Stage II considered the subjects in the seven treatment groups to assess the effects of starting time and dose for two sets of groups: those with short 1 h and long h duration of infusions of drug. For starting time, the range assessed for the short-duration infusions was min; for long duration, the range was min. For each set, neither starting time nor dose had a statistically significant effect. Stage III considered all subjects in all groups and reassessed the effect of duration. This relation was nonlinear with a steep slope in the first min of reperfusion but only a small change in slope between and min.
Therefore, extending the duration of treatment with MPG up to 3 h resulted in substantial further reduction in infarct size, but treatment beyond 3 h added less benefit. In summary the statistical analysis of relations between the groups led to the following conclusions regarding treatment of infarct size with MPG:. MPG, a glutathione analog, has been used previously to treat reperfusion injury. In two studies, Mitsos et al.
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In another study, Tsao et al. In this study, we sought further information regarding the timing and dosages in which administration of MPG was effective in limiting myocardial infarct size.
By taking advantage of the short plasma half-time 7 min and rapid diffusibility into cells of MPG, we were able to gain information about the timing of oxidant processes contributing to lethal myocardial injury during reperfusion. In the lower dose, there was no difference in myocardial infarct size between the 3- and 4-h infusions.
Therefore, the first 30 min of reperfusion was not a critical period for prevention of lethal injury during reperfusion. These conclusions were more stringently evaluated by further statistical analysis of the entire set of treatment variables. This analysis demonstrated that duration of treatment with MPG was a powerful predictor of infarct size. There was benefit from infusions of only 1 h, within the first 3 h of reperfusion, but the effect was small. However, increasing the duration of treatment to 3 h substantially reduced myocardial infarct size.
Extending treatment beyond 3 h had only a small benefit. This conclusion is compatible with prior studies in which treatment during reperfusion with MPG for h was only moderately effective 5,6 , and treatment for 4 h highly effective 4 in limitation of lethal myocardial injury in various animal models. The starting time of the MPG infusions, within the first hour after reperfusion began, was not an important predictor of infarct size. When groups in which duration of treatment was short 60 min were analyzed, there were no statistical differences whether treatment commenced at 0, 60, or min of reperfusion.
From these results, it appears that there was a continuous deleterious effect of reactive oxygen species throughout the first 3 h of reperfusion, with decreasing effect thereafter. Therefore, because treatment initiated at any time during the first hour was effective, it was not necessary to begin precisely at the onset of reperfusion. Based on reports that there is a burst of reactive oxygen species during the first few minutes of reperfusion after myocardial ischemia , it has often been assumed that antioxidant measures for a relatively brief time early in reperfusion would suffice to prevent oxidant injury 2,7,9, The most likely sources of excessive quantities of reactive oxygen metabolites in the first min of reperfusion are generation by the myocardial mitochondrial electron transport or P systems or through the xanthine oxidase system in endothelial cells or myocardium During cardiac reperfusion after ischemia of an hour or more, there is an inflammatory response that results in accumulation of polymorphonuclear leukocytes in the myocardium or in the coronary microcirculation throughout the first 2 h of reperfusion Dreyer et al.
This accumulation of leukocytes is the most likely source of reactive oxygen species involved in lethal myocardial reperfusion injury Once invading polymorphonuclear leukocytes become bound to myocardial adhesion sites, hydrogen peroxide is released In conclusion, there are several important findings in this report. First, we reinforced the hypothesis that administration of a diffusible antioxidant during reperfusion markedly reduces lethal myocardial injury in hearts exposed transiently to 90 min of ischemia in a long-term canine model.
We cannot exclude the possibility that with longer periods of ischemia in this or other models, the timing of the susceptibility to oxidant injury would be altered. Although canine myocardial infarcts have many similarities to human infarcts, species differences also cannot be excluded.
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To the extent that this animal model can be cautiously extrapolated to treatment of reperfusion in humans, these observations could be useful in designing pharmacologic strategies with antioxidant drugs. It is probably not essential that administration be done in a manner that assures effectiveness immediately when reperfusion begins. As long as there is antioxidant effectiveness within the first hour of reperfusion, substantial reduction in reperfusion injury is possible. However, very brief interventions of an hour or less would be unlikely to be effective.
High antioxidant activity for several hours offers a higher likelihood of meaningful benefit. Clearly the optimal timing of administration of other agents would depend on each drug's pharmacokinetics, diffusibility, and mechanism of action, but regardless, they should probably be therapeutically active during the period defined earlier. Acknowledgment: We acknowledge the assistance of Juliann S. Wallner and Nancy A. Sherman with measurements of myocardial perfusion and preparation of MPG.
Rachel M. Henderson assisted with surgery and M. Gloria Icaza assisted with the statistical analysis. Myocardial ischemia ; Free radicals ; Reactive oxygen species ; Nmercaptopropionyl glycine; Myocardial reperfusion injury. You may be trying to access this site from a secured browser on the server.
