weak pulse and thin pulse(P<0.05);there were no statistical differences between the two groups in chest tightness,shortness of breath,fatigue,little breath and lazy speech,palpitation,dyspnea,sleeplessness,spontaneous sweating,white moss,white and smooth moss,blue and purple tongue,sunken pulse and knotted pulse(P>0.05).(2)Comparison of the distribution of evidence elements between the two groups: Heart,Lung,Spleen and Kidney were the pathological evidence elements with significant differences in distribution(P<0.05);Qi deficiency,Yang deficiency and water retention had significant differences in the distribution of pathological evidence elements(P<0.05).(3)Results of cluster analysis in the diuretic resistance group: 18 cases of Heart-Yang deficiency,Blood-stasis and Water-drink stagnation;15 cases of Yang deficiency and Water-pangs;7 cases of Spleen-Kidney Yang deficiency,Blood-stasis and Water-drink stagnation;8 cases of Zong-Qi subsidence and Water-drink stagnation in San-Jiao;2 cases of Yin-Yang deficiency.(4)Independent influencing factors: whether or not there was a combination of coronary heart disease,NT-pro BNP,abdominal distension and weak pulse were independent influencing factors of diuretic resistance,which could significantly affect the occurrence of diuretic resistance(P<0.05).Conclusions:1.the duration of disease,the presence of comorbid coronary artery disease,diabetes mellitus and NT-pro BNP were significantly associated with the development of diuretic resistance in heart failure;2.significant and diverse differential metabolites between the diuretic-resistant and non-diureticresistant groups,with the differential metabolites mainly enriched in metabolic pathways such as amino acids;3.among the TCM clinical symptoms: abdominal distension,oedema(moderate or above),chest pain,low urine output,pale and fat tongue,stasis on the tongue,weak pulse and thin pulse are all associated with the development of diuretic resistance;there are significant differences in the distribution of pathological sites and pathological elements such as heart,lung,spleen and kidney;Qi deficiency,Yang deficiency and water-drinking;4.among the clinical diuretic resistance patterns: Heart-Yang deficiency and Blood-Stasis-Drink Stagnation are the most distributed;5.coronary heart disease,NT-pro BNP,abdominal distension and weak pulse were the independent influencing factors of diuretic resistance. |
PDF Full Text Request