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Biomedical subjects

K A Reimer

Publications and source records attributed to K A Reimer.

At least 55 records · Page 3Linked to original sources
PubMed1990

Glutathione protects cardiac and skeletal muscle from cyclophosphamide-induced toxicity.

Administration of cyclophosphamide at a dose which is lethal to 10% of control athymic nude mice resulted in sudden death within 3 h in all mice that had been pretreated with the glutathione synthesis inhibitor L-buthionine-SR-sulfoximine. In Fischer 344 rats pretreated with L-buthionine-SR-sulfoximine, the cyclophosphamide dose producing 100% acute toxicity was lowered from 500-150 mg/kg; cardiac monitoring revealed ventricular fibrillation to be the cause of death. These and additional studies reported demonstrate that cytoplasmic glutathione is an important protectant against the cardiac and skeletal muscle toxicity of cyclophosphamide and indicate that such toxicity may be substantially increased by glutathione depletion. Since diet and many drugs (including cyclophosphamide itself) are known to affect glutathione levels, the present studies suggest that cardiac and skeletal muscle glutathione content is likely to be a clinically significant determinant of the frequency and severity of the adverse drug interactions and systemic toxicity sometimes observed during cyclophosphamide therapy.

Animals↗
PubMed1990

Cardiac rupture, mortality and the timing of thrombolytic therapy: a meta-analysis.

This study examined the relation between the risk of cardiac rupture and the timing of thrombolytic therapy for acute myocardial infarction. To test the hypothesis that cardiac rupture is prevented by early thrombolytic therapy but is promoted by late treatment, randomized controlled trials of thrombolytic agents for myocardial infarction were pooled. A logistic regression model including 58 cases of cardiac rupture among 1,638 patients from four trials showed that the odds ratio (treated/control) of cardiac rupture was directly correlated with time to treatment (p = 0.01); at 7 h, the odds ratio was 0.4 (95% confidence limits 0.17 to 0.93); at 11 h, it was 0.93 (0.53 to 1.60) and at 17 h, it was 3.21 (1.10 to 10.1). Analysis of data from the Gruppo Italiano per lo Studio della Streptochinasi nell'Infarto Miocardico (GISSI) trial independently confirmed the relation between time to thrombolytic therapy and risk of cardiac rupture (p = 0.03). Analysis of 4,692 deaths in 44,346 patients demonstrated that the odds ratio of death was also directly correlated with time to treatment (p = 0.006); at 3 h, the odds ratio for death was 0.72 (0.67 to 0.77); at 14 h, it was 0.88 (0.77 to 1.00) and at 21 h, it was 1 (0.82 to 1.37). Thrombolytic therapy early after acute myocardial infarction improves survival and decreases the risk of cardiac rupture. Late administration of thrombolytic therapy also appears to improve survival but may increase the risk of cardiac rupture.

Drug Administration Schedule↗
PubMed1990

Oxygen-derived free radicals and postischemic myocardial reperfusion: therapeutic implications.

Oxygen-derived free radicals have been implicated in the pathogenesis of various disease states, including myocardial ischemia and reperfusion. In this article, we review 1) the evidence linking free radical production and myocardial injury during myocardial ischemia and reperfusion and 2) results of studies of the effects of the pharmacological therapies available potentially to prevent free radical-mediated injury. Free radicals can be produced during ischemia and reperfusion by several different biochemical pathways. Of these, the xanthine oxidase reaction and the output of free radicals by neutrophils that have accumulated in damaged tissue have been studied extensively. When produced, free radicals can potentially damage myocytes or endothelial cells through peroxidation of membrane lipids or damage to proteins or nucleic acids. Using electron spin resonance spectroscopy, several studies have shown a 'burst' of oxygen free radicals immediately after reperfusion. Moreover, exogenous generation of intravascular free radicals has been shown to produce marked vascular and myocyte damage, as well as contractile dysfunction. 'Anti-free radical' interventions, such as xanthine oxidase inhibitors and free radical scavengers have been reported to prevent contractile dysfunction and reperfusion-induced arrhythmias after an episode of reversible ischemic injury. However, after more severe episodes of ischemia, such interventions have had conflicting effects on myocardial infarct size. 'Anti-free radical' interventions could be of potential use in situations where reversible ischemic injury occurs. In situations where reperfusion is achieved after irreversible ischemic injury has occurred, the potential beneficial effect of these treatments on infarct size is more doubtful.

