| To reopen the infarction related artery(IRA) has become the first choice in the treatment of acute myocardial infarction. Although percutaneous coronary intervention(PCI) has the merits of more rapid and complete repatency of IRA, lower residual stenosis and better prognosis of short-term and long-term compared with thrombolysis. The repantency of epicardial artery does not always indicate the improvement of tissue perfusion. With gradually deepening research on AMI, recent studies showed that the related arteriole and capillary were damaged so seriously correspondingly once coronary artery occluded that disturbance of distal blood flow in microcirculation in ischemia area might still exist after revascularization, which was defined as slow reflow phenomenon(SRP) or no reflow penomenon(NRP) [1,2].Now, reopening the infarction related artery in time with percutanous coronary intervention(PCI) has been an effective and satisfactory therapy for most of AMI patients, but NRP exists in 10~30% patients with AMI after PCI that myocardial tissue hasn't gained complete perfusion, which will surely influence the remodeling process of left ventricle and the incidence of adverse cardiac events. The incidence of in-hospital mortality and reinfarction was 5-10 times increased in patients with NRP as a complication. NRP is also one of the predictor factors of continue ischemia of myocardium, ventricular remodeling and recovery obstacle of heart function. Therefore, to make clear the mechanisim of NRP and choose the best method to prevent and treat NRP after PCI has become a great difficulty, challenge and the study emphasis in the field of coronary intervention. The judgement and defination of NRP in clinical is the premise to prevent and treat it. The evaluation of myocardial tissue perfusion only according to the judgement of TIMI flow grade exists obvious limitation, while TIMI frame counts(TFCs), TIMI myocardial perfusion grading(TMPG) and coronary Doppler flow wire could reflect objectively the level of myocardial tissue perfusion, which might be a simple and feasible method to evaluate the cardiac tissue perfusion. How to quickly and completely recovery the myocardial perfusion when NRP happened is a difficult problem puzzled the interventional cardiologists. The effect of treatment on NRP was not satisfied because NRP may be the result of interaction of many factors, the mechanism of which is complex and unclear. Because of many side effects on pressure decrease and bradycardia, such medicines as diltiazem, adenosine, nitroprusside can't gain satisfactory effects, Therefore, seeking for a ideal medicine to improve NRP has become an important subject of the interventional cardiologists.Anisodamine(Ani) is an alkaloid extracted from nightshade henbane in China. Being an M-choline receptor blocker, Ani can not only increase coronary perfusion pressure, improve microcirculation, inhibit thrombus formation, but also show obvious effect and safety on shock with large dose of it. The purpose of this study is that base on the establishing of NRP model with AMI in York swines, the changes of TMPG, TFCs, coronary flow velocity, hemodynamics and the effect on myocardial infarction size were observed and monitored after intracoronary administration of Ani and compared with that of adenosine in this study. As a result, it will offer experimental foundation for clinical application to prevent and treat NRP. On the other hand, the aim of clinical study is to explore the clinical effect, safety and feasibility of combining intracoronary administration of medicines (anisodamine and tirofiban) with different mechanisms. Finally, the safety and feasibility of Ani in treatment of NRP after PCI via observing the effect on NRP judged by myocardial blush grade(MBG) and the influence on ventricular function and ventricular systolic synchrony after intracoronary administration of Ani were studied. The study is comprised of four parts described as follows:Part I: The animal model establishment of no-reflow phenomenon in acute myocardial infarction swine via intracoronary injection of microsphere and blood suspensionObjective: The swine models of NRP were established by injecting polyethylene microspheres and blood suspension(PMBS) into LAD after superselecting LAD with 4F catheter to explore the feasibility of establishing NRP model by injecting PMBS with 4F microcatheter technique .Methods: Total of 16 York swines (4±1 months) were included in this study. Left and right coronary angiography were performed by 4F microcatheter technique, and PMBS was injected intermittently into the sueprselected LAD. The coronary blood flow and the level of myocardial tissues perfusion were quantitatively