Clinical Study On The Effect Of Zhenyuan Capsule On Cardiorespiratory Fitness In Patients With Stable Coronary Artery Disease And Mechanism Discussion

Chronic stable coronary artery disease(SCAD)is the main clinical type of coronary heart disease(CHD),which seriously endangers human health.There are still many problems in SCAD treatment,such as restenosis after intervention,increased cardiovascular events,and decreased quality of life.Cardiorespiratory fitness(CRF)is the main measurement component of cardiac rehabilitation(CR),which is a marker of whole-body health.A higher CRF can improve the clinical benefit of SCAD.Although exercise therapy is a major component of CR,it is highly dependent on patient compliance,and its therapeutic effect is greatly reduced in patients with low compliance.Pharmacological prescription,one of the "five prescriptions" for CR,not only improves cardiopulmonary function,but is also more acceptable to patients.According to traditional Chinese medicine(TCM),the main etiology of CHD is qi deficiency and blood stasis,with qi deficiency as the main cause and blood stasis as the symptom,and the patient’s CRF can be improved by regulating qi and blood.As a representative of beneficial qi medicine,ginseng has the effect of a great tonic,which can benefit qi in order to invigorate blood and nourish blood.Among them,Zhenyuan capsule,which is mainly composed of total ginsenoside,has been used in the clinical treatment of coronary heart disease and diabetes.However,no study has been conducted to investigate the effect of Zhenyuan capsule on the cardiopulmonary function of coronary heart disease and its possible mechanism of action.Based on the theory of Qi and Blood,this study was conducted to objectively evaluate the effect of Zhenyuan capsule on the cardiopulmonary function of stable coronary heart disease by using a randomized,double-blind,placebo-controlled clinical study,and to explore its possible targets and mechanisms of action by means of proteomics.Part 1 Effect of ZhenYuan capsule on cardiorespiratory fitness in patients with SCAD with Qi deficiency and Blood stasis:a randomized,double-blind,placebocontrolled studyObjective:To evaluate the efficacy and safety of Zhenyuan capsule on cardiopulmonary function in patients with SCAD with Qi deficiency and blood stasis.Methods:Using a randomized,double-blind,placebo-controlled clinical study trial design,100 patients with SCAD were enrolled according to the nadir criteria and randomly divided into the group taking Zhenyuan capsules(trial group,n=50)and the group taking placebo(control group,n=50).In both groups,patients were treated with secondary prevention medication for coronary heart disease,with the addition of 2 capsules of Zhenyuan capsule 3 times a day for 12 weeks in the experimental group and 2 capsules of placebo 3 times a day for 12 weeks in the control group,with a follow-up of 1 month after the end of treatment.Subjects underwent cardiopulmonary exercise test(CPET)at 3 time points before enrollment,after 12 weeks of treatment,and after 1 month of follow-up.The primary efficacy index is the metabolic equivalent improvement value and the secondary efficacy indexes are Peak oxygen uptake(VO2 peak),Respiratory exchange ratio(RER),maximum heart rate,1 min Heart Rate Recovery(HRR1),2 min Heart Rate Recovery(HRR2),Oxygen pulse(O2 Pulse),duration of exercise,Borg score,angina-related indicators,TCM signs and symptoms,Seattle Angina Questionnaire(SAQ),Self-Rating Depression Scale(SDS),Self-Rating Anxiety Scale(SAS),and Left ventricular ejection fraction(LVEF),left ventricular end-diastolic diameter(LVEDD)and other diagnostic parameters.Safety indicators included vital signs,blood and urine routine,liver and kidney function,electrocardiogram and adverse events.Full analysis set(FAS)and per protocol set(PPS)were performed for the efficacy indicators,and sensitivity analysis was performed for both sets.Results:1 Basic information of the study:A total of 100 subjects were included in the study,with 3 cases of shedding,and the total shedding rate was 3%;among them,there was 1 case of shedding in the test group,and 1 case of shedding and 1 case of loss of visit in the control group.2 Analysis of baseline data:In the FAS set,there were no significant differences between groups in demographic characteristics,history of hemodynamic reconstruction,risk factors,laboratory indicators,medication use,and season of treatment(P>0.05),and the groups were comparable;in the PPS set,there were significant differences between groups in smoking status,hyperlipidemia,and diabetes mellitus(P<0.05),and no significant differences in the remaining indicators(P>0.05).3 Comparative analysis between groups(FAS set):The results of this study used the metabolic equivalent improvement value as the main efficacy index.At the anaerobic threshold level,the metabolic equivalent improvement value was 0.58±0.89 Mets in the test group and 0.1 5±1.06 Mets in the control group;at the maximum level,the metabolic equivalent improvement value was 0.69±0.92 Mets in the test group and 0.19±0.93 Mets in the control group;both at the anaerobic threshold level and at the maximum level,the results of comparison between groups showed statistically significant differences(P<0.05),and the efficacy of the test group was better than that of the control group.Regarding the secondary efficacy indexes,the expected increase in VO2 peak%after treatment was 4(-7,11)%in the test group and 3(-6.75,11.50)%in the control group,which was significantly higher in the test group than in the control group after treatment(P<0.05);VO2 peak,HRR1,HRR2,O2 pulse,exercise duration,angina