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Biomedical subjects

M D Ezekowitz

Publications and source records attributed to M D Ezekowitz.

At least 37 records · Page 2Linked to original sources
PubMed1998

Local delivery of a tissue factor antibody reduces early leukocyte infiltration but fails to limit intimal hyperplasia in experimental vein grafts.

BACKGROUND: Tissue Factor-mediated thrombin generation involves the generation of VIIa and Xa and has been implicated in the pathogenesis of intimal hyperplasia. In experimental vein grafts, Tissue Factor protein is increased over the first 3 days and colocalized with CD18-positive leukocytes; this increase in Tissue Factor precedes the development of intimal hyperplasia. This study further evaluates the potential role of Tissue Factor in vein graft intimal hyperplasia by directly inhibiting Tissue Factor protein. METHODS: New Zealand white rabbits underwent interpositional bypass grafting of the common carotid artery using the external jugular vein. Perioperatively, murine anti-rabbit Tissue Factor antibody (109 microg/ml gel, 12,500x IC50 of Tissue Factor activity) was applied to the adventitial surface of the graft, using a pluronic gel (30% soln.). Tissue Factor antibody treated vein grafts were compared to control and empty gel-treated vein grafts. Vein grafts were examined at 3 days to assess CD18-positive leukocyte infiltration and the presence of residual antibody by Western blotting. At 28 days, intimal and medial dimensions were quantified using videomorphometry. RESULTS: At day 3, there was marked reduction in CD18-positive leukocytes in the Tissue Factor antibody versus control vein grafts (6.3 +/- 4.7 vs 20.8 +/- 7.4 per 200x field, P < 0.05). At 28 days, intimal hyperplasia was similar for the control (70 +/- 4 microm, mean +/- SEM), gel (73 +/- 4 microm), and Tissue Factor antibody (75 +/- 4 microm) vein grafts. However, medial thickness (76 +/- 4 microm;, P < 0.05) was significantly increased compared to the gel treated vein graft (61 +/- 5 microm). CONCLUSION: Local delivery of pharmacologic doses of an anti-rabbit Tissue Factor antibody decreased CD18-positive leukocyte infiltration but failed to limit intimal hyperplasia in experimental vein grafts. The results suggest that inhibition of Tissue Factor protein modulates polymorphonuclear leukocyte-endothelial interactions but not in the subsequent development of intimal hyperplasia. It implies that the relationship between the extrinsic coagulation cascade and intimal hyperplasia in vein grafts is complex.

Animals↗
PubMed1997

Modulation of tissue factor protein expression in experimental venous bypass grafts.

Vein graft failure is a major limitation of coronary artery and peripheral vascular surgery. Tissue factor (TF), a transmembrane glycoprotein, generates thrombin by initiating the extrinsic coagulation cascade and plays a major role in the response to arterial injury. This study was designed to examine changes in TF protein expression in response to venous bypass grafting. New Zealand White rabbits underwent interposition bypass grafting of the common carotid artery via the ipsilateral external jugular vein. The contralateral control jugular veins (n = 6), early vein grafts (1 or 3 days after grafting, n = 18), and late vein grafts (14 or 28 days after grafting, n = 8) were examined by immunohistochemistry. The presence or absence of TF immunostaining in the intima was assessed in each vessel quadrant. In control veins, intimal TF staining was present in 5 of 24 vessel quadrants. In early vein grafts, TF staining was markedly increased in the intima (72 of 72 quadrants, P < .001 vs control veins), and TF immunostaining colocalized with CD18-positive leukocytes but not with endothelial cells, vascular smooth muscle cells, or RAM11-positive macrophages. In late vein grafts with intimal hyperplasia, TF expression was low or absent in the intima (6 of 32 quadrants, P < .001 vs early vein grafts; P = NS vs control veins), although medial smooth muscle cells expressed TF. Marked changes in TF expression occur in vein grafts. In early vein grafts, TF protein was greatly increased in the intima for at least 3 days and was associated with CD18-positive leukocytes. In late vein grafts with intimal hyperplasia, however, TF protein was not seen in the intima. These findings may have important implications for the development of therapeutic strategies to limit vein graft failure.

Animals↗
PubMed1996

Antithrombotic potential of polymer-coated stents eluting platelet glycoprotein IIb/IIIa receptor antibody.

