Manifestation Of Reperfusion Injury Research Articles

Combined Right and Left Ventricular Reperfusion Injury following Percutaneous Coronary Intervention: Role of Myocardial Contrast Echocardiography

Right ventricular myocardial infarction (RVMI) occurs in up to half of the patients of inferior wall myocardial infarction. RVMI results in edema and increased right ventricular (RV) mass, and hence, it should be possible to visualize microvascular obstruction as a manifestation of reperfusion injury. Reperfusion injury of the RV myocardium following primary percutaneous coronary intervention has been rarely reported. This report describes a patient with the left ventricular inferior and RVMI who showed echocardiographically detected reperfusion injury of the RV-free wall and left ventricular basal inferolateral wall and conformed by myocardial contrast perfusion study despite successful percutaneous revascularization of the right coronary artery.

Reperfusion Arrhythmia in Acute Myocardial Infarction: Clinical Implication and Management

Reperfusion is a critical component of myocardium survival in acute myocardial infarction to minimize infarct size and improve clinical prognosis. Reperfusion, on the other hand, may result in increased and accelerated myocardial injury, a condition known as reperfusion injury. Following reperfusion, several arrhythmias are observed, and it is called reperfusion arrhythmia. Reperfusion arrhythmia is one manifestation of reperfusion injury. Numerous modest studies have evaluated what reperfusion arrhythmias are defined. It is described as an arrhythmia that occurs immediately or within the first minutes after coronary blood flow is restored. Traditionally, Accelerated Idioventricular Rhythm (AIVR) has been seen as a reperfusion arrhythmia. However, reperfusion may reveal any arrhythmia (or none at all); conversely, AIVR may occur in the absence of reperfusion. Calcium excess within the cells is thought to be a significant factor in the development of reperfusion arrhythmias. This may affect the significant delay following depolarization and the regional heterogeneity of regional blood flow restoration inside the ischemic zone, resulting in reperfusion arrhythmia. In some studies, it was mentioned that these arrhythmias may be due to ongoing myocardial cell damage and ischemia. Arrhythmias associated with reperfusion require special attention since hemodynamics can deteriorate quickly. In this review, clinical significance and management of reperfusion arrhythmia, as well as its link with reperfusion injury will be discussed.

Exercise-induced ventricular arrhythmia in coronary cameral fistula: A manifestation of reperfusion injury.

Presentation, Investigation and Management of Coronary fistula and its arrhythmic complications.

Influence of a short-term acute ischemia and reperfusion on skeletal muscle metabolism and morphology in rabbits

The duration of the ischemia and reperfusion of the limbs determines the extent of tissue damage. The purpose of this study was to validate anin vivo model of ischemia-reperfusion injury with a short-term ischemic period of 1 hour which is comparable to several clinical situations. Thirteen New Zealand rabbits were randomly assigned to either (1) the sham operation (control), or (2) ischemiareperfusion group response to 1 hour of ischemia followed by 2 hours of reperfusion. Ischemia was created by clamping bilateral common femoral arteries and tourniquet occlusion of collateral circulation. Alterations of plasma potassium, malondialdehyde (MDA), muscle tissue intercellular thromboxane B2 (TxB2) concentrations, and morphometric determinations of skeletal muscle were parameters used to quantify reperfusion injury. Interstitial edema (median fraction of muscle interfiber area was 16.57% vs 13.39% in control,p=0.02), muscle cell shrinkage (median muscle fiber area was 3.70×103 μm2 vs 4.55×103 in control,p= 0.04), increased plasma potassium (median 4.7 mmol/L vs 3.6,p=0.02) in 2 hours and increased interstitial TxB2 in 1 hour were manifestation of reperfusion injury. We conclude that expansion of the extracellular space not accompanied by changes of plasma MDA may indicate that lipidperoxidation in reperfused muscle was negligible and interstitial edema was related to thromboxane A2 synthesis.

