Myocardial reperfusion injury: mechanisms and management--a review.
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Animals↗
Biomedical subjects
G Ambrosio
Publications and source records attributed to G Ambrosio.
The relationship between oxygen radical generation and impairment of myocardial energy metabolism following post-ischemic reperfusion.
Oxygen radical toxicity has been implicated in the pathogenesis of myocardial reperfusion injury. In the present study we sought to document the existence of a precise temporal relationship between the time course of free radical generation and the time course of alterations of myocardial energy metabolism during early reperfusion. Rabbit hearts perfused within the bore of a 31-Phosphorous NMR spectrometer were subjected to 30 min of total global ischemia at 37 degrees C. At reflow, 12 control hearts received a bolus of normal perfusate and 12 hearts recombinant human superoxide dismutase (h-SOD) as a 60,000 IU bolus followed by a 100 IU/ml infusion for 15 min. Ischemia resulted in similar depletion of tissue ATP and phosphocreatine (PCr) in the two groups. During the first minute of reflow, recovery of PCr was similar in both groups. However, PCr recovery arrested in control hearts after 2 min, at 63% of baseline, and averaged 64 +/- 4% after 45 min of reperfusion. In contrast, h-SOD treated hearts recovered 86.7% of baseline PCr content after 2 min, 102% after 10 min of reperfusion (P less than 0.001), and 93 +/- 6.4% at the end of the 45 min of reflow (P less than 0.01). The time course of free radical formation during reperfusion was assessed by EPR spectroscopy using both the frozen tissue and the spin trapping methodologies. In control hearts, peak generation of oxygen radicals was reached after 20 s of reflow. h-SOD treatment decreased concentrations of the oxygen-centered radicals in myocardial tissue and of the radical-adducts in the coronary effluent by approximately 80%. Thus, in reperfused hearts peak oxygen radical generation is followed by the occurrence of alterations in the recovery of high energy phosphate metabolism. Both events were largely prevented by administration of h-SOD at reflow. These results provide strong support for a link between oxygen free radical generation and post-ischemic reperfusion injury.
Adenosine Triphosphate↗
Multisystem involvement of the central nervous system in Strümpell's disease. A neurophysiological and neuropsychological study.
The multisystem involvement of the central nervous system (CNS) in familial spastic paraplegia (FSP) has not been fully investigated by means of complete neurophysiological and neuropsychological examinations. The classification which distinguishes pure and complicated forms of FSP, is based on clinical features and does not take into account the possibility that clinically silent lesions of the CNS can be identified by means of adequate tests. The study was intended to assess the subclinical and multisystem involvement of the CNS in a group of 11 patients affected by FSP, clinically distinguished in 7 pure forms and 4 complicated forms. Neurophysiological tests included saccadic eye movements analysis, visual and auditory brain stem evoked responses. Neuropsychological examination was devised by means of a special purpose mental deterioration battery. Our results, showing a high incidence of multisystemic subclinical involvement of the CNS, confirm and extend the concept that FSP is a multisystemic degenerative disease of the CNS, and that the existence of "pure" forms should be reconsidered.
Adolescent↗
Cellular electrophysiological basis for oxygen radical-induced arrhythmias. A patch-clamp study in guinea pig ventricular myocytes.
