Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0151744 (myocardial ischemia)
 31,282 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The purpose of this study was to determine whether normal fibrinogen contributes to the development of myocardial reperfusion injury by acting as a substrate in vivo for neutrophil adhesion. This was tested in a dog model of acute myocardial infarction that used pentobarbital anesthetized dogs subjected to 90 min regional myocardial ischemia and 5 h reperfusion. Dogs were treated with 1 unit/kg Ancrod (venom from the Malayan pit viper, Agkistrodon rhodostoma) or vehicle i.v. 60 min after left circumflex coronary artery occlusion. Therapeutic defibrination was verified in Ancrod-treated dogs by measurements of clottable fibrinogen, alpha-2 antiplasmin and plasminogen, by the activated partial thromboplastin time and by immunoelectrophoresis. Fibrinogen was depleted to below detectable limits of the assay (less than 0.05 mg/ml) after treatment with Ancrod. The defibrination effect was accomplished by the expected activation of the fibrinolytic system: alpha-2 antiplasmin was decreased by 10% and plasminogen activity was decreased by 30% with Ancrod treatment. There were no measureable differences between the two treatment groups in heart rate, mean arterial blood pressure, rate pressure product or circumflex coronary blood flow throughout the 90 min of regional ischemia or during the 5 h of reperfusion. The relative severity of ischemia between the two treatment groups was similar when assessed with radiolabeled microsphere measurement of myocardial blood flow. The accumulation of neutrophils (measured by myeloperoxidase activity) within the myocardium after reperfusion was not reduced by prior depletion of fibrinogen.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Therapeutic defibrination with ancrod does not protect canine myocardium from reperfusion injury. 170 37

The benefit of thrombolytic agents to reduce myocardial infarct size, improve left ventricular (LV) function, and prolong survival in human subjects is generally recognized, although the precise mechanism is poorly defined. This study was designed to evaluate the cardioprotective effects of streptokinase (SK) in rats, a species less responsive to plasminogen activators, using a model of mechanical occlusion and release of the left coronary artery. Myocardial injury and polymorphonuclear leukocyte (PMN) infiltration were determined by measuring creatine phosphokinase (CPK) specific activity and myeloperoxidase (MPO) activity, respectively, in the LV free wall (LVFW). After coronary artery occlusion for 0.5 h and reperfusion for 24 h (myocardial ischemia, MI/R), CPK specific activity decreased from 7.0 +/- 0.3 U/mg protein in the sham + vehicle group to 5.6 +/- 0.5 U/mg protein in the MI/R + vehicle group (n = 19, p less than 0.01), while MPO activity increased from 0.14 +/- 0.03 U/g tissue in the sham + vehicle group to 2.8 +/- 0.7 U/g in the MI/R + vehicle group (p less than 0.001). Administration of SK (100,000 IU/kg + 50,000 IU/kg/h for 2 h beginning 15 min before coronary artery reperfusion) reduced the loss of CPK specific activity from reperfused myocardium (6.8 +/- 0.5 U/mg protein, n = 23, p less than 0.05 as compared with the MI/R + vehicle group) and attenuated the increase in MPO activity (1.3 +/- 0.4 U/g tissue, p less than 0.05 as compared with the MI/R + vehicle group). This dose of SK did not change plasma fibrinogen concentration, slightly reduced plasminogen activity (i.e., 20% from control value), and markedly reduced alpha 2-antiplasmin activity (i.e., 60% from control values). A lower dose of SK (i.e., 10,000 IU/kg + 5,000 IU/kg/h for 2 h) did not reduce myocardial injury, did not attenuate the increase in MPO activity, and had no effect on the measured hemostatic parameters. Survival in all MI/R groups ranged from 62 to 66%, and there were no differences in survival between any of the groups (p greater than 0.05). In a model of arachidonic acid-induced rat hindpaw inflammation, SK had no effect on the increase in MPO activity, suggesting that the increase in myocardial MPO activity was not due to a direct effect on inflammatory cell accumulation. In in vitro studies, SK (1-1,000 U/ml) did not scavenge superoxide anion produced by purine (10 mM) and xanthine oxidase (10 mU/ml), nor did it reduce superoxide release, beta-glucuronidase release, or neutrophil aggregation of rabbit peritoneal neutrophils activated with fMLP.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Reduction in myocardial ischemic/reperfusion injury and neutrophil accumulation after therapeutic administration of streptokinase. 172 70

