| Direct percutaneous coronary intervention(PCI)is recognized as the most effective method for the treatment of acute ST-segment elevation myocardial infarction(STEMI).PCI can open the infarction-related artery(IRA)in a short time and restore the forward coronary flow.With the development of PCI treatment technology,the vascular reconstruction of STEMI has made great progress.However,after the opening of infarction-related artery,myocardial tissue reperfusion is not complete or even non-reperfusion,i.e.myocardial ischemia-reperfusion injury(IRI),which can greatly increase the risk of complications such as myocardial damage,ventricular remodeling and heart failure,thereby weakening the clinical benefits of PCI and making myocardial perfusion possible.The effect of injection is greatly reduced,which seriously affects the prognosis of patients.Reperfusion injury has become the main adverse event after PCI.It has a high incidence in patients with acute myocardial infarction(AMI),and its mechanism is extremely complex.So far,there is no complete cure plan.At present,the treatment of myocardial reperfusion injury in patients with acute myocardial infarction-percutaneous coronary intervention(AMI-PCI)mostly adopts drug/mechanical therapy after vascular opening,which belongs to remedial therapy.How to intervene with drugs before opening IRA and restoring anterior coronary blood flow,so as to make the myocardial tissue of infarcted myocardium adapt to the regulation of reperfusion,and effectively reduce the myocardial injury after opening IRA,has become an urgent problem in clinical work.Rosuvastatin,as a new long-acting drug in the statin family,has attracted more and more attention due to its independence from lipid regulation.In recent years,the protection of myocardial reperfusion and cardiac function in patients undergoing PCI has also attracted the attention of scholars at home and abroad.Previous basic and clinical studies conducted by our center have confirmed that rosuvastatin can benefit patients with AMI during the peri-PCI period.We further assume that most patients with sudden AMI have no previous oral history of statins.For these patients,whether increasing the dosage of rosuvastatin,taking oral dosage immediately before operation and continuing administration after operation will effectively reduce the risk of IRI,increase the possibility of short-term benefit,whether the medium-term and long-term benefit is dose-dependent and increase the risk of adverse reactions? There is no definite conclusion.By studying the mechanism of no-reflow,some scholars believe that vasoconstriction is the most important and reversible factor.Clinical and basic studies have shown that diltiazem,a calcium antagonist,can attenuate coronary spasm and effectively reverse the no-reflow phenomenon in patients with AMI undergoing direct PCI.However,at present,the administration of diltiazem mainly focuses on intravenous administration and intraoperative administration of diltiazem at the coronary orifice,while there are few studies on other administration routes.In this study,an improved coronary drug delivery scheme was proposed,which can make the drug reach the distal end of the culprit’s blood vessel sufficiently and play a more powerful role,so as to reduce the risk of IRI,improve the microcirculation blood supply of the distal end and increase the benefit of patients.Diltiazem has side effects such as slowing heart rate and lowering blood pressure,and its clinical application is limited.Therefore,it has become a new subject to find a safe drug regimen that can not only fully exert the positive effect of diltiazem,improve the myocardial perfusion level and cardiac function,but also effectively reduce its negative effect.The purpose of this study was to explore the different administration schemes and routes of rosuvastatin and diltiazem in the direct PCI treatment of AMI patients,as well as the combination regimen,with a view to establishing a more complete treatment regimen,taking into account the short-term and long-term benefits of patients,minimizing the risk of reperfusion injury,inhibiting ventricular remodeling,improving cardiac function and changing "downstream remediation".Treatment is "upstream preventive treatment".This series of studies is divided into three parts,all of which focus on patients with acute STEMI who are treated with direct PCI.The first part explores the preventive effect of different doses of rosuvastatin on no-reflow after PCI,the protective effect of myocardial reperfusion and cardiac function,and its dose-effect relationship.The second part is to compare the effects of diltiazem on myocardial reperfusion injury during direct PCI.The third part compares the effects of combination therapy and single therapy on myocardial reperfusion injury and cardiac function in direct PCI treatment on the basis of the first and second part of the optimal scheme,in order to maximize the effectiveness of "strong-strong combination".Part one Effects of different doses of rosuvastatin on myocardial reperfusion and cardiac function in patients with acute STEMI undergoing direct PCIObjective:To investigate the protective effect of rosuvastatin on myocardial reperfusion and cardiac function in patients with acute STEMI without previous oral history of statins before and after PCI.Methods:According to the principles of prospective,randomized and controlled,patients with primary acute STEMI who underwent direct PCI within 12 hours of onset were selected.All patients were randomly divided into two groups at a ratio of 1:1:Routine dose group(n=30):patients were given 10 mg of rosuvastatin as early as possible after admission,and continued to take 10 mg of rosuvastatin once a day for a long time after operation;high dose group(n=30):patients were given 20 mg of rosuvastatin as early as possible after admission,and continued to take 20 mg of rosuvastatin once a day,12 mg of rosuvastatin after operation.After a week,the reduction was changed to 10 mg of rosuvastatin once a day for a long time.The baseline clinical data of the two groups were observed;the changes of CK-MB and cTnT markers of myocardial injury before and 24 hours after operation were compared between the two groups;the changes of serum biomarkers CT-1 and BNP before,24 hours after operation,1 week and 4 weeks after operation were compared between the two groups;the TIMI blood flow grading and TMPG grading before and after operation were measured,and the electrocardiogram(90 minutes after operation)was performed.STR was used to indirectly evaluate myocardial reperfusion after coronary artery recanalization;Simpson’s echocardiography(LVEDD,LVEF)was used to evaluate ventricular remodeling and cardiac function changes in the two groups on the day,4 weeks and 12 weeks after operation;major adverse cardiac events(MACEs)during follow-up within 6 months after operation were recorded as the main endpoint events.Other adverse reactions.SPSS 17.0 statistical software was used for data statistics,and the P value of both sides was less than 0.05.The difference was statistically significant.Result:In order to ensure the authenticity and objectivity of the results,there were no statistical differences in general clinical data,basic medication,preoperative routine examination,infarction-related data and PCI treatment-related indicators between the two groups.There was no significant difference in the percentage of TIMI grade 3(76.67% vs 86.67%,P=0.317),TMPG grade 3(80% vs 83.33%,P=0.739)and STR recovery rate(80% vs 86.67%,P=0.488)between the routine dose group and the high dose group after PCI.There was no significant difference in CK-MB,cTnT,CT-1 and BNP levels between the two groups before and 24 hours after operation.CT-1(252.44±26.39 vs 140.46±18.82,P<0.001)and BNP(422.15±17.64 vs 326.79±21.25,P<0.001)levels detected one week after operation and CT-1(181.67±20.13 vs 62.05±14.73,P<0.001)and BNP(128.91±18.61 vs 72.17±17.66,P<0.001)levels detected four weeks after operation were significantly lower in the high dose group than in the conventional dose group,with statistical difference.There was no statistical difference in the echocardiographic parameters measured on the day after PCI between the two groups.Compared with the LVEDD(5.27 ± 0.24 cm vs 4.45 ± 0.23 cm,P<0.001)and LVEF(55.22 ± 3.76% vs 58.01 ± 4.05%,P=0.007)measured at 4 weeks after PCI and 