| Objective1.Experimental ResearchTo explore the effect of Panaxatriol Saponins on myocardium rat I/R injury,and whether its mechanism is related to the PI3K/Akt signaling pathway by establishing the isolated rat heart with ischemia/reperfusion injury model of simulating MIRI process at the organ level.2.Clinical ResearchTo provide reliable evidence based medicine by using Meta analysis to systematically evaluate the efficacy and safety of Panax notoginseng saponins in the treatment of myocardial ischemia/reperfusion injury.Methods1.Experimental ResearchExperiment one:Totally 40 healthy male Wistar rats were divided into the control group,the IR model group and low,medium and high dose PTS groups(PTSL group,PTSM group,PTSH group),with 8 rats in each group.In the control group,proximal branch of the left anterior descending coronary artery was threaded without ligaturing.K-H buffer was continuously reperfused for 105 min.In the IR model group,proximal branch of the left anterior descending coronary artery was threaded and ligatured for 30 min,and then the ligation was loosened.K-H buffer was reperfused for 75 min.In PTSL group,PTSM group and PTSH group,the proximal branch of the left anterior descending coronary artery was threaded and ligatured for 30 min,and K-H buffer respectively containing 5,10and 20 mg/L PTS were reperfused for 75 min.The levels of creatine kinase isoenzyme(CK-MB)and lactated hydrogenase(LDH)were measured by collecting the perfusate of balanced perfusion 20 min,local ischemia 30 min and reperfusion 15 and 75 min in 5 groups.The cardiac hemodynamic parameters recorded by polysomnography including heart rate,left ventricular end systolic pressure(LVESP),left ventricular end diastolic pressure(LVEDP),left ventricular development pressure(LVDP),maximum rate of left ventricular pressure rise/fall(±dp/dt max)and the ratios of LVESP,LVDP,+dp/dt max to final equilibrium difference value were compared among 5 groups at balanced perfusion 20 min,focal ischemia 30 min and reperfusion 15 and 75 min.Experiment two:Forty male Wistar rats were randomly divided into 5 groups with 8 rats in each group.In the control group,I/R group,PTS group,LY294002 group,LY294002+PTS group.In the control group,proximal branch of the left anterior descending coronary artery was threaded without ligaturing.K-H buffer was continuously reperfused for 105 min.In the IR model group,proximal branch of the left anterior descending coronary artery was threaded and ligatured for 30 min,and then the ligation was loosened.K-H buffer was reperfused for 75 min.In LY294002 group,the proximal branch of the left anterior descending coronary artery was threaded and ligatured for 30 min,and K-H buffer respectively containing 15 ?g/L LY294002 were reperfused for 75 min.In PTS group,the proximal branch of the left anterior descending coronary artery was threaded and ligatured for 30 min,and K-H buffer respectively containing 10mg/L PTS were reperfused for 75 min.In LY294002+PTS group,the proximal branch of the left anterior descending coronary artery was threaded and ligatured for 30 min,and K-H buffer respectively containing 15 ?g/L LY294002 were reperfused for 15 min,and then K-H buffer respectively containing 10mg/L PTS were reperfused for 60 min.The Langendorff isolated cardiac perfusion device was used to establish a cardiac ischemia/reperfusion model,and the perfusion fluid at different times was collected to measure myocardial enzyme indexes(CK-MB,LDH),and record left ventricular hemodynamic parameters(HR,LVESP,LVEDP,LVDP,±dp/dt max)at different moments;Westerm blot detection of Akt,pAkt,GSK-3 ?,pGSK-3 ? expression in myocardial tissue,immune Histochemical detection of Bax,Bcl2,Caspase-3 expression.2.Clinical ResearchThrough a comprehensive search of all databases,ramdomized controlled trials of conventional treatment of PCI patients with Panax notoginseng saponins combined with western medicine since the establishment of the database until January 1,2021 were included,and then a Meta-analysis of relevant outcome indicators was conducted using RevMan5.3 software.Results1.Experimental ResearchExperiment one:At reperfusion for 15,75 min,the levels of CK-MB and LDH in perfusate of the IR model group were higher than those in the control group[CK-MB:(234±51)U/L vs(12±6)U/L,(203±63)U/L vs(14±3)U/L;LDH:(63.9±9.4)U/L vs(6.2±4.6)U/L,(52.1±9.5)U/L vs(6.3±4.8)U/L](all P<0.05).The levels of CK-MB at the reperfusion for 75 min and LDH at the reperfusion for 15 min in perfusate of PTSL,PTSM and PTSH groups were lower than those in the IR model group,and the levels of LDH at reperfusion for 75 min in PTSL and PTSH groups were lower than those in the IR model group(all P<0.05).There were no significant differences in myocardial enzyme levels at different time points in the control group(all P>0.05).Compared with the control group,the LVDP and+dp/dt max at reperfusion for 15,75 min in the IlR model group were decreased,and LVEDP,-dp/dt max and the ratios of LVESP,LVDP,+dp/dt max to final equilibrium difference value in the IR model group were increased(all