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Biomedical subjects

M D Ezekowitz

Publications and source records attributed to M D Ezekowitz.

At least 19 recordsLinked to original sources
PubMed2001

Effects of atorvastatin on early recurrent ischemic events in acute coronary syndromes: the MIRACL study: a randomized controlled trial.

CONTEXT: Patients experience the highest rate of death and recurrent ischemic events during the early period after an acute coronary syndrome, but it is not known whether early initiation of treatment with a statin can reduce the occurrence of these early events. OBJECTIVE: To determine whether treatment with atorvastatin, 80 mg/d, initiated 24 to 96 hours after an acute coronary syndrome, reduces death and nonfatal ischemic events. DESIGN AND SETTING: A randomized, double-blind trial conducted from May 1997 to September 1999, with follow-up through 16 weeks at 122 clinical centers in Europe, North America, South Africa, and Australasia. PATIENTS: A total of 3086 adults aged 18 years or older with unstable angina or non-Q-wave acute myocardial infarction. INTERVENTIONS: Patients were stratified by center and randomly assigned to receive treatment with atorvastatin (80 mg/d) or matching placebo between 24 and 96 hours after hospital admission. MAIN OUTCOME MEASURES: Primary end point event defined as death, nonfatal acute myocardial infarction, cardiac arrest with resuscitation, or recurrent symptomatic myocardial ischemia with objective evidence and requiring emergency rehospitalization. RESULTS: A primary end point event occurred in 228 patients (14.8%) in the atorvastatin group and 269 patients (17.4%) in the placebo group (relative risk [RR], 0.84; 95% confidence interval [CI], 0.70-1.00; P =.048). There were no significant differences in risk of death, nonfatal myocardial infarction, or cardiac arrest between the atorvastatin group and the placebo group, although the atorvastatin group had a lower risk of symptomatic ischemia with objective evidence and requiring emergency rehospitalization (6.2% vs 8.4%; RR, 0.74; 95% CI, 0.57-0.95; P =.02). Likewise, there were no significant differences between the atorvastatin group and the placebo group in the incidence of secondary outcomes of coronary revascularization procedures, worsening heart failure, or worsening angina, although there were fewer strokes in the atorvastatin group than in the placebo group (12 vs 24 events; P =.045). In the atorvastatin group, mean low-density lipoprotein cholesterol level declined from 124 mg/dL (3.2 mmol/L) to 72 mg/dL (1.9 mmol/L). Abnormal liver transaminases (>3 times upper limit of normal) were more common in the atorvastatin group than in the placebo group (2.5% vs 0.6%; P<.001). CONCLUSION: For patients with acute coronary syndrome, lipid-lowering therapy with atorvastatin, 80 mg/d, reduces recurrent ischemic events in the first 16 weeks, mostly recurrent symptomatic ischemia requiring rehospitalization.

Aged↗
PubMed2001

Local treatment with recombinant tissue factor pathway inhibitor reduces the development of intimal hyperplasia in experimental vein grafts.

BACKGROUND: Tissue factor (TF)-initiated thrombin generation has been implicated in the development of intimal hyperplasia after arterial injury. An increase in intimal TF expression has been shown to precede the development of intimal hyperplasia in vein grafts. This study examines the effects of local treatment with recombinant human tissue factor pathway inhibitor (rTFPI) in experimental vein grafts. METHODS: Thirty-six male New Zealand white rabbits underwent bypass grafting of the carotid artery by use of the reversed ipsilateral jugular vein and were divided into four groups. Twenty animals had ex vivo incubation with rTFPI treatment (50 microg x mL(-1); n = 10) or placebo vehicle (control; n = 10). Sixteen animals received both ex vivo incubation and in vivo gel treatment with rTFPI (50 microg. mL(-1); n = 8) or without rTFPI (gel-control; n = 8). After operation, vein grafts were harvested at 3 days for immunohistochemical and Western analyses and at 28 days for histomorphologic study. RESULTS: Western analysis demonstrated a 6.2-fold reduction in the expression of TF protein with rTFPI treatment in comparison to without rTFPI treatment. CD-18 leukocyte staining was diminished, whereas Tie-2 endothelial staining was increased in all rTFPI-treated vein grafts, compared with control and gel-control vein grafts. Intimal thickness was reduced by 21% with ex vivo rTFPI treatment compared with placebo (69 +/- 4 versus 87 +/- 5 microm; P <.05) and by 30% with the addition of rTFPI in vivo compared with gel-control (60 +/- 4 versus 86 +/- 5 microm; P <.01). CONCLUSION: Local administration of rTFPI exerts early beneficial effects and limits the development of intimal hyperplasia in vein grafts. Therefore blocking TF-mediated pathway may offer new therapeutic options to reduce vein graft failure.

Animals↗
PubMed2001

Beneficial effect of glycoprotein IIb/IIIa inhibitor (AZ-1) on endothelium in Escherichia coli endotoxin-induced shock.

