Effects Of Early Dexmedetomidine Administration On Ischemic Ventricular Arrhythmias Of Canines

Part one Effects of acute anterior myocardial infarction on cardiac sympathetic activity and electrophysiological characteristics in caninesObjective:To observe the changes in cardiac sympathetic activities and electrophysiological properties after ligation induced acute myocardial infarction in canine models.To investigate the density of nerve fibers with immunohistochemical techniques.Methods:12 mongrel dogs were randomly assigned into two groups,the sham group(n = 6)and MI group(n = 6).The animals in MI group underwent ligation of the first diagonal branch(D1)of the left anterior descending coronary artery to establish the model of acute myocardial infarction.No artery ligation was performed in the sham group.NE and E concentrations in the coronary sinus vein were measured during baseline and 1h after acute myocardial infarction.ERP,MAPD90,TDR was measured.The incidence of ventricular arrhythmias was recorded.The density of GAP-43 and TH nerves were detected with immunohistochemical techniques.Results:1.All canines in the MI group had successful establishment of acute myocardial infarction that was confirmed by elevation of the ST segments in leads I and av L in addition to regional cyanosis of cardiac tissue.2.NE level in MI group became higher after ligation(407.83±64.81ng/L vs 166.33±46.61ng/L,p<0.01).There were no significantly changes in the sham group(177.00±28.23 ng/L vs 172.17±28.18ng/L,p>0.05).No statistical differences in E concentrations were observed between two groups before and after ligation.3.Heart rates and systolic blood pressures in MI group increased significantly after ligation(169±4 bmp vs 152±5 bmp,p<0.01;158±9mm Hg vs 144±3mm Hg,p<0.05).No significant changes in heart rates and systolic blood pressures were observed in sham group.4.MAPD90 values in MI group were significantly shortened after ligation(infarcted area: 192.7±8.1ms vs 215.5±4.2ms,p<0.01;non-infarcted area: 207.5±5.5ms vs 214.5± 3.5ms,p<0.05).MAPD90 values in infarcted area were shorter than the other areas(192.7±8.1ms vs 207.5±5.5ms,p<0.01),while sham group displayed no differences.5.In MI group,TDR values were prolonged after ligation(infarcted area: 57.3±5.2ms vs 23.5±4.1ms,p<0.01;non-infarcted area: 30.5±4.4ms vs 23.8±3.5ms,p<0.05).Compared with the non-infarcted areas,the infarcted areas have longer TDR values.No differences were observed in the control group.6.ERP in the MI group was shorter following ligation in comparison to before ligation,especially in the infarcted area(LV M1 130.7±6.4ms vs 158.0±9.6ms,p<0.01),while ERP in sham group was not significantly different.ERP values in both groups were significantly shorten in response to left stellate ganglion stimulation(sham: 145.0±12.4ms vs 157.3±9.4ms,p<0.01;MI: 122.7±3.5ms vs 130.7±6.4ms,p<0.01),especially on the infarcted area in the MI group(MI vs sham:122.7±3.5ms vs 145.0±12.4ms,p<0.01).7.The arrhythmias score in the MI group was higher than that of the control group(3.0±2.4 vs 0.3±0.8,p<0.05).There was no significant difference of incidence of ventricular arrhythmias between the two groups.8.Pathology showed no significant myocardial damage in sham group.MI group showed regional myocardial infarction changes such as coagulation necrosis,edema and neutrophil infiltration.The density of TH positive sympathetic nerve fibers in the MI group was lower than the sham group(MI vs sham:585.58±105.82?m2/mm2 vs 1644.80 ± 113.03?m2/mm2,p<0.01).GAP-43 staining failed to demonstrate results in this study.Conclusion:1.The regional NE concentrations,heart rates and systolic blood pressures in MI group were significantly increased after acute myocardial infarction.2.ERP in MI canine models was significantly shorter,TDR was prolonged and there were uneven changes of ERP and TDR among different regions.The arrhythmias score was higher in the MI group compared with that in the control group.3.The densities of sympathetic nerve fibers were significantly decreased on the infarcted area.Part Two The effects of early intravenous dexmedetomidine on cardiac sympathetic activity and electrophysiology in canine models following anterior myocardial infarctionObjective:To observe the electrophysiological effects of