evaluated by TIMI frame counts (TFC) TMPG and coronary Doppler flow wire. The model of NRP after AMI was considered as success when TIMI blood flow is less than grade 2 or TFC more than 36.2 counts or TMPG less than grade 1. Left ventriculography was performed with 4F Pigtail and left ventricular systolic, diastolic pressure and LV±dp/dtmax were recorded with hemodynamics monitor systems. Pulmonary capillary wedge pressure (PCWP) were measured with 5F Swan-Ganz floating catheter, and cardiac output(CO) was measured by thermodilution method. At the same time ECG and blood pressure(BP) were monitored, CK-MB, TnI and blood gas analysis were performed in all swines at 5, 60, 120, 180min. 4% thioflavin-S 1mL/kg was injected into ventricle 3 hours after NRP, so that the reperfusion area and no reperfusion area can be differentiated by being dyed or not. The percentage of no reflow area in left ventricle was measured. Ischemic region, normal region and borderline were scissored respectively, the size of which was 0.3cm×0.3cm, and 6 pieces of myocardial tissues were sent to check for pathology, then myocardial tissues were sliced and put in triphenyltetrazolium chloride( pH7.4, 37℃) for 15 minutes to differentiate the necrotic and non-necrotic myocardium. The percentage of no reflow myocardial area and necrotic myocardial area in left ventricle were calculated respectively.Results: (1) According to the standards of NRP, 12 animals achieved the criteria of NRP model after AMI successfully, success rate of model establishing was 75%(12/16), average times of injection of PMBS were 3.4±0.5. (2) When the model of NRP was established, instant ECG showed that ST segment elevated and formed single-direction curve with high T wave, and R wave was gradually depressed. Changes of intracoronary ECG were similar to the surface ECG. The intraventricular conduction block with widened R wave occurred in 1 model. (3) cTnI and CK-MB were increased significantly after NRP models were successfully established [(cTnI 117.29±28.46 ng/ml vs 14.87±4.52 ng/ml), (CK-MB 162.24±32.68ng/ml vs 17.82±4.53ng/ml)]. (4) PaO2 and PaCO2 were decreased slightly after establishment of NRP model (PaO2: 76.3±5.8mmHg vs. 85.1±4.7mmHg, PaCO2: 33.2±2.6mmHg vs. 41.7±3.9mmHg). (5) PCWP and LVEDP were increased with statistical significance at instant, 30, 60, 120, 180min after NRP with AMI, (Pall<0.05). LVSP, maximal speed of upgrading intraventricular pressure(+dp/dtmax) in systole and maximal speed of descending intraventricular pressure(-dp/dtmax) in diastole were decreased after successful establishment of NRP model, which reached the lowest value at 1 hour after NRP(LVSP: 113.0±14.2 vs. 132.5±10.8; +dp/dtmax 2374±142 vs 2676±283 mmHg/s; -dp/dtmax:2052±163 vs. 2283±367mmHg/s, P all< 0.05). Heart rate was increased slightly when the PMBS was firstly injected into LAD, but decreased when NRP happened (114±15 vs. 132±16bpm) (P<0.05). CSP and CDP was significantly decreased from 138.6±11.4/ 94.8±12.8 mmHg to 113.0±14.2/77.8±9.7 mmHg (P<0.05) after successful establishment of NRP model. (6) The average peak velocity(APV) was decreased while the ratio of diastolic and systolic peak velocity(DSVR)of coronay was slightly increased, before the use of adenosine compared with that of the normal coronary(15.3±1.8 vs. 23.4±2.2;1.72±0.14 vs. 1.68±0.16, P>0.05); after use of adenosine post NR, APV and DSVR were increased obviously compared with that without use of adenosine(23.3±2.7 vs. 15.3±1.8, P<0.001; 1.84±0.16 vs. 1.72±0.14, P<0.05), but still lower than that after use adenosine in normal coronary(23.3±2.7 vs. 56.3±3.4, P <0.001). CFR of coronary with NRP was obvious lower than that of normal coronary (1.52±0.18 vs. 2.41±0.32, P<0.001). (7)Pathological examination showed that myocardium fiber swelling, sarcolysis, reticular formation and local liquefaction necrosis occurred. The percentage of no reflow area of myocardium to the left ventricle area was (52.6±5.3)%. The percentage of necrotic area of myocardium to the left ventricle area was (28.4±6.2)%. Conclusions: With 4F catheter-based skills and sequential injection of PMBS by superselecting LAD under CAG, the model of NRP with AMI could be established in swines whose heart anatomy and characteristics of coronary artery were more similar to that of human being. This model had advantages of direct-viewing, simplicity, repeatitiveness, mild trauma, closed chest, high achievement rate and more similar to NRP after PCI compared with that made by other methods such as coronary ligation. It might provide better experimental animal model for the reseach on microcirculation disturbance after AMI.Part II: Comparative study between the influence of intracoronary administration