A Serial Study Of Effect On Myocardial Microcirculation Using Thrombolysis Combined With Anisodamine In Patients With STEMI

The key idea of the treatment of ST-segment elevation myocardial infarction(STEMI)is to shorten the entire time of myocardial ischemia as far as possible.A timely and effective reperfusion treatment is an important approach to reduce mortality in acute phase as well as improve the prognosis in STEMI.At present,intravenous thrombolysis therapy(TT)and primary percutaneous coronary intervention(pPCI)are still the most two strategies of the reperfusion treatment of STEMI.With the development of coronary intervention,the efficacy and safety of pPCI has been fully testified.However,for the insufficient medical resource and limited capacity of STEMI aid teams in China,most patients with STEMI are not effectively treated within 120 minutes through pPCI.Therefore,exploring and improving thrombolysis,the alternative reperfusion strategy which is more feasible and practicable,becomes much momentous in nowadays.Moreover,many infarct related arteries(IRA)of STEMI patients suffered with heavy load of thrombus.High thrombus load not only severely affects the reperfusion of antegrade blood flow and the improvement of the microcirculatory perfusion,but also hinders the process of balloon dilations and stent implantations in PCI.Currently as the foremost solution against the high thrombus load,thrombus aspiration(TA)has the risk of making the thrombus moving to the lower reaches of the coronary system,which may further obstructs microcirculation and deteriorates the myocardial perfusion.As one of the third generation thrombolysis drugs,Prourokinase has been successful developed and applied in clinic.It has many advantages such as high targeting affinity and strong ability of infiltration for thrombosis and therefore a higher rate of opening IRAs.Especially the pharmacological characteristic of disintegrating and dissolving thrombosis can play a role of cleaning and dredging in the entire coronary system from micro to large vessels,which benefit to the protection and improvement for myocardial microcirculation.Therefore it is probably more beneficial to use thrombolysis therapy in STEMI patients particularly in those with high thrombus load.Meanwhile,the new route of directly administrating in coronary gives a better chance to make the drugs effective that can enhance the efficacy of cleaning the thrombus and protecting the structure and performance of microcirculation.All of these are attracting more and more scholars' attention recently.Anisodamine is an unique medicine of China in microcirculatory dilation conditioning.By the means of our over ten years researches about STEMI both in animals and clinic,we have repeatedly proved that intracoronary injecting Anisodamine has excellent haemodynamic and microcirculatory protective effects,as well as good safety and practicability.Besides,several studies of Anisodamine's intracoronary injection with different doses also provide reliable evidences to select an appropriate dose for intracoronary administration.On these basis,it is meaningful to further research its efficiency and usage in clinic.In conclusion,this serial study includes three parts which explored the microcirculatory protecting and improving effects of thrombolysis therapy and the microcirculatory improving drug Anisodamine in the treatment of STEMI: In the first part,we compared advantages in various aspects between the strategies of intravenous thrombolysis combined with early PCI and primary PCI,through these we explored the efficiency and new usage of thrombolysis therapy in STEMI's reperfusion treatment.By studying in the realm of intracoronary thrombolysis,the second part of this dissertation indicated the therapeutic feasibility of intracoronary thrombolysis combined with microcirculatory improving medicine in STEMI patients.It also showed Anisodamine's effect to microcirculatory system.In the third part,through the comparison between the traditional thrombus aspiration and the novel combination of intracoronary thrombolysis and microcirculation improving medicine,it implied the latter one's superiority of antagonizing high thrombus load,and inspired a new approach in the therapy of STEMI.Part One A compared study on influence of myocardial microci-rculation between using early thrombolysis combined with PCI and primary PCI in patients with STEMI: an integrated analysis by CAG,IMR and SPECT investi-gation.Objects: Using index of microcirculatory resistance(IMR),singlephoton emission computed tomography(SPECT)and other methods