Animals↗
PubMed1990

Electrophysiological effects of monophasic and biphasic stimuli in normal and infarcted dogs.

Though some biphasic waveforms significantly decrease the energy required for defibrillation, little is known about the effect of biphasic stimulation on the determination of other electrophysiological parameters in normal and infarcted hearts. To evaluate this, nine normal dogs and 12 dogs with myocardial infarction had activation threshold (AT), effective refractory period (ERP), strength-interval curves, and ventricular fibrillation threshold (VFT) determined with constant current stimulation to a pair of right ventricular plunge electrodes, and upper limit of vulnerability (ULV) and defibrillation threshold (DFT) determined with truncated exponential shocks delivered to a pair of wire electrodes coiled to contour the right and left ventricular epicardium. Each electrophysiological parameter was determined with a 5.5 msec monophasic and 5.5-msec biphasic (3.5 msec first phase) waveform. Though AT and VFT were not significantly different for the two waveforms, the ERP was significantly longer, the strength-interval curve shifted rightward, and the threshold for repetitive responses higher for biphasic stimuli. Compared to the monophasic waveform, the ULV and DFT were significantly decreased in a parallel fashion for the biphasic waveform. Neither the presence nor size of myocardial infarction significantly affected any of the measured electrophysiological parameters. In six additional dogs, sigmoid defibrillation probability curves were constructed from biphasic shocks of four energies including that of the DFT and ULV. The ULV energy predicted an effective dose that defibrillated 97% of the time (range 90%-100%). In conclusion, the increased defibrillation efficacy of the biphasic waveform is independent of its ability to activate fully repolarized myocardium and cannot be explained by a greater ability of biphasic waveforms to activate partially depolarized tissue. The parallel decrease in the ULV and DFT for biphasic stimulation and the finding that the ULV energy defibrillates with a high probability of success suggest similar underlying mechanisms for the ULV and defibrillation.

Animals↗
PubMed1990

Ischemic preconditioning slows energy metabolism and delays ultrastructural damage during a sustained ischemic episode.

We have shown previously that preconditioning myocardium with four 5-minute episodes of ischemia and reperfusion dramatically limited the size of infarcts caused by a subsequent 40-minute episode of sustained ischemia. The current study was undertaken to assess whether the same preconditioning protocol slowed the loss of high energy phosphates, limited catabolite accumulation, and/or delayed ultrastructural damage during a sustained ischemic episode. Myocardial metabolites and ultrastructure in the severely ischemic subendocardial regions were compared between control and preconditioned canine hearts. Hearts (four to 10 per group) were excised after 0, 5, 10, 20, or 40 minutes of sustained ischemia. All groups had comparable collateral blood flow. Preconditioned hearts developed ultrastructural injury more slowly than controls; evidence of irreversible injury was observed after 20 minutes in controls but not until 40 minutes in preconditioned hearts. Furthermore, after 40 minutes of ischemia, irreversible injury was homogeneous in controls but only focal in preconditioned myocardium. Preconditioning reduced starting levels of ATP by 29%. Nevertheless, it also slowed the rate of ATP depletion during the episode of sustained ischemia, so that after 10 minutes of ischemia, preconditioned hearts had more ATP than controls. However, after 40 minutes, ATP contents were not significantly different between groups. Preservation of ATP resulted from reduced ATP utilization and was not due to increased ATP production. Accumulation of purine nucleosides and bases (products of adenine nucleotide degradation) was limited in preconditioned myocardium. Accumulation of glucose-1-phosphate, glucose-6-phosphate, and lactate also was reduced markedly by preconditioning, due to reduced rates of glycogen breakdown and and anaerobic glycolysis. We propose that preconditioning reduces myocardial energy demand during ischemia, which results in a reduced rate of high energy phosphate utilization and a reduced rate of anaerobic glycolysis. Either preservation of ATP or reduction of the cellular load of catabolites may be responsible for delaying ischemic cell death.

Adenine Nucleotides↗
PubMed1990

Evidence against the "early protection-delayed death" hypothesis of superoxide dismutase therapy in experimental myocardial infarction. Polyethylene glycol-superoxide dismutase plus catalase does not limit myocardial infarct size in dogs.