of different doses of anisodamine and adenosine on no reflow phenomenon in swinesObjective: To investigate the effect of intracoronary administration different doses of anisodamine on NRP with adenosine as positive contrast by observing the changes of TMPG, TFCs, coronary flow velocity and evalue its influence on heart function and hemodynamics.Methods: Total of 30 york swines (4±1months old ) were included in this study, 24 York swines with stable NRP were randmized into saline group(n=6), anisodamine group(n=9) and adenosine group(n=9). Left and right coronary angiography was performed by 4F angiography catheter to observe the distribution and shape of coronary artery. After the NRP models were established, saline 4ml, Ani 2000μg/4ml, Adenosine 24μg/4ml were injected into LAD three times at 5 minutes interval in the three groups respectively, and coronary flow velocity was quantitatively measured by TFCs, TMPG and coronary Doppler flow wire. PCWP was monitored with 5F Swan-Ganz floating catheter and CO was measured with thermodilution method. 4F pigtail was inserted into left ventricular via femoral artery to perform left ventriculography and the left ventricular end diastolic pressure(LVEDP), the left ventricular systolic pressure (LVSP), maximal ascending speed of intraventricular pressure(+dp/dtmax) and maximal descending speed of intraventricular pressure (-dp/dtmax) were measured instant, 5, 10 minutes after injection of saline, anisodamine or adenosine respectively. The ECG was recordered and analyzed.Results: (1)TFCs were significantly decreased after intracoronary administration of adenosine at different time compared with that of baseline and saline group (P<0.05). While TFCs were decreased by 52.76%,64.73%,63.35% instant, 5,10min after administration of anisodamine and coronary blood flow reached TIMI 2+-3 grade (P<0.05). Anisodamine had better effect on NRP than adenosine did, but there was no statistical significance. (2) The coronary average peak velocity(APV) and the ratio of diastolic and systolic peak velocity were significantly increased after intracoronary administration of 6000ug anisodamine compared with that of baseline and saline group(P<0.05), but had no significance compared with that of adenosine group (P>0.05).(3)Blood pressure, mean coronary pressure and heart rate were significantly increased after administration of Anisodamine compared with that of baseline, saline group and adenosine group(P<0.05). PCWP and LVEDP were significantly decreased while CO was significantly increased after administration of anisodamine or adenosine compared with that of baseline and saline group (P<0.01), and anisodamine had longer time of effect on hemodynamics than adenosine did.(4)LVSP, and±dp/dtmax were increased significantly in anisodamine group and adenosine group after intracoronary administration medicines compared with that of baseline and saline group (P<0.05); LVSP was increased more in anisodamine group than that of adenosine group. The value of CO and–dp/dtmax were higher in anisodamine group than that in the adenosine group 10 minutes after administration of medicine(P<0.05).±dp/dtmax were increased and LVEDP was decreased after administration of Ani compared with that saline group(P<0.05), and the descending degree of LVEDP in Ani group was more than Ade group(P<0.05). (5)ΣST was decreased significantly in anisodamine group and adenosine group after administration of medicine compared with that of baseline and saline group.ΣST was decreased from 26.3±2.8mm to 6.1±0.9mm in anisodamine group(P<0.01).The largest ST fallback rate in anisodamine group was 78.3%, which has no significance compared with that in adenosine group, whose largest ST fallack rate was 75.6%,(P>0.05). Though heart rate was increased significantly after administration of Ani, no malignant arrhythmia occurred. (6)The percentage of no reflow area to the LV area were (54.7±7.2) %,(32.4±5.7)% and (30.9±5.2)% in saline, Ade and Ani group respectively, and the necrosis area to the LV area were (36.4±6.2), (23.6±3.7)% and (21.4±3.3)% in saline, Ade and Ani group respectively,which had statistical significance in Ani and Ade group compared with that of saline group(P<0.01), but no statistical significance between that of Ani group and Ade group(P>0.05). (7)At 5 minutes after intracoronary administration of anisodamine, MCP and HR were not found obvious change among that of the dose of 2000μg, 4000μg or 6000μg, TFC or TMPG had no significant difference between that of 4000μg and 2000μg or between that of 6000μg and 4000μg, but had significant difference between that of 6000μg and 2000μg.Conclusions: 1. TFCs were significantly decreased and TMP was improved after intracoronary of Ani, which indicated that anisodaminecould reverse NRP after AMI at a certain extent. 