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)

Angiography in patients with unstable angina or myocardial infarction with subtotal coronary occlusion often reveals eccentric stenoses with irregular borders, suggesting ruptured atherosclerotic plaques and thrombosis, as documented by angioscopy and at autopsy. We have simulated and studied these processes in an ex vivo perfusion chamber and in an in vivo swine model. Our results suggest that specific local factors at the time of plaque disruption influence the degree of thrombogenicity, the stability of the growing thrombus, and, therefore, possibly also the various clinical syndromes. These factors can be divided into two groups: local vessel wall-related factors and systemic factors with local action at the area of risk. These factors include the following. 1) Exposed substrate-related effects: Plaque rupture produces a rough surface and stimulates the development of occlusive thrombus in proportion to the degree of damage. 2) Fluid dynamics-related factors: The more severe the stenotic lesion after plaque rupture, the higher the local shear rate, resulting in enhanced platelet deposition and thrombus formation. 3) Vasoconstrictive effects: Vasospasm is an important contributor to the pathogenesis of ischemic heart disease. 4) Systemic factors: There is clinical and experimental evidence to suggest that various systemic factors at the time of plaque rupture may enhance thrombogenicity (i.e., levels of epinephrine, levels of serum cholesterol, impaired fibrinolysis). We have investigated the role of residual thrombus on the process of rethrombosis and found that a residual thrombus is a very thrombogenic surface that may significantly contribute to reocclusion even in heparinized blood. Using recombinant hirudin as a pharmacological tool in our flow studies, we observed that rethrombosis is partially caused by thrombin bound to fibrin in the original thrombus, because the effect is abolished by the specific thrombin inhibitor.
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PMID:Thrombus formation on ruptured atherosclerotic plaques and rethrombosis on evolving thrombi. 142 53

The synergistic antithrombotic properties of G4120, a synthetic Arg-Gly-Asp (RGD) containing peptide which strongly inhibits platelet aggregation, and of Argatroban, a synthetic thrombin inhibitor, were examined in a reproducible quantitative hamster femoral vein platelet-rich mural thrombosis model. Bolus injections of G4120 and Argatroban inhibit thrombus formation in a dose-dependent way; 50% inhibition (ID50) is obtained with 11 micrograms/kg G4120 and with 2 mg/kg Argatroban. Combined bolus injections of 3 micrograms/kg G4120 with 0.5, 0.75 or 1 mg/kg Argatroban and of 1 mg/kg Argatroban with 1.5 or 3 micrograms/kg G4120 caused linear dose-dependent inhibition of thrombus formation, whereas 3 micrograms/kg G4120 or 1 mg/kg Argatroban alone had very little effect (less than 20% inhibition). ID50 was obtained with the combination of 3 micrograms/kg G4120 and 0.5 mg/kg Argatroban, corresponding to an equi-effective fractional combination of 0.62 with a 95% confidence interval of 0.50 to 0.74. Alternatively the ID50 was obtained with the combination of 1 mg/kg Argatroban and 1.3 micrograms/kg G4120, corresponding to an equi-effective fractional combination of 0.52 with a 95% confidence interval of 0.18 to 0.86. In both instances these results are indicative of a significant synergistic interaction. Bolus injection of 10 mg/kg aspirin, 100 U/kg heparin or the combination did not inhibit thrombus formation. The synergistic effect of the combination of platelet inhibiting RGD-peptides and synthetic thrombin inhibitors could be useful in the prevention of arterial occlusion with platelet-rich thrombus in patients with ischemic heart disease following thrombolytic therapy or angioplasty, although this combination is not expected to reverse platelet thrombus formation.
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PMID:Synergistic antithrombotic properties of G4120, a RGD-containing synthetic peptide, and argatroban, a synthetic thrombin inhibitor, in a hamster femoral vein platelet-rich thrombosis model. 144 May 1

