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Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tissue hypoperfusion during cerebral ischemia results from occlusion of large and small vessels. Combination treatment strategies using fibrinolytics to thrombolyse an embolic clot and antiplatelet agents to prevent reocclusion and the formation of new platelet thrombi in the microcirculation may offer advantages over single-agent therapy. The authors report on the effects of tissue plasminogen activator (rt-PA), a glycoprotein (GP) IIb/IIIa receptor antagonist, 7E3 F(ab') 2, or a combination of the two agents in a focal embolic model of cerebral ischemia in Wistar rats. Focal ischemia was produced by introducing an autologous thrombus into the right side middle cerebral artery. Forty-six male Wistar rats were randomly divided into 6 groups: control (n = 8), 7E3 F(ab') 2 (n = 9, 6 mg/kg), rt-PA (n = 9, 10 mg/kg), rt-PA (n = 6, 20 mg/kg), and 7E3 F(ab') 2 with either 10 mg/kg (n = 10) (low-dose combination) or 20 mg/kg (n = 6) (high-dose combination) rt-PA. Evaluation of neurobehavioral scores, cerebral angiography, bleeding time, and measurement of brain infarction volume were used to determine efficacy. All actively treated groups showed a significant reduction in the infarct volume. Animals treated with 7E3 F(ab') 2 showed reduced infarction volumes (24.0 +/- 5.1%) compared with controls (42.43 +/- 5.6%, P < 0.02). Treatment with rt-PA significantly reduced infarction volume (20.7 +/- 3.3, = 0.01) at 10 mg/kg and at 20 mg/kg (19.5 +/- 8.2%, P < 0.05). Compared with vehicle-treated animals, the low-dose combination (16.4 +/- 5.5, P < 0.003) and high-dose combination (23.7 +/- 6.2%, P < 0.05) showed significant reduction in infarction volume. Cerebral angiography revealed significantly better recanalization in the combination group (5/6 animals in the high dose and 4/6 in low dose) compared with animals treated with 7E3 F(ab') 2 (3/10) or rt-PA alone (2/6). Bleeding time significantly increased from 11.25 +/- 1.9 minutes in the control group to 17 +/- 3.1 minutes in the rt-PA group, 24.5 +/- 2.6 minutes in the 7E3 F(ab') 2 group, 25.7 +/- 3.1 minutes in the low-dose combination group, and 32.5 +/- 4.7 minutes in the high-dose combination group. The incidence of intercerebral hemorrhage was highest in the high-dose combination group (6 of 6 animals) and lowest in the single treatment with 7E3 F(ab') 2 alone (1 of 10 animals) ( P < 0.05). Our data show that murine 7E3 F(ab') 2 alone has therapeutic effects when used after cerebral ischemia. Although this study suggests that higher doses of thrombolytic combined with anti-GPIIb/IIIa therapy may increases the risk of intracranial hemorrhage, the data also support the notion that anti-GPIIb/IIIa agents can safely be combined with low doses of thrombolytic agent to produce significant attenuation of neuronal damage with no increase in the incidence of cerebral hemorrhage.
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PMID:Glycoprotein IIb/IIIa antagonist, murine 7E3 F(ab') 2, and tissue plasminogen activator in focal ischemia: evaluation of efficacy and risk of hemorrhage with combination therapy. 1182 19

Cyclic coronary flow variation (CCFV), a phenomenon related to repetitive accumulation of platelet aggregates at sites with endothelial injury, was reported to predict the acute ischemic complication after percutaneous coronary intervention. Platelet activation also stimulates neointimal proliferation, which is essential in the late restenosis process. Abciximab, a nonspecific antagonist to the platelet membrane glycoprotein IIb/IIIa as well as other integrins, may eliminate CCFV. A randomized study was conducted to evaluate the effect of abciximab on CCFV and restenosis in morphologically high-risk lesions. Forty-six coronary arteries with objective ischemia on the corresponding vascular territories were successfully treated. The use of abciximab successfully suppressed the occurrence of CCFV (p < or = 0.001) after balloon dilatation. In the follow-up study 3 months later, the use of abciximab predicted a lower loss index and less clinical recurrence (p = 0.008 and 0.03, respectively). The occurrence of CCFV, however, did not affect the angiographic or clinical outcome. The reduction of restenosis and clinical recurrence by the use of abciximab may thus be related to its nonglycoprotein IIb/IIIa effects, in addition to platelet inhibition.
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PMID:Suppression of cyclic coronary flow variation and reduction of restenosis with abciximab for morphologically high-risk lesions undergoing percutaneous coronary intervention. 1202 85