BACKGROUND: Monoclonal anti-rabbit platelet glycoprotein (GP) IIb/IIIa antibody (AZ1) was adsorbed onto cellulose polymer-coated intracoronary stents to enhance their thromboresistance. We evaluated the antithrombotic efficacy of AZ1 antibody-eluting stents. METHODS AND RESULTS: Twenty-three polymer-coated stents with AZ1 antibody bound by passive adsorption (AZ1-eluting) were compared with 23 control polymer-coated stents adsorbed with either no antibody (base-polymer, n = 12) or isotype-matched irrelevant antibody (anti-CMV-eluting, n = 11) by implantation into balloon-damaged, flow-reduced iliac arteries of New Zealand White rabbits. In 13 animals (acute group), flow measurements were made with transit-time flow probes and platelet adhesion was ascertained by use of 111In-labeled autologous platelets. In the other 10 animals (chronic group), stent occlusion was assessed macroscopically after they were killed 28 days after stenting. Arteries with AZ1-eluting stents had significantly less platelet deposition (15.8 +/- 4.5 x 10(7)) than either base-polymer (32.1 +/- 4.3 x 10(7)) or anti-CMV-eluting (35.2 +/- 8.8 x 10(7)) controls (ANOVA, P < .0001). Compared with base-polymer or anti-CMV-eluting controls, arteries with AZ1-eluting stents showed a marked reduction in cyclic blood flow variation (P < .0001) and a significantly greater mean blood flow 2 hours after stent deployment (P < .0001). There was a significant improvement in the patency rate of AZ1-eluting stents compared with controls at both 2 hours (92% versus 46%, P = .034) and 28 days (100% versus 40%, P = .015). CONCLUSIONS: Platelet GP IIb/IIIa antibody eluting from polymer-coated stents reduces platelet deposition, improves blood flow, virtually abolishes cyclic flow variation, and improves patency rates after stent implantation in a rabbit iliac artery model. Its potential for reducing stent-related thrombosis in humans warrants further evaluation.

Adsorption↗
PubMed1996

Monoclonal antibody against tissue factor shortens tissue plasminogen activator lysis time and prevents reocclusion in a rabbit model of carotid artery thrombosis.

BACKGROUND: Tissue factor (TF)-dependent activation of the coagulation is important in the pathophysiology of intravascular thrombus formation. We tested the effects of a monoclonal antibody against TF (AP-1) on lysis time induced by tissue-type plasminogen activator (TPA) and on reocclusion rate in a rabbit model of carotid artery thrombosis. METHODS AND RESULTS: Intravascular thrombosis was obtained by placing an external constrictor around carotid arteries with endothelial injury. Carotid blood flow velocity ws measured continuously with a Doppler flow probe. Thirty minutes after thrombus formation, the rabbits received either AP-1 (0.15 mg/kg IV, n=8) or placebo (n=8). All rabbits also received TPA (80 microg/kg bolus plus 8 microg x kg(-1) x min(-1) infusion for up to 90 minutes or until reperfusion was achieved) and heparin (200 U/kg IV as a bolus). At reperfusion, TPA was discontinued, and the rabbits were followed for an additional 90 minutes. AP-1 shortened lysis time from 44+/-8 minutes (mean+/-SEM) in control rabbits to 26+/-7 minutes in AP-1 rabbits (P<.01). Reocclusion occurred in all control rabbits in 10+/-3 minutes, whereas it occurred in only two of eight AP-1 treated rabbits in 72 and 55 minutes (P<.01). No changes in prothrombin time and ex vivo platelet aggregation in response to various agonists were observed after AP-1 administration, indicating the absence of systemic effects by this antibody. CONCLUSIONS: TF exposure and activation of the extrinsic coagulation pathway play an important role in prolonging lysis time and mediating reocclusion after thrombolysis in this model. AP-1, a monoclonal antibody against TF, might be suitable as adjunctive therapy to TPA.

Animals↗
PubMed1996

Prevention of thromboembolism in patients with atrial fibrillation.

New insights into atrial physiology based on observations using transesophageal echocardiography are presented. The approach to anticoagulation of patients with both acute and chronic atrial fibrillation is reviewed within the context of the results of the major multicenter trials. These have provided some useful risk stratification guidelines for therapy. Presently available data suggest that the role of transesophageal echocardiography as a precardioversion screen is promising but requires further definition through clinical trials.