We previously found that superoxide dismutase (SOD) did not limit myocardial infarct size after 40 or 90 minutes of ischemia and 4 days of reperfusion in dogs. Because some other studies have shown limitation of infarct size after shorter periods of reperfusion, we postulated that our negative results might be due to late reperfusion injury mediated by superoxide anions produced after excretion of SOD. To test this "early protection-delayed death" hypothesis, we have examined whether SOD, conjugated to polyethylene glycol (PEG-SOD) to prolong its circulating half-life, limited myocardial infarct size. The circumflex artery was occluded for 90 minutes followed by 4 days of reperfusion. PEG-SOD (total dose, 10,000 units/kg) and catalase (55,000 units/kg) were given during the 30 minutes before reperfusion. Plasma SOD levels in the treated group were 330 +/- 20 units/ml at the onset of reperfusion and 140 +/- 10 units/ml on day 4 (circulating half-life, 75 +/- 5 hours) versus 5 +/- 1 units/ml in controls. Histological infarct size was 37.1 +/- 4.2% of the area at risk in the treated group (n = 11) versus 44.5 +/- 6.2% in controls (n = 10) (p = NS). Infarct size and collateral blood flow were inversely related in controls; PEG-SOD and catalase did not shift this regression (p = NS by analysis of covariance). Thus, infarct size was not limited when measured after 4 days of reperfusion, even though plasma SOD exceeded 100 units/ml throughout this reperfusion period.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Evaluation of free radical injury in myocardium.

Abundant evidence now is available that free radicals are produced in excess when myocardium is reperfused following an episode of ischemia and that free radicals can injure myocytes and endothelial cells. Free radicals may contribute to either reversible or irreversible manifestations of cell injury from ischemia and reperfusion. Several investigators have observed that post-ischemic contractile dysfunction (myocardial stunning) can be attenuated by a variety of anti-free radical therapies, and there seems to be general agreement that free radical injury contributes to stunning. Whether free radicals are an important cause of lethal myocyte injury ("lethal reperfusion injury") remains controversial. Using similar interventions and animal models, both positive and negative results have been reported from a growing number of studies done to test the effect of anti-free radical therapies on infarct size. Proposed explanations include differences in: 1) dose of drug and onset or duration of treatment, 2) duration of occlusion or reperfusion, 3) methods of measuring infarct size or area at risk, and 4) failure of some studies to control for baseline variation in the major determinants of infarct size, e.g., collateral blood flow. At present, none of these explanations seems sufficient to resolve the question.

Animals↗
PubMed1990

Development of cell injury in sustained acute ischemia.

Sudden induction of ischemia by occlusion of a major branch of a coronary artery in mammalian heart sets into motion a series of events that culminates in the death of markedly ischemic myocytes. The changes begin within 8-10 seconds of occlusion and include 1) cessation of aerobic metabolism, 2) depletion of creatine phosphate, 3) onset of anaerobic glycolysis (AG), and 4) accumulation of products of anoxic metabolism in the ischemic tissue. Functional defects appear simultaneously, including depressed contractile activity and electrocardiographic changes. The demand of the ischemic myocytes for energy exceeds the supply of high-energy phosphate (approximately P) possible from AG; as a consequence, myocyte adenosine diphosphate increases, and adenylate kinase is activated to capture the approximately P bond of adenosine diphosphate. Adenosine monophosphate is a product of this reaction; it accumulates and is progressively degraded to nucleosides and bases that are lost from the myocyte. The pace of development of the short-term metabolic changes slows after 40-60 minutes of ischemia, at which time most of the severely ischemic myocytes are irreversibly injured. Early in the irreversible phase of injury tissue is characterized as follows by: 1) very low approximately P content (creatine phosphate less than 1-2% and adenosine triphosphate less than 10% of control), 2) a depressed adenine nucleotide pool that consists principally of adenosine monophosphate, 3) virtual cessation of AG, 4) low pH and low glycogen content, 5) high inosine and hypoxanthine contents, 6) a markedly increased osmolar load consisting chiefly of lactate, and 7) characteristic ultrastructural changes including cell swelling and evidence of generalized mitochondrial and marked sarcolemmal damage. Sarcolemmal disruption is the feature that we hypothesize causes irreversibility; however, its pathogenesis is unknown.

Acute Disease↗
PubMed1989

Correlates of survival in patients with postinfarction ventricular septal defect.