BACKGROUND: Oxygen radicals have been implicated in the pathogenesis of reperfusion arrhythmias. However, the basic electrophysiological alterations accompanying the effects of oxygen radicals on action potential (AP) are poorly understood. METHODS AND RESULTS: We investigated the effects of oxygen radicals generated by dihydroxyfumarate (DHF, 5 mM) on AP parameters and on ionic currents in patch-clamped guinea pig ventricular myocytes. DHF consistently caused a marked prolongation of AP duration, which was already significant after 60 seconds of exposure and continued to increase over time. Within 5 minutes, the majority of cells developed early afterdepolarizations (EADs) or became unexcitable. Both AP prolongation and occurrence of EADs were completely prevented in the presence of the oxygen radical scavengers superoxide dismutase (SOD) and catalase (CAT). Prolongation of AP duration was accompanied by a marked decreased in time-dependent potassium current (IK) and calcium current (ICa). The inward rectifier K current (IK1) was unaffected, suggesting no widespread changes in membrane properties. IK and ICa alterations were also significantly reduced by SOD and CAT. In additional experiments, intracellular calcium levels were kept constantly low by addition of 200 microM ethyleneglycol-bis(beta-aminoethyl ether)-N,N,N',N'-tetra-acetic acid (EGTA) to the pipette solution. Under these conditions, the effects of DHF on AP duration and the occurrence of EADs were largely prevented. However, EGTA did not prevent cells from becoming unexcitable, nor did it affect the decrease in both IK and ICa upon exposure to DHF. CONCLUSIONS: Exposure to an exogenous source of oxygen radicals may induce major electrophysiological alterations in isolated myocytes, which might be related to changes in specific ionic currents and in level of intracellular calcium. These alterations occur with a time course consistent with the rapid onset of ventricular arrhythmias in reperfused hearts.
Action Potentials↗
Oxygen radicals generated at reflow induce peroxidation of membrane lipids in reperfused hearts.
To test whether generation of oxygen radicals during postischemic reperfusion might promote peroxidation of cardiac membrane lipids, four groups of Langendorff-perfused rabbit hearts were processed at the end of (a) control perfusion, (b) 30 min of total global ischemia at 37 degrees C without reperfusion, (c) 30 min of ischemia followed by reperfusion with standard perfusate, (d) 30 min of ischemia followed by reperfusion with the oxygen radical scavenger human recombinant superoxide dismutase (h-SOD). The left ventricle was homogenized and tissue content of malonyldialdehyde (MDA), an end product of lipid peroxidation, was measured on the whole homogenate as well as on various subcellular fractions. Reperfusion was accompanied by a significant increase in MDA content of the whole homogenate and of the fraction enriched in mitochondria and lysosomes. This phenomenon was not observed in hearts subjected to ischemia but not reperfused, and was similarly absent in those hearts which received h-SOD at reflow. Reperfused hearts also had significantly greater levels of conjugated dienes (another marker of lipid peroxidation) in the mitochondrial-lysosomal fraction. Again, this phenomenon did not occur in ischemic hearts or in reperfused hearts treated with h-SOD. Unlike the effect on tissue MDA and conjugated dienes, reperfusion did not significantly stimulate release of MDA in the cardiac effluent. Treatment with h-SOD was also associated with significant improvement in the recovery of cardiac function. In conclusion, these data directly demonstrate that postischemic reperfusion results in enhanced lipid peroxidation of cardiac membranes, which can be blocked by h-SOD, and therefore is most likely secondary to oxygen radical generation at reflow.
Acetylglucosaminidase↗
[Human low-density lipoproteins are peroxidized by free radicals via chain reactions triggered by the superoxide radical].
Low-density lipoproteins (LDL) oxidized by oxygen radicals (OR) are a potent atherogenic stimulus. Chemically modified LDL are internalized by macrophages via a specific cell surface receptor that was termed the scavenger receptor, and may induce foam cells transformation. A free radical is any chemical species that has an unpaired electron. This property renders it highly chemically reactive. When a radical reacts with a non radical another free radical is generated. This characteristic enables radicals to trigger chain reactions. Oxygen radicals are: superoxide anion (.O2-), hydroxyl radical (.OH) and hydrogen peroxide (H2O2). It is unknown whether LDL are modified via direct lipid oxidation by OR, or whether LDL are subsequently oxidized via chain reactions after initial OR attack. To distinguish between these 2 mechanisms, LDL were exposed to OR formed by xanthine/xanthine oxidase (X/XO). Peroxidation was measured from malonyldialdehyde (MDA) levels. Parallel experiments were performed in presence of the superoxide radical scavenger superoxide dismutase (SOD; 330 U/ml), or the hydrogen peroxide scavenger catalase (CAT; 1000 U/ml), or by adding the chain-reaction inhibitor butylhydroxytoluene (BHT; 1 mM) at selected time points. SOD, but not CAT prevented LDL peroxidation, indicating an obligatory role for superoxide radicals. Superoxide generation in this model lasts only a few minutes, however, MDA levels continued to increase over several hours. Furthermore, this phenomenon was blocked when BHT was added at various times after X/XO. These data show that LDL peroxidation is triggered by initial OR generation but then involves chain reactions which do not require continuous exposure to OR.(ABSTRACT TRUNCATED AT 250 WORDS)
Free Radicals↗
Functional and morphological abnormalities in the retina of albino rats fed with a low protein diet after weaning.