12 weeks after PCI,the LVEDD(5.31 ± 0.34 cm vs 4.47 ± 0.25 cm,P<0.001)and LVEF(61.31 ± 3.16% vs 67.27 ± 3.03%,P<0.001)in the high dose group were significantly lower and the LVEF was significantly higher than that in the conventional dose group.There was no significant difference in the incidence of MACEs and adverse reactions between the two groups within 6 months after PCI.Conclusion:For patients with acute STEMI treated by direct PCI without previous oral history of statins,rosuvastatin was administered orally and continuously after operation.This study confirms that:1.It can effectively reduce the risk of IRI,improve cardiac function and increase the long-term benefits of patients.The improvement of high dose regimen is more obvious than that of conventional dose regimen,which confirms that its application is dose-dependent.2.Compared with the conventional dose regimen,the short-term benefit of patients is not as much improved as the long-term benefit.Considering that patients did not use statins in the past,they only took them once before operation,which led to the end of the operation,and the drug did not reach the peak blood concentration,so it did not play an effective role in the operation.3.The results showed that the high-dose regimen did not significantly increase the risk of adverse reactions and had good safety.Part two The efficacy of diltiazem on myocardial reperfusion injury in patients with acute STEMI treated by direct PCI through different routes of administrationObjective:To compare the protective effects of diltiazem on myocardial reperfusion injury and cardiac function in patients with acute STEMI treated by direct PCI,and to explore the safety of diltiazem.Methods:According to the principles of prospective,randomized and controlled,patients with STEMI who underwent direct PCI within 12 hours of onset were selected.All patients were randomly divided into three groups at the ratio of 1:1:1.Group A(n=30):Diltiazem was given intravenous micro-pump(3-5 ug/kg/min)according to the actual blood pressure and heart rate of patients before operation.Normal saline was injected into the coronary artery before the opening of infarction-related artery(IRA)(After the guide wire passes through the infarct site of the culprit’s blood vessel,the coronary artery has forward blood flow before balloon dilation.Same below)and diltiazem was continuously pumped into the coronary artery(3-5 ug/kg/min)for 24-36 hours.Group B(n = 30):Before IRA was opened,diltiazem was prophylactically injected from the coronary artery orifice to the coronary artery by pellet administration with a guided catheter,500 mg to 2 mg at a time.Group C(n=30):Diltiazem was given by intravenous micropump(3-5 ug/kg/min)according to the actual blood pressure and heart rate of patients before operation.After IRA was opened and the lead wire passed through the infarct site of the culprit’s blood vessel,before balloon dilatation,when the coronary artery had forward blood flow,the distal break of the balloon was injected with diltiazem,and the drug was given by pellet,500 ughs to 2 mg at a time,then diltiazem was injected.Continuous intravenous pump(3-5 ug/kg/min)was administered for 24-36 hours.After PCI,TIMI blood flow grading and corrected CTFC were recorded according to the results of angiography,and ECG(90 min STR)was performed to evaluate myocardial reperfusion after coronary artery recanalization.Myocardial microcirculation function was evaluated by immediate myocardial coronary flow reserve fraction(FFR);intraoperative systolic blood pressure(SBP),diastolic blood pressure(DBP),mean arterial pressure(MBP)and heart rate(HR)were measured by invasive pressure catheter to evaluate the safety of diltiazem in different administration routes;ventricular function was evaluated by LVEF one week after operation;After 24 hours,hs-cTnI,hs-CRP,MPV,WBC and neutrophil counts indirectly evaluated the severity of myocardial ischemiareperfusion injury.The main endpoints were the occurrence of MACEs during hospitalization and 6 months after discharge.SPSS 17.0 statistical software was used for data statistics,and the P value of both sides was less than 0.05.The difference was statistically