| Background:Stable coronary artery disease(SCAD)is the main type of coronary heart disease,which seriously endangers human life and health.Exercise tolerance is the strongest predictor of prognosis in patients with SCAD,which is closely related to myocardial ischemia and quality of life.In this study,based on the major health problem of SCAD,taking the improvement of exercise tolerance as a breakthrough point,angina pectoris curative effect,traditional Chinese medicine(TCM)curative effects and quality of life as the secondary indicators,we carried out the non inferior randomized controlled trial on Qishendanshao granules(QSDSG,formerly known as Yiqi Huoxue decoction)improving exercise tolerance of patients with SCAD.Then,the network pharmacology study was performed to explore the mechanisms of the efficacy.Objectives:1.To evaluate the efficacy and safety of QSDSG on exercise tolerance of SCAD patients based on the non inferior randomized controlled trial.2.To explore the possible mechanism of QSDSG in improving exercise tolerance of SCAD patients based on network pharmacology.Methods:1.Clinical trialTrimetazidine(TMZ)was selected as the positive control drug in the prospective,randomized,paralleled,positive controlled,non inferiority trial.The SCAD subjects,screened by inclusion and exclusion criteria,were randomly divided into two groups:the experimental group and the control group with a ratio of 1:1.On the basis of routine western medicine treatment,the experimental group were given QSDSG,twice a day,one bag per time;the control group were treated with TMZ,one tablet(20mg)each time,three times a day,and orally taken during three meals.The treatment course of both groups was 4 weeks.The primary outcome was the enhancement of metabolic equivalent(METs)compared with baseline after 4 weeks of treatment.The secondary outcomes were the changes of other indexes of treadmill exercise test[duration of exercise test,positive condition of exercise test,angina pectoris induced by exercise,time from exercise to ST segment depression of 0.1 mv,maximum decrease of ST segment during exercise,worst ST segment,Duke treadmill score(DTS),maximum heart rate,rate pressure product(RPP)],angina related indicators(angina efficacy,angina score,angina pectoris attack times,nitroglycerin stop reduction rate),TCM syndromes and major symptoms(syndrome efficacy,symptom efficacy,syndrome score),and quality of life score[Seattle Angina Questionnaire(SAQ)and SF-36 Health Survey(SF-36)].The safety indexes included vital signs,ECG,laboratory examinations[blood routine,liver function(ALT,AST),renal function(CREA,BUN,blood glucose)and urine routine],adverse events,etc.The long-term follow-up(6 months and 12 months)was set,and the major adverse cardiovascular events(MACE)incidence was the focus index.The full analysis set(FAS)and per protocol set(PPS)were analyzed by intention to treat(ITT)analysis and per protocol(PP)analysis respectively,and the sensitivity of the two data sets was analyzed.Non inferiority test and multivariate analysis were only performed on the primary outcome,and the non inferiority test was one-sided test.2.Network pharmacology studyThe main active components of QSDSG were obtained via TCMSP database combined with Chinese Pharmacopoeia(2020 edition)and comparative experimental literature.The corresponding targets of the active compounds were predicted by TCMSP database and Swiss Target Prediction.Genecards,NCBI,CTD and TTD databases were used to obtain targets of SCAD and exercise tolerance respectively.The potential targets of QSDSG on improving exercise tolerance of patients with SCAD were predicted via intersection of active compound targets and disease targets.Protein protein interaction network(PPI)was constructed by using STRING database.Drugs-compounds-targets-diseases network was constructed by using Cytoscape 3.7.2 software.The targets with degree higher than the average degree in PPI network and whole chain network were extracted as the core targets.Based on R 3.6.3 and clusterprofiler software package,go function enrichment and KEGG pathway enrichment of core targets were analyzed with P<0.01.Combined with the results of enrichment analysis and the related literature research of SCAD&exercise tolerance and core targets,the potential mechanism network of QSDSG intervening SCAD&exercise tolerance was constructed,and the path Builder Tool 2.0 was used to visualize it.Results:1.Clinical trial? In FAS,there were 54 cases in the experimental group and 54 cases control group.In PPS,there were 52 cases in the experimental group and 49 cases control group.1 case,in control group,who refused to obtain the primary outcome after treatment and 6 lost cases were not put into PPS.?Baseline:ITT analysis and PP analysis showed that no statistical differences were found in the demographic data,medical history,usage of drugs,risk factors for SCAD and other basic clinical features(P>0.05)between the two groups.? Comparison between groups:Both the ITT analysis and PP analysis revealed that the improvement of metabolic equivalent in the experimental group was not inferior to that in the