| Acute myocardial infarction(AMI)is one of the major cardiovascular diseases that seriously endanger human health.And the age at set of AMI is becoming younger and its incidence is on the rise,which has become one of the important public health problems in China.With the continuous progress of the disease,a series of complex pathological changes caused by AMI will lead to ventricular remodeling(VR),which can cause heart failure,malignant arrhythmia,and even sudden cardiac death,and is crucial to the prognosis of AMI.At present,western medicine treatment and reperfusion treatment can improve post-infarct VR to a certain extent,but there are still unsatisfactory in terms of efficacy,cost,side effects,and drug resistance.Traditional Chinese medicine(TCM)has the characteristics of multi-channel,multi-level,multi-link and multi-target therapeutic effects,which can safely and effectively improve ventricular remodeling and show therapeutic advantages.Yugeng Tongyu Formula(YGTY),an empirical prescription of Academician Keji Chen,is one of the representative prescriptions for the treatment of myocardial infarction,which has been clinically applied in the treatment of patients with acute and convalescent myocardial infarction,with remarkable effects on improving ventricular remodeling and prognosis.However,there are few relevant clinical studies on the prevention and treatment of post-infarct VR with this formula,and its mechanism is still unclear.Therefore,we condcuted a retrospective study and an animal study to explore the efficacy and mechanism of YGTY in the prevention and treatment of post-infarct VR,in order to provide an objective theoretical basis for this formula in the prevention and treatment of post-infarct VR.Part I A retrospective study on cardiac function and ventricular remodeling following acute myocardial infarction treated with YGTYObjective:To explore the clinical efficacy and advantages of YGTY in the prevention and treatment of cardiac function and ventricular remodeling in patients with acute myocardial infarction.Methods:This study was designed as a retrospective cohort study where some data related to AMI patients with qi-deficiency and blood-stasis syndrome were collected who received treatment in the cardiovascular clinic or in the ward in Xiyuan Hospital,Chinese Academy of Chinese Medical Sciences from October 2015 to October 2021.On the basis of routine treatment of western medicine,whether it was combined with YGTY or not was set as an exposure factor,and then the patients were divided into an exposed group(YGTY combined with routine treatment of western medicine)and a non-exposed group(routine treatment of western medicine).The clinical efficacy and advantages of YGTY in preventing and treating post-infarct VR were discussed by comparing the TCM syndrome scores,Killip cardiac function classification,left ventricular ejection fraction(LVEF),left ventricular end-diastolic diameter(LVEDD),N-terminal pro-brain natriuretic peptide(NT-proBNP),hypersensitive C-reactive protein(hs-CRP)and major adverse cardiovascular events(MACE)before and after 4 weeks of treatment in the two groups.Results:(1)Baseline information:A total of 211 patients were included in this study,where 106 patients were assigned to the exposed group and 105 patients in the non-exposed group.There were no statistical differences between the two groups in terms of risk factors,anamneses,treatment and serological indexes,indicating that they were comparable(P>0.05).(2)TCM syndrome:Before treatment,there was no statistical difference in single and total TCM syndrome scores between the exposed group and the non-exposed group(P>0.05).After treatment,single and total TCM syndrome scores in the two groups were significantly lower than those before treatment,and single and total TCM syndrome scores in the exposed group with higher total effective rate of TCM syndrom,were lower than those in the non-exposed group,which made statistically significant differences(P<0.01).(3)Killip cardiac function classification:Before treatment,there was no statistical difference in Killip cardiac function classification between the two groups(P>0.05).After treatment,the improvement in Killip cardiac function classification in the exposed group was better than that in the non-exposed group,which made statistically significant differences(P<0.01).(4)Echocardiography parameters:Before treatment,there was no statistical difference in LVEF and LVEDD between the two groups(P>0.05).After treatment,LVEF was significantly increased and LVEDD was significantly decreased in both two groups compared with those before treatment.Besides,the increase in LVEF and decrease in LVEDD in the exposed group were more remarkable than those in the non-exposed group,which made statistically significant differences(P<0.01).