Lipoprotein (a) [Lp(a)] appears to be involved in atherogenesis and in vitro studies have suggested that it may interfere with thrombolysis. In this study, Lp(a) serum levels were determined by radioimmunoassay in 124 patients with ischemic heart disease. Of these, 47 had acute myocardial infarction, 13 had unstable angina, and 64 were age-matched patients with stable angina. Of the 60 patients with acute coronary artery disease, 34 received thrombolysis and 26 did not. In addition to Lp(a), serum plasminogen, alpha 2 antiplasmin, fibrinogen, and D-dimer (cross-linked fibrin degradation products) levels were measured. These tests were repeated after 6 hours in patients with myocardial infarction and unstable angina. No significant difference was found for admission Lp(a) levels among patients with myocardial infarction (0.324 +/- 0.047 g/liter), unstable angina (0.435 +/- 0.123 g/liter) and stable angina (0.431 +/- 0.023 g/liter), between patients with myocardial infarction with or without thrombolytic treatment, nor between late and early measurements in patients with unstable angina and acute myocardial infarction. Plasminogen, alpha 2 antiplasmin and fibrinogen values decreased significantly after thrombolytic treatment. The size of this decrease correlated positively with higher Lp(a) blood levels (p less than 0.05). Patients with Lp(a) greater than 0.25 g/liter had a 66% decrease in fibrinogen and a 53% decrease in anti-plasmin, compared with 35 and 32%, respectively, in patients with Lp(a) level less than or equal to 0.25 g/liter (p less than 0.05). Plasminogen levels revealed a similar trend, with a 61% decrease for the higher values and a 45% decrease for the lower values.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Lipoprotein (a) blood levels in unstable angina pectoris, acute myocardial infarction, and after thrombolytic therapy. 153 Dec 83

Unstable angina is a clinical syndrome of recurrent myocardial ischemia. In some cases, this reflects episodic platelet activation and coronary thrombosis. Thus, the biosynthesis of thromboxane A2, which is largely derived from activated platelets, is increased, often coincident with chest pain. The major role of platelets in unstable angina may influence the response to plasminogen activators. Platelets increase the resistance of thrombi to lysis, by inducing clot retraction and cross-linking and by releasing inhibitors. Thus, coronary thrombi in unstable angina may be resistant to lysis. Furthermore, both t-PA and streptokinase cause platelet activation and thrombin formation in vivo, possibly via plasmin. Plasmin can activate platelets and factor V directly. These prothrombotic effects of plasminogen activators may limit their activity in unstable angina. At the very least, their therapeutic efficacy may be highly dependent on the coadministration of potent antiplatelet agents and anticoagulants.
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PMID:Platelet activation in the pathogenesis of unstable angina: importance in determining the response to plasminogen activators. 189 67

In a randomised, double-blind study 1258 patients were allocated to receive either anistreplase (anisoylated plasminogen streptokinase activator complex [APSAC], 'Eminase') or placebo within 6 h of onset of suspected acute myocardial infarction. At 30 days, 40 (6%) of 624 patients on anistreplase had died, compared with 77 (12%) of 634 patients on placebo (odds reduction 50.5%). On long-term follow-up a survival benefit was still observed: at 12 months, 69 (11%) patients treated with anistreplase had died, compared with 113 (18%) patients given placebo (odds reduction 43%; p = 0.0007, 95% confidence interval 21-59%). This effect on mortality was not related to time between onset of symptoms and treatment or to any patient characteristic. Site of infarction and age were the most important influences on 1-year survival in both treatment groups; tachycardia (over 100 beats/min) on admission and previously diagnosed ischaemic heart disease were also associated with increased risk. Major complications of acute myocardial infarction were less frequent in patients treated with anistreplase than in controls. As for other thrombolytic agents, haemorrhage was more common, but usually minor. These findings indicate that anistreplase is an effective and acceptably safe thrombolytic with long-term survival benefits for patients with acute myocardial infarction.
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PMID:Long-term effects of intravenous anistreplase in acute myocardial infarction: final report of the AIMS study. AIMS Trial Study Group. 196 67