Myocardial ischemia inhibits endothelium-dependent relaxation stimulated by the coagulant peptide, thrombin. To investigate whether activation of endogenous thrombin contributed to this reduction in relaxant sensitivity, the effects of pretreatment of dogs with the coumarin anticoagulant, brodifacoum, were studied. Experiments were performed in both normal coronary vasculature and coronary vasculature exposed to 90 min of myocardial ischemia, with or without 60 min of subsequent reperfusion. Ischemia was induced in the left anterior descending artery (LAD); nonischemic vessels from the left circumflex (LCX) artery of the same animals were used as control. Thrombin caused dose-dependent relaxation in isolated LCX preconstricted with prostaglandin F2 alpha (Emax of 89.1 +/- 2.33%). Relaxation was reduced by 90 min of ischemia (Emax of 27.5 +/- 8.0%; p less than 0.05), and further reduced after subsequent reperfusion (Emax of 8.7 +/- 8.7%). However, maximum relaxations to acetylcholine, calcimycin, and isoproterenol were unchanged after ischemia (Emax greater than 90% in all groups). Brodifacoum had no effect on thrombin-induced relaxation in control vessels (Emax of 83.0 +/- 3.5%), or on relaxation in response to acetylcholine, calcimycin, or isoproterenol (Emax greater than 90%). In contrast, brodifacoum markedly reduced thrombin-induced relaxation after ischemia (Emax of 3.3 +/- 3.3%; p less than 0.05) yet significantly preserved the relaxant response to thrombin after ischemia and reperfusion (Emax of 36.6 +/- 4.3%). Infusion of the thrombin inhibitor, D-phenylalanyl-L-prolyl-L-arginine chloromethyl ketone (PPACK), during ischemia and reperfusion also preserved in part the relaxant response induced by thrombin (Emax of 30.0 +/- 5.1%; p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Inhibition of thrombin-induced endothelium-dependent relaxation after coronary ischemia in the dog: possible role of the coagulation cascade. 171 94

Both aspirin and beta-adrenergic blocking drugs have been shown to reduce the risk of death or acute myocardial infarction (AMI) in patients with unstable angina, but their effect during chronic use on the presentation of acute coronary syndromes is less well defined. Calcium antagonists and oral nitrates are also widely prescribed for patients with coronary disease, but their effect on presentation of acute myocardial ischemia is unknown. We retrospectively examined the effects of prior aspirin and anti-ischemic medical therapy on clinical events in 410 patients hospitalized for unstable angina. Ischemic pain occurred at rest for a duration of 5 to 60 minutes. During hospitalization, 97% of patients received aspirin and all received the direct thrombin inhibitor bivalirudin for at least 72 hours. Despite being older and more likely to have risk factors for coronary disease and poor outcome, patients receiving aspirin before admission were less likely to present with non-Q-wave AMI (5% vs 14% in patients not on aspirin, p = 0.004). Prior beta blocker, calcium antagonist, or nitrate administration did not appear to modify presentation as unstable angina or non-Q-wave AMI. In a multivariate model, the combined incidence of death, AMI not present at enrollment, or recurrent angina was best predicted by age (adjusted odds ratio [95% confidence interval] 2.38 [1.14 to 3.98]) and presence of electrocardiographic changes with pain on presentation (adjusted odds ratio 2.83 [1.50 to 5.35]) but was not related to prior or in-hospital medical therapy. Thus, aspirin but not anti-ischemic therapy before hospitalization of patients with unstable angina was associated with a decreased incidence of non-Q-wave AMI on admission.
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PMID:Effects of prior aspirin and anti-ischemic therapy on outcome of patients with unstable angina. TIMI 7 Investigators. Thrombin Inhibition in Myocardial Ischemia. 952 73