significant.Results:The baseline clinical data of the three groups were comparable without statistical difference.After PCI,the proportion of TIMI blood flow grading to grade 3 was higher in group C than that in group A or group B(76.7% vs 83.3% vs 90%,P(C/A)=0.116,P(C/B)=0.448),but there was no statistical difference;CTFC in group C was significantly lower than that in group A or group B(29.5±3.8 vs 28.4±3.6 vs 24.9±2.8,P(C/A)<0.001,P(C/B)<0.001),with statistical difference.The mean FFR of the three groups was higher than 0.75 immediately after PCI,and the difference was significant in group C compared with group A or group B(0.79 vs 0.84 vs 0.91,P(C/A)<0.001,P(C/B)<0.001).The percentage of complete STR at 90 minutes after operation showed the highest trend in group C(76.7% vs 80% vs 90%,P(C/A)=0.116,P(C/B)=0.278),but did not reach the statistical difference.Compared with group A or B,group C had the lowest hs-cTnI(61.2±20.1 vs 58.3±15.3 vs 50.1±14.5,P(C/A)=0.019,P(C/B)=0.041),inflammatory factors(hs-CRP(27.4±8.2 vs 24.5±5.5 vs 21.3±6.8,P(C/A)=0.003,P(C/B)=0.048),white blood cell count(11.8±3.2 vs 10.4±3.1 vs 8.7±3.2,P(C/A)<0.001,P(C/B)=0.044),percentage of neutrophils(75.8% vs 71.5% vs 62.9%,P(C/A)<0.001,P(C/B)=0.016)and MPV(11.2±1.7 vs 10.5±0.9 vs 9.1±1.1,P(C/A)<0.001,P(C/B)<0.001),and the highest LVEF(51.2±3.2 vs 54.8±4.1 vs 58.5±3.6,P(C/A)<0.001,P(C/B)=0.001)one week after PCI.Compared with the corresponding data of A or B groups,there were statistical differences.There was no significant difference in intracoronary pressure and heart rate between the three groups before and after diltiazem administration.There was no significant difference in the incidence of MACEs and adverse reactions between the three groups during hospitalization and 6 months after discharge.Conclusion:1.Compared with the other two drug regimens,the improved distal injection of diltiazem can significantly improve the myocardial microcirculation and alleviate myocardial ischemia-reperfusion injury in patients after PCI.2.Diltiazem was used in perioperative period of PCI.The improvedregimen had stronger inhibitory effect on inflammatory factors.Echocardiogram after PCI showed that the protective effect of Diltiazem on cardiac function was more obvious.3.There were no significant or fatal adverse reactions such as hypotension,bradycardia,atrioventricular block,heart failure and so on.According to this,although the negative muscle strength,negative frequency and negative conduction of diltiazem have some concerns in its application,the adverse reactions can be effectively controlled as long as the dosage,method of use,timing of administration and proper application of diltiazem are accurately grasped.Part three Study on myocardial protection of high-dose rosuvastatin combined with diltiazem in patients with acute STEMI undergoing direct PCIObjective:To study the protective effect of combined administration of rosuvastatin and diltiazem on myocardial reperfusion injury and cardiac function in patients with acute STEMI treated by direct PCI,and to evaluate the safety of combined administration of rosuvastatin and diltiazem.Methods:According to the principles of prospective,randomized and controlled,patients with primary acute STEMI who underwent direct PCI within 12 hours of onset were selected.All patients were randomly divided into two groups in a ratio of 1:1:single drug group(n=30):patients were given 10 mg rosuvastatin as early as possible after admission,and continued to take 10 mg rosuvastatin once a day for a long time after operation;patients in the combined drug group(n=30):patients were given 20 mg rosuvastatin as early as possible after admission,and continued to take 20 mg rosuvastatin once a day after operation.After 12 consecutive weeks,the dosage of rosuvastatin was reduced by 10 mg and was taken orally for a long time.Diltiazem was administered by intravenous micro-pump(3-5 ug/kg/min)according to the actual blood pressure of the patients before operation.After IRA was opened,diltiazem was injected into the distal end of the balloon through the infarction lesion to the distal end of the blood vessel.Diltiazem was injected into the distal end of the balloon by