to comprehensively assess myocardial perfusion level in early thrombolysis combined with PCI and primary PCI patients with STEMI,to explore the protective effect of myocardial microcirculation and efficacy and safety of the method of early thrombolysis combined with PCI in patients with STEMI.Method: STEMI patients who hospitalized into our hospital or cooprative hospital were enrolled this study from Jun 2016 to Dec 2017.These patients were randomly divided into intravenous thrombolysis(TT)group and primary PCI(pPCI)group.TT group firstly use Prourokinase 20mg+30mg iv,then preform CAG and/or PCI in 2-24 hours.The p PCI group followed a standard PCI routine of STEMI.Use the quantitive assessment of coronary blood perfusion,IMR,SPECT and other ways to evaluate the effect of reperfusion of myocardial microcirculation.Meantime,compared markers of myocardial necrosis,left ventricular ejection fraction and change of ECG,a 60-day follow up was aslo lunched to track MACEs and bleeding events.Result: Sixty and nine patients patients were finally enrolled,and distributed to TT group(n=31)and pPCI group(n=38).TT group's Onset-B and FMC-B time was longer than pPCI group[10.0(6.75,13.5)vs 4.5(3.5,6.0)hours;6.0(4.5,9.75)vs 2.0(1.0,3.0)hours,all P <0.001].Though the mean rank comparison we found TT group had much better TIMI flow,TMPG and thrombus grade than pPCI group before PCI(43.55 vs 28.03;44.92 vs 22.91;27.90 vs 40.79 mean rank,all P<0.05).TT groups implanted less stents and used less thrombus treatment than pPCI group(16.1 vs 55.3%,P<0.001;28.56 vs 40.25 mean rank,P= 0.002).When the PCI finished,we found both group's TIMI flow,CTFC,TMPG,IMR were not significantly different.The postprocedural ST-regime recession,myocardial necrosis markers,LVEF and perfusion descending area(PDA)had no significant differences(all P>0.05).The 60 days follow-up indicated that there're no differences of MACEs between two groups.No major bleeding event happened in both group,but the rate of minor bleeding events of TT group was higher than p PCI group(54.4 vs 10.6%,P<0.001).Conclusion: Via comprehensive usage of quantified CAG,SPECT,IMR features it implied the strategy of combined early Prourokinase intravenous thrombolysis and PCI has non-inferiority compared with pPCI in protection of microcirculation and myocardial reperfusion.And it can extend threuputic window of reperfusion,is a safe and reliable method in STEMI patients.Part Two A Study of targeting intracoronary thrombolysis combined With Anisodamine injection: dissolve efficacy of thrombus and protective effect of microcirculation in STEMI patientsObjects: Through the comparison of differences of the microcirculatory situations between targeting thrombolysis and Anisodamine injection,which based on it,during PCI,to explore Anisodamine's protective and ameliorative effect in STEMI patients who suffered a high thrombosis load.Method: STEMI patients with high thrombosis load who hospitalized into our hospital or cooprative hospital and received CAG or primary PCI were enrolled this study from Dec 2016 to Feb 2018.We divided the patients into two groups randomly.One group received targeting intracoronary thrombolysis combined with Anisodamine(TCA),and the other group only received targeting intracoronary thrombolysis(IT),but not include anisodamine injection.We used variety interventional skills such as micro-catheter and child-in-mother catheter to got close to or sTablebed into the thrombosis,then injected recombinant human Prourokinase(Pro-UK)(10-20 mg,20ml)in both group's IRAs to preform the thrombolysis.At the time of thrombolysis start and end,we injected Anisodamine into IRA(4mg,10ml).Then record parameters of blood dynamics,included TIMI flow grades,corrected TIMI frame counts(CTFC),TIMI myocardial perfusion frame counts(TMPFC)and the thrombus grades.We also measured the index of microcirculatory resistance(IMR)after thrombolysis.A re-CAG was proceeded after 7 days,in which we recorded features of blood dynamics again,and performed echocardiography and SPECT myocardial perfusion imaging.A 60 days follow-up of MACEs and bleeding event were also conducted.Result: Sixty and nine patients were finally enrolled and randomly divided into TCA group(n=20)and IT group(n=22).Patients from TCA group and IT group had no significant differences in TIMI flow grade,CTFC,TMPG,TMPFC as well as thrombus grade(all P>0.05).After the thrombolysis,TIMI flows from both group were obviously increased,and more than 75% patients reached TIMI 3 flow grade(75.0%,80.0%).In the assessment of IMR,the result showed TCA group had a lower IMR(29.33±8.56 