Thrombin has been suggested as one of the main pharmacologic targets in unstable coronary syndromes. Electrocardiographic signs of ischemia during continuous monitoring convey prognostic information in these patients. This study assessed the anti-ischemic and clinical effects of the novel low-molecular weight thrombin inhibitor inogatran in patients with unstable angina and non-Q-wave infarction without persistent ST-segment elevation on hospital admission. Within 24 hours of the last episode of chest pain, 324 patients were randomized to 72 hours of treatment with inogatran or heparin. Continuous ST-segment analysis with computerized vectorcardiography was used to monitor ischemia for 24 hours. The occurrence of cardiac events during the first 7 days were studied and compared with ischemic episodes during the initial 24 hours. The heparin-treated patients had less episodes of ischemia (ST vector magnitude [ST-VM]: 1 +/- 2.6 vs 2 +/- 4.5, p < 0.001 and ST change vector magnitude [STC-VM]: 3 +/- 4.7 vs 6 +/- 7.6, p < 0.001) than the patients receiving inogatran. This was paralleled by a lower incidence of the combined end point of death, nonfatal infarction, refractory or recurrent angina during the first 7 days for the heparin-treated patients (35%) compared with the inogatran-treated patients (50%) (p < 0.05). Patients who had episodes of ischemia in spite of anti-ischemic therapy were at increased risk of all events studied. Heparin is more effective than inogatran in suppressing myocardial ischemia and clinical events at short-term follow-up. Continuous ST-segment monitoring with vectorcardiography identifies nonresponders who are at an increased level of risk.
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PMID:Heparin is more effective than inogatran, a low-molecular weight thrombin inhibitor in suppressing ischemia and recurrent angina in unstable coronary disease. Thrombin Inhibition in Myocardial Ischemia (TRIM) Study Group. 957 50

We have previously shown that atherosclerotic apolipoprotein E-deficient (apoE(-/-)) x LDL receptor-deficient (LDLR(-/-)) mice develop myocardial infarction when exposed to hypoxic stress. This study was performed to assess the role of thrombin and thrombosis in this process. ApoE(-/-) x LDLR(-/-) mice were fed a cholesterol-rich diet for 8 mo and were then subjected to hypoxic stress while receiving isoflurane anesthesia. One group received a bolus dose (5.6 micromol/kg) of the thrombin inhibitor melagatran, and control animals received PBS 10 min before the hypoxic stress. The mice were exposed to 10 min of hypoxia followed by normoxia. Ten minutes after the stress, Alzet pumps delivering melagatran (20 nmol x kg x (-1)min(-1)) or PBS were implanted, and the mice were allowed to recover for 48 h. The cardiac response was analyzed by histology, immunohistochemistry, and serum troponin T assay. All animals showed reversible ECG changes as a sign of ischemia during hypoxic stress, and 50% developed infarctions afterward as judged by troponin T levels. The group that received thrombin inhibitor had significantly lower troponin T and smaller myocardial infarctions than the PBS-treated group. These data show that thrombin generation is an important pathogenetic factor and suggest that coronary thrombosis is involved in myocardial infarction in atherosclerotic mice. Exposure of atherosclerotic mice to hypoxia leads to myocardial infarction through a two-phase pathway in which acute transient ischemia is followed by thrombin-dependent, irreversible, myocardial ischemia and myocardial cell death.
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PMID:Thrombin inhibitor reduces myocardial infarction in apoE-/- x LDLR-/- mice. 1503 Nov 24

Activation of the coagulation cascade during myocardial ischemia and reperfusion may contribute to the post-ischemic inflammatory response, mostly via generation of thrombin. We assessed the effect of the anticoagulants unfractionated heparin (UFH), low molecular weight heparin (LMWH) and r-hirudin on leukocyte adhesion and emigration after ischemia and reperfusion in rats. The rat cremaster muscle was prepared for intravital microscopy. One hundred and twenty minutes of ischemia were followed by 90 min of reperfusion. Saline (control), UFH, LMWH or r-hirudin were given 15 min prior to reperfusion and infused for the rest of the observation period. Dosages per kilogram of body weight were (bolus, infusion): saline, 3 ml, 3 ml/h; UFH, 400 IU, 100 IU/h; LMWH, 100 IU, 3 ml/h saline; or r-hirudin, 0.3 mg, 0.15 mg/h. In collecting venules, rolling, adherent, and extravasated leukocytes were counted from recordings of the intravital microscopy. All three anticoagulants similarly attenuated post-ischemic endothelial leukocyte adhesion. In contrast, emigration of leukocytes was only attenuated by r-hirudin. The emigration efficiency of adherent leukocytes (control, 1.21) was unchanged after UFH (1.74), and LMWH (1.51) but decreased after r-hirudin treatment (0.12). The different efficacy of the three anticoagulants in affecting emigration of adherent leukocytes suggests a specific role for the direct thrombin inhibitor r-hirudin in attenuating the post-ischemic inflammatory response. This effect may contribute to the benefits of direct thrombin inhibitors seen in clinical studies after treatment for acute coronary syndromes.
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PMID:Effects of unfractionated heparin, low molecular weight heparin and r-hirudin on leukocyte adhesion in ischemia/reperfusion. 1520 85