Concentrations of cross-linked fibrin degradation products (XL-FDPs) in plasma, measured by enzyme-linked immunosorbent assays (ELISAs) based on monoclonal antibodies (MAbs) raised against fragment D-dimer of cross-linked fibrin, increase when patients are given fibrinolytic agents. Whether XL-FDPs derive from circulating cross-linked fibrin polymers in plasma, compared with clot-associated fibrin, has been questioned because increases in XL-FDP are measured by some assays after fibrinolysis in vitro in the absence of clot. We characterized the source of XL-FDP immunoreactivity in plasma of patients with acute myocardial infarction and ischemic heart disease and the response to plasminogen activation in vitro induced by pharmacological concentrations of tissue-type plasminogen activator (t-PA) and streptokinase. XL-FDPs were measured with two different ELISA. One, "pan-specific tag ELISA," was based on a capture MAb specific for XL-FDP and a tag MAb that recognizes an epitope exposed in the fragment D region of both fibrin and fibrinogen, whereas the other, "fibrin-specific tag ELISA," was based on a capture and tag MAbs both specific for fibrin. After plasminogen activation was induced in vitro in plasma from patients with myocardial infarction, increased concentrations of XL-FDP were measured by the pan-specific tag ELISA; however, concentrations measured with the fibrin-specific tag ELISA were not increased. To determine the mechanism for this discrepancy, plasma was subjected to immunoadsorption with a MAb specific for fragment D-dimer before and after in vitro activation of the fibrinolytic system and immunoblotting with a fragment D-dimer-specific MAb and with the pan-specific MAb. Increased concentrations of fragment D-dimer, as well as fibrinogen fragment D at high concentrations, were recognized by the specific MAb. Non-cross-linked fragments were also shown by immunoblotting with the pan-specific MAb to coprecipitate with cross-linked fibrin fragments. This suggested the increased concentrations of XL-FDP measured by the pan-specific tag ELISA after in vitro activation of the fibrinolytic system were due to detection of non-cross-linked fibrinogen fragments. However, fibrin fragment D-dimer concentrations were found to increase in plasma of 15 patients given t-PA for acute myocardial infarction. We conclude fragment D-dimer in plasma of patients during thrombolysis does not originate from circulating soluble cross-linked fibrin but rather is a marker of solid-phase fibrin dissolution, which may be quantitated with assays based on capture and tag antibodies that do not detect fibrinogen or its degradation products.
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PMID:Validity of enzyme-linked immunosorbent assays of cross-linked fibrin degradation products as a measure of clot lysis. 240 Oct 81

Basal venous blood levels of several components of the fibrinolytic enzyme system (plasminogen activator, plasminogen, fibrin degradation products, alpha 2-antiplasmin, and alpha 2-macroglobulin) were measured in 100 white men with angiographically defined coronary artery disease. The tests of fibrinolysis were not related to the severity of coronary artery disease, as indicated either by the number of vessels involved or by a coronary score system. Fibrinogen levels, however, did show a modest association with the extent of coronary atheroma (r = 0.21, p less than 0.05). Triglyceride levels were associated with the inhibitors of fibrinolysis: positively with alpha 2-antiplasmin (r = 0.31, p less than 0.005) and negatively with alpha 2-macroglobulin (r = -0.25, p less than 0.05). The alpha 2-antiplasmin levels were significantly elevated in patients with hypertriglyceridaemia. Neither smoking nor beta-blockade had any effect on the tests of fibrinolysis. This study adds support to the association of plasma fibrinogen with ischaemic heart disease.
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PMID:Severity of coronary artery disease and basal fibrinolysis. 244 4