control group(P<0.05).In FAS,the metabolic equivalent in experimental group increased 1.33±1.88 METs,and the control group 1.05 ± 1.73 METs;in PPS,the metabolic equivalent in the experimental group increased 1.39±1.90 METs,and the control group 1.16±1.79 METs.The experimental group was better,compared with the control group,in the improvement of TCM related indexes,SAQ score and physical limitation(PL)score(P<0.05).Between the two groups,duration of exercise test,the maximum ST segment decline,the worst ST segment level,the maximum heart rate,DTS,RPP,exercise-induced angina pectoris,the positive condition of exercise test and other exercise tolerance indexes,angina pectoris efficacy,angina symptom score,angina attack times,nitroglycerin stopping rate and other angina related indexes,TCM symptoms-relative efficacy(chest pain,chest tightness,shortness of breath,palpitation and spontaneous sweating),and SAQ angina stability score,treatment satisfaction score,disease perception score,SF-36 score,physical component summary(PCS)score,mental component summary(MCS)score and other quality of life indexes were not found to be statistically different(P>0.05).?Comparison within groups:Both ITT analysis and PP analysis showed that there were statistical differences between two groups in terms of the improvement of metabolic equivalent,duration of exercise test,DTS,angina symptom score,angina pectoris attack times,TCM syndrome score,SAQ score,SAQ sub items' core,SF-36 score,MCS score,and PCS score(P<0.05).?Sensitivity analysis results:Except for the changes of SAQ angina frequency score,the results of ITT analysis and PP analysis were consistent,indicating that lost cases had no significant effects on the results of this study.?Multivariate analysis of the primary outcome showed that the increase of metabolic equivalent was negatively correlated with baseline metabolic equivalent(P<0.05)after controlling other factors such as group,resting heart rate,and so on.If we relax the restriction of P value to 0.2,the increase of metabolic equivalent will be negatively correlated with the baseline CCS angina classification(P<0.2),and positively correlated with the baseline SAQ score(P<0.2).?No serious adverse events occurred in the two groups during the treatment period.In the long-term follow-up,3 cases of MACE occurred in the control group and no case of MACE occurred in the experimental group.2.Network pharmacology study?The drugs-compounds-targets-diseases network was constructed,involving 167 active compounds,126 intersection targets and 62 core targets.?Core active compounds:Quercetin,kaempferol,luteolin,stigmasterol,?-sitosterol and other compounds play an important role in the whole network,which may be the core compounds of QSDSG on improving exercise tolerance of SCAD patients.?Core target proteins:IL6?VEGFA?CASP3?HIF1??COX1 and other core targets played an important role in improving exercise tolerance of SCAD patients.?Enrichment analysis:835 biological processes,55 molecular functions,and 29 cell components were obtained by GO enrichment analysis(P<0.01).98 signal pathways were screened out by KEGG pathway enrichment analysis(P<0.01),including IL17 signaling pathway,TNF signaling pathway,PI3K/AKT signal pathway and so on.?The potential mechanism diagram of QSDSG in improving exercise tolerance of SCAD patients was obtained.Conclusions:1.QSDSG can improve the exercise tolerance of SCAD patients,of which the curative effect is not inferior to that of TMZ.The QSDSG treatment is effective,safe,and beneficial to the long-term prognosis.2.There may be the following rules in improving METs of test drugs:Under the control of group,heart rate,RPP,?-blocker use,TCM syndrome score and other factors,the enhancement of metabolic equivalent is negatively correlated with the baseline metabolic equivalent and CCS angina classification,and positively correlated with the SAQ score.3.QSDSG can relieve angina pectoris in patients with SCAD,of which the curative effect has no significant difference with that of TMZ.4.QSDSG can improve TCM syndromes and the symptoms of chest tightness,chest pain,fatigue,shortness of breath,spontaneous perspiration and palpitation in patients with SCAD,and is better than TMZ in improving the TCM syndromes and the symptom of fatigue.5.QSDSG can improve the quality of life of SCAD patients.And it is better than TMZ in improving the coronary heart disease-related quality of life(SAQ),especially PL score.6.QSDSG may have effect on IL6,VEGFA,APOB,CASP3,HIF1?,COX1 and other targets via quercetin,kaempferol,luteolin,stigmasterol,?-sitosterol and other core compounds,which can regulate IL17 signaling pathway,TNF signal pathway,PI3K/AKT signal pathway,and other pathways to intervene inflammation,fluid shear stress,lipid deposition,angiogenesis,apoptosis,autophagy,oxidative stress,thrombosis and other biological processes,and thus restrain atherosclerosis,promote collateral circulation formation and optimize myocardial energy metabolism to comprehensively relieve angina symptoms and improve exercise tolerance of SCAD patients. |
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