The American College of Cardiology/American Heart Association Task Force on Practice Guidelines has published recommendations regarding diagnosis and treatment of patients with non-ST-segment elevation (NSTE) acute coronary syndromes (ACS). The acute ischemia pathway presented in these guidelines encompasses both an early invasive strategy and an early conservative strategy. The recognition of the role of platelet biology in ACS led to the development of glycoprotein (GP) IIb/IIIa receptor antagonists for the management of patients with NSTE ACS. Based on studies of risk stratification models for NSTE ACS, as well as a better understanding of the underlying biology of serum markers of myocardial necrosis, refinements have been made in identifying which patients benefit most from intravenous platelet receptor antagonism and the use of early invasive strategies. The available data suggest that for the NSTE ACS patient with intermediate- to high-risk features, the early initiation of intravenous platelet receptor antagonism with a small molecule GP IIb/IIIa receptor blocker, followed by timely cardiac catheterization with attempts at revascularization is the superior management strategy. In the majority of cases where such patients present to a facility without cardiac catheterization capability, stabilization with antiplatelet, antithrombotic, and anti-ischemic therapies should be undertaken prior to timely tertiary percutaneous coronary intervention referral.
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PMID:The role of pharmacotherapy and catheter-based intervention in the management of patients with non-ST-segment elevation acute coronary syndromes. 1205 65

Acute limb ischemia (ALI) has long been a major clinical problem, producing significant risks for limb loss and death. It is most commonly caused by arterial thrombosis in the setting of underlying atherosclerotic peripheral vascular disease or by arterial embolism, usually of cardiac origin. Over the past several decades, preferred treatment options for ALI have alternated between medical and surgical approaches. More recently, direct intra-arterial thrombolysis became the standard of care after several randomized trials demonstrated the benefit of this approach as compared with acute surgical intervention. Despite all of the experience with direct intra-arterial thrombolysis for the treatment of ALI, the optimal thrombolytic approach not been clearly established. Current investigation is directed at identifying the ideal thrombolytic agent for this purpose and the appropriate dosing regimen. In addition, there is interest in the newer mechanical thrombectomy devices and the use of platelet glycoprotein IIb/IIIa inhibitors to speed the time to reperfusion of the acutely ischemic limb.
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PMID:The management of acute limb ischemia: techniques for dealing with thrombus. 1205 46

Genetic variants are risk factors for coronary disease, but their role in recurrent events and in response to treatment is less clear. We genotyped genetic variants implicated in primary coronary disease in 924 Caucasians with acute coronary syndromes participating in the OPUS-TIMI16 trial of the GPIIb/IIIa antagonist orbofiban. These were the platelet glycoprotein (GP) receptors GPIIIa, GPIa, GPIbalpha; platelet ligands beta-fibrinogen and von Willebrand Factor (vWF); interleukins (IL) IL-1RN, and IL-6; adhesion proteins E-selectin and P-selectin; and metalloproteinase MMP-9. Cox modelling of all genetic variants demonstrated no significant impact on the composite endpoint (P = 0.88), which included myocardial infarction (MI), death, recurrent ischemia, urgent revascularisation and stroke, but a significant impact on recurrent myocardial infarction alone (chi(2) = 20.4, 10 df, P = 0.04). There was a significant interaction of the polymorphisms with orbofiban treatment influencing bleeding outcomes (P = 0.004). Thus, genetic polymorphisms may be associated with subsequent myocardial infarction, and may also be associated with treatment-associated bleeding among coronary patients.
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PMID:The contribution of genetic factors to thrombotic and bleeding outcomes in coronary patients randomised to IIb/IIIa antagonists. 1208 90