vs36.47±7.35,P=0.030).In the re-CAG 7 days later,both of two groups showed more improvement of TIMI flow,over 80% patients had gained TIMI 3 flow grade(90.0%,86.1%).CTFC,TMPG and residual thrombus grade also has no significant difference(all P>0.05).ST-regime recession,R-wave reserve and peaks of myocardial necrosis markers did not indicate obviously discrepancy(all P>0.05).However,the SPECT's result showed TCA groups had a smaller myocardial perfusion descended area(14.4±8.5 vs 18.6±5.3%,P=0.046).Follow-up in 60 days did not implied differences in MACEs and bleeding events between two groups.Conclusion: Use Prourokinase to perform the targeting intracoronary thrombolysis could reduce the thrombus load in IRA,recover and improve antegrade flow in STEMI patients.On the basis of this therapy,combined with intracoronary Anisodamine injection is able to reduce resistance of myocardial microcirculation,enhance the level of microcirculatory perfusion.Part Three Contradistinctive study of influences on myocardial microci-rculatory perfusion between targeting intracoronary thrombolysis combined Anisodamine via catheter and thrombus aspiration in patients with STEMIObjective: To compare the microcirculatory perfusion influences between the method of intracoronary injection of new type plasmin(Prourokinase,Pro-UK)combined with Anisodamine and the method of thrombus aspiration in high thrombus burdened STEMI patients.In order to evaluate the effect,safety and feasibility to severy STEMI patients and explore optimizing combination of drugs of STEMI's therpy.Method: STEMI patients who were suffered chest pain within 12 hours and hospitalized into our hospital or cooprative hospital,and received CAG or primary PCI with high thrombosis load(whose thrombus grade?3)were enrolled this study from January 2017 to January 2018.They were randomly divided into the Thrombolysis Combined with Anisodamine(TCA)group and the Thrombus Aspiration(TA)group.The TCA group used targeting intracoronary thrombolysis therapy via catheter(Pro-UK 10-20mg/10ml/ 10min/IC)and Anisodamine(4mg*2/10ml/2-5min/IC).The TA group follows the standard thrombus aspiration process.Electrophysiological and cardiologic features were continuously mornitored during PCI.Quantitatively compared the differences of coronary blood flow features between two groups before and after corresponding therapies.The features included TIMI flow grade,corrected TIMI frame counts(CTFC),TIMI myocardial perfusion grade(TMPFC)and thrombus grade.After thrombolysis process,measured the index of microcirculatory resistance(IMR).Perform CAG again 7 days later,measure and record each coronary blood flow features again.And preformed echocardiography exam to measure the left ventricular ejection fraction(LVEF)as well as the SPECT myocardial perfusion imaging to measure the perfusion descending area(PDA).Then followed up all MACEs events and TIMI bleeding events in 90 days.Result: Thirty-nine patients were enrolled in this study.In the first undergoing CAG/PCI,TIMI grade of TCA group had a significant difference with the TA group(P<0.001)when correspondent therapies were finished.TCA group's patients with TIMI 3 blood flow were significantly higher than those in TA group.(75.0 vs 52.6%,P=0.041).Meanwhile,its CTFC and TMPFC were all less than which in TA group(21.57±10.18 vs 28.59±9.94 frames,P<0.001;119.3±37.5 vs 135.3±42.9frames,P=0.025).TCA group had an obvious ascend of thrombus grade than TA group.Patients from TCA group had a lower IMR score compare with patients from TA group(29.33±8.56 vs 40.47±9.35 U,P<0.001).There's no difference of the rate of stent implatation between two groups.Although according to the 7 days later re-CAG's result,both of two groups had no significant difference in TIMI flow grade and CTFC(all P>0.05),there're more TCA group's patients reached the TMPG 3 grade(90.0% vs 47.4%,P=0.030),and had a lower TMPFC than TA group(99.3±41.5 vs 114.0±48.2,P=0.047).Postprocedural ST-regime recession(STR),R-wave reserve,peak of myocardial necrosis markers and LVEF had no significant difference(all P>0.05).SPECT myocardial perfusion imaging indicated that TCA group had a smaller PDA than TA group(14.4±8.5vs 19.6±3.3%,P=0.041).Postprocedural 90 days' follow-up showed there were no difference of MACEs and bleeding events between two groups(all P>0.05).Conclusion: Comparing with the thrombus aspiration,targeting intracoronary thrombolysis combined with Anisodamine has rapider and safer efficacy of opening IRA and reducing the thrombus grade.It aslo has better effect of microcirculatory protection and improvement.