| Acute myocardial infarction(AMI) is a very common disease of the emergency disease. To reopen the infarction related artery(IRA) has become the key therapy(first choice) in the treatment of acute myocardial infarction. It can restore tissue perfusion rapidly, rescue more myocardium, improve heart function and decrease mortality. In recent years, although IRA of epicardial artery was reopened by thrombolysis or percutanous coronary intervention (PCI), many clinical trials showed that the survival rate did not improve in some patients with AMI. The reason may be that the repatency 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). Now, reopening the infarction related artery in time with percutanous coronary intervention(PCI) is an effective and satisfactory therapy for most of AMI patients. But NRP exists in 10~30% patients with AMI after PCI whose 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 rate of in-hospital mortality and reinfarction were 5-10 times increased in patients with NRP as a complication. With the restoration of blood to ischemic area , myocardium with long-term ischemia was damaged. It was defined as ischemia/reperfusion injury(I/RI). With gradually deepening research on I/RI, the microcirculation injury was the key step in I/RI. In nature, NRP is invalid reperfusion. The microcirculation dysfunction is its nature. The microcirculation dysfunction is also one of the predictor factors of continue ischemia of myocardium, ventricular remodeling and recovery obstacle of heart function. Therefore, to protect the microcirculation function and decrease the I/RI, to elucidate the mechanisim of NRP and choose the best method to prevent and treat NRP after PCI have become a great challenge in the field of coronary intervention.In the past, an assess the coronary stenoses was through coronary angiography .The evaluation of myocardial tissue perfusion only according to the judgement of TIMI flow grade , TIMI frame counts(TFCs) or TIMI myocardial perfusion grading(TMPG) has limitations. The shortcomings of these approaches to assess the physiological significance and microcirculation function of coronary artery have been recognized for decades. With the development of techniques, coronary pressure measurement has emerged over the past few years as a major step forward in the assessment of coronary artery disease. Especially the conception of fractional flow reserve(FFR) was advanced, it has been used to evaluate the function of artery stenoses and interventional therapy. It is the best index to assess the artery stenoses in epicardium because of no influence by heart rate or blood pressure. But it has limitations, microvascular disease may influence it. Coronary flow reserve(CFR) is one of a sensitive indexes to indicate the hemodynamics of coronary artery. It is not only related to the stenoses of artery in epicardium, but also related to the physiological status of the coronary microcirculation. Coronary Doppler flow wire is a correct method to obtain the CFR. But CFR can not distinguish the lesion between epicardial artery and microvascular. So, it can reflect objectively the coronary microcirculation and the level of myocardial tissue perfusion by the intracoronary pressure and Doppler flow assess simultaneously.How to reduce or avoid I/RI and NRP when the myocardial perfusion was quickly and completely recovered is a difficult problem puzzling the interventional cardiologists. The effect of treatment on NRP was not satisfying because I/RI and NRP may be the result of interaction of many factors, the mechanism of which is complex and unclear. Some drugs such as dilthazam, adenosine, nitroprusside have used to treat NRP, but they have side effects of pressure and heart rate. Therefore, seeking for a ideal medicine or method to reduce the I/RI and improve NRP has become an important subject for the interventional cardiologists. Anisodamine is a alkaloid isolated from nightshade henbane in China. Being a M-choline receptor blocker, Anisodamine 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 on the base of establishing acute ischemia-reperfusion injury model and NRP model in York swines, to observe the status of microcirculation in coronary artery, hemodynamics, as well as the effect on myocardial infarction size by the the intracoronary pressure wire and Doppler guidewire assessment simultaneously. At the same time, the effect on the microcirculation and the protection