| Background:Chronic congestive heart failure(CHF),the end-stage manifestation and the primary cause of death caused by cardiovascular diseases,has been the focus of the study field of cardiovascular diseases for a long time.Blood ultrafiltration,as an approach to improve the retention of water and sodium caused by diuretic resistance in patients with refractory heart failure,can replace part of the Kidney function in the sense of "form" and avoid physiological dehydration and electrolyte disorder,but it still cannot replace the warming function of Kidney in the sense of "function" and cannot separate the clear from the turbid,so that the ultrafiltration process includes not only urine but also normal body fluid,so called Yin fluid.Yin deficiency syndromes such as dry mouth and tongue and sphoria with feverish sensation in chest,palms and soles occur in patients with Yin fluid deficiency,then Yang Qi loses if the body fluid is lost too much.It is likely to cause injuries of both Qi and Yin,and more likely to cause manifestations of deficiency of both Yin and Yang.Therefore,traditional Chinese medicine(TCM)was adopted to strengthen body resistance and nourish heart combined with blood ultrafiltration clinically to reduce the diuretic resistance of patients while tonify Qi and strengthen body resistance,correct the side effects caused by ultrafiltration treatment,and remain more conducive to decreasing the long-term readmission rate and the mortality rate of patients with heart failure.We evaluated the efficacy and safety of TCM combined with ultrafiltration in the comparison between TCM combined with ultrafiltration and ultrafiltration alone by retrospective study.At the same time,the relationship between pharmacology and mechanism of action of TCM was explored in depth by network pharmacology analysis of the therapeutic targets of treatment of CHF with TCM for strengthening body resistance and nourishing Heart.Non-targeted metabonomic study has been carried out for ultrafiltration treatment of CHF patients in previous studies,so further targeted metabonomic studies based on the results are helpful to explain the action pathway of ultrafiltration treatment.Objective:1.To conduct retrospective studies on the efficacy and safety of TCM combined with ultrafiltration in the treatment of patients with acute onset of CHF.2.To find the potential action target of TCM for strengthening body resistance and nourishing Heart in the treatment of CHF by network pharmacology method,and to further explore the relationship between pharmacology and the mechanism of action of TCM.3.To find the differences of metabolic substances in patients with heart failure before and after ultrafiltration treatment by the targeted metabolomic study method,which is helpful to explain the action pathway of ultrafiltration treatment of heart failure.Methods:1.45 patients with acute onset of CHF,cardiopulmonary Qi deficiency,Yang deficiency and liquid running disorders meeting the inclusion criteria hospitalized for blood ultrafiltration treatment from December 2017 to December 2019 were observed retrospectively,including 25 patients in the TCM for strengthening body resistance and nourishing Heart combined with ultrafiltration group and 20 patients in the ultrafiltration group.The therapeutic indexes were observed:hs-CRP,NT-proBNP,and the safety indexes:ions(K+,Na+,Cl-),HCT,creatinine and urea nitrogen,data statistics of which were carried out at 3 time nodes,namely,before ultrafiltration,after the first ultrafiltration and 10 days after ultrafiltration respectively.The TCM syndromes of palpitation,intolerance of cold and cold limbs,shortness of breath,asthma,facial swelling,fatigue,cough,expectoration,abdominal distension,tongue coating,etc.were scored and body weights were evaluated at 2 time nodes before ultrafiltration and 10 days after ultrafiltration.Through the comparison of indexes within groups,between groups and the regression analysis of the relationship between each factor and the final therapeutic effect,the efficacy and safety of the therapy of TCM combined with western medicine in the treatment of CHF were clarified,the role of blood ultrafiltration technology and TCM in the clinical treatment of heart failure was played in a better way,which provides high-quality study evidence for its clinical application2.On Integrative Pharmacology-based Research Platform of Traditional Chinese Medicine V2.0(TCMIP V2.0),target prediction was carried out on chemical information of TCM for strengthening body resistance and nourishing Heart,and the protein-protein interaction(PPI)network was constructed on the target information of heart failure-related diseases,key targets of drug intervention diseases were analyzed by enrichment analysis,and interaction networks of TCM chemical components,key action targets and heart failure disease-related pathways were constructed.The main components acting on these key targets,i.e.,the chemical components related to the drug efficacy,were obtained by analysis and quality markers for the treatment of heart failure by TCM for strengthening body resistance and nourishing Heart were predicted according to the quality markers combined with literature reports.3.17 patients with acute onset of CHF treated by blood ultrafiltration were included.Peripheral venous blood of 5ml before and after ultrafiltration was extracted.Metabolite spectra before and after ultrafiltration were compared and analyzed by LC-MS(liquid chromatography-mass spectrometry),metabolic patterns before and after ultrafiltration were detected,and landmark metabolic groups were screened outResults:1.Retrospective Study1.1 Comparison between Groups before and after Treatment and 10 days after Treatment After the first ultrafiltration,there was no significant difference in the efficacy indexes NT-proBNP and hs-CRP between the ultrafiltration group and the TCM+ultrafiltration group,but the level of Na+in the TCM+ultrafiltration group after treatment was higher than that in the ultrafiltration group,with statistical significance(P<0.05),while the levels of NT-proBNP and Na+10 days after treatment in the two groups showed statistically significant differences(P<0.05),which also showed that the efficacy indexes in the TCM+ultrafiltration group was higher than that in the ultrafiltration group.Na+ is the most important cation in the extracellular fluid,and the primary factor