(5)Serological indexes:Before treatment,there was no statistical difference in NT-proBNP and hs-CRP levels between the two groups(P>0.05).After treatment,NT-proBNP and hs-CRP levels in both two groups were significantly lower than those before treatment,and NT-proBNP and hs-CRP levels in the exposed group were lower than those in the non-exposed group,which made statistically significant differences(P<0.01).(6)MACE:There was no statistical difference in the incidence of MACE between the two groups after treatment(P>0.05).Conclusion:Western medicine combined with YGTY could effectively alleviate the clinical symptoms of patients with AMI,improve the clinical efficacy,increase LVEF,decrease LVEDD,lower NT-proBNP and hs-CRP,improve cardiac function and delay ventricular remodeling.Moreover,the therapeutic effect was better than that of western medicine treatment alone.Part II:Study on the effect and mechanism of YGTY on ventricular remodeling following acute myocardial infarction in ratsObjective:To evaluate the efficacy and explore the possible mechanism of YGTY on ventricular remodeling following acute myocardial infarction in rats.1 Study on cardiac function and ventricular remodeling following acute myocardial infarction treated with YGTY in ratsMethods:A rat model with acute myocardial infarction was constructed by ligating the left anterior descending coronary artery,and the rats were randomly divided into five groups:sham operation group(Sham),model group(Model),positive drug captopril group(ACEI),low-dose YGTY group(L-YGTY),and high-dose YGTY group(H-YGTY),with 9 rats in each group received continuous intervention for 4 weeks.There were different test methods in this study,including echocardiography used to assess cardiac function,TTC staining used to observe the size of myocardial infarction,HE staining used to observe the pathological morphology of myocardium,Masson staining used to observe myocardial fibrosis,ELISA used to detect the levels of CK-MB,BNP,AngII,TNF-α,IL-6,IL-10,SOD and MDA in serum,which could evaluate the efficacy of YGTY on cardiac function and ventricular remodeling following acute myocardial infarction in rats.Results:(1)Compared with Sham group,LVEDD and LVESD in Model group were significantly increased(P<0.01),while LVEF and LVFS were significantly decreased(P<0.01).Compared with Model group,L-YGTY group had no significant improvement in the LVEDD,LVESD,LVEF,and LVFS(P>0.05),while LVEDD and LVESD were decreased(P<0.05),LVEF and LVFS were increased(P<0.05)in H-YGTY group and ACEI group.(2)Compared with Sham group,the size of myocardial infarct in Model group was significantly larger(P<0.01).Compared with Model group,the size of myocardial infarct in L-YGTY group,H-YGTY group and ACEI group were significantly smaller(P<0.01).Compared with Sham group,HWI in Model group was significantly higher(P<0.01).Compared with Model group,HWI in H-YGTY group and ACEI group were significantly lower(P<0.01),while there was no statistical difference in L-YGTY group(P>0.05).(3)Compared with Sham group,myocardial tissues in Model group were disordered,loose and widened,accompanied by a large number of inflammatory cell infiltration and fibrosis changes.Compared with Model group,the pathological changes in myocardial tissue in L-YGTY group,H-YGTY group and ACEI group were significantly alleviated.(4)Compared with Sham group,CVF in Model group was significantly higher(P<0.01).Compared with Model group,CVF in L-YGTY group and H-YGTY group and ACEI group were lower,and CVF in H-YGTY group and ACEI group were significantly lower(P<0.01).(5)Compared with Sham group,CK-MB,AngII and BNP levels in Model group were significantly higher(P<0.01).Compared with Model group,CK-MB,AngⅡ and BNP levels in H-YGTY group and ACEI group were significantly lower(P<0.01);CK-MB and BNP levels were significantly lower(P<0.01)in L-YGTY group,but there was no significant improvement on AngII level in L-YGTY group(P>0.05).(6)Compared with Sham group,TNF-α and IL-6 levels were significantly higher in Model group(P<0.01),and IL-10 level was significantly lower(P<0.01).Compared with Model group,the TNF-α and IL-6 levels were significantly lower in L-YGTY group,H-YGTY group and ACEI group(P<0.01);IL-10 level was significantly higher(P<0.01).