on I/RI were observed after intracoronary administration of Anisodamine in this study. The study is comprised of four parts described as follows:Part I: The study of the myocardial microcirculation function in ischemia reperfusion york swines by intracoronary pressure and Doppler flow assessment simultaneouslyObjective: Minipigs were selected in this study for the similarity to human being in cardiovascular biological features. The swine models of I/RI were established by superselecting left anterior descending artery (LAD) with 6F catheter, dilating balloon to occlude the flow of the coronary and withdrawing the balloon. The characteristics of the myocardial microcirculation in I/RI models were explored by intracoronary pressure wire and Doppler guidewire assess simultaneously.Methods: Total of 8 york swines (4±1 months) were included in this study. 6F catheter were performed in two sides deep femoral approach by Seldinger's puncture. Left and right coronary angiography were performed by 4F micro-catheter technique. LAD was superselected with 6F guiding catheter , then the pressure wire and Doppler guidewire were transferred into coronary respectively through guiding catheter. The pressure and blood flow of the coronary artery were measured with ComboMap System Model 6800. LAD was occluded for 45 minutes by balloon which was chosen according to LAD diameter,and then perfused by withdrawing the balloon.The coronary pressure and flow velocity were recorded simultaneously at baseline, instant,30, 60 minutes after reperfusion. The aortic pressure (Pa),coronary distal pressure (Pd), average peek velocity (APV), microvascular resistance (MR) were obtained at rest and maximal hyperemia induced by intracoronary bolus of 10mg cardoverine. At the same time, fractional flow reserve (FFR) and coronary flow reserve (CFR) were obtained. CK-MB and TnI were measured in all swines at baseline, 30, 60, 120, 180min after reperfusion. Pulmonary capillary wedge pressure (PCWP) was measured by 5F Swan-Ganz floating catheter, and cardiac output(CO) was measured by thermodilution method. Left ventricular systolic pressure (LVSP) and left ventricular end diastolic pressure were monitored continuely with 4F Pigtail. At the same time ,ECG was recorded. The myocardium oxygen consumption was reflected by pressure rate index (PRI).The animals were sacrificed after the trial finished. Ischemic region, normal region and borderline were sectioned respectively and 6 pieces of myocardial tissues were sent to check for pathology.Results: (1) According to the standards of I/RI, 7 animals achieved the I/RI model of AMI successfully, success rate of model establishing was 87.5% (7/8). (2) While the balloon was dilating , instant ECG showed that ST segment elevated and formed single-direction curve with high T wave, after reperfusion, ST segment was gradually depressed. (3) cTnI and CK-MB were increased significantly after I/RI models were successfully established [(cTnI 118.21±27.51 ng/ml vs 13.96±4.42 ng/ml),(CK-MB 164.21±30.78ng/ml vs 16.85±4.52ng/ml)]. (4) The Pa and Pd at rest and hyperemia were decreased significantly at different time after reperfusion, especially at reperfusion instant t[b-Pa(109.3±11.4 vs 89.7±9.5,P<0.05),h-Pa (108.9±11.6 vs 89.4±9.3, P<0.05), b-Pd ( 109.1±10.9 vs 89.2±9.6, P<0.05 ), h-Pd (108.4±11.3 vs 89.3±7.9, P<0.05)]. The change of Pd was the same to Pa. FFR did not change before and after reperfusion(0.99±0.03 vs.0.99±0.04, P>0.05). APVb was increased significantly, it was higher than that of before reperfusion(21.0±2.9 vs.17.3±7.9, P<0.05). b-MR was decreased after reperfusion, it was lower than that of before reperfusion ( 4.77±0.85 vs.7.42±1.65, P<0.01). APVh was lower than that of baseline(40.5±10.1 vs.62.6±12.3, P<0.01), while h-MR was increased significantly(2.51±0.12 vs.2.01±0.31, P<0.05). CFR was lower than that of baseline(1.93±0.35 vs.3.69±0.76, P<0.01). (5) MVO2 was decreased significantly. PCWP and LVEDP were increased significantly at instant, 30 and 60min after I/RI with AMI (P all<0.05). LVSP and CO were decreased after successful establishment of I/RI model. (6) Pathological examination showed the occurrence of myocardium fiber swelling, sarcolysis, reticular formation and local liquefaction necrosis.Conclusion: It is feasible to establish the model of I/RI by superselecting LAD under CAG ,dilating balloon and withdrawing balloon .The model of I/RI could be established in swines