Coronary heart disease is the number one cause of death in the world and acute coronary syndromes (ACS) continue to be associated with high rates of morbidity. ACS refers to the spectrum of acute myocardial ischemia, including unstable angina, ST segment elevation myocardial infarction (STEMI), and acute MI without ST segment elevation (NSTEMI). Current guidelines indicate both aspirin and glycoprotein IIb/IIIa receptor antagonists (if catheterization/revascularization are planned) as class IA recommendations in ACS. Anticoagulant therapy, in the form of heparin, is a class IA recommendation for the acute hospital phase of ACS. The risk of recurrent thrombotic events following ACS remains high in the post-hospital phase, creating a rationale for the use of oral direct thrombin inhibitors such as ximelagatran, in both the acute and long-term settings. The Efficacy and Safety of the Oral Direct Thrombin Inhibitor Ximelagatran in Patients with Recent and Myocardial Damage (ESTEEM) trial, a placebo-controlled, double-blind study of post-MI patients, evaluated 4 dosing regimens of ximelagatran versus placebo in the initial months following an ACS and found an encouraging reduction in the end points of death, MI, and stroke with the use of an oral direct thrombin inhibitor.
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PMID:Reducing cardiac events after acute coronary syndromes. 1561 14

Myocardial ischemia and other acute coronary syndromes are leading causes of death worldwide, and often result from a thrombus that blocks an atherosclerotic coronary artery. A key enzyme in thrombus formation is the serine protease thrombin, which is responsible for both the conversion of soluble fibrinogen into insoluble fibrin, as well as the activation of the GPCRs, PAR1 and PAR4, which stimulate platelet aggregation. Thus, thrombin is an attractive target for anticoagulant and antithrombotic therapy. Previous studies in our laboratory led to the development of lead compound FM 19 (D-Arg-Oic-Pro-D-Ala-Phe(p-Me)-NH2), which shows modest potency as a thrombin inhibitor. The recently determined X-ray structure of FM 19 in the active site of thrombin has revealed potential sites for modification to improve potency. This study reports replacements to the first residue (D-Arg1) of FM 19, which seek to improve potency by removing the N-terminal amine to eliminate an adverse electrostatic interaction, and alterations to the length of the side chain to eliminate an unfavorable eclipsed conformation observed in the X-ray structure. This study produced two compounds, 1 and 9, with improved alpha-thrombin inhibition (IC50 values of 0.66 +/- 0.20 microM and 0.57 +/- 0.12 microM, respectively).
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PMID:Structure-based design of residue 1 analogs of the direct thrombin inhibitor pentapeptide FM 19. 1995 32

Abstract The limits of traditional anticoagulants, such as heparin and warfarin, have prompted the search for new agents for prophylaxis and treatment of arterial and venous thromboembolism, including factor Xa and thrombin inhibitors. These agents can be given orally, and their most significant advantage is that no laboratory monitoring is needed. The anti-Xa inhibitor rivaroxaban and the direct thrombin inhibitor dabigatran etexilate are licensed for prophylaxis of venous thromboembolism (VTE) in high-risk orthopedic surgery. They are at least as safe and effective as heparins but much more expensive. Dabigatran, rivaroxaban, and other agents currently in the pipeline of clinical development have the potential to replace warfarin in the two most frequent indications for anticoagulation, i.e. secondary prophylaxis of VTE and atrial fibrillation. Prevention and treatment of coronary artery thrombosis in patients with ischemic heart disease is another area of investigation for the role of new anticoagulants. These drugs have the potential to meet some currently unmet needs of traditional anticoagulants, but available clinical data warrant confirmation and expansion. Lack of specific antidotes for anticoagulation reversal and the high cost are important limitations of their use.
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PMID:Old and new anticoagulant drugs: a minireview. 2125


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