| Though standard secondary preventive medicine has been widely used in patients with stable coronary artery diseases(CAD),there are still substantial residual cardiovascular risks in these patients(5%-10%).Therefore,how to further improve the prognosis of stable CAD remains challenging.In our previous studies,we found that blood stasis could result in toxin and the interaction of blood stasis and toxin would lead to adverse cardiovascular events.On basis of this finding,we established the criteria for identifying interaction of toxin and blood stasis in pateints with stable CAD.Qingxin Jieyu Granule,a Chinese medicine formula with blood circulation activating and toxin dissolving property,was developed under guidance of"blood stasis and toxin leading to events" theory from the famous Yugeng Tongyu decoction of academician KJ Chen.However,there is a lack of evidence whether Qingxin Jieyu Granule will further reduce adverse cardiovascular events in patients with stable CAD.Therefore,we conducted a multicenter,double blinded,placebo controlled randomized trial to evaluate efficacy and safety of Qingxin Jieyu Granule for patients with stable CAD.Besides,a proteomicsstudy was also conducted to explore potential mechanism of effects of Qingxin Jieyu Granule on adverse cardiovascular events in stable CAD.Part 1 Effect of Qingxin Jieyu Granuleon cardiovascular events in patients with stable coronary artery disease:a multicenter,double blinded,placebo controlled randomized trialObjective:To evaluate efficacy and safety ofQingxin Jieyu Granule developed under guidance of the "blood stasis and toxin leading to events" theory for reducing cardiovascular events in patients with stable CAD.Methods:1500 patients with stable CAD were enrolled and randomized in a 1:1 ratio to Qingxin Jieyu Granule or placebo in a multicenter,double blinded,placebo controlled randomized trial.Patients in Qingxin Jieyu Granule group received Qingxin Jieyu Granule(twice daily for 6 months)in addition to standard medical therapy for CAD,while patients in the control group received placebo.After 6 months medication,patients will be followed up for another 6 months.The primary outcome was a composite of cardiovascular death,nonfatal myocardial infarction and revascularization.The secondary outcome was a composite of all-cause death,stroke and rehospitalization for unstable angina or heart failure or malignant arrhythmia.Results:Baseline characteristics including ages,sex and cardiovascular risk factors are all comparable in the two groups(P>0.05).At the time of 12 months,the lost to follow-up rate between the two groups was similar with 66 patients(8.67%)in Qingxin Jieyu Granule group versus 71 patients(9.47%)in placebo group(P=0.65).There was a reductiontrend of the primary outcome in the Qingxin Jieyu Granule group with 5 events in the Qingxin Jieyu Granule group versus 10 events(1.47%)in placebo group(cumulative event rates:1.59%vs.1.62%;adjusted hazard ratio,0.41;95%CI,0.13-1.28;P=0.12).A similar nonsignificant reduction of the secondary outcome was also observed in the Qingxin Jieyu Granule group(cumulative event rates:1.28%vs.3.47%;adjusted hazard ratio,0.41;95%CI,0.16-1.08;P=0.07).Further analysis showed that Qingxin Jieyu Granule significantly reduced incidence of nonfatal myocardial infarction(cumulative event rates:0.16%vs.0.82%;adjusted hazard ratio,0.82;95%CI,0.01-0.95;P=0.045)and the commonly used composite outcome of cardiovascular death,nonfatal myocardial infarction and stroke(cumulative event rates:0.31%vs.1.30%;adjusted hazard ratio,0.06;95%CI,0.01-0.53;P=0.012).A prespecified composite outcome composed of cardiovascular death,nonfatal myocardial infarction,stroke,and rehospitalization for unstable angina or heart failure or malignant arrhythmia was also significantly reduced(cumulative event rates:2.84%vs.4.89%;adjusted hazard ratio,0.43;95%CI,0.21-0.90;P=0.025).A significant reduction of high-sensitivity C-reactive protein(hs-CRP)in male patients at the time of 12months was observed(P=0.03).No difference of adverse reactions between the two groups was observed(P=0.06).Conclusion:Among patients with stable CAD,the addition of Qingxin Jieyu Granule to standard medical therapy could safely reduce the incidence of myocardial infarction,the composite outcome of cardiovascular death,nonfatal myocardial infarction and stroke and the composite outcome of cardiovascular death,nonfatal myocardial infarction,revascularization,stroke and rehospitalization for unstable angina or heart failure or malignant arrhythmia.Part 2 Preliminary mechanism study by proteomics of effects of Qingxin Jieyu Granule on stable coronary artery diseasesObjective:To identify differently expressed serum proteins after administration of Qingxin Jieyu Granuleby proteomicsin order to explore potential mechanism of Qingxin Jieyu Granule in treating stable CAD.Methods:Ten patients with stable CADand with obviously reduced hs-CRP level after takingQingxin Jieyu Granulewere selected from one of the clinical trial center Anzhen Hospital,Capital Medical University after completion of the clinical trial.Serum samples were takenat the time of randomizationand 3 months after,and were then divided into two groups with samples taken at the time of randomization as group A,and samples taken 3 months after as group B.Proteomics methods were adopted to identify the differently expressed protein before and after administration of Qingxin Jieyu Granule.Thenbioinformatics analyses were conducted to further analysis the potential functiona of the identified proteins.Results:20 differently expressed proteins were identified before and after the administration of Qingxin Jieyu Granule.Among them,expression of 4 proteins were up-regulated,namely CASP8 and FADD-like apoptosis regulator(CFLAR),Serotransferrin,Apolipoprotein A-IV(APOA4)andclose homologue of L1;Expression of 16 of the 20 protein were down-regulated,including complement factor B(CFB),apolipoprotein B(APOB),Complement C1 subcomponent(CIS),Protein tyrosine phosphatase(non-receptor type substrate 1,PTPNS1),Xylosyltransferase 2(XYLT2),Growth hormone receptor(GHR),Ferritin light chain(FTL),EH domain-containing protein 3(EHD3),Complement C4-A(C4A),Trans-Golgi network integral membrane protein 2(TGONL2),mesencephalic astrocyte-derived neurotrophic factor(MANF),Ankyrin repeat domain-containing protein 23(ANKRD23),complement C2(C2),keratin 6B(Keratin,type Ⅱ cytoskeletal 6B),keratin 16(Keratin,type I cytoskeletal 16),keratin A(HCG2039812).Results of thebioinformatics analysesshowed that the identified proteins are involved in many biological processes and molecular function such as immune regulation,cholesterol transportation,lipoprotein synthesis,iron ion binding,mitochondrial autophagy caused by vacuole formation and by mitochondrial depolarization,macroautophagy,mitochondrial degradation,organelle degradation,iron transport,scaffold protein binding activity,cell response to growth factors,and positive regulation endocytosis,et al.Enrichment analysis of signaling pathwayrevealed that the identified proteins were involved in necroptosis pathway,mineral absorption pathway,and the glycosaminoglycan biosynthesis-chondroitin sulfate/dermatan sulfate pathway.Conclusion:Qingxin Jieyu Granule may have the ability of stabilizingatherosclerotic plaque by inhibiting necroptosis and apoptosis of atherosclerosis-related cells,reducing deposition of lipoproteins under endothelium,and inhibiting activation of the complement system. |
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