whose heart anatomy and characteristics of coronary artery were more similar to human beings. This model had advantages of direct-viewing, simplicity, reproducibility, mild trauma, closed chest and high achievement ratio. At present, it is an advanced, objective, and reliable method to evaluate the microcirculation in ischemia-reperfusion coronary by intracoronary pressure wire and Doppler wire assessment simultaneously. The manifestation of myocardial microcirculation in I/RI model is that : The APVb is increased,b-MR is decreased , APVh is decreased, h-MR is increased, CFR is obviously decreased, myocardial oxygen consumption is decreased.Part II: The study of the myocardial microcirculation function in no- reflow york swines by intracoronary pressure and Doppler flow assessment simultaneouslyObjective: This study was aimed to probe the feasibility of establishing no-reflow model in AMI Yorkpigs by balloon-occlusion-reperfusion- intracoronary injection of sterile microembolus via superselecting LAD with 6F guiding catheter. To explore the characteristics of the myocardial microcirculation in NRP models by intracoronary pressure wire and Doppler guidewire assessment simultaneously.Methods: Total of 12 york swines (4±1 months) were included in this study. 6F catheter were performed in two sides deep femoral approach by Seldinger's puncture. Left and right coronary angiography were performed by 4F micro-catheter technique. LAD was superselected with 6F guiding catheter , than the pressure wire and Doppler guidewire were transfer into coronary artery respectively through guiding catheter. LAD was occluded for 45 minutes by balloon which was chosen according to LAD diameter, and then perfused by withdrawing the balloon. After deflating the balloon, the sterile microembolis were injected into LAD intermittently. The coronay 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 of AMI was considered as success while TIMI blood flow being less than grade 2 or TFC more than 36.2 counts or TMPG less than grade 1. The pressure and blood flow of the coronary were measured with ComboMap System Model 6800. The coronary pressure and flow velocity were recorded simultaneously at baseline, instant, 30 and 60 minutes after NRP . The Pa, Pd, APV, MR were obtained at rest and maximal hyperemia. At the same time FFR and CFR were obtained. The maximal hyperemia was induced by intracoronary bolus of 10 mg cardoverine . CK-MB and TnI were measured in all swines at baseline, 30, 60,120 and 180min after NRP. PCWP was measured by 5F Swan-Ganz floating catheter, and CO was measured by thermodilution method. LVSP and left ventricular end diastolic pressure were monitored continuously with 4F Pigtail. At the same time ECG was recorded. The myocardium oxygen consumption was reflected by PRI.The animals were sacrificed after the trial finished. Ischemic region, normal region and borderline were sectioned respectively. 6 pieces of myocardial tissues were sent to check for pathology. Results: (1) (1) According to the standards of NRP, 9 animals achieved the NRP model of AMI successfully, success rate of model establishing was 75% (9/12), average times of injection of microembolus was 3.0-4.0. (2) While 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. (3) cTnI and CK-MB were increased significantly after NRP models were successfully established[(cTnI 120.18±27.25 ng/ml vs 13.69±4.37 ng/ml),(CK-MB 171.34±32.75ng/ml vs 16.87±4.54ng/ml)]. (4) PCWP and LVEDP were increased with statistical significance at instantly, 30, 60min after NRP with AMI (P all<0.05). LVSP and CO were decreased after successful establishment of NRP model.(5) MVO2 was decreased significantly. (6)The Pa and Pd at rest and hyperemia were decreased significantly at different time after NRP, especially at 30 min after NRP [b-Pa(83.2±6.4 vs 109.6±12.7, P<0.05),h-Pa (82.0±9.5 vs 109.2±12.1, P<0.05)]. The change of Pd was same to Pa. FFR did not change before and after NRP(0.98±0.06 vs.0.99±0.04, P>0.05). APV at rest and hyperemia were all decreased significantly, they were lower than that before NRP(11.0±8.9 vs. 17.3±7.9;20.4±10.6 vs. 62.6±12.3, P<0.05). b-MR was decreased after reperfusion, it was lower than that before NRP(4.77±1.65 vs.7.42±2.31, P<0.05 ) .MR at rest and hyperemia were all increased significantly(9.47±3.57 vs. 7.42±2.31;4.96±0.91 vs.2.01±0.61, P<0.05). CFR was lower than that of baseline(1.85±0.31 vs.3.61±0.76, P<0.05). (7) Pathological