Previously, we have reported a morphological study of the retina in albino rats fed with a low protein diet. The aim of this study is to verify our previous data and to obtain further informations about morphological and functional damages of the retina following low protein diet in albino rats. For this purpose the retinas of a group of weanling albino rats fed with a hypoproteic diet were studied with Light Microscopy (LM), Electron Microscopy (EM) and Electroretinography (ERG). Our results pointed out a correlation between the anatomic and functional ocular damages and proteinic malnutrition. LM showed a vacuolar degeneration of the optic fiber layer; the EM confirmed these results showing an optic fiber cytoskeleton modification together with glial proliferation. The functional damage as well seems to be correlated to the nutritional imbalance: the scotopic ERG in the experimental group shows a significant decrease (p less than 0.001) of the b-wave amplitude.
Animals↗
[Metabolic changes and their mechanical consequences in acute myocardial ischemia].
The recent advances in cardiovascular pathophysiology have changed our interpretation of the interplay between myocardial metabolism and contractile function which takes place during acute ischemia. For instance, the use of nuclear magnetic resonance (NMR) spectroscopy has allowed to document that the rapid impairment in contractility seen during acute myocardial ischemia is not directly related to depletion of high energy phosphate levels, nor to decreased availability of intracellular calcium. Rather, acidosis and inorganic phosphate accumulation cooperate to decrease myofilament sensitivity to calcium. Marked alterations of cardiac function and metabolism may also accompany the postischemic period. Positron emission tomography studies have shown that myocardial uptake of glucose remains disproportionately elevated in areas of myocardium which have been rendered transiently ischemic by an episode of stress-induced angina in patients with coronary artery disease. This phenomenon may have important practical applications, as it may be used as a metabolic marker to detect areas of myocardium which is viable, but potentially at risk for ischemic episodes. Reduced ATP levels are another biochemical alteration which can be typically found in postischemic hearts. Again, NMR spectroscopy has allowed to establish that these hearts often display near-normal mitochondrial function, and that the delayed resynthesis of ATP is due to lack of purine nucleotide precursors. A most interesting functional peculiarity of postischemic hearts is represented by the prolonged impairment of contractility, which largely outlasts the duration of the period of flow deprivation. This phenomenon, which eventually subsides over the course of hours or days, has been termed myocardial stunning, to underline its occurrence despite the absence of ultrastructural signs of irreversible damage.(ABSTRACT TRUNCATED AT 250 WORDS)
Acute Disease↗
[The possible limits of thrombolysis: reocclusion and reperfusion damage].
The availability of safe and potent thrombolytic drugs has made reperfusion within the initial few hours the treatment of choice in a vast number of patients with acute myocardial infarction. However, there remain several problems which may substantially reduce the possible beneficial effects of timely reperfusion of ischemic hearts. One important aspect is represented by the possible reocclusion of the infarct-related vessel. Many clinical studies have documented that in a relatively large proportion of patients, the infarct-related vessel may reocclude within few hours after discontinuation of thrombolytic therapy. This phenomenon would obviously hamper the results of thrombolysis in these patients. Investigation on the mechanisms responsible for this early reocclusion represents an area of active research. The results of several large clinical trials have shown that this phenomenon occurs despite full anticoagulation therapy, and it is apparently unrelated to the specific thrombolytic agent employed. On the other hand, experiments performed with animal models which reproduce the setting of a thrombogenic stimulus in the presence of a coronary artery stenosis have indicated that platelet activation plays a key role in the process of intracoronary thrombus formation, suggesting that antiplatelet interventions may be of benefit in this setting. Another potential problem which might partly offset the benefits of thrombolytic therapy is represented by the occurrence of a form of myocardial injury specifically associated with reperfusion. Several experimental studies have now demonstrated that a large amount of toxic oxygen metabolites (oxygen radicals) can be generated at the time of postischemic reperfusion, and that interventions with agents which can inactivate oxygen radicals, or prevent their formation, can significantly improve recovery of contractility and reduce infarct size in reperfused hearts. Although the actual incidence of this phenomenon is still debated, this issue has received considerable attention, because of the possibility of further expanding the benefits of thrombolysis should reperfusion injury be preventable in man.