Cardiovascular Death in Dialysis Patients

Cardiovascular events are the dominant cause of death in patients with ESRD. Until recently, plaque rupture due to atherogenic dyslipoproteinemias was presumed to be a major mechanism of cardiovascular events in dialysis patients. But how reasonable was that hypothesis and was it entirely discredited by the results of 4D and AURORA? This article places the conventional lipids-cholesterol and triglyceride-within the more physiologic framework of the apoB lipoproteins. Viewed from the perspective of atherogenic particle number, the failure of statins to lower cardiovascular mortality in hemodialysis patients versus the continuing potential for success in peritoneal dialysis patients becomes comprehensible. In the former, apoB is characteristically not elevated and therefore apoB-lowering therapy can have only limited effect; in the latter, apoB is characteristically high and therefore apoB-lowering therapy might have considerable clinical benefit. Nevertheless, plaque rupture is only one mechanism leading to cardiac death. In addition to those previously noted, a new mechanism is suggested for consideration-recurrent reperfusion injury. The coronaries of dialysis patients are often narrowed, the microcirculation underdeveloped, and the left ventricle hypertrophied-all of these plus transient hypotension could produce severe ischemia followed by reperfusion necrosis. The minor but common elevations of troponin that are so well known yet widely disregarded may be markers of an adverse sequence of events that could each trigger a fatal arrhythmia and tend to reduce left ventricular function. Thus sudden death due to arrhythmia and slow progressive death due to heart failure could be manifestations of reperfusion injury.

Dietary fish oil alters cardiomyocyte Ca 2+ dynamics and antioxidant status

The n-3 polyunsaturated fatty acids (PUFAs) found in fish oil (FO) have been shown to protect against reperfusion arrhythmias, a manifestation of reperfusion injury, which is believed to be induced by the formation of reactive oxygen species (ROS) and intracellular calcium (Ca 2+) overload. Adult rats fed a diet supplemented with 10% FO had a higher proportion of myocardial n-3 PUFAs and increased expression of antioxidant enzymes compared with the saturated fat (SF)-supplemented group. Addition of hydrogen peroxide (H 2O 2) to cardiomyocytes isolated from rats in the SF-supplemented group increased the proportions of cardiomyocytes contracting in an asynchronous manner, increased the rate of Ca 2+ influx, and increased the diastolic and systolic [Ca 2+] i compared with the FO group. H 2O 2 exposure increased the membrane fluidity of cardiomyocytes from the FO group. These results demonstrate that dietary FO supplementation is associated with a reduction in the susceptibility of myocytes to ROS-induced injury and this may be related to membrane incorporation of n-3 PUFAs, increased antioxidant defenses, changes in cardiomyocyte membrane fluidity, and the ability to prevent rises in cellular Ca 2+ in response to ROS.

In vivo assessment of the influence of cold preservation time on microvascular reperfusion injury after experimental small bowel transplantation.

This study describes the impact of prolonged cold storage on microvascular reperfusion injury of transplanted rat small bowel isografts. In vivo fluorescence microscopy was used to assess intestinal microcirculation after 6, 12, 18 and 24 h of cold (4 degrees C) ischaemia in University of Wisconsin solution and 20-90 min of reperfusion. Sham-operated animals served as controls. Whereas 6 and 12 h of ischaemia did not affect functional capillary density of the intestinal graft mucosa, villous perfusion was significantly impaired after 18 and 24 h of cold preservation. Similarly, microvascular perfusion of circular and longitudinal muscle was not affected after 6 h, but deteriorated following prolonged cold ischaemia. Leucocyte-endothelial cell interaction in submucosal venules was significantly enhanced after 6 h of ischaemia with peak values after 12 and 18 h. A progressive reduction of lymphatic capillary drainage indicated an ischaemia time-related deterioration in graft function. The results provide evidence that leucocyte-endothelial cell interaction in submucosal venules of the transplanted intestine is a primary step in the manifestation of reperfusion injury following short periods of cold ischaemia.