examination showed the occurrence of myocardium fiber swelling, sarcolysis, reticular formation and local liquefaction necrosis.Conclusion: It is feasible to establish the model of NRP by superselecting LAD under CAG , dilating balloon, withdrawing balloon and injecting microembolus. The model of NRP could be established in swines whose heart anatomy and characteristics of coronary artery were more similar to human being. This model had advantages of direct-viewing, simplicity, reproducibility, mild trauma, closed chest, high achievement ratio. It might provide better experimental animal model for the research on microcirculation dysfunction after AMI. It is a advanced, objective, and reliable method to evaluate the microcirculation in NRP models by intracoronary pressure wire and Doppler wire assessment simultaneously. The manifestation of myocardial microcirculation in NRP is that : FFR is normal before or after NRP, The APV at rest and hyperemia is decreased,b-MR and h-MR are increased , CFR is obviously decreased.Part III: The effects of anisodamine on the coronary microvascular disfunction in no-reflow swines by intracoronary pressure and Doppler flow assessment simultaneouslyObjective:To investigate the effect of intracoronary administration of Anisodamine on NRP with saline as contrast by intracoronary pressure wire and Doppler guidewire assessment simultaneously. It will maybe provide evidence for clinical use. Methods Total of 9 york swines (4±1months old ) were included in this study, 9 York swines with stable NRP were randmized into saline group(n=4), Anisodamine group(n=5). 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 5ml, Anisodamine 2000μg were injected into LAD three times with 5 minutes interval in the two groups respectively, and coronary flow velocity was quantitatively measured by TFCs and TMPG at instant, 5, 10 min after administration. LAD was superselected with 6F guiding catheter , then the pressure wire and Doppler guidewire were transferred into coronary artery respectively through guiding catheter. The pressure and blood flow of the coronary were measured with ComboMap System Model 6800. The coronary pressure and flow velocity in two groups were recorded simultaneously at baseline, instant,5 and 10 minutes after administration. The Pa, Pd, APV, MR were obtained at rest and maximal hyperemia. At the same time FFR and CFR were obtained. The maximal hyperemia was induced by intracoronary bolus of 10mg cardoverine. 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. The LVSP and LVEDP were measured instant, 5, 10 minutes after injection of saline, Anisodamine respectively.Results: (1)TFCs were significantly decreased by 52.44%,54.30%,54.20% instant, 5,10 min after intracoronary Anisodamine compared with that of baseline and saline group (P<0.05). At same time coronary blood flow reached TIMI2+-3 grade (P<0.05). (2) There were no difference in Pa and Pd at rest and hyperemia , FFR, APV at rest and hyperemia ,b-MR and h-MR and CFR after saline administration. While in Anisodamine group, after administration of 6000 ug Anisodamine, the Pa and Pd at rest and hyperemia were all increased significantly at different time, especially at 5min after administration[ b-Pa (98.1±11.6 vs 86.1±10.5, P<0.05),h-Pa (92.1±10.6 vs . 85.3±10.1, P<0.05)]. There were significance between two groups [b-Pa(98.1±11.6 vs. 86.7±11.7,P<0.05),h-Pa (92.1±10.6 vs. 86.5±10.3,P<0.05)]. The change of Pd was same to Pa. FFR did not change between before and after administration in two groups. APVb and APVh were all increased significantly in Anisodamine group. There were significance between two groups [APVb(15.7±13.7 vs. 11.3±8.7, APVh (46.3±12.2 vs.20.6±10.6, P<0.05)]. b-MR and h-MR were decreased obviously in Anisodamine group ( 7.62±2.23 vs.9.19±4.08 ; 2.86±0.47 vs.4.89±0.86, P<0.05), they were better than those of saline group [b-MR (7.62±2.23 vs. 8.98±2.87,P<0.05), h-MR (2.86±0.47 vs. 4.89±0.88, P<0.05]. CFR was increased , it was higher than that of baseline and saline group[(2.98±0.75 vs.1.88±0.60, P<0.05), (2.98±0.75 vs. 1.83±0.41,P<0.05)].