Although common genetic variants in platelet collagen receptors influence platelet activation and thrombosis, the impact of polymorphisms in collagen genes on cardiovascular disease is unknown. To evaluate this, we genotyped a highly polymorphic intronic tandem repeat of the COL3A1 gene, encoding collagen type III, alpha 1. This revealed 4 common alleles (COL3A1-1, -2, -3, and -4). The 2 populations studied were as follows: (1) a cross-sectional study of 703 acute coronary syndrome (ACS) patients with myocardial infarction (MI) and unstable angina, and (2) a prospective study of 924 Caucasian patients from the OPUS (Orbofiban in Patients with Unstable coronary Syndromes)-TIMI-16 trial of the oral GPIIb/IIIa antagonist orbofiban. In addition, we studied 306 control subjects and 224 patients with stable angina. In the case-control population, COL3A1-4 carriers were protected against ACS (odds ratio [OR] = 0.57, 95% CI = 0.35-0.91, P =.02) and stable angina (OR = 0.35, 95% CI = 0.16-0.74, P =.006). In the OPUS population, allele 4 again appeared protective against composite end points (death, MI, stroke, recurrent ischemia, and urgent rehospitalization) (relative risk [RR] = 0.41, 95% CI = 0.17-1.00). There were significant interactions between COL3A1-1 and -3 variants and treatment. Allele COL3A1-3 was associated with an increased risk of the composite end point (RR = 1.65, 95% CI = 1.07-2.55) in patients randomized to orbofiban, but appeared protective in placebo patients (RR = 0.53, 95% CI = 0.28-0.98). We conclude that variants in the COL3A1 gene, the product of which is a vessel-wall protein and platelet ligand, modulate the risk of coronary artery disease and could also modulate the response to antithrombotic therapy. This is the first reported association between polymorphisms of extracellular matrix components and cardiovascular risk.
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PMID:Genetic variability in the extracellular matrix as a determinant of cardiovascular risk: association of type III collagen COL3A1 polymorphisms with coronary artery disease. 1214 1

In recent studies, we could demonstrate a myocardial dysfunction induced by homologous platelets in ischemic and reperfused guinea pig hearts. Aim of the current study was to find out whether or not this is a phenomenon specific for platelets isolated from guinea pigs and to further examine the mechanisms of a possible cardiodepressive effect of human platelets. Isolated guinea pig hearts were exposed to a 30 min low-flow ischemia (1 ml/min) and reperfused. Human thrombocytes were administered as bolus (20.000 thrombocytes/microl perfusion buffer) in the 15(th) min of ischemia or in the 1(st) or 5(th) min of reperfusion in the presence of thrombin. Recovery of external heart work (REHW) and intracoronary platelet retention (RET) were quantified in percent. In additional experiments, the GPIIb/IIIa-blocker tirofiban (10 microg/ml perfusion buffer) or the radical scavenger superoxide dismutase (SOD-10 U/ml perfusion buffer) were added. Platelet application in the absence of tirofiban, either during ischemia (REHW 75.4 +/- 4%, RET 22.2 +/- 2%) or the 1st min (REHW 71.6 +/- 1%, RET 31.2 +/- 2%) or the 5th min of reperfusion (REHW 63.2 +/- 4%, RET 40.5 +/- 1%) led to a significant reduction of REHW and a significant increase of RET. The coapplication of tirofiban, on the other hand, prevented RET at all three times of platelet application (1.1 +/- 1.7%, 0% or 2.1 +/- 1.2%, respectively). An improvement of REHW, however, could only be noticed during ischemia (89 +/- 2%), whereas coapplication of tirofiban in early (72.9 +/- 3%) or in late reperfusion (74.6 +/- 2%) did not lead to a significant increase of REHW. Coapplication of SOD, on the other hand, significantly improved REHW in early (88.1 +/- 1) or late (95.9 +/- 1) reperfusion but not during ischemia (83.5 +/- 2). Corresponding to REHW, RET was changed significantly by coapplication of SOD during early (1 +/- 2%) or late (0%) reperfusion but not during ischemia (21.1 +/- 4%). We conclude that human thrombocytes are able to induce a myocardial dysfunction in ischemic and reperfused guinea pig hearts mediated by reactive oxygen species and independent of intracoronary platelet adhesion.
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PMID:Human thrombocytes are able to induce a myocardial dysfunction in the ischemic and reperfused guinea pig heart mediated by free radicals-role of the GPIIb/IIIa-blocker tirofiban. 1221 79

Leukocyte interaction with platelets and endothelial cells as cause of myocardial stunning was investigated. Mice were anesthetized and, after thoracotomy, the LAD was ligated for 20 min. Where indicated, rhodamine 6G for leukocyte labeling, fluorescence-labeled platelets, and the GPIIb/IIIa antagonist Tirofiban were infused at the onset of reperfusion in vivo. After 15 min, hearts were quickly excised and analyzed by fluorescence microscopy or assessed for left ventricular developed pressure (LVDP). After in vivo ischemia and reperfusion, leukocyte retention in the heart was 55 +/- 5/field in wild-type hearts, 38 +/- 3/field in P-selectin-/- hearts, and 23 +/- 4/field in P-selectin/intercellular adhesion molecule-1 (ICAM-1)-/- hearts. Postischemic LVDP (48+/-4 mmHg in wild-type hearts) improved in P-selectin-/- and P-selectin/ICAM-1-/- hearts (58+/-4 and 79+/-6 mmHg). Tirofiban reduced platelet adhesion (23+/-4/field vs. 61+/-2/field in wild-type hearts) and leukocyte recruitment (34+/-2/field), improving LVDP (63+/-4 mmHg). Whereas wild-type platelets displayed similar adherence to P-selectin/ICAM-1-/- hearts as platelets from the same genetic strain (63+/-3 vs. 61+/-4 platelets/field), wild-type platelet infusion restored postischemic leukocyte recruitment in P-selectin/ICAM-1-/- hearts (55+/-4/field vs. 23+/-4/field), an effect sensitive to Tirofiban inhibition (23+/-4 leukocytes/field, 22+/-3 platelets/field). We conclude that platelets contribute postischemic leukocyte adhesion in the heart via P-selectin and GPIIb/IIIa.
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PMID:Molecular mechanisms of platelet-mediated leukocyte recruitment during myocardial reperfusion. 1222 12

