Study Of Effect Of Ischemic Preconditioning And Postconditioning On Myocardial Ischemia-reperfusion Injury And The Mechanism Involved

PartⅠStudy of Effect of Ischemic Preconditioning and Postconditioning on Rabbit Hearts with Acute Myocardial Ischemia-Reperfusion Injury and the Mechanism InvolvedBackground:Acute myocardial infarction is the major cause of death in the world.With the widespread application of thrombolytic therapy,percutaneous transluminal coronary angioplasty and coronary artery bypass graph in the clinic,coronary reperfusion therapy has become established for the management of acute myocardial infarction.However,restoration of blood flow to previously ischemic myocardium results in so-called ischemia-reperfusion injury.The different clinical manifestations of ischemia-reperfusion injury include myocardial stunning,reperfusion arrhythmia,myocyte death and endothelialand microvascular dysfunction including the no-reflow phenomenon. Consequently,ischemia-reperfusion injury has become a target for treatment strategies aimed at limiting damage secondary to ischemia.In 1986,Murry et al.first described the concept of a powerful endogenous protective strategy termed ischemic preconditioning in which multiple brief ischemic episodes in canine hearts protected the myocardium from a subsequent sustained ischemic insult.Preconditioning has been reported to attenuate the incidence and severity of post-ischemic arrhythmias,enhance the recovery of cardiac function after global ischemia,and reduce infarct sizes and the appearance of apoptosis in hearts subjected to ischemia-reperfusion injury.This approach however depends crucially on intervening before the ischemic event, which is difficult,given the unpredictable onset of an acute coronary artery occlusion.However,the implementation of cardioprotective therapy at the time of reperfusion is clinically feasible because the onset of reperfusion is more predictable and is under the clinician's control.Recently,Zhao et al.reported another endogenous form of cardioprotection that exerted cardioprotection similar to that observed with preconditioning.In their study,a short series of repetitive cycles of brief reperfusion and re-occlusion of the coronary artery applied immediately at the onset of reperfusion,termed "postconditioning",was also cardioprotective by reducing infarct size,coronary artery endothelial dysfunction,and neutrophil accumulation in the area at risk.This protection was similar in extent to ischemic preconditioning.In 1993,Przyklenk et al.first reported that 4 cycles of 5 min left circumflex coronary artery occlusion and 5 min reperfusion reduced infarct size following 1 h sustained left anterior descending coronary artery occlusion and 4.5 h reperfusion in anesthetized dogs.Subsequently,cardioprotection by remote preconditioning from intestine,kidney and limb of several species was reported. This phenomenon was named inter-organ preconditioning or remote preconditioning.Recently,Kerendi et al.reported that in an in vivo anesthetized rat model of myocardial infarction induced by coronary artery occlusion and reperfusion,remote postconditioning produced by a single 5-min episode of renal artery occlusion and reperfusion applied immediately before the onset of coronary artery reperfusion protects the myocardium from reperfusion injury by mechanisms involving endogenous adenosine receptor activation.Objective:In this study,we tested the hypothesis that limb ischemic postconditioning, which is induced by a single 5-min episode of femoral artery occlusion and reperfusion applied just before the onset of coronary artery reperfusion,and limb ischemic preconditioning produced by repetitive brief episodes of ischemia just before sustained coronary artery ischemia and reperfusion protect the myocardium from reperfusion injury,and compared this strategy with myocardial ischemic preconditioning and postconditioning,then examined the mechanism involved.Methods:In anesthetized open-chest rabbits,the left anterior descending artery(LAD) was occluded for 30 min and reperfused for 180 min.All rabbits were randomly divided into five groups(n=10 in each group):1)Control(Con):LAD occlusion and reperfusion only,with no other intervention;2)Myocardial Ischemic Preconditioning(MIPre):Three cycles of myocardial ischemia(5 min)and reperfusion(5 min)preceded the index ischemia/reperfusion protocol;3) Myocardial