2. Ani improved the myocardial perfusion,at the same time, improved hemodynamics and heart function such as MCP,±dp/dtmax, LVEDP and CO. 3. Increasing of myocardial microcirculation perfusion accompanied with the decrease in no reflow area induced decrease of miniature myocardium infarction after intracoronary administration of Ani, which could decrease the whole infarct area of myocardium. 4. With the dose increasing of anisodamine(from 2000μg to 6000μg), the myocardium perfusion and coronary flow were improved further, but MCP or HR was not found increasing correspondingly with the dose increasing.Part III: Effect, safety and feasibility of intracoronary combining administration of anisodamine and tirofiban on"no reflow"phenomenon following PCI in patients with AMIObjective: To evaluate the feasibility, safety and clinical effect of intracoronary combining administration of anisodamine and tirofiban on the reversing no-reflow phenomenon post percutaneous coronary intervention in acute myocardial infartion patients.Methods: Forty seven patients (male 38,female 9,age 63.6±11.7yrs) who had suffered from no-reflow phenomenon post-PCI out of 252 patients that admitted in our department for AMI and performed PCI from March, 2004 to August, 2006 were enrolled in this study and randomized into two groups: Group A (Tirofiban Group, 23 cases, male 18,female 5, mean age 62.8±12.4yrs) and Group B(Combining use of anisodamine and tirofiban Group, 24 cases,male 20,female 4,age 64.1±11.6yrs).Tirofiban 10ug/kg was injected into IRA after being diluted, and 0.075ug.kg-1.min-1 continuously pumped for 48 hours in group A, the treatment of patients in group B was same to that of group A except that anisodamine 1500ug was injected into IRA after the intracoronary injection of tirofiban. The TMPG, the TIMI flow frame counts were analyzed 1,3,10 minutes after intracoronary administration of tirofiban with or without anisodamine; The changes of invasive intracoronary pressure, heart rate, LVEDP, PCWP were monitored by PC Scout Monitor 90309 via guiding catheter, pigtail, or Swan-Ganz catheter and recorded.The platelet aggregation rate and myocardial enzyme were measured. Echo cardiogram were performed 1 week and 6 months after PCI to measure the wall motion index(WMI), left ventricle ejection fraction(LVEF), cardiac index(CI), stroke volume index (SVI), LVEDV and LVESV to evaluate the changes of heart function. Side effects of the medicines and main adverse cardiac events(MACE) during in-hospital and 6 months'follow-up were recorded.Results: 1. There was no significant difference between the two groups in age, percentage of male, patients with hypertention, hyperlipidemia or diabetes, percentage of smoking, time from onset to balloon, pre-infarctional angina, number of lesion vessles, distribution of IRA, peak value of CK and Killip's classification of heart function(P >0.05). 2. TFC was decreased by 66.8%,68.7% and 67.0% from 85.24±11.52 at baseline to 28.33±5.39, 26.72±4.34 and 28.14±5.35 at 1,3 and 10 minutes after intracoronary administration of tirofiban respectively(P all<0.001) accompanied with the TMPG being increased from grade 1.34±0.32 to grade 2.61±0.27, while TFC was decreased by 72.1 %,74.3 % and 71.3 % from 86.45±12.32 to 24.16±5. 32, 22.23±5.21 and 24.78±4.92 1,3 and 10 minutes after intracoronary administration of tirofiban and anisodamine respectively(P all < 0.001), accompanied with the TMPG being increased from grade 1.17±0.34 to grade 2.88±0.23, which had statistic significance between the two groups (P=0.036). 3. No significant change happened in the invasive intracoronary pressure, heart rate, LVEDP and PCWP in Group A, while the intracoronary pressure, heart rate were increased significantly in Group B (P<0.05); LVEDP as well as PCWP was decreased in group B, but no significance compared with that in group A. 4. The fallback rate of ST was better in group B than that in group A (91±8)% vs. (87±11)%(P=0.002), and the time to the largest fallback of ST segment was shorter in group B than that in Group A(6.7±2.6 min vs. 10.3±3.2 min, P=0.0001). 5 The parameters of heart function 6 months after PCI were obviously improved than that 1 week after PCI in both of the two groups, the WMSI, LVESV and LVEDV were decreased (1.18±0.14 vs. 1.43±0.24, 62±11ml vs. 82±14ml and 135±16ml vs. 146±21ml in group B and 1.28±0.18 vs. 1.46±0.31,68±14 vs. 84±17 and 146±18 vs.155±23 in group A, (P all< 0.05); while LVEF,CI and SVI were increased 55.4±5.2% vs. 43.8±5.2%, 3.76±0.52 L/min.m2 vs. 2.41±0.38 L/min.m2 and 54.7±8.4ml/m2 vs. 40.3±6.8 ml/m2 in group B and 52.7±5.6 vs. 42.5±4.6,3.58±0.43vs. 2.38±0.42 and 52.8±8.2 vs. 39.7±7.2 in group A, (P all<0.001).The WMSI, LVEF and LVEDV was better in group B than that in group A 6 months after PCI (1.18±0.14 vs1.28±0.18, 55.4±5.2 vs 52.7±5.6 and 135±16 vs 146±18), P<0.05. 