early dexmedetomidine administration in post myocardial infarction canines.To discuss the safety and the effects on arrhythmias of early dexmedetomidine administration in the MI canine model.To observe the effect of dexmedetomidine in sympathetica nerve regeneration.Methods:18 mongrel dogs were randomly assigned into three groups,the MI group(n=6),dexmedetomidine group(Dex group,n=6)and metoprolol group(Met group,n=6).The D1 was ligated to produce the canine model of AMI.After ligation,the Dex group was gived dexmedetomidine 1?g/Kg loading dose in ten minutes immediately by intravenous injection,followed by 30 minutes infusion of 0.5?g/Kg/h.The Met group was gived metoprolol 10 mg immediately by intravenous injection.NE and E concentrations,MAPD90,TDR,ERP were all measured during the experiments.The incidence of ventricular arrhythmias was monitored.Pathological examination of the infarcted area and the infarcted border zone were performed.Results:1.NE concentrations in all groups compared with preligation levels were significantly higher,especially in MI group(MI:439.00±65.02ng/L vs 142.83±16.18ng/L,p<0.01;Dex:266.50±45.79ng/L vs 140.67±20.68ng/L,p<0.01;Met:300.83±58.29ng/L vs 146.17 ±20.82ng/L,p<0.01).There were no statistical differences of E concentrations among the three groups before and after ligation.2.Heart rates in the MI group increased significantly(167±4 bmp vs 150±5 bmp,p<0.01),while heart rates in Dex and Met groups were decreased(Dex:129±5 bmp vs 151±6 bmp,p<0.01;Met 123±5 bmp vs 153±6 bmp,p<0.01).The Dex and Met groups demonstrated no significant difference.3.Systolic blood pressures in the MI group increased significantly(158±8 mm Hg vs 143±4 mm Hg,p<0.01).Systolic blood pressures in the Met group decreased significantly(123±5 mm Hg vs 143±3 mm Hg,p<0.01),while no significant changes in systolic blood pressures in the Dex group were observed(139±4 mm Hg vs 142±5 mm Hg,p>0.05).4.MAPD90 values shorten after ligation in the MI group(infarcted area: 192.3±7.5ms vs 217.2±5.7ms,p<0.01;non-infarcted area: 208.0±4.1ms vs 216.5±4.4ms,p<0.05).MAPD90 values in the Dex and Met groups were prolonged,but there were no significant differences between the infarcted area and non-infarcted area.5.TDR in MI group was prolonged compared with the measurement before ligation(infarcted area: 56.0±5.7ms vs 23.2±3.3ms,p<0.01;non-infarcted area: 28.5±3.7ms vs 22.8±3.8ms,p<0.05).TDR values in the Dex and Met group were also prolonged after ligation(Dex:32.3±3.9ms vs 23.2±5.1ms,p<0.01;26.3±4.6ms vs 23.8±3.5ms,p<0.05;Met:33.5±6.1ms vs 23.3±4.5ms,p<0.01;26.7±3.2ms vs 23.5±2.4ms,p<0.05).6.?TDR values of infarcted area in MI group were significantly longer than those in the Dex and Met group(32.8±7.0 ms vs 9.0±2.0 ms,p<0.01;32.8±7.0 ms vs 10.2±5.7 ms,p<0.01).?TDR values of infarcted area in MI group were significantly longer than those of non-infarcted area(32.8±7.0 ms vs 5.7±4.8 ms,p<0.01).7.ERP in the MI group was significantly shorter compared with that before ligation,especially in the infarcted area(130.7±6.4 ms vs 160.8±8.9 ms,p<0.01).8.ERP values in Dex and Met group were also shorten after ligation,but the shorten-values of infarcted area in the two groups were significantly lowed than MI group(Dex vs MI:17.3±7.3ms vs 30.2±6.0ms,p<0.01;Met vs MI:18.7±6.9ms vs 30.2±6.0ms,p<0.01).9.The arrhythmias score in the MI group was higher than other two groups(MI vs Dex:3.8±1.9 vs 1.2±2.0,p<0.05;MI vs Met:3.8±1.9 vs 1.2±2.0,p<0.05).There were no significant difference of incidence of ventricular arrhythmias among the three groups(MI:83.3%;Dex:33.3%;Met:33.3%;p>0.05).10.Pathology showed regional changes such as coagulation necrosis,edema and neutrophil infiltration,which was most severly in the MI group.11.TH staining showed that the densities of sympathetic nerve fibers in MI group were lower than the Dex and Met group(MI vs Dex :579.83±103.19?m2/mm2 vs 881.67±113.31?m2/mm2,p<0.01;MI vs Met : 579.83±103.19?m2/mm2 vs 923.33± 108.93?m2/mm2,p<0.01).GAP-43 staining did not see a postive result,failed to observe the effects on regeneration of sympathetic nerve fibers.Conclusion:1.Early dexmedetomidine administration suppressed the sympathetic activity,and showed similar effects on blood pressure compared with metoprolol.Dexmedetomidine could be applied