pectoris CCS classification efficacy,TCM evidence efficacy,TCM single symptom efficacy(chest tightness,palpitation,shortness of breath,fatigue,insomnia and dreaminess,purple lips,spontaneous sweating)and LVEF were higher in the test group than in the control group after treatment,and RER,maximal HR,LVEDD and CK-MB were lower than those of the control group,but there was no significant difference between groups in these indices(P>0.05).4 Within-group comparative analysis(FAS set):Metabolic equivalent at anaerobic threshold increased from 3.24±0.74 Mets to 3.81±0.93 Mets,metabolic equivalent at maximum from 4.82±0.94 to 5.49±1.15 Mets,VO2 peak increased from 1193.24±295.66 ml/min to 1274.10±333.92 ml/min,RER values increased from 1.02(0.96,1.11)to 1.09(1.03,1.16),HHR1 increased from 15.92±8.74 to 19(12,30)beats/min,HRR2 increased from 24.10±10.24 to 28(20,31)beats/min,and TCM evidence score decreased from 10(8,14)to 4(4,6),total SAQ score increased from 82(80,84)to 87(85,88),SDS score decreased from 34.54±5.97 to 31(26,33),SAS score decreased from 30.98±4.93 to 25.76±3.09,left ventricular end-diastolic internal diameter decreased from 48(45,50)mm decreased to 46(44,48)mm,and these indicators were significantly different before and after treatment(P<0.05).In the control group,the RER increased from 1.01(0.94,1.10)to 1.09(1.02,1.16)after treatment,the TCM evidence score decreased from 9(8,12)to 4(4,5),the total SAQ score increased from 82(80,85)to 87(86,89),the SDS score decreased from 33.54±5.10 to 29(25,32),and the SAS score decreased from 29.88±4.20 to 25.35±1.97,and these indicators were significantly different before and after treatment(P<0.05).5 Sensitivity analysis:The results of ITT analysis and PP analysis remained consistent on the efficacy index,indicating that the detached cases had no effect on the results of this study.6 Safety analysis and short-term prognosis:During the 12-week dosing period of this study,no serious adverse events occurred in patients in both the test and control groups.One adverse event occurred in each of the test and control groups,which was considered unrelated to study drug administration;relevant safety indicators were within the normal range before and after treatment in both groups.During the 1-month short-term followup,no adverse events occurred in either group;the metabolic equivalent at the maximum level increased from 4.79 ± 0.95 Mets at baseline to 5.16 ± 1.30 Mets at 1-month followup in the test group,with a significant difference(P<0.05)before and after comparison.Conclusions:1 Zhenyuan capsule can significantly improve the cardiopulmonary function of patients with stable coronary artery disease,and its efficacy is better than placebo control,and it has high safety and good short-term prognosis.2 The HRR1 and HRR2 of patients with stable coronary artery disease increased significantly after treatment with Zhenyuan capsule,but the maximum heart rate did not increase significantly,and Zhenyuan capsule could improve the heart rate recovery ability of patients with stable coronary artery disease.3 Zhenyuan capsule can improve the TCM symptoms and signs of patients with stable coronary heart disease.4 Zhenyuan capsule can improve SAQ total score and each dimension score,reduce depression self-assessment scale and anxiety self-assessment scale,and improve the quality of life of patients with stable coronary artery disease.5 Zhenyuan capsule was able to reduce the left ventricular end-diastolic diameter in patients with stable coronary artery disease.Part 2 Exploration of the mechanism of improving cardiorespiratory fitness in SCAD patients based on proteomic zhenyuan capsuleObjective:To detect and analyze serum differential proteins before and after treatment with Zhenyuan capsules using Label-free proteomics technology,and to preliminarily investigate the possible mechanism of action of Zhenyuan capsules in improving cardiopulmonary function in stable coronary artery disease.Methods:After the clinical trial,eight SCAD patients with significantly improved Mets values after 3 months of treatment with Zhenyuan capsule were selected from Xiyuan Hospital,Chinese Academy of Traditional Chinese Medicine.Proteomics techniques were used to identify the serum differential protein expression profiles of patients before(A)and after(B)treatment with Zhenyuan capsules,and the differential proteins identified were further analyzed by bioinformatics analysis methods.Results:The qualitative analysis of serum proteins yielded 5496 peptides and 489 proteins,and the Label-free quantification results showed that there were 17 differential proteins involved in the occurrence of cardiopulmonary function improvement in patients with stable coronary heart disease by Zhenyuan capsules,among which 4 differential proteins were significantly upregulated and 13 differential proteins were significantly downregulated.The action targets of Zhenyuan capsule to improve the cardiopulmonary function of patients with stable coronary heart disease may be Beta-2-microglobulin,HLAA,Fibronectin,Clusterin,Properdin and other differential proteins The mechanism of action involves signaling pathways such as antigen processing and presentation,and cholesterol metabolism.Conclusions:Zhenyuan capsules may inhibit the release of cytokines and inflammatory mediators from immune cells associated with monocytes/macrophages by downregulating the levels of differential proteins such as β2M,Clusterin and Fibronectin,reducing damage to the vascular endothelium and attenuating stromal remodeling by mechanisms that may involve pathways such as antigen processing and presentation and cholesterol metabolism.