Pharmacological tools for the limitation of myocardial reperfusion injury Experimental evidence

Prompt re-establishment of coronary flow following coronary occlusion is mandatory for the preservation of myocardial tissue. The establishment of reperfusion treatment, originally by thrombolysis and subsequently by coronary interventions, was a major improvement in the management of patients with myocardial infarction. Myocardial damage is still seen even after very early initiation of successful reperfusion. Some of this damage has been ascribed to what has been labelled as reperfusion injury. Clinical manifestations of reperfusion injury include ventricular arrhythmia, compromised myocardial contractility and, most important for the subsequent prognosis, extension of the final infarct size. Many factors may contribute to the reperfusion injury. Among them is the release of free oxygen radicals with subsequent lipid peroxidation of cellular membranes. Intracellular calcium overload may cause excessive myofilament activation and impaired mitochondrial function, limit metabolic recovery and also activate proteases. Inflammatory activity and neutrophil activation are other factors of importance, as are endothelial dysfunction causing disturbances in nitric oxide (NO) availability and a compromised microvascular blood flow (the ‘noreflow’ phenomenon). Moreover, there is evidence that activation of the renin-angiotensin system may cause harm, e.g., by increasing the calcium content in the myocytes, by coronary vasoconstriction, and by modulation of the cardiac and vascular sympathetic activity. Some of these mechanisms may be interrelated. From considerations of their nature, an attractive hypothesis has been that some or several of these harmful effects may be counteracted by pharmacological interventions. This hypothesis has mainly been studied in the experimental setting. On the basis of the multiplicity of mechanisms that seem to be involved in the creation of reperfusion injury, a number of pharmacological agents have been investigated for their protective effect. Results from studies of some of them, namely beta-blockers, free oxygen radical scavengers, anti-oxidants, calcium channel blockers, inhibitors of the renin-angiotensin system and the combination of several of these drugs, are reviewed. Apart from beta-blockers, all these compounds have given effective protection from myocardial reperfusion damage. By studying them in different experimental settings and protocols, insight has been gained about important factors for possible future clinical applications of some or several of these drugs.

A New Model for the Assessment of Lung Allograft Ischemia/Reperfusion Injury

Lung edema is the main clinical manifestation of reperfusion injury following lung transplantation. The evaluation of strategies to prevent this injury is of high clinical importance. Therefore we developed a large-animal model to study the mechanisms of ischemia/reperfusion injury including dynamics of posttransplant reperfusion edema and their prevention. Left lung allotransplantation was performed in 6 weight-matched pigs (25-31 kg). Donor lungs were flushed with 1.5 L low-potassium dextran (LPD) solution (4oC) and preserved for 20 h at 1oC. One hour after reperfusion the recipient contralateral right lung was excluded from perfusion and ventilation to assess graft function only. Extravascular lung water index (EVLWI), intrathoracic blood volume (ITBV), and cardiac output (CO) were assessed (q = 30 min) with a lung water computer (Cold Z-021, Partig, Munich, Germany) by the thermo-dye technique during a 5-h observation period. Gas exchange (FIO2 = 1.0) was measured hourly, and hemodynamics were monitored continuously. The EVLWI of the recipient contralateral lung together with the donor left lung at the time of reperfusion was 6.5 +/- 1.1 ml/kg, increasing to 7.1 +/- 1.0 ml/kg at 60 min after reperfusion. After occlusion of the recipient right lung, EVLWI in the graft further increased within 80 min from 8.1 +/- 0.5 ml/kg to a peak of 11.4 +/- 1.3 ml/kg, followed by a decrease to 8.5 +/- 0.8 ml/kg at 5 h after reperfusion in 5 of 6 animals. In 1 animal a severe alveolar edema developed with subsequent deterioration of gas exchange and death 4.5 h after reperfusion. In this animal, peak EVLWI reached 16.8 ml/kg, PaO2 deteriorated from 60.1 to 7.8 kPa, and CO decreased from 3.1 to 1.4 L/min. In all other animals, ITBV (515 +/- 51 ml), left atrial pressure (LAP), central venous pressure (CVP), and CO (2.9 +/- 0.3 L/min) were stable during the 5-h assessment period. We conclude that EVLWI measurement is a reliable and very sensitive method to quantify lung allograft reperfusion edema. It may prove useful in early assessment of lung allograft reperfusion injury in the clinical setting and in experimental models.