for edema in CHF patients is the increase of total sodium in the body,so the core to relieve retention of sodium and water is sodium.Diuretics excrete hypotonic urine,and sodium retention still occurs after sufficient diuresis Ultrafiltration is isotonic diuresis,which increases sodium excretion more than diuretics.1.2 Comparison within GroupLevels of NT-proBNP and Na+i n the ultrafiltration group showed statistical differences before and after treatment(P<0.05),while weight loss and TCM syndrome scores also showed statistically significant differences(P<0.01);NT-proBNP also showed statistically significant differences before and after treatment in the TCM+ultrafiltration group.The weight loss and TCM syndrome scores showed statistically significant differences,while ions did not show statistically significant changes.It proved that ultrafiltration had obvious therapeutic effects on the acute onset of CHF patients,and can relieve symptoms such as asthma,facial and limb edema,especially lower limb edema,cough,and foam phlegm in cough caused by congestion in pulmonary circulation or systemic circulation obviously.The TCM syndrome scores in the TCM+ultrafiltration group was more obvious,and there was no ion change.It was considered that it corrected symptoms such as injuries of both Qi and Yin caused by massive dehydration1.3 Regressive Effect of Various Variables on Therapeutic EffectSingle-factor analysis results in regression analysis showed that the group was a protective factor of the target therapeutic effect,indicating that the TCM++ultrafiltration group had a better therapeutic effect than the ultrafiltration group;After 10 days of treatment,TCM score was a risk factor,indicating that the lower the score after the ultrafiltration treatment,the better the therapeutic effect;The level of Na+ 10 days after ultrafiltration was a risk factor for the therapeutic effect,indicating that the higher the level of Na+10 days after the ultrafiltration treatment,the worse the therapeutic effect.After multi-factor regression analysis of three single factors with statistical differences,it could be seen that the group was a protective factor and the TCM syndrome score was a risk factor.The lower the score,the better the therapeutic effect.Therefore,it could be proven that the therapeutic effect of the TCM+ ultrafiltration group was significantly better than that of the ultrafiltration group and the TCM syndrome scores could be adopted as evaluation criteria.Conclusion:Compared with simply blood ultrafiltration,TCM combined with blood ultrafiltration can better improve symptoms such as asthma symptoms,facial and limb edema,especially lower limb edema,cough and foam phlegm in cough of CHF patients due to congestion in pulmonary circulation or systemic circulation without ionic changes.At the same time,NT-proBNP and hs-CRP were improved as the treatment time increases obviously.2.Network Pharmacology88 core targets were obtained for the treatment of heart failure by TCM for strengthening body resistance and nourishing Heart.There were 4 common targets for TCM and diseases,namely ATP1A1,ATP1A2,TNF and PIK3CG;gene functions mainly involve many items such as mitochondrial electron transfer,redox process,ethanol oxidation,the metabolism process of fatty acid,etc.The main action pathway involved respiratory electron transfer,complex biochemistry,adenosine receptor,PKA activation,etc.The possible mechanism of action of TCM for strengthening body resistance and nourishing Heart in treatment of heart failure was analyzed accordinglyConclusion:In this study,various disciplines were integrated based on big data and model calculation on the TCMIP V2.0 platform,and the multi-level and multi-link integrated study proved that the main active components of TCM in TCM for strengthening body resistance and nourishing Heart could act on CHF through multiple targets and pathways.These targets and pathways were consistent with the relevant mechanisms reported in literatures and the latest studies,which also proved the accuracy of the TCMIP platform.This study was a calculation and prediction based on this platform.It is hoped that further studies can be conducted in the future to inherit and carry forward the famous and experienced prescription.3.Targeted Metabolomic StudyPrevious metabonomic studies showed that the contents of acylcarnitine and amino acids in patients after ultrafiltration were abnormal.Targeted metabonomic studies showed that 11 acylcarnitine components such as C2 acylcarnitine,C8 acylcarnitine,C10 acylcarnitine and Cl2:1 acylcarnitine decreased.The contents of aspartic acid,leucine,valine,ornithine and creatinine in amino acids decreased obviously.Conclusion:Acylcarnitine can participate in oxidation of fatty acid directly,which is closely related to myocardial energy metabolism.On the one hand,they accumulate in the myocardium to inhibit β-oxidation of fatty acid,leading to metabolic disorder of heart failure.On the other hand,the up-regulation of acylcarnitine may affect the production of acetyl coenzyme α,thus causing direct damage to the myocardium.The decrease of acylcarnitine in patients after ultrafiltration treatment proved that ultrafiltration had good effects on patients with heart failure.Blood ultrafiltration mainly affects aspartic acid,ornithine and creatinine,which are closely related to arginine metabolism and urea circulation.Changes of these components in patients after blood ultrafiltration might indicate that they have regulated arginine metabolism in patients.However,the contents of arginine and citrulline did not change significantly in this study,suggesting that blood ultrafiltration and its effect on the whole circulation system of arginine and urea still needed further exploration.Aspartic acid and ornithine are substrates for the synthesis of urea and glutamine provided by the body,while glutamine and urea are detoxification products of ammonia.Ornithine is almost involved in the whole process of the activation of urea cycle and ammonia detoxification.The reduction of the content of these components by blood ultrafiltration may indicate that the blood ultrafiltration decreases the content of blood ammonia,plays a certain detoxification role,relieves the pressure in the body,and thus leads to the decrease of the content of aspartic acid and ornithine in the body. |
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