during the early phase of acute myocardial infarction.2.Compared with MI group,?TDR and ?ERP values were smaller,and the arrhythmia score was lower in Dex group.3.The damages of sympathetic nerve fibers on the infarcted area were less severly in Dex and Met groups.Part Three Effects of early dexmedetomidine administration on cardiac sympathetic remolding and its correlation with electrophysiological characteristics after myocardial infarctionObjective:To investigate the effects of early dexmedetomidine administration on sympathetic remolding and cardiac elecrophysiological properties after myocardial infarction.To investigate its antiarrhythmic mechamism.Methods:18 mongrel dogs were randomly divided into three groups,MI group(n=6),intervention group 1(Met group,n =6)?intervention group 2(Dex+Met group,n=6).After ligation the coronary artery,the Dex+Met group was administrated dexmedetomidine immediately by intravenous injection.The dogs in Met and Dex+Met group received oral metoprolol tartrate(12.5mg,twice a day)within 12 hours after operation.One month after surgery,all surviving animal underwent a second surgery.ERP,MAPD90,TDR of the infarcted border zone were measured with the programmed stimulation during baseline and left sympathetic ganglion stimulation.Ventricular fibrillation threshold(VFT)was determined during the experiments.Immunohistochemical was performed to identify GAP-43 and TH positive nerve fibers.The levels of GAP-43 and TH protein were detected with Western blot technique.Results:1.One dog in MI group died during follow-up.17 surviving canines underwent a second thoracotomy.There were no statistical differences in MAPD90 at the infarcted border zone among the three groups.TDR values in the MI group were the longest,those in Dex+Met group were the shortest among the three groups(MI vs Met:34±3ms vs 25±4 ms,p<0.05;MI vs Dex+Met:34±3ms vs 20±3ms,p<0.01;Met vs Dex+Met:25±4ms vs 20±3 ms,p<0.05).2.While the left stellate ganglion was stimulated,MAPD90 shortened in all groups.MAPD90 in MI group had the largest change,while MAPD90 in Dex+Met had the least change(MI vs Met:187±10ms vs 197±5ms,p<0.05;MI vs Dex:187±10ms vs 206±7 ms,p<0.01;Met vs Dex+Met:197±5ms vs 206±7ms,p<0.05).3.While the left stellate ganglion was stimulated,TDR increased in all groups.TDR in MI group had the largest change,while TDR in Dex+Met had the least change(MI vs Met:59±7ms vs 40±6 ms,p<0.01;MI vs Dex:59±7 ms vs 32±5 ms,p<0.01;Met vs Dex+Met:40±6ms vs 32±5ms,p<0.05).?TDR values in MI group was significantly longer than in Dex and Met groups(MI vs Met:25±8ms vs 15±6ms,p<0.05;MI vs Dex+Met:25±8ms vs 12±5ms,p<0.01).4.While the left stellate ganglion was stimulated,ERP shorten in all groups.ERP in MI group had the largest change,while ERP in Dex+Met had the least change(MI vs Met:128.8±7.4ms vs 139.3±6.5ms,p<0.05;MI vs Dex+Met:128.8±7.4ms vs 145.0± 9.5ms,p<0.01).?ERP values in MI group was significantly longer than in Dex and Met groups(MI vs Met:32.4±5.0ms vs 21.0±8.1ms,p<0.05;MI vs Dex+Met:32.4±5.0ms vs 15.0±8.2ms,p<0.01).5.VFT value in the MI group was shortest among the three groups(MI vs Met:11.2±1.8V vs 14.2±1.6V,p<0.05;MI vs Dex+Met:11.2±1.8V vs 16.5±1.2V,p<0.01;Dex+Met vs Met:16.5±1.2V vs 14.2±1.6V,p<0.05).6.The density of GAP-43 and TH positive nerve fibers was greater in the infarcted border.In MI group,Some nerve fibers cluster together aroud the infarcted border.In Dex+Met group,both GAP-43 postive nerve and TH positive nerve density were lower than the other two groups.The distributions of GAP-43 postive nerve and TH positive nerve fibers were normalized.7.The expression levels of GAP-43 and TH protein in MI group showed significant higher than those of Met and Dex+Met groups both at the infarcted border and non-infarcted LVFW.Compared with Met group,the expression levels of GAP-43 and TH protein showed significant decrease in the Dex+Met group.Conclusion:1.TDR increased in response to sympathetic nerve stimulation,and early intravenous application dexmedetomidine followed by metoprol alleviated it.2.Long-term application of metoprolol improved sympathetic remodeling,increased VFT.3.Compared with simple oral metopolol,Dex+Met treatment following acute myocardial infarction significantly suppressed sympathetic remodeling,and increased VFT.