(7)Compared with Sham group,MDA level in Model group was significantly higher(P<0.01),and SOD level was significantly lower(P<0.01).Compared with Model group,MDA level in H-YGTY group,and ACEI group were significantly lower(P<0.01),and SOD level was significantly higher(P<0.01);MDA level in L-YGTY group was significantly lower(P<0.01),but there was no significant improvement on SOD level in L-YGTY group(P>0.05).Conclusion:YGTY could alleviate myocardial injury,reduce collagen volume fraction,decrease the size of myocardial infarction and heart weight index,improve cardiac function,inhibit inflammation and oxidative stress,and improve ventricular remodeling.2 Experimental study on the effect of YGTY on TGF-β/Smads pathway in rat heart after acute myocardial infarctionMethods:The animals were modelled,grouped and intervened as in the previous section.There were different test methods in this study,including TUNEL staining used to detect apoptosis,Western Blot used to detect protein expressions of Collagen Ⅰ,Collagen Ⅲ,Bax,Bcl-2,Cleaved-Caspase3,TGF-β1,Smad2,Smad3,p-Smad2,p-Smad3,and Smad7 in myocardial tissues,RT-qPCR used to detect gene expressions of TGF-β1,Smad2,Smad3,and Smad7 in myocardial tissues,which could further clarify the mechanism of YGTY.Results:(1)Compared with Sham group,the protein expressions of Collagen Ⅰ and Collagen Ⅲ in myocardial tissue in Model group were significantly higher(P<0.01).Compared with Model group,the protein expression of Collagen Ⅲ in myocardial tissue in L-YGTY group was lower(P<0.05),and there was no statistical difference in the protein expression of Collagen Ⅰ in L-YGTY group(P>0.05);In H-YGTY group,the protein expressions of Collagen Ⅰ and Collagen Ⅲ in myocardial tissue were lower(P<0.05),and the protein expression of Collagen Ⅲ was significantly lower(P<0.01);The protein expressions of Collagen Ⅰ and Collagen Ⅲ in myocardial tissue in ACEI group were significantly lower(P<0.01).(2)Compared with Sham group,AI in Model group was significantly increased(P<0.01).Compared with Model group,AI in H-YGTY group(P<0.05)and ACEI group was decreased,and the decrease in ACEI group was more significant(P<0.01);However,there was no statistical difference in AI in L-YGTY group(P>0.05).(3)Compared with Sham group,the protein expressions of Bax and Cleaved-Caspase3 in myocardial tissuein in Model group were significantly higher(P<0.01),while the protein expression of Bcl-2 was significantly lower(P<0.01).Compared with Model group,the protein expression of Cleaved-Caspase3 in myocardial tissue in L-YGTY group was significantly lower(P<0.01),while there was no statistical difference in the protein expressions of Bax and Bcl-2(P>0.05);In H-YGTY group,the protein expression of Bcl-2 were higher(P<0.05),while the protein expressions of Bax(P<0.05)and Cleaved-Caspase3 were lower,and the protein expression of Cleaved-Caspase3 was significantly lower(P<0.01);The protein expression of Bcl-2 in ACEI group was higher(P<0.05),while the protein expressions of Bax and Cleaved-Caspase3 were significantly lower(P<0.01).(4)Compared with Sham group,the protein expression of Smad7 in myocardial tissue in Model group was significantly lower(P<0.01),while the protein expressions of TGF-β1,p-Smad2/Smad2(P<0.05),and p-Smad3/Smad3(P<0.05)were higher,and the protein expression of TGF-β1 was significantly higher(P<0.01).Compared with Model group,the protein expressions of TGF-β1,p-Smad2/Smad2,and p-Smad3/Smad3 in myocardial tissue in H-YGTY group and ACEI group were lower(P<0.05),and the protein expression of Smad7 was significantly higher(P<0.01);there was no statistical difference in the protein expressions of TGF-β1,p-Smad2/Smad2,p-Smad3/Smad3 and Smad7 in myocardial tissue in L-YGTY group(P<0.05).(5)Compared with Sham group,the mRNA expression of Smad7 in myocardial tissue in Model group was significantly lower(P<0.01),while the mRNA expressions of TGF-β1,Smad2 and Smad3 were significantly higher(P<0.01).Compared with Model group,the mRNA expressions of TGF-β1 and Smad3 in L-YGTY group were significantly lower(P<0.01),while there was no statistical difference in the mRNA expressions of Smad2 and Smad7 in L-YGTY group(P>0.05);the mRNA expressions of TGF-β1,Smad2 and Smad3 in h-YGTY group and ACEI group were significantly lower(P<0.01),while the mRNA expression of Smad7 was significantly higher(P<0.01).Conclusion:YGTY could regulate protein expressions of Collagen I and Collagen III to inhibit myocardial fibrosis.It could also reduce apoptosis index and regulate apoptotic protein expressions of Bcl-2,Bax and Cleaved-Caspase3 to inhibit apoptosis.And it might inhibit myocardial fibrosis and apoptosis by regulating TGF-β/Smads pathway to improve ventricular remodeling. |
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