Magnesium and cardiovascular disease.

Magnesium and cardiovascular disease.

Influence of a short-term acute ischemia and reperfusion on skeletal muscle metabolism and morphology in rabbits

The duration of the ischemia and reperfusion of the limbs determines the extent of tissue damage. The purpose of this study was to validate an in vivo model of ischemia-reperfusion injury with a short-term ischemic period of 1 hour which is comparable to several clinical situations. Thirteen New Zealand rabbits were randomly assigned to either (1) the sham operation (control), or (2) ischemiareperfusion group response to 1 hour of ischemia followed by 2 hours of reperfusion. Ischemia was created by clamping bilateral common femoral arteries and tourniquet occlusion of collateral circulation. Alterations of plasma potassium, malondialdehyde (MDA), muscle tissue intercellular thromboxane B2 (TxB2) concentrations, and morphometric determinations of skeletal muscle were parameters used to quantify reperfusion injury. Interstitial edema (median fraction of muscle interfiber area was 16.57% vs 13.39% in control,p=0.02), muscle cell shrinkage (median muscle fiber area was 3.70×103 μm2 vs 4.55×103 in control,p= 0.04), increased plasma potassium (median 4.7 mmol/L vs 3.6,p=0.02) in 2 hours and increased interstitial TxB2 in 1 hour were manifestation of reperfusion injury. We conclude that expansion of the extracellular space not accompanied by changes of plasma MDA may indicate that lipidperoxidation in reperfused muscle was negligible and interstitial edema was related to thromboxane A2 synthesis.

Absence of lethal reperfusion injury after 3 hours of reperfusion. A study in a single-canine-heart model of ischemia-reperfusion.

Whether reperfusion can cause necrosis of previously viable myocytes (lethal reperfusion injury) remains controversial. Numerous studies examined the ability of various agents to prevent or limit reperfusion injury, but the results were contradictory. In a single-canine-heart model of ischemia-reperfusion, we previously demonstrated that 5 minutes of reperfusion does not increase the transmural extent of necrosis. Since the 5-minute period of reperfusion is considered by some to be too short for the full manifestation of reperfusion injury, we reexamined the issue of lethal reperfusion injury using a modification of the single-heart model of ischemia-reperfusion that allowed extending the reperfusion period to 3 hours. In anesthetized, open-chest dogs, the distal half of the left anterior descending coronary artery (LAD) segment between the last diagonal branch and the apex was perfused via a shunt from the left carotid artery. The shunt was closed for periods of 90 to 180 minutes, depending on the ECG severity of ischemia, and reperfused for 3 hours. While the distal region was perfused from the carotid artery, the LAD was occluded proximal to the last diagonal branch for the same period of time as the distal region had been earlier. The time of occlusion was chosen such that the end of the occlusion period coincided with the end of the experiment. Thus, both regions of the LAD territory were subjected to identical periods of ischemia, but only the distal region was reperfused. At the end of the experiment, the boundary between the proximal (nonreperfused) and distal (reperfused) area was delineated by blue dye, and the heart was arrested, cut into slices 1 cm thick parallel to the LAD, and placed in triphenyltetrazolium chloride. The epicardial edges of necrosis in the reperfused and the nonreperfused regions were examined for any shift that might suggest a difference in the transmurality of necrosis. The areas of necrotic and viable myocardium were measured by planimetry within 1 cm on either side of the boundary. In all 14 dogs, the epicardial edges of necrosis ran as a single line across the boundary, and no shift was present. There was also no difference in the transmurality of necrosis between the reperfused and nonreperfused regions (64.9 +/- 20.7% versus 66.1 +/- 17.0% of left ventricular wall thickness, respectively, P = .32 by paired t test). In a single-canine-heart model of ischemia-reperfusion, there was no evidence of lethal reperfusion injury after 3 hours of reperfusion.