6 There was no malignant arrhythmia(ventricular tachycardia, ventricular fibrillation and no urine retention or allergic reaction happened after intracoronary administration of anisodamine except sinus tachycardia happened in two patients. There was no contrast stagnant in the coronary artery after intracoronary administration of tirofiban. No serious bleeding complication happened except bleeding at the site of puncture and being ceased after repression and bandage in one patient during the pumping of tirofiban. There was no main adverse cardiac events such as death, reinfarction, revascularization of target vessle and angina happened during in-hospital and 6 months'follow-up.Conclusions: Intracoronary administration of anisodamine and tirofiban can further improve the coronary flow of IRA suffered from NRP in AMI patients performed PCI compared with that only administration of tirofiban, which in turn would improve the heart function and decrease the incidence of MACE. Combining intracoronary administration of anisodamine and tirofiban is safe and easy for practicing with definite effect and a good combination of medicines in the treatment of NRP that deserved to be widely applied in the clinical practices.Part IV: The effect of intracoronary administration of anisodamine on heart function and ventricular systolic synchrony in AMI patients with no reflow phenomenon post PCI identified by myocardial blush gradeObjective: To evaluate the influence of intracoronary administration of anisodamine on myocardial blush grade (MBG) and left ventricular regional and global systolic function and synchrony in the acute myocardial infarction(AMI) patients with no-reflow phenomenon post percutaneous coronary intervention (PCI) identified by MBG.Methods: A total of 54 cases patients with no-reflow phenomenon identified by MBG (MBG 0-1) from 258 cases of acute myocardial infarction patients that left anterior descending artery was firstly occluded and performed PCI within 12 hours from onset were randomized into two groups: Group A(male 18 and female 6, mean age 64.23±12.27) and group B (male 20 and female 7, mean age 62.72±11.48).The treatments were same in the two groups except that intracoronary administration of anisodamine 2000μg was only in group A, The left ventriculography (LVG) was performed 30 minutes after PCI to measure the left ventricular volume (LVESV and LVEDV), pressure parameters (LVEDP) and wall motion score(WMS). Equilibrium radionuclide angiography(ERNA) was performed 1 week after PCI to determine the parameters of left ventricular regional, global systolic function and systolic synchrony. Six month after AMI, follow-up LVG and ERNA were performed and all the above mentioned parameters were reinvestigated. During the 6 months follow-up period, all the major adverse cardiac events(MACE) were recorded.Results: The MBG in group A were increased from grade 0.59±0.09 to grade 2.45±0.18 after intracoronary administration of anisodamine 2000μg. Follow-up at 6 months after AMI-PCI, the values of LVESVI, LVEDVI, WMS and LVEDP were significantly decreased in group A compared with that in group B respectively, (40.53±8.12)ml/m2 vs. (50.32±8.26)ml/m2, (80.13±9.74)ml/m2 vs.(87.17±10.25)ml/ m2 , (8.24±1.31) vs.(10. 23±1. 82) , (13.36±4.21)mmHg (1 mm Hg = 0.133kPa) vs. (16.38±3.21)mmHg, P all < 0.05. The values of LVEF, PER, PFR of the ERNA parameters were significantly increased in group A compared with that in group B [(44.02±5.86)% vs. (38.52±5.18) %, (1.86±0.09) EDV/s vs. (1.61±0.09) EDV/s, (2.19±0.32) EDV/s vs. (1.78±0.17) EDV/s, all P<0.05]. (2) The values of LrEF2-LrEF8 in group A were increased by 13.96%, 25.02%,30.36%,22.86%, 27.67%, 22.07% and 18.71% respectively compared with that in group B. (3) Phase analysis showed that the values of PS, FWHM and PSD of left ventricular systolic synchrony parameters were also smaller in group A than those in group B (46.04±8.93)°vs. (53.19±162)°, P<0.05; (23.02±6.27)°vs. (25.02±5.31)°, P>0.05; (7.92±4.12)°vs. (11.76±4.11)°, P<0.05. (4) During the 6 months of follow-up, the incidence rate of main adverse cardiac events(MACE) in group A was much less than that in group B.Conclusions: Intracoronary administration of anisodamine can obviously reverse the no-reflow phenomenon identified by MBG, improve the left ventricular systolic function and synchrony and lower the incidence of MACE in patients with no-reflow phenomenon post AMI-PCI.
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