(3) Blood pressure, mean coronary pressure and heart rate were significantly increased after administration of Anisodamine compared with those of baseline and saline group (P<0.05). PCWP and LVEDP were significantly decreased while CO was significantly increased after administration of anisodamine compared with that of baseline and saline group (P<0.01). (4) LVSP and±dp/dtmax were increase significantly in Anisodamine group after intracoronary administration medicine compared with those of baseline and saline group(P<0.05).Conclusion: Administration of intracoroanary Anisodamine could increase APVb and APVh in NRP microcirculation, decrease b-MR and h-MR, improve CFR in NRP and improve microcirculation dysfunction .Part IV: Protective effects of anisodamine on the coronary microcirculation function in ischemia- reperfusion swinesObjective: To investigate the effect of intracoronary anisodamine on coronary microcirculation function in ischemia-reperfusion swine model by intracoronary pressure wire and Doppler wire assessment simultaneously.Methods: Total of 10 swines were divided into saline group (n=5) and Anisodamine group (n=5). Two milliliter saline and 2 mg Anisodamine were injected into LAD respectively in the two groups. Left and right coronary angiography were performed by 4F micro-catheter technique. LAD was superselected with 6F guiding catheter , then the pressure wire and Doppler guidewire were transferred into coronary respectively through guiding catheter. The pressure and blood flow of the coronary were measured with ComboMap System Model 6800. LAD was occluded for 45 minutes by balloon which was chosen according to LAD diameter, and then perfused by withdrawing the balloon. The coronary pressure and flow velocity were recorded simultaneously at baseline, 30 and 60 minutes after reperfusion . The Pa, Pd, APV, MR were obtained at rest and maximal hyperemia in two groups. At the same time FFR and CFR were obtained. The maximal hyperemia was induced by intracoronary bolus of 10mg cardoverine. CK-MB and TnI were measured in all swines at baseline, 30, 60, 120 and 180min after reperfusion . PCWP was measured by 5F Swan-Ganz floating catheter, and CO was measured by thermodilution method. LVSP and left ventricular end diastolic pressure were monitored continuously with 4F Pigtail. At the same time ECG was recorded. The myocardium oxygen consumption was reflected by PRI. The animals were sacrified after the trial finished. Ischemic region, normal region and borderline were sectioned respectively, the size of which was 0.3cm×0.3cm, and 6 pieces of myocardial tissues were sent to check for pathology. All parameters were compared between two groups.Results: (1) Success rate of model establishing was no difference. (2) ΣST of ECG was obviously increased in two groups, but it was obviously decreased after preventive intracoronary administration of Anisodamine compared with that of contrast group (P<0.05). (3) PCWP and LVEDP were significantly increased while CO was significantly decreased in two groups, but they were better in anisodamine group than those in saline group (P<0.05). (4) cTnI and CK-MB were all increased significantly in two groups, but were increase significantly in saline group compared with that of anisodamine group (P<0.05). (5) The Pa and Pd at rest and hyperemia were all decreased significantly at different time after reperfusion, especially at reperfusion instant in two groups with obvious in Saline group.The change of Pd was same to Pa. FFR did not change before and after reperfusion in two groups. APVb was increased significantly in two groups, it was higher than that of before reperfusion, but it was different between two groups(18.8±8.2 vs. 21.0±9.9,P<0.05). B-MR was decreased after reperfusion, it was lower than that of before reperfusion, there were difference between two groups (5.96±1.98 vs. 4.77±1.65,P<0.05). APVh was lower than that of baseline, while h-MR was increased significantly. CFR was lower than that of baseline in two groups, but it was higher in Anisodamine group than that of in Saline group(2.59±0.41 vs. 1.93±0.35,P<0.05). Myocardial oxygen consumption was decreased more in saline group than in anisodamine group. (6) The necrosis area to the LV areas were (34.6±3.2) % and (21.3±3.8)% in saline and Anisodamine group respectively,which had statistical significance in Anisodamine group compared with that of saline group(P<0.05).Conclusion: Preventive intracoronary administration of Anisodamine can maintain coronary mean perfusion pressure, decrease the microcirculation resistance of coronary artery, increase the reperfusion of myocardial microcirculation, protect the coronary microcirculation function and ischemic-reperfusion myocardium.
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