Thrombolysis with pharmacologic agents is a valuable modality for treatment of acute myocardial infarction. The results of several clinical studies indicate that early recanalization can be elicited with intravenous agents and that it is associated with substantial reductions of infarct size, improvement of ventricular function, and reduction in mortality. The recently introduced fibrin-selective agent, rt-PA, appears to represent a significant pharmacologic advance. Its use intravenously elicits high recanalization rates without marked derangements of the coagulation system, reflecting its relative fibrin selectivity. The efficacy of thrombolysis with any drug given by any route, unfortunately, is not 100 per cent. Bleeding remains an important risk. The optimal approach to management of residual stenosis after thrombolysis has not yet been delineated. Currently available information appears to justify the following conclusions: 1. Transmural myocardial infarction usually is caused by an acute obstructing coronary thrombus superimposed on a chronic atherosclerotic lesion. Myocardial necrosis following interruption of blood flow generally is complete within several hours. 2. The thrombus can be lysed and blood flow can be restored with intravenous agents that activate plasminogen. Intravenous rt-PA, a relatively fibrin-specific agent, elicits recanalization in 70 to 75 per cent of infarct-related arteries. 3. Recombinant t-PA evokes only modest depletion of fibrinogen (16 to 36 per cent reduction from baseline). 4. Early reperfusion preserves myocardium and ventricular function and reduces mortality. 5. The extent of benefit after pharmacologic reperfusion is correlated strongly with the brevity of myocardial ischemia prior to initiation of therapy. The greatest benefit is realized in patients treated within the first few hours of onset of acute myocardial infarction. 6. The incidence and optimal means of prevention of reocclusion and reinfarction following successful pharmacologic reperfusion are not yet entirely clear. Mechanical recanalization with PTCA in conjunction with thrombolysis is promising, but its routine immediate use on an emergency basis does not appear to be beneficial. Vigorous educational efforts are needed to heighten the awareness of prospective patients and all members of the health care team to the value of prompt diagnosis of incipient or evolving infarction so that prompt implementation of thrombolysis in appropriate candidates can be facilitated.
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PMID:Thrombolytic therapy in acute myocardial infarction: Part II--rt-PA. 249 16

Pharmacologic intervention is critical to the management of myocardial ischemia. Four classes of drugs are now used in therapeutic regimens for ischemia. beta-Adrenergic blockers decrease ischemia by blocking beta 1-mediated inotropic and chronotropic effects, thereby decreasing myocardial oxygen consumption. Calcium channel blockers alter fast- and slow-response action potentials by decreasing transmembrane calcium flux, resulting in decreased conduction velocity and heart rate and prolonged effective refractory period. These effects positively influence ischemia and atrial dysrhythmias. Additionally, these agents decrease excitation-contraction coupling in vascular smooth muscle, resulting in coronary and peripheral vasodilation. Organic nitrates and nitrites decrease vascular smooth muscle contraction and preload, and afterload, precipitating a decrease in myocardial oxygen consumption and ischemia. They also improve blood flow to areas of compromised flow. Thrombolytic agents are administered in acute situations to dissolve the occluding thrombus, but they must be used within a few hours of the injury. These drugs activate the conversion of plasminogen to plasmin, which breaks down the clot into fibrin degradation products. The choice of agents is determined by the etiology of the patient's ischemia, his or her response to the drug, and the presence of concomitant disease processes.
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PMID:Pharmacologic management of myocardial ischemia. 257 Jan 35

Circadian variations have been observed for a number of hemodynamic and cardiovascular events including heart rate, systemic blood pressure, coronary artery blood flow, ischemic cerebrovascular accidents, myocardial ischemia, myocardial infarction, and sudden cardiac death. In addition, circadian variations in platelet response to aggregating stimuli, plasma fibrinogen, coagulation factor concentration, and intrinsic fibrinolytic activity (as determined primarily by inhibitors of plasminogen activation) have been documented. Observed periodicities in thrombogenic capacity and cardiovascular events seem to correlate directly, suggesting a cause-effect relationship. Circadian variations in thrombotic tendency may influence the therapeutic response to anticoagulants and thrombolytic agents, particularly rt-PA. This area of cardiovascular disease is of profound clinical importance and warrants further investigation.
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PMID:Circadian variations in cardiovascular disease. 268 90


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