Anticoagulants↗
PubMed1995

Silent cerebral infarction in patients with nonrheumatic atrial fibrillation. The Veterans Affairs Stroke Prevention in Nonrheumatic Atrial Fibrillation Investigators.

BACKGROUND: Cerebral infarction in patients with atrial fibrillation may vary from being clinically silent to catastrophic. The prevalence of silent cerebral infarction and its effect as a risk factor for symptomatic stroke are important considerations for the evaluation of patients with atrial fibrillation. METHODS AND RESULTS: This Veterans Affairs cooperative study was a double-blind controlled trial designed primarily to determine the efficacy of warfarin for the prevention of stroke in neurologically normal patients with nonrheumatic atrial fibrillation. It also was designed to evaluate patients with silent cerebral infarction. Computed tomography scans of the head were performed at entry, at the time of any subsequent stroke, and at termination of follow-up on all patients who completed the study without a neurological event. Of 516 evaluable scans performed at entry, 76 (14.7%) had evidence of one or more silent cerebral infarcts. Age (P = .011), a history of hypertension (P = .003), active angina (P = .012), and elevated mean systolic blood pressure (P < .001) were associated with the presence of this finding. Silent cerebral infarction occurred during the study at rates of 1.01% and 1.57% per year for the placebo and warfarin treatment groups, respectively (NS). Silent cerebral infarction at entry was not an independent predictor of later symptomatic stroke, but active angina was a significant predictor; 15% of the placebo-assigned patients with angina developed a stroke compared with 5% of the placebo-assigned patients without angina. CONCLUSIONS: Silent cerebral infarction is frequently seen in asymptomatic patients with atrial fibrillation. Age, history of hypertension, active angina, and elevated mean systolic blood pressure were associated with silent infarction at entry. The sample size was too small to determine whether warfarin had an effect on the incidence of silent infarction during the trial. Active angina at baseline was the only significant independent predictor for the later development of symptomatic stroke.

Aged↗
PubMed1995

Amlodipine in chronic stable angina: results of a multicenter double-blind crossover trial.

The efficacy and safety of amlodipine, 10 mg, a new long-acting calcium antagonist, was compared with placebo in 103 patients with stable angina pectoris in a multicenter double-blind crossover study. The trial consisted of an initial 2-week single-blind placebo period followed by a first period of 4 weeks of double-blind therapy, which was followed by a 1 week washout period and then a second 4-week double-blind period after treatments were crossed over. Twenty-four-hour Holter electrocardiographic monitoring was carried out in 12 patients at three centers. In the first double-blind period amlodipine produced a significantly greater increase in symptom-limited exercise duration (amlodipine 478.5 to 520.6 vs placebo 484.6 to 485.2 seconds; change +8.8% vs +0.1%, respectively; p = 0.0004) and total work (amldipine 2426 to 2984 vs placebo 2505 to 2548 kilopondmeters; change +24% vs +1.7%, respectively; p = 0.0006) and a decrease in angina attack frequency (from 3 to 1 per week; p = 0.016) and nitroglycerin consumption (from 2 to 0.5 tablets/wk; p = 0.01) compared with placebo. Holter monitoring revealed significant reductions in numbers (amlodipine 4.65 to 2.22 vs placebo 1.84 to 1.54; change -52% vs +84%, respectively; p = 0.06), absolute total area (amlodipine 87.66 to 11.43 vs placebo 5.76 to 35.24; change -87% vs +513%, respectively; p = 0.02), and duration (amlodipine 12.29 to 2.95 vs 1.66 to 7.74 seconds; change -76% vs +367%, respectively; p = 0.008) of ST-segment depressions after treatment with amlodipine compared with placebo. After the treatments were crossed over changes continued to favor amlodipine.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1995

Role of transesophageal echocardiography in the detection of left atrial thrombus in patients with chronic nonrheumatic atrial fibrillation.