The early use of glycoprotein (GP) IIb/IIIa-receptor inhibitors in patients with non-ST-segment-elevation (NSTE) acute coronary syndromes (ACSs) is discussed. Unstable angina and NSTE myocardial infarction, collectively known as NSTE ACSs, are among the leading causes of morbidity and mortality in the United States. Updated guidelines from the American College of Cardiology and the American Heart Association for the management of NSTE ACSs strongly recommend that patients with intermediate- to high-risk features (e.g., ST-segment depression, elevated cardiac markers, and recurrent ischemia) be managed with an early invasive or other aggressive strategy (diagnostic angiography within 48 hours and, if warranted, percutaneous or surgical revascularization) and immediate treatment with a GP IIb/IIIa-receptor inhibitor. In low-risk patients, either an early invasive or an early conservative strategy (diagnostic angiography only for recurrent or refractory ischemia or a positive stress test result) is appropriate. For patients managed with an early conservative approach, the guidelines recommend GP IIb/IIIa-receptor inhibitor therapy with eptifibatide or tirofiban hydrochloride, especially in high-risk patients. Abciximab should not be used in patients in whom percutaneous coronary intervention is not planned. Greater implementation of the recommendations concerning the early use of GP IIb/IIIa-receptor inhibitors may result in reduced mortality rates. A large body of clinical evidence supports the updated ACC and AHA recommendations for managing patients with NSTE ACSs.
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PMID:Early use of glycoprotein IIb/IIIa-receptor inhibitors in non-ST-segment-elevation acute coronary syndromes. 1243 11

ST-segment elevation acute myocardial infarction (AMI) in patients who have undergone previous coronary artery bypass grafting (CABG) is associated with low reperfusion rates and poor outcome after fibrinolytic therapy. The efficacy of a combination strategy (reduced fibrinolytic plus platelet glycoprotein IIb/IIIa agent) in this setting is unknown. In the Global Use of Streptokinase and TPA for Occluded coronary arteries V (GUSTO V) trial, 553 patients with a history of CABG were treated with standard-dose reteplase (n = 273), or half-dose reteplase and full-dose abciximab (n = 280) in the first 6 hours of evolving ST-segment elevation MI. Mortality at 30 days was significantly higher in patients who underwent prior CABG compared with patients with no prior CABG (odds ratio [OR] 1.64, 95% confidence interval [CI] 1.21 to 2.24, p = 0.001). In patients who underwent prior CABG, mortality at 7 days was reduced 15% with combination therapy compared with reteplase alone, which was not statistically significant (OR 0.85, 95% CI 0.40 to 1.81, p = 0.66). Patients who underwent prior CABG treated with the combination therapy had fewer episodes of recurrent ischemia (OR 0.60, 95% CI 0.37 to 0.96, p = 0.02), high degree atrioventricular block (OR 0.17, 95% CI 0.02 to 0.82, p = 0.01), and ventricular tachycardia (OR 0.29, 95% CI 0.07 to 0.96, p = 0.04). There was a trend toward reduced urgent revascularization (OR 0.61, 95% CI 0.36 to 1.03, p = 0.06) but no significant difference in reinfarction (OR 0.61, 95% CI 0.31 to 1.52, p = 0.40). In the GUSTO V trial, patients who underwent prior CABG had significantly higher event rates compared with patients without CABG. As in the overall trial, combination therapy in patients who underwent prior CABG led to a consistent reduction in key secondary complications of AMI, including recurrent ischemia and a trend toward reduced urgent revascularization.
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PMID:Outcome of acute myocardial infarction in patients with prior coronary artery bypass grafting treated with combination reduced fibrinolytic therapy and abciximab. 1245 May 98


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