Coronary Vessels↗
Reduction in infarct size by the phospholipase inhibitor quinacrine in dogs with coronary artery occlusion.
It has been suggested that activation of tissue phospholipases may contribute to the development of ischemic cell injury. In the present study we sought to assess whether administration of the phospholipase inhibitor quinacrine would reduce the extent of myocardial necrosis after coronary artery occlusion. In open-chest, anesthetized dogs the left anterior descending coronary artery was ligated, and technetium-99-labeled albumin microspheres were injected into the left atrium to measure the area at risk. The animals were then randomly divided into a control group (n = 8) and a group receiving quinacrine (5 mg/kg intravenous bolus followed by a 40 micrograms/kg/min infusion for 6 hours; n = 9). The animals were killed 6 hours after occlusion, and the infarcted area was delineated by triphenyltetrazolium chloride staining. The extent of the risk region was similar in the two groups (32.3 +/- 2.1% of the left ventricle in control dogs and 34.2 +/- 3.4% in quinacrine-treated dogs). Infarct size was 86.4 +/- 8.8% of the risk region in control animals, whereas in treated dogs it averaged 62.3 +/- 6.4% of the risk region (p = 0.05). No differences were found in heart rate, arterial pressure, and rate-pressure product between the two groups. Thus administration of the phospholipase inhibitor quinacrine reduced the extent of myocardial necrosis in a model of fixed coronary artery occlusion. Preservation of membrane phospholipids, reduced formation of lipoxygenase metabolites, or both may mediate this phenomenon.
Animals↗
Paradoxical effects of cardiac arrest by multidose potassium cardioplegia on myocardial lysosome integrity and phospholipid content.
Multidose potassium cardioplegia is known to result in greater preservation of myocardial ATP content and better recovery of function as compared to cardiac arrest induced by aortic clamping. The present study was undertaken to assess the effects of this procedure on biochemical markers of tissue damage. Rat hearts undergoing either multidose cardioplegia or ischemic cardiac arrest were maintained at 18 degrees C for 1 or 2 hr and processed without reperfusion. Control hearts were processed at time zero. The activity of two lysosomal enzymes (beta-glucuronidase and acid phosphatase), as well as membrane phospholipid content, was measured in cardiac homogenates. One hour of arrest by either technique did not induce significant changes in these parameters. Two hours of arrest affected lysosomal integrity, as indicated by release of lysosomal enzymes into the cytosol. Soluble acid phosphatase activity averaged 44.7 +/- 1.3 mU/mg of protein in the hearts processed after 2 hr of cardioplegic arrest, and was significantly higher than that of control hearts (12.3 +/- 3.8 mU/mg of protein; P less than 0.01) and that of hearts subjected to 2 hr of ischemic arrest (29.2 +/- 4.5 mU/mg of protein; P less than 0.01 vs cardioplegic arrest; P less than 0.01 vs controls). Phospholipid content in hearts subjected to 2 hr of cardioplegic arrest was lower than in controls (0.49 +/- 0.06 micrograms Pi/mg of protein vs 0.76 +/- 0.03 micrograms Pi/mg of protein; P less than 0.01). In conclusion, 2 hr of hypothermic cardiac arrest was associated with biochemical indices of tissue damage.(ABSTRACT TRUNCATED AT 250 WORDS)
Acid Phosphatase↗
Reduced aerobic metabolic efficiency in globally "stunned" myocardium.