Prognostic indicators of survival in 42 consecutive patients (21 men and 21 women) with postinfarction ventricular septal defect were reviewed. Infarct location was anterior in 57%, inferior in 33%, and combined in 10%. The hospital mortality among 9 patients not receiving surgical therapy was 100%. Of the 33 surgically treated patients, 19 (58%) survived. Time from diagnosis to operation, ventricular function, and presence or absence of shock were analyzed in a logistic regression model to determine which factors carried independent prognostic value. Shock was independently predictive of operative mortality (p less than 0.01). Of additional variables examined, nonsurvivors were characterized by a shorter time from postinfarction ventricular septal defect to operation, a relatively higher incidence of inferior infarction, moderate right ventricular dysfunction and mild left ventricular dysfunction, and a lower right ventricular systolic pressure. Results of postmortem examination were available for 15 nonsurvivors. Quantitative analysis of percent ventricle infarcted revealed that in patients with inferior infarctions, a mean of 31% of the right ventricle was infarcted compared with 10% in patients with anterior infarction (p = 0.059). Kaplan-Meier survival estimates revealed 1-year survival of 70%, 5-year survival of 55%, and 10-year survival of 20%. Seventy percent of survivors were in New York Heart Association class I or II. These data show that, irrespective of ventricular function or timing of operation, the development of shock is the most important predictor of survival in postinfarction ventricular septal defect. The higher mortality in patients with inferior infarction may be associated with a greater degree of right ventricular infarction and consequent dysfunction. Finally, long-term survival and excellent functional recovery can be achieved in patients undergoing operation.

Aged↗
PubMed1989

Total ischemia III: Effect of inhibition of anaerobic glycolysis.

The effect of inhibition of glycolysis with sodium iodoacetate (IAA) on the changes induced by total ischemia was studied in canine left ventricle. Hearts were excised from phenobarbital anesthetized dogs and the circumflex (LCC) and anterior descending (LAD) branches of the left coronary artery were perfused in order to expose the LCC region to 48 mumol of IAA (about 1.5 mumol/g wet wt). The LAD regions of the same hearts served as untreated control myocardium. Hearts then were subjected to total ischemia in vitro at 37 degrees C. Metabolites, ultrastructure, and the capacity of thin incubated slices of heart to maintain volume and ion gradients were studied in the control and IAA-treated regions. Depletion of ATP to levels of 3-4% of control occurred in only 4-5 min of ischemia in the IAA-treated myocardium, but similar depletion required 90 min of total ischemia in untreated myocardium. These low levels of ATP were associated with marked contracture-rigor. Depletion of ATP in the IAA treated region was accompanied by a marked increase in adenosine levels in the tissue at the onset of rigor (approximately 5 min); at this time, as much as 50% of the adenine nucleotide pool (sigma Ad) was in the form of adenosine. In contrast, inosine was the predominant catabolite at 5 min in control myocardium, and only composed 16% of the sigma Ad pool. Thus, pretreatment with IAA produced an enormous acceleration in the rate at which the sigma Ad pool was consumed in totally ischemic myocardium. Lactate, the principal glycolytic intermediate which accumulates in totally ischemic tissue, was not formed in the IAA-treated heart. Moreover, IAA treatment did not accelerate the rate at which ultrastructural evidence of lethal injury developed in the poisoned myocytes. Thus, in a setting in which lactate accumulation did not occur, totally ischemic myocytes tolerated a very low level of high energy phosphate for a longer period of time than did untreated tissue before ultrastructural signs of cell death developed. The results indicate that marked ATP depletion, pe se, does not necessarily cause prompt sarcolemmal disruption.

Adenine Nucleotides↗
PubMed1989

Effect of a critical coronary stenosis on myocardial neutrophil accumulation during ischemia and early reperfusion in dogs.

In many experimental models of ischemia and reperfusion, reperfusion is performed abruptly, allowing full reactive hyperemia to occur. In the clinical setting, however, reperfusion after thrombolysis is often limited by residual stenosis. Some experimental models attempt to mimic this situation with a "critical stenosis" (defined as a coronary constriction sufficient to abolish reactive hyperemia without altering baseline flow). The purpose of this study was to determine whether preventing reactive hyperemia during the initial phase of reperfusion would modify the transmural distribution of myocardial blood flow or the myocardial accumulation of polymorphonuclear leukocytes (PMNs). The left circumflex artery was occluded for 90 minutes and then reperfused for 60 minutes in anesthetized, open-chest dogs. Autologous PMNs were isolated, labeled with 111In, and reinjected 1 hour before coronary occlusion. 125I-labeled albumin was injected simultaneously to correct for 111In associated with plasma proteins and to permit calculation of the number of PMNs in the inner, middle, and outer thirds of nonischemic and ischemic-reperfused tissue. The presence of a critical stenosis abolished reactive hyperemia during the first 5 minutes of reperfusion, but did not substantially affect blood flow measured after 55 minutes of reperfusion. In both groups, there was a significant accumulation of PMNs in all layers of the ischemic-reperfused bed compared with the nonischemic bed, and the magnitude of this PMN accumulation was not altered by the presence of a critical stenosis. Moreover, infarct size, estimated by triphenyl tetrazolium chloride (TTC) loss after 60 minutes of reperfusion, was not affected by the presence of a critical stenosis. Thus, the presence of a critical stenosis abolished the hyperemic blood flow after reperfusion but did not influence the early PMN response to ischemia and reperfusion or the early loss of TTC staining.