A clinical research study for the treatment of Myocardial Reperfusion Injury
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Please try after some time. Received July 17, ; revision accepted May 22, Analysis of relations between myocardial infarct size and t Cyclophilin D has peptidyl-prolyl cis - trans isomerase activity, which in response to the onset of reperfusion leads to conformation changes in other less clearly defined membrane proteins and the eventual formation of the pore. The role of ANT has been less clearly delineated. Cyclosporine A is known to have a high affinity for the CyP protein family.
Cyclosporine A has been previously shown to bind to CyP-A and contribute to immunosuppression in renal transplant patients. Cyclosporine A was initially shown to inhibit calcium-induced permeability transition in isolated cardiac mitochondria 15, Subsequently, Nazareth et al. They reported an increase in isolated myocyte viability following hypoxia-reoxygenation with CsA treatment. Subsequently, Griffiths and Halestrap 26 demonstrated CsA-induced cardioprotection on isolated rat hearts following 30 min of ischemia and 15 min of reperfusion.
Xu et al. In further studies, Griffiths and Halestrap 9 delineated the timing of MPTP formation, which was shown to occur during reperfusion, and not the initial ischemic period.
These authors subjected isolated perfused rat hearts to ischemia 30 min followed by 15 min of reperfusion and reported an increased yield of intact mitochondria with CsA treatment compared with controls. Additional experiments with mitochondrial fractions from isolated hearts subjected to ischemia-reperfusion I-R demonstrated an increased uptake of radiolabeled glucose with CsA treatment. These findings suggested that MPTP closure with CsA treatment would trap increased levels of radiolabeled glucose within the mitochondrial matrix 9.
These finding in either myocytes or isolated perfused hearts demonstrated the potent ability of CsA to inhibit MPTP opening during reperfusion in vitro. Subsequently, experiments were performed to assess whether improvement in cardiomyocyte mitochondrial health may lead to attenuation of myocardial injury during reperfusion. For example, Debio, also known as alisporivir, was developed and has been investigated as a novel CyP-binding agent to inhibit human immunodeficiency virus type 1 Altering the structure of CsA to produce Debio removes the calcineurin-binding domain, which was shown to abolish its immunosuppressive capacity 29— In addition, Debio was shown to have an increased infinity for CyP In in vivo experiments using a graft-versus-host rat model, NIM was reported to have no immunosuppressive activity, whereas CsA administration in this model inhibited lymph node enlargement In addition, Rosenwirth et al.
However, in rats treated with NIM, both markers of renal injury remained unchanged 32 , suggesting less nephrotoxicity than CsA. Myocardial reperfusion injury following reestablishment of myocardial perfusion following an ischemic cardiac event leads to secondary injury. The initial ischemic damage to the adult heart occurs during coronary artery occlusion. Specific regions of the myocardium undergo irreversible damage; however, other regions may have potentially viable tissue if apoptotic events can be attenuated. Argaud et al. Cyclosporine A or NIM a nonimmunosuppressive analog of cyclosporine treatment was given intravenously either 10 min before sustained ischemia or 1 min before reperfusion.
They reported a significant reduction in infarct size ratio of reduced area of necrosis to area at risk with CsA and NIM treatment at both time points. There was no difference in infarct size between CsA- and NIMtreated groups at 10 min before ischemia or 1 min before reperfusion. However, there was no difference between CsA- and NIMtreated groups at 10 min before ischemia or 1 min before reperfusion. Nevertheless, NIM is an attractive treatment option because of the proposed reduction in adverse effects compared with CsA.
Leshnower et al. FK is also a potent calcineurin inhibitor used in solid-organ transplant; however, it directly binds FKbinding proteins to inhibit calcineurin. These authors subjected adult rabbits to 30 min of ischemia and 3 h of reperfusion and observed a decreased infarct size in only the CsA-treated group, with FKtreated rabbits being similar to placebo-treated controls.
Ischemia/Reperfusion Injury: R&D Systems
On further examination of isolated cardiomyocytes at the end of the experiment, they reported a significantly reduced apoptotic index in the CsA-treated group compared with both placebo-treated controls and FKtreated rabbits. Lim et al. Gomez et al. This was the first study using a specific MPTP inhibitor to suggest that functional preservation of cardiac function may lead to improved survival. A pilot clinical trial was performed by Piot et al. They randomly assigned 58 patients presenting with acute ST-elevation myocardial infarct to either receive cyclosporine i.
A significant reduction in infarct size 5 days after MI as seen with cardiac magnetic resonance imaging was found in the CsA-treated group. Although these data are preliminary and require confirmation in larger clinical trials, it further supports the potential preventive role for cyclosporine in myocardial reperfusion injury.
Related Management of Myocardial Reperfusion Injury
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