Ischemic Postconditioning(MIPost):After 30 min of LAD occlusion,reperfusion was initiated for 30 s followed by 30 s reocclusion.Three cycles of myocardial ischemia(30 s)and reperfusion(30 s)followed the index ischemia/reperfusion protocol.4)Limb Ischemic Preconditioning(LIPre):Three cycles of femoral artery ischemia(5 min)and reperfusion(5 min)preceded the index ischemia/reperfusion protocol;5)Limb Ischemic Postconditioning (LIPost):After 24 min of LAD occlusion,the femoral artery was occluded for 5 min and released for 1 min before 180 min of LAD reperfusion.During the experiment,heart rate and blood pressure were monitored. Myocardial infarct size and tissue myeloperoxidase(MPO)activity were determined at the end of the experiment.Plasma creatine kinase(CK)activity and malondialdehyde(MDA)activity were measured at baseline,the end of ischemia,and after 180 min of reperfusion respectively.Results:1.There were no significant differences among the five groups at baseline. During coronary occlusion,there were trends for a decrease in mean arterial pressure and an increase in heart rate.But these changes were not significant compared with their respective baseline value.2.Myocardial infarct size was significantly reduced in MIPre(15.0±1.7%), MIPost(16.2±2.1%),LIPre(16.7±1.9%)and LIPost(17.1±1.7%)(P＜0.01) compared to Con(31.5±1.3%).There was no statistical difference in infarct size between MIPre,MIPost,LIPre and LIPost group.Results were confirmed by plasma CK activity(MIPre 15.9±1.5,MIPost 16.7±1.5,LIPre 16.9±1.7,LIPost 18.1±1.6 vs.Con 45.6±5.5).3.Plasma MDA(μM/ml),a product of lipid peroxidation,was significantly. less at 180 min of reperfusion in MIPre(2.1±0.3),MIPost(2.2±0.2),LIPre (2.3±0.3)and LIPost(2.2±0.3)(P＜0.01)than that in Con(3.5±0.3).There was no statistical difference between MIPre,MIPost,LIPre and LIPost group.4.Neutrophil accumulation(MPO,U/100g)in the area at risk was less in MIPre(1.4±0.3,P＜0.01),MIPost(2.3±0.2,P＜0.01),LIPre(2.4±0.4,P＜0.01) and LIPost(2.5±0.3,P＜0.01)than that in Con(5.4±0.4).However,MPO activity in the area at risk of MIPre was significantly lower than that of MIPost, LIPre and LIPost(P＜0.05).There was no statistical difference between MIPost, LIPre and LIPost group.Conclusions:Remote limb preconditioning and postconditioning provide potent myocardial infarct size reduction,which is similar to the cardioprotective effect of myocardial ischemic preconditioning and postconditioning.The potential mechanism of this remote preconditioning and postconditioning phenomenon might be associated with decreasing the injury caused by oxygen free radicals and strengthening the action of antioxidation. PartⅡEffect of Myocardial Ischemic Preconditioning and Postconditioning on Prognosis of Patients with Acute Myocardial Infarction Underwent Primary Percutaneous Coronary InterventionBackground:Timely and sustained patency of the infarct-related coronary artery is the best method in the patients with acute myocardial infarction(AMI)to rescue the myocardium at risk and limit the area of myocardial infarct and therefore prevent left ventricular remodeling and reduce the mortality.With the application of thrombolytic therapy and percutaneous coronary intervention (PCI)in the clinic,coronary reperfusion therapy has become established for the management of acute myocardial infarction.And PCI therapy has been widely used because of its quality of higher revascularization rate and lesser residue vascular stenosis.However,reperfusion has been referred as the "double edged sword" because reperfusion itself may lead to accelerated and additional myocardial injury beyond that generated by ischemia alone.This results in a spectrum of reperfusion-associated pathologies,collectively called "reperfusion injury".Reperfusion injury has been a hot issue and interest of cardiologists in the "reperfusion time" of myocardial infarction.In 1986,Murry et al first introduced the concept of ischemic preconditioning.Preconditioning has been reported to reduce infarct size, preserve vascular endothelial function,decrease polymorphonuclear neutrophil accumulation,and reduce apoptosis.In the clinic,many doctors found that the onset of angina before myocardial infarction may precondition the heart. However,doctors and patients can not usually predict when ischemia is established,so the clinical implementation of preconditioning cardioprotective therapy is