Animals↗
PubMed1988

The xanthine oxidase inhibitor oxypurinol does not limit infarct size in a canine model of 40 minutes of ischemia with reperfusion.

Free radicals such as superoxide (.O2-) produced by xanthine oxidase might cause cell death during reperfusion after myocardial ischemia. The effect of the xanthine oxidase inhibitor allopurinol on infarct size in ischemia-reperfusion models has been variable, possibly because of differences in treatment duration. Adequate inhibition of xanthine oxidase may require a sufficient pretreatment period to permit conversion of allopurinol to oxypurinol, the actual inhibitor of superoxide production. To test more definitively whether xanthine oxidase-derived free radicals cause cell death during reperfusion, the effect of oxypurinol on infarct size was evaluated in an ischemia-reperfusion model. Open chest dogs underwent 40 min of circumflex coronary artery occlusion followed by reperfusion for 4 days. Twelve dogs were treated with oxypurinol (10 mg/kg body weight intravenously 10 min before occlusion and 10 mg/kg intravenously 10 min before reperfusion) and 11 control dogs received drug vehicle alone (pH 10 normal saline solution). Nine control dogs from a concurrent study also were included. Infarct size was measured histologically and analyzed with respect to its major baseline predictors, including anatomic area at risk and collateral blood flow (measured with radioactive microspheres). Infarct size as a percent of the area at risk averaged 23.8 +/- 2.7% (mean +/- SEM) in the oxypurinol group (n = 10) and 23.1 +/- 4.2% in the control group (n = 17) (p = NS). Collateral blood flow to the inner two thirds of the ischemic wall averaged 0.08 +/- 0.01 ml/min per g in the oxypurinol group and 0.09 +/- 0.02 ml/min per g in the control group.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1988

Chondrosarcoma metastatic to the heart.

This review summarizes the clinical manifestations and results of treatment of chondrosarcoma metastatic to the heart. Including the patient in the present report, a total of 18 patients have been reported. The most common site of cardiac metastasis was the right atrium. Dyspnea and pleuritic chest pain were the most common symptoms associated with cardiac metastases. The median time from the initial diagnosis of primary chondrosarcoma to death was 36 months, and the median time from the initiation of cardiac symptoms to death was 2 months. Treatment of primary chondrosarcoma included local radical resection in 14 patients. Treatment of cardiac metastases consisted of palliative support in 13 patients and surgical resection in 5 patients. Median survival following the development of cardiac symptoms was 2 months for patients treated nonsurgically and 18 months for those who underwent resection of cardiac metastases. The longest survival (24 and 28 months) was obtained in 2 patients with metastases confined to the heart that were successfully resected soon after development of cardiac symptoms. These results suggest that surgical resection of cardiac metastases in patients without widespread other metastases can result in substantial prolongation of life.

Chondrosarcoma↗
PubMed1988

Complete global myocardial ischemia in dogs.

Complete global myocardial ischemia or zero coronary arterial flow in dogs results in a series of well-defined changes which begin when the myocardium converts from aerobic to anaerobic metabolism. These processes continue until the myocardium dies. The products of anaerobic metabolism, chiefly glycolytic intermediates, inorganic phosphate, H+, and creatine, are produced intracellularly and accumulate in the tissue. Because the demand for high-energy phosphates (HEP) in the tissue exceeds the supply available from anaerobic glycolysis and HEP reserves, net ATP level declines, approaching zero after 100 min of ischemia at 37 degrees C. At this time, the changes in totally ischemic tissue in vitro are equivalent to those seen in myocytes irreversibly injured by severe ischemia in vivo. During reoxygenation after total ischemia, the resumption of effective contractile activity depends partly on the metabolic changes and degree of myocyte injury sustained during ischemia.

Animals↗