pellet,500 ughs to 2 mg in total at a time,and then diltiazem was continuously pumped into the vein(3-5 ug/kg/min)for 24-36 hours.After PCI,the TIMI blood flow grading and corrected CTFC were recorded according to the angiographic results,and the cardiogram(90 min STR)was performed to evaluate the myocardial reperfusion after coronary artery recanalization;SBP,DBP,MBP and HR were measured by invasive pressure catheter during the operation to evaluate the safety of medication;CK-MB and hs-cTnI were detected before and 24 hours after operation,and indirectly to evaluate the heart.Myocardial injury degree;N-terminal B-type natriuretic peptide(NT-proBNP),matrix metalloproteinase-9(MMP-9)and hs-CRP were detected before and 24 hours,1 week and 4 weeks after operation to indirectly evaluate ventricular remodeling;LVEF was measured on the day,4 weeks and 12 weeks after operation to evaluate the changes of cardiac function;the occurrence of major adverse cardiac events(MACEs)during the follow-up of 6 months after operation was recorded as the occurrence of cardiac adverse events(MACEs).Main endpoint events;other adverse reactions were recorded in all patients.SPSS 17.0 statistical software was used for data statistics,and the P value of both sides was less than 0.05.The difference was statistically significant.Results:The baseline clinical data of the two groups were comparable,and there was no statistical difference.After PCI,CTFC in the combined drug group was significantly lower than that in the single drug group(29.71±3.21 vs 23.83±2.42,P<0.001),with statistical difference.The proportion of TIMI blood flow grading to grade 3(76.67% vs 93.33%,P=0.071)and the proportion of complete STR in 90 minutes after PCI(83.33% vs 93.33%,P=0.129)in the combined drug group were higher than that in the single drug group,but there was no statistical difference.There was no significant difference in CK-MB and hs-cTnI levels between the two groups before operation.The levels of CK-MB(198.49 ± 11.17 vs 169.46 ± 9.86,P<0.001)and hs-cTnI(62.25 ± 0.76 vs 49.83 ± 0.59,P<0.001)in the combined drug group 24 hours after operation were significantly lower than those in the single drug group,reaching statistical difference.The levels of hs-CRP(25.47±8.21 vs 20.54±5.72,P=0.009),NT-proBNP(2145.46±212.62 vs 1583.55±189.47,P<0.001)and MMP-9(480.05±89.23 vs 389.32±54.63,P<0.001)detected before operation had no difference between the two groups;hs-CRP,NT-proBNP,MMP-9 detected 24 hours after operation;hs-CRP(16.95±2.21 vs 11.76±1.88,P<0.001),NT-proBNP(1538.58±254.84 vs 658.58±221.92,P<0.001),MMP-9(372.65±23.78 vs 293.45±19.88,P<0.001)detected one week after operation,and hs-CRP(12.51±1.63 vs 7.72±0.58,P<0.001),NT-proBNP(1278.49±189.62 vs 512.17±147.61,P<0.001),MMP-9(259.32±14.56 vs 176.35±12.36,P<0.001)detected 4 weeks after operation had significant decreases in the combined drug group,with statistical differences.There was no difference in the measured LVEF between the two groups on the day after PCI.Compared with the measured LVEF at 4 weeks after PCI(55.13±1.85 vs 59.64±2.17,P<0.001)and 12 weeks after PCI(62.84±2.29 vs 68.85±3.21,P<0.001),there was a significant increase in the combined drug group compared with the single drug group.There was no significant difference between the two groups in measuring intracoronary pressure and heart rate by invasive pressure guide wire before and after diltiazem administration.There was no significant difference in the incidence of MACEs and adverse reactions between the two groups during hospitalization and 6 months after discharge.Conclusion:1.Compared with single drug regimen,combined drug regimen can make drugs enter coronary microcirculation more quickly,reduce the risk of IRI,achieve effective reperfusion,and improve the short-term benefits of patients.2.Compared with single drug regimen,combined drug regimen caneffectively inhibit inflammatory factors,protect myocardium,inhibit ventricular remodeling,improve cardiac function,and make the long-term benefits of patients more obvious.3.The combination regimen did not significantly increase the risk of adverse reactions,and had good safety. |
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