Transesophageal echocardiography was used to assess cardiac abnormalities associated with embolization in patients who had completed the Department of Veterans Affairs Cooperative Study of Stroke Prevention in Nonrheumatic Atrial Fibrillation at the Minneapolis and West Haven Department of Veterans Affairs Medical Centers without an embolic event. Patients were men, 71 +/- 7 years old, with atrial fibrillation of 6.2 +/- 4.3 years' duration who had received warfarin (n = 32) or placebo (n = 23) for 2 years. Thrombi were found in 5 of 55 patients (warfarin 4 and placebo 1; p = 0.39); spontaneous echo contrast was seen in 4 of 5 patients. Other abnormalities identified included spontaneous echo contrast (47%), patent foramen ovale (54%), atrial septal aneurysm (7.3%), and left ventricular thrombus (3.6%). During 34 months of posttreatment follow-up, 5 patients had a stroke (1 fatal), and 10 died. Potential sources of emboli did not predict subsequent outcome. Thus warfarin therapy did not preclude the presence of thrombi. Stroke reduction likely involves the prevention of emboli from sources in addition to the atrial appendage.

Aged↗
PubMed1995

Contemporary management of atrial fibrillation.

The incidence of atrial fibrillation approximately doubled for every 10-year increment in age in the Framingham Heart Study cohort; thus physicians will be faced with an increasing patient population with atrial fibrillation. Hypertension is observed to be the most common associated risk factor in both sexes. The management of patients with atrial fibrillation is evolving as a result of a number of published studies. Calcium channel blockers and beta-blockers are emerging as the preferred choices for rate control rather than digoxin. Low-dose anticoagulation therapy has shown beneficial effects not only in primary prevention, but also for secondary prevention of thromboembolism. Thus, patients who cannot be successfully cardioverted should be anticoagulated if there are no contraindications (Table 3) and if they do not fall into the low-risk group--defined as patients under the age of 65 without risk factors (hypertension, diabetes, previous stroke). Patients not eligible for anticoagulation should be on aspirin therapy. Patients with lone atrial fibrillation are not at higher risk for thromboembolism than the general population; therefore, they can be managed without anticoagulation or antiplatelet therapy. Antiarrhythmic treatment should be approached cautiously; amiodarone in low doses is the most effective and safe treatment, but this remains controversial.

Anti-Arrhythmia Agents↗
PubMed1995

Aurintricarboxylic acid reduces platelet deposition in stenosed and endothelially injured rabbit carotid arteries more effectively than other antiplatelet interventions.

In the present study we tested the effects of different antithrombotic interventions on platelet deposition in experimentally-stenotic rabbit carotid arteries with endothelial injury. Platelet deposition, quantitated by labeling autologous platelets with 111In-oxine, was significantly reduced compared to control animals by all interventions tested, i.e., R 68070, a drug with thromboxane A2 synthase and receptor blocking properties, BN 52021, a PAF receptor antagonist, aurintricarboxylic acid (ATA), an inhibitor of platelet glycoprotein (Gp) Ib/von Willebrand factor (vWf) interaction, AZ-1, a monoclonal antibody against rabbit GP IIb/IIIa, the platelet receptor for fibrinogen, and AP-1, a monoclonal antibody against rabbit tissue factor. ATA was significantly more effective than all the other interventions in reducing platelet deposition in the stenotic vessels. We conclude that inhibition of Gp Ib/vWf interaction may be a more suitable target for antithrombotic therapy under conditions of high shear stress, like those produced in this model.

Analysis of Variance↗
PubMed1994

Preparation, characterization, and evaluation of a monoclonal antibody against the rabbit platelet glycoprotein IIb/IIIa in an experimental angioplasty model.

The deposition of platelets at the site of balloon angioplasty is thought to play a major role in the pathogenesis of restenosis. The antibody AZ-1, which binds to the rabbit platelet glycoprotein IIb/IIIa receptor and inhibits platelet function both in vitro and in vivo, was produced and tested in an experimental model of angioplasty. Atherosclerosis was induced by desiccation injury of the femoral artery, followed by a 28-day diet with 2% cholesterol and 6% peanut oil. Rabbits were randomized to receive an infusion of saline, a single infusion of 0.5 mg/kg of AZ-1, or an infusion of 0.6 mg/kg AZ-1 before angioplasty. The latter group received a second infusion of 0.6 mg/kg 72 hours later. Functional platelet inhibition was demonstrated by prolongation of the bleeding time in all treated animals. Angiography was performed at baseline, immediately after a standardized angioplasty, and again 28 days after angioplasty on a total of 42 vessels. There were no significant differences between the antibody-treated group and the control group in the mean angiographic minimum luminal diameter at any of the time points. There was also no difference in the initial improvement after angioplasty (acute gain), in the decrease in luminal diameter from immediately after angioplasty to 28 days after angioplasty (late loss), or in the overall improvement from before angioplasty to 28 days after angioplasty. Quantitative histological analysis confirmed the lack of a beneficial effect of AZ-1. There were no significant differences in the area of the intima, the media, or the combined intima and media between the antibody-treated groups and the control group. Thus, potent platelet inhibition for up to 6 days after balloon angioplasty using a monoclonal antibody that inhibits platelet aggregation did not reduce the response to vascular injury after balloon angioplasty in this rabbit model of experimental atherosclerosis.