Timing of Arterialization in Liver Transplantation

This study analyzed the pathophysiologic sequela of different modes of graft reperfusion in liver transplantation. The grafted liver may be reperfused either immediately after completion of portal anastomosis followed by delayed arterial reconstruction or simultaneously by portal and arterial blood if all vascular anastomoses are completed during the anhepatic period. Delayed arterialization, that is, arterial reperfusion 8 minutes after portal revascularization (n = 12), was compared with simultaneous arterialization (n = 8) using the model of syngeneic orthotopic liver transplantation in male Lewis rats. After cold storage for 24 hours in University of Wisconsin (UW) solution, intravital fluorescence microscopy was employed 30 to 90 minutes after reperfusion to assess hepatic microvascular perfusion, leukocyte accumulation, and phagocytic activity of Kupffer cells. Compared with delayed arterialization, the number of both nonperfused acini and nonperfused sinusoids was reduced after simultaneous reperfusion by 71% (p = 0.008) and 78% (p < 0.001), respectively. Leukocyte accumulation in sinusoids and postsinusoidal venules after simultaneous arterialization decreased by 17% (p = 0.01) and 64% (P < 0.001), respectively. In addition, simultaneous revascularization was able to attenuate Kupffer cell activation, indicated by significantly slower adherence of latex beads injected 80 minutes after reperfusion. Improved hepatocellular excretory function after simultaneous arterialization was demonstrated by increased bile flow during the observation period of 90 minutes after reperfusion (2.24 +/- 0.7 vs. 0.95 +/- 0.4 mL/100 g liver [mean +/- SEM], p < 0.05). Timing of arterial reperfusion in liver transplantation may be of critical importance in the prevention of various manifestations of reperfusion injury.

Oxygen-derived free radicals and myocardial reperfusion injury: An overview

Reperfusion of acutely ischemic myocardium is associated with various distinctive pathophysiologic derangements, which are collectively referred to as reperfusion injury. Among these, three have been attributed to oxygen radicals: a) arrhythmias, b) transient mechanical dysfunction ("stunning"), and c) cell death. a) Reperfusion-induced arrhythmias. Although the precise mechanism for reperfusion arrhythmias remains to be determined, considerable evidence suggests that oxygen radicals play an important pathogenetic role in these rhythm disturbances. b) Transient mechanical dysfunction ("myocardial stunning"). Studies suggest that this abnormality is caused by events occurring in the initial seconds of reperfusion, and therefore represents a manifestation of sublethal, reversible reperfusion injury. Although our understanding of the mechanism of myocardial stunning is still fragmentary, there is overwhelming evidence for a pathogenetic role of oxygen radicals. c) Cell death. The evidence that reperfusion causes extension of the infarct produced by the antecedent ischemia is highly controversial. Although several studies have reported reduction of infarct size with antioxidants applied at the time of reperfusion, numerous other investigations have failed to reproduce these results. At present, there is no obvious explanation for this discrepancy. What is clear is that short-term administration of antioxidants at the time of reperfusion will not produce sustained limitation of infarct size. However, the possibility that long-term administration of antioxidants will produce sustained limitation of infarct size merits further consideration. In conclusion, there is strong evidence that the generation of oxygen radicals upon reperfusion plays an important pathogenetic role in two manifestations of reperfusion injury, namely, arrhythmias and stunning. Intense controversy persists regarding whether oxygen radicals contribute to extending cell death upon reperfusion and whether reperfusion in itself causes cell death. On the basis of the evidence available at this time, oxygen radicals appear to be important in the genesis of relatively mild, sublethal forms of myocellular damage, but their role in the genesis of lethal myocellular injury remains to be established.