P<0.05).LVEDP at reperfusion for 15 min in PTSL group,and LVEDP at reperfusion for 75min in PTSM group were lower than those in IR model group;LVDP,+dp/dt max at reperfusion for 75 min in PTSM group were lower than those in IR model group;-dp/dt max at local ischemia for 30 min and reperfusion for75 min in PTSM group were higher than those in IR model group;the ratios of LVESP,LVDP,+dp/dt max to final equilibrium difference value of PTSL,PTSM and PTSH groups were higher than those in IR model group(all P<0.05).The heart rate at balanced perfusion for 20 min in PTSL group and PTSH group,and that at balanced perfusion for 20 min,local ischemia for 30 min and reperfusion for 15,75 min of PTSM group were higher than those in IR model group(all P<0.05).Experiment two:(1)Hemodymamic paramelers:the HR of the control group did not change significantly al different time points(P>0.05),the other groups increased to varying degrees,and the remaining four groups except the control group had no significant difference at 75 minutes of reperfusion(P>0.05).There was no significant change in LVESP,LVEDP,LVDP,±dp/dt max in the control group at different time points,and the other groups decreased to varying degrees over time.At 75 minutes of reperfusion,the PTS group was significantly lower than the model group(P<0.05),while the LY294002+PTS group was not significantly different from the model group,but was significantly different from the PTS group(P<0.05).(2)CK-MB,LDH:The control group did not change significantly at different time points,and the myocardial enzyme levels in the other groups were significantly increased after reperfusion compared with 30 min ischemia(P<0.05).There was no significant difference between the groups at 20 min of equilibrium(P>0.05);at 30 min of ischemia,there was no statistical difference between the CK-MB groups(P>0.05),while the LDH groups were higher than the control group(P<0.05);at 15min and 75min of reperfusion,all groups were significantly higher than the control group,the PTS group was significantly lower than the model group,and the LY294002+PIS group was higher than the PTS group(all P<0.05).(3)Expression of Akt,pAkt,GSK-3?,and pGSK-3 ?:After ischemia-reperfusion injury,there was no statistical difference in the expression of Akt and GSK 3 ? in myocardial tissue of each group(P>0.05).pAkt and pGSK were expressed in the PTS group Compared with the model group,there was a significant increase(P<0.05).The expression in the two groups using LY294002 was significantly lower than that in the model group(P<0.05),and the difference between LY294002 +PTS and PTS group was statistically significant(P<0.05).(4)The expression of Bax,Bcl-2 and Caspase-3:Bax and Caspase-3 in the model group were significantly higher than those in the control group(P<0.05),and the expression of Bax and Caspase-3 in the PTS and LY+PIS 2 groups was lower than that in the model group(P<0.05).The control group was Bcl-2 strongly positive,the model group was significantly lower than the control group(P<0.05),the PTS group was significantly higher than the model group(P<0.05),and the LY294002+PTS group was significantly lower than the PTS group(P<0.05).2.Clinical Research35 studies were included,the research sites were all in China,a total of 2963 cases were reported,including 1488 in the observation group and 1475 in the control group,totally 4 kinds of Panax notoginseng saponins preparations were involved.Statistical outcome index:Meta-analysis of continuous variables was performed for CK-MB?cTnT?LVEF?LVEDD?BNP?hs-CRP?IL-6?TNF-??TC?TG?LDL-C?HDL-C and TIMI blood flow grading during coronary perfusion,the results:CK-MB(SMD=-2.09,95%CI:[-3.04,-1.13],I2=97%,P<0.0001)?cTnT(SMD=-2.37,95%CI:[-3.31,-1.43],I2=97%,P<0.00001)?LVEF(WMD=3.97,95%CI:[2.58,5.36],I2=83%,P<0.00001)?LVEDD(WMD=-3.18,95%CI:[-4.33,-204],I2=85%,P<0.00001)?BNP(SMD=-1.89,96%CI:[-2.68,-1.11],I2=96%,P<0.00001)?hs-CRP(SMD=-1.46,95%CI:[-2.02,-0.90],12=96%,P<0.00001)?IL-6(SMD=-1.87,95%CI:[-2.33,-1.41],I2=91%,P<0.00001)?TNF-?(SMD=-1.22,95%CI:[-1.85,-0.59],I2=94%,P<0.0001)?TC(WMD=-0.57,95%CI:[-0.87,-0.27],I2=84%,P=0.0002)?TG(WMD=-0.27,95%CI:[-0.46,-0.08],I2=84%,P=0.005)?LDL-C(WMD=-0.32,95%CI:[-0.61,-0.03],12=85%,P=0.03)?HDL-C(WMD=0.02,95%CI:[-0.13,0.17],I2=84%,P=0.75)?TIMI blood flow grading during coronary perfusion(WMD=0.34,95%CI:[0.26,0.42],I2=30%,P<0.00001).and of adverse reactions were analyzed by the Meta-analysis of dichotomous variables.The results:the incidence of MACEs(RR=0.48,95%CI:[0.33,0.70],12=4%,P=0.0002)?the incidence of adverse reactions(RR=0.73,95%CI:[0.51,1.04],12=0%,P<0.08).Conclusion1.In the model of isolated-heart local IR injury of rats,PTS can reduce the release of myocardial enzymes and relieve left ventricular systolic and diastolic dysfunction,which may be related to the regulation of PI3K/Akt signaling pathway.2.Panax notoginseng saponins preparations have a positive effect on myocardial protection in patients with PCI,especially in improving coronary perfusion and cardiovascular adverse events. |
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