Post-ischemic "stunned" myocardium appears to be metabolically inefficient, since oxygen consumption is preserved, while mechanical work is depressed. The present study investigated whether this metabolic inefficiency represents a basal functional abnormality present in the quiescent myocardium (e.g. abnormal mitochondrial coupling) or is specifically related to muscle contraction. Isolated perfused rabbit hearts (n = 7) were exposed to 20 min zero-flow ischemia to produce post-ischemic myocardial stunning. After 10 min of reperfusion, mean rate-pressure product (mmHg/min), was reduced to 56.1% of baseline in stunned hearts, while mean oxygen consumption (mumol O2/min/g LV) was reduced to only 71.8% of baseline. The ratio of oxygen consumption to rate-pressure product remained significantly elevated throughout 40 min of reperfusion when compared with non-ischemic controls (P less than 0.01). Despite inappropriately high oxygen consumption in the beating stunned heart, basal oxygen consumption measured after KCl arrest was not significantly different from controls (1.07 +/- 0.07 vs. 1.03 +/- 0.04, respectively). These results indicate that the metabolic inefficiency found in stunned myocardium is not a basal abnormality, but rather is related specifically to abnormalities in contraction or electromechanical coupling.
Animals↗
The contribution of saccadic eye movements analysis, visual and auditory evoked responses to the diagnosis of multiple sclerosis.
A number of tests have been used to identify paraclinical evidences of central nervous system (CNS) lesions in multiple sclerosis (MS). The present study was aimed to test and compare the diagnostic value of saccadic eye movements (SEM) analysis, and visual and auditory brain stem evoked responses (VER, ABER) in MS, and to study the correlation between electrophysiologic findings and clinical data. The reference group for epidemiological and statistical analysis was selected from the group of 109 suspected MS patients included in the study. SEM analysis resulted at least as sensitive as VER and ABER. SEM analysis showed good sensitivity and positive predictive value. Saccade latency resulted the most sensitive SEM parameter. Subclinical internuclear ophthalmoparesis resulted highly specific. We suggest that SEM analysis could be included into the electrophysiologic tests for identifying paraclinical evidences of CNS lesions in MS. Correlations between electrophysiologic findings and clinical data are discussed.
Adolescent↗
Timing of treatment with oxygen radical scavengers and its influence on reperfusion injury.
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Free Radicals↗
Effects of ATP precursors on ATP and free ADP content and functional recovery of postischemic hearts.
It has been proposed that administration of adenine nucleotide precursors might accelerate replenishment of myocardial ATP and "free" ADP, thus improving recovery of depressed contractility of postischemic hearts. To test this hypothesis, Langendorff-perfused rabbit hearts were subjected to 20 min of global ischemia and reperfused for 2 h with normal perfusate (n = 8) or perfusate containing 100 mumol/l of the ATP precursors adenosine (n = 8) or 5-amino-4-imidazolecarboxamide riboside (AICAriboside; n = 8). After reperfusion, developed pressure in untreated hearts averaged 70-80% of base line, whereas ATP content was reduced to approximately 70% of preischemic values. AICAriboside administration did not increase tissue ATP levels or contractility. However, in every heart that received adenosine during reperfusion, ATP content increased from a mean value of 65 +/- 4% of base line to 84 +/- 5% at the end of reperfusion (P less than 0.001). Free ADP also increased in adenosine-treated hearts from 40 to 50% of base line at the beginning of reperfusion, to normal levels by 60 min. However, no improvement in contractility was observed in the hearts that received adenosine. These results support the hypothesis that decreased availability of nucleotide precursors is responsible for depressed ATP levels in postischemic hearts; however, reduced ATP and free ADP levels may not be directly responsible for the depressed function of stunned myocardium.
Adenosine Diphosphate↗
Progressive impairment of regional myocardial perfusion after initial restoration of postischemic blood flow.