Reduction of Postischemic Reperfusion Injury by the Vasoactive Drug Buflomedil

The effect of buflomedil on postischemic reperfusion injury was studied in the dorsal skin fold chamber preparation of awake hamsters. Microvascular events were investigated in the striated skin muscle by means of intravital fluorescence microscopy prior to 4 h of pressure-induced ischemia and 30 min, 2 and 24 h after reperfusion. In untreated control animals, ischemia and reperfusion provoked marked leukocyte sticking and macromolecular leakage while functional capillary density was reduced. Treatment with buflomedil (3 mg/kg b.w. in 0.3 ml saline, administered as bolus of 0.1 ml 10 min prior to release of ischemia followed by i.v. infusion of 0.2 ml during the first 20 min of reperfusion) significantly reduced leukocyte sticking and macromolecular leakage, while functional capillary density was effectively preserved. No differences in macro- and microhemodynamic parameters were observed between buflomedil-treated and untreated animals. These findings support the concept that activated leukocytes are involved in the microvascular manifestation of reperfusion injury and indicate that leukocyte sticking and its sequelae can be efficiently prevented by treatment with buflomedil.

Marked reduction of free radical generation and contractile dysfunction by antioxidant therapy begun at the time of reperfusion. Evidence that myocardial "stunning" is a manifestation of reperfusion injury.

Recent evidence suggests that postischemic myocardial dysfunction ("stunning") may be mediated by oxygen free radicals, but the exact time window during which the critical radical-mediated damage develops remains unknown. Furthermore, the evidence for the oxyradical hypothesis is indirect and, therefore, inconclusive. Thus, the potent and cell-permeable antioxidant N-(2-mercaptopropionyl)-glycine (MPG) was administered as an intra-coronary infusion (8 mg/kg/hr) to three groups of open-chest dogs undergoing a 15-minute coronary occlusion followed by 4 hours of reperfusion. In group I (n = 8), the infusion of MPG was started 15 minutes before occlusion and ended 2 hours after reperfusion; in group II (n = 9), MPG was started 1 minute before reperfusion and ended 2 hours thereafter; in group III (n = 10), MPG was started 1 minute after reperfusion and ended 2 hours and 15 minutes thereafter. Control dogs (group IV) (n = 10) received vehicle. Recovery of contractile function (assessed as systolic wall thickening) was equivalent in groups I and II, and in both groups it was substantially greater than in controls (p less than 0.005 at 4 hours). In contrast, in group III recovery of function was indistinguishable from controls. To determine whether the protection afforded by MPG was due to inhibition of free radical reactions, myocardial production of free radicals was directly assessed by intracoronary infusion of the spin trap alpha-phenyl N-tert-butyl nitrone (PBN). In control dogs (group VII, n = 6), radical adducts of PBN were released in the coronary venous blood after reperfusion, with a burst occurring in the first 5 minutes. MPG given as in group II (group V, n = 5) markedly suppressed myocardial production of PBN adducts (delta = -98% over 3 hours, p less than 0.01 vs. controls); this effect was evident immediately after reperfusion. MPG given as in group III (group VI, n = 5) also suppressed PBN adduct production (delta = -83% over 3 hours, p less than 0.025 vs. controls), but this effect was delayed. Hence, the radicals important in myocardial stunning appear to be those generated immediately after reperfusion. In vitro studies demonstrated that MPG is an exceptionally powerful scavenger of .OH (rate constant = 8.1 x 10(9) M-1 sec-1 by pulse radiolysis) but has no significant effect on .O2- (rate constant less than 10(3) M-1 sec-1), H2O2 (rate constant = 1.6 M-1 sec-1), or non-.OH-initiated lipid peroxidation, suggesting that removal of .OH is the major mechanism of the beneficial effects of MPG.(ABSTRACT TRUNCATED AT 400 WORDS)