Angioplasty↗
PubMed1993

Potentiation of the vasospastic response to angioplasty by pretreatment with fluoxetine. A study in the atherosclerotic rabbit.

There is evidence that angioplasty-induced vasospasm is mediated by serotonin (5-hydroxytryptamine [5-HT]) release from platelets. We tested the hypothesis that pretreatment of the atherosclerotic rabbit with fluoxetine, a platelet-uptake inhibitor of 5-HT, would reduce vasospasm after balloon angioplasty. Short-term administration of fluoxetine reduced platelet 5-HT uptake to 4% of baseline. Daily administration of fluoxetine for 7 days reduced whole-blood 5-HT levels to 28% of baseline. Thus, fluoxetine inhibited platelet 5-HT uptake in this model as predicted. Contrary to our expectations and despite the substantial reduction in whole-blood 5-HT levels, pretreatment with fluoxetine for 1 week resulted in augmentation of angioplasty-induced vasospasm in atherosclerotic rabbits. Intraperitoneal administration of fluoxetine produced vasoconstriction in normal rabbits that was augmented by 5-HT and not reversed with LY53857, a specific serotonin receptor antagonist. We postulate that this new observation is probably a result of the inhibition of the clearance mechanism for serotonin, with resultant enhancement of the effect of serotonin released by the activated platelets that are deposited on the vessel wall surface at the time of angioplasty. A direct effect of fluoxetine on serotonergic receptors is a second possible mechanism for the observed effect.

Angioplasty↗
PubMed1992

Warfarin in the prevention of stroke associated with nonrheumatic atrial fibrillation. Veterans Affairs Stroke Prevention in Nonrheumatic Atrial Fibrillation Investigators.

BACKGROUND: Nonrheumatic atrial fibrillation is common among the elderly and is associated with an increased risk of stroke. We investigated whether anticoagulation with warfarin would reduce this risk. METHODS: We conducted a randomized, double-blind, placebo-controlled study to evaluate low-intensity anticoagulation with warfarin (prothrombin-time ratio, 1.2 to 1.5) in 571 men with chronic nonrheumatic atrial fibrillation; 525 patients had not previously had a cerebral infarction, whereas 46 patients had previously had such an event. The primary end point was cerebral infarction; secondary end points were cerebral hemorrhage and death. RESULTS: Among the patients with no history of stroke, cerebral infarction occurred in 19 of the 265 patients in the placebo group during an average follow-up of 1.7 years (4.3 percent per year) and in 4 of the 260 patients in the warfarin group during an average follow-up of 1.8 years (0.9 percent per year). The reduction in risk with warfarin therapy was 0.79 (95 percent confidence interval, 0.52 to 0.90; P = 0.001). The annual event rate among the 228 patients over 70 years of age was 4.8 percent in the placebo group and 0.9 percent in the warfarin group (risk reduction, 0.79; P = 0.02). The only cerebral hemorrhage occurred in a 73-year-old patient in the warfarin group. Other major hemorrhages, all gastrointestinal, occurred in 10 patients: 4 in the placebo group, for a rate of 0.9 percent per year, and 6 in the warfarin group, for a rate of 1.3 percent per year. There were 37 deaths that were not preceded by a cerebral end point--22 in the placebo group and 15 in the warfarin group (risk reduction, 0.31; P = 0.19). Cerebral infarction was more common among patients with a history of cerebral infarction (9.3 percent per year in the placebo group and 6.1 percent per year in the warfarin group) than among those without such a history. CONCLUSIONS: Low-intensity anticoagulation with warfarin prevented cerebral infarction in patients with nonrheumatic atrial fibrillation without producing an excess risk of major hemorrhage. This benefit extended to patients over 70 years of age.

Aged↗