The "no-reflow" phenomenon, the occurrence of areas with very low flow in hearts reperfused after ischemia, is thought to be largely established at the time of reperfusion as a result of microvascular damage induced by ischemia. In the present study we sought to determine whether additional impairment of tissue perfusion might also occur during the course of reperfusion. Open-chest dogs were subjected to 90 minutes of left circumflex coronary artery occlusion and reperfused for 2 minutes (n = 7) or 3.5 hours (n = 8). Myocardial perfusion was visualized in left ventricular slices following in vivo injection of the fluorescent dye thioflavin-S just before killing. The area of impaired perfusion (absent thioflavin) averaged 9.5 +/- 3.0% of the risk region in dogs reperfused for 2 minutes, whereas it was nearly three times as large in dogs reperfused for 3.5 hours (25.9 +/- 8.2% of the risk region, p less than 0.05). Serial measurements of flow by microspheres during reperfusion demonstrated zones within the postischemic myocardium that were hyperemic 2 minutes after reperfusion, with adequate flow still present at 30 minutes, but with a subsequent marked fall in perfusion. After 3.5 hours these areas showed negligible flow (0.13 +/- 0.3 ml/min/g) and no thioflavin uptake. Tissue samples showing postischemic impairment in perfusion has received virtually no collateral flow during ischemia (less than 0.01 ml/min/g), whereas collateral flow was significantly higher in adjacent thioflavin-positive zones (0.04 +/- 0.01 ml/min/g in endocardial samples and 0.07 +/- 0.02 ml/min/g in samples from the midmyocardium, p less than 0.001 vs. thioflavin-negative areas). Areas that showed late impairment of flow invariably demonstrated contraction band necrosis, which contrasted with the pattern of coagulation necrosis observed in areas of "true" (i.e., immediate) no-reflow. Intracapillary erythrocyte stasis and marked intravascular neutrophil accumulation (to levels greater than 20-fold that found after 2 minutes reperfusion) were typically observed in areas of delayed impairment to flow. Obstruction to flow at the capillary level was confirmed in additional dogs in which the heart was injected postmortem with silicone rubber to delineate the microvascular filling pattern. Areas of absent capillary filling were much more extensive after 3.5 hours than after 2 minutes reperfusion. Thus, this study shows that the occurrence of areas of markedly impaired perfusion in postischemic myocardium is related only in part to an inability to reperfuse certain areas on reflow. A more important factor is represented by a delayed, progressive fall in flow to areas that initially received adequate reperfusion.(ABSTRACT TRUNCATED AT 400 WORDS)
Animals↗
Effects of pharmacological treatment of acute myocardial infarction on left ventricular function.
Impairment of left ventricular function is a major consequence of acute myocardial infarction. Several interventions have been proposed to reduce the extent of myocardial tissue undergoing necrosis after cornoracy artery occlusion. Therapy for patients with acute myocardial infarction has long relied on interventions aimed at reducing oxygen consumption, such as administration of beta-blockers and nitrates. However, despite clinical evidence that these interventions can reduce mortality or prevent left ventricular dilatation, no clear benefit has been observed on left ventricular function. Over the past few years, treatment of acute myocardial infarction has radically changed. Availability of several thrombolytic agents has made reperfusion of ischemic myocardium a routine procedure. Early reperfusion has been shown to be the most powerful intervention to reduce infarct size and minimize left ventricular dysfunction in experimental preparations. Several clinical trials have also demonstrated that patients with acute myocardial infarction may greatly benefit from early thrombolysis, as this procedure is associated with improvement of global and regional left ventricular function and reduction in mortality. However, in spite of its obvious advantages, reperfusion might result in a paradoxical tissue damage that may blunt the net beneficial effect of restoring perfusion of ischemic myocardium. Reperfusion-mediated myocardial injury has been shown to occur in several experimental preparations and it has been proposed that generation of toxic oxygen metabolites at the moment of reflow is responsible for the occurrence of this phenomenon. Indeed, administration of free radical scavengers may significantly reduce the extent of reperfusion injury and improve contractile recovery in experimental preparations.(ABSTRACT TRUNCATED AT 250 WORDS)
Heart↗
Electroretinographic findings in inherited ataxias.
Electroretinogram was performed in 18 patients with inherited ataxias. Eight had Friedreich's disease, 9 autosomal dominant cerebellar ataxia and one early onset cerebellar ataxia with retained tendon reflexes. Abnormalities were found in one patient for each group. The most frequent were decreased b-wave amplitude in photopic and scotopic conditions and prolonged implicit time.
Adolescent↗