limited.Therefore the possibility to protect the heart by intervening at the time of reperfusion provides an approach that is more suitable.In 2003,Zhao et al introduced the concept of ischemic postconditioning,in which brief intermittent repetitive interruptions of reperfusion after a prolonged period of ischemia,reduced myocardial injury to an extent comparable to ischemic preconditioning.This offers a novel approach to myocardial protection.Unlike preconditioning,postconditioning can be applied during percutaneous coronary intervention for patients with AMI.To date,cardioprotection by postconditioning has been reported by independent laboratories in several species(i.e.dog,rabbit,and rat),in isolated perfused heart,in vivo and cell culture models.Few reports describe the effect of pre-and postconditioning on prognosis of patients with AMI underwent primary PCI.Our study observed the influence of postconditioning on coronary blood flow velocity and cardiac function in patients with acute myocardial infarction underwent primary PCI.Objective:Our study observed the effect of ischemic preconditioning,postconditioning and preconditioning plus postconditioning simultaneous on coronary blood flow velocity and prognosis in patients underwent primary PCI and explore effective preventive strategy of ischemia-reperfusion injury.Methods:One hundred and forty one patients with a first AMI who underwent revascularization within 12 h of symptom onset by primary PCI at Shandong Provincial Hospital were recruited in the study.Thirty five patients with preinfarction angina before the onset of acute myocardial infarction were classified as ischemic preconditioning(IPre)group.Thirty seven patients with ischemic postconditioning procedure(three cycles of 30 s reperfusion followed by 30 s reocclusion within 1 min of reperfusion using rapid reiterative balloon inflations and deflations)were classified as ischemic postconditioning(IPost) group.Thirty five patients with preconditioning and postconditioning simultaneous were classified ischemic preconditioning plus postconditioning (IPre+IPost)group.Thirty four patients with only ischemia-reperfusion intervention were ischemia-reperfusion(IR)group.Corrected TIMI frame count(CTFC)was used to evaluate velocity of coronary blood after PCI. Creatine kinase(CK),CK-MB and malondialdehyde(MDA)were measured before and after PCI respectively.Wall motion score index(WMSI)was assessed by two-dimensional echocardiography 8 weeks after angioplasty.Results:1.There were no significant differences between the four groups with regard to age,sex,presence of angiographically visible collaterals,and elapsed time from the onset of symptoms until perfusion.The blood pressure,heart rate and morbidity of hypertension and diabetes mellitus were similar in the four groups.2.The peaks of CK and CK-MB in the group of IPre,IPost and IPre+IPost were much lower than that of IR group(CK peak:1242.35±801.37, 1236.57±813.21,1233.35±807.91 vs.1697.36±965.74,P＜0.05;CK-MB peak: 121.87±78.24,116.92±75.83,119.97±70.28 vs.172.41±92.64,P＜0.05).There was no significant difference between IPre,IPost and IPre+IPost group on the peak of CK and CK-MB levels.3.The plasma MDA levels were higher in all the patients before PCI than that in control healthy people(0.66±0.38μmol/L).After PCI,the concentration of MDA significantly increased compared with baseline values and reached at their peak 1 h after PCI.Then the MDA level gradually declined,and higher values were maintained until 48 h after the PCI procedure.However,in the blood samples withdrawn at the same time point in the IPre group,IPost group and IPre+IPost group,MDA-reactive products were significantly lower than that in the IR group.4.Patients of IPre group,IPost group and IPre+IPost group had much faster CTFC than patients of IR group(27.03±5.85,26.97±5.72,27.12±5.14 vs. 31.03±7.46,P＜0.05).After 8 weeks,the WMSI of IPre group,IPost group and IPre+IPost group were much lower than that of IR group(1.17±0.23,1.18±0.22, 1.16±0.12 vs.1.31±0.26,P＜0.05).Conclusion:Postconditioning is a simple interventional procedure for increasing coronary blood flow velocity and improving cardiac function.It could be used widely in the clinic and better the prognosis of patients with acute myocardial infarction. No additive cardioprotective effects by preconditioning and postconditioning simultaneous were observed in our study.