OBJECTIVE: To investigate the effects of AZ-1, a murine monoclonal antiglycoprotein-IIb/IIIa antibody, on endothelium and on hemostasis in a rabbit endotoxic shock model. DESIGN: Prospective laboratory study. SETTING: University laboratory. SUBJECTS: Thirty-five male New-Zealand rabbits. INTERVENTIONS: In vitro vascular reactivity, endothelium CD31-PECAM1 immunohistochemistry, plasma coagulation factors, and monocyte tissue factor determination were performed 1 day and/or 5 days after onset of endotoxic shock (0.5 mg/kg, intravenous bolus,Escherichia coli lipopolysaccharide) with or without treatment by AZ-1 (0.5 mg/kg intravenously) given 1 hr after lipopolysaccharide injection. MEASUREMENTS AND MAIN RESULTS: Metabolic acidosis and coagulation activation confirmed the presence of shock. AZ-1 treatment improved endothelial-dependent relaxation at 1 day (maximal effect = 87.2 +/- 4.0% vs. 60.9 +/- 5.2% in the nontreated group, p <.05) and at 5 days (maximal effect = 84.5 +/- 3.5% vs. 56.6 +/- 8.2% in the nontreated group, p <.05). Endotoxin-induced endothelial injury was decreased significantly by AZ-1 at 1 day (6.4 +/- 1.9% vs. 10.3 +/- 0.8% in the nontreated group, p <.05) and at 5 days (6.3 +/- 2.0% vs. 20.2 +/- 1.2% in the nontreated group, p <.05). Monocyte tissue factor expression was significantly reduced at 5 days. CONCLUSIONS: These data indicate that potent inhibition of platelet function via antiglycoprotein-IIb/IIIa receptor blockade can inhibit coagulation activation and protect against endothelial dysfunction and histologic injury in endotoxin-induced shock.

Animals↗
PubMed2001

Exercise tolerance and quality of life in elderly patients with chronic atrial fibrillation.

BACKGROUND: Atrial fibrillation is the most common arrhythmia affecting the elderly. Although the risk of cardioembolic stroke is well defined, the effects of chronic atrial fibrillation on exercise tolerance and quality of life have been less well quantified. METHODS: We compared a group of 52 elderly patients with chronic atrial fibrillation to a group of 48 control patients in sinus rhythm. Each patient underwent an interview that incorporated the Short Form-36 Health Survey (SF-36) to quantify individual perceptions on quality of life. In addition each person underwent physiologic testing that included a Modified Bruce Protocol exercise tolerance test, 24-hour ambulatory monitor test, and an echocardiogram. RESULTS: Both groups were elderly, 77 vs 76 years of age (P=0.35). The two groups had similar ejection fractions, 55.4% vs 58.4% (P=0.10). The atrial fibrillation patients demonstrated a higher level of comorbidity based on the Charlson Comorbidity Index, 2.46 vs 1.57 (P=0.03). On formal exercise testing there was no statistical difference in exercise duration between the two groups 9.0 vs 10.1 minutes (P=0.24). Similarly the Physical Summary Score (PCS) and the Mental Summary Score (MCS) of the SF-36 quality of life survey did not demonstrate a statistical difference between the two groups. PCS: 43.0 vs 45.9 (P=0.24); MCS: 52.5 vs 55.7 (P=0.07). CONCLUSIONS: Despite a higher level of comorbidity, elderly, ambulatory patients with chronic atrial fibrillation demonstrate similar exercise tolerance and report similar quality of life to a group of age-matched control patients in sinus rhythm. There is a cohort of patients in chronic atrial fibrillation in whom a strategy of rate control and anticoagulation may be appropriate.

Aged↗
PubMed2000

Basic fibroblast growth factor increases tissue factor expression in circulating monocytes and in vascular wall.

BACKGROUND: Basic fibroblast growth factor (bFGF) promotes vascular repair and angiogenesis and can induce in vitro tissue factor (TF), a potent agent initiating thrombogenesis, which probably plays a role in angiogenesis. We investigated whether bFGF administration induced TF expression by monocytes and vascular cells. METHODS AND RESULTS: We studied TF expression in normally fed (n=16) and cholesterol-fed (2% for 6 weeks, n=16) rabbits. Animals were then randomized to receive intravenous bFGF (2.5 microg twice weekly for 3 weeks) or saline injections. TF expression was evaluated in mononuclear cells from arterial blood and in aortic sections by an immunohistochemical assay using a monoclonal anti-rabbit TF antibody (activator protein 1). Monocyte TF expression was increased by bFGF administration in both normal and hypercholesterolemic rabbits (129+/-45 versus 19+/-3 mU TF/1000 monocytes, P<0.05, and 31+/-12 versus 7+/-1 mU TF/1000 monocytes, P<0.005, respectively) and was further increased by stimulation of monocytes by endotoxin in vitro. TF expression was lower in hypercholesterolemic rabbits than in normal rabbits. In the media of the vascular wall, bFGF induced strong TF expression in normal rabbits and only weak TF expression in hypercholesterolemic ones. CONCLUSIONS: This study demonstrates that systemic administration of bFGF induces an impressive increase of TF expression in circulating monocytes and in the vascular wall in normal and to a lower extent in hypercholesterolemic rabbits. The significance of this observation in terms of inducing thrombosis in vivo needs clarification.

Animals↗
PubMed2000

Management of arrythmias.

The management of arrhythmias in elderly patients with congestive heart failure, including atrial fibrillation, ventricular tachyarrhythmias, and bradyarrhythmias, is described. Patients with atrial fibrillation can be treated with rate control anticoagulation for stroke prevention or by attempt at cardioversion and maintenance of sinus rhythm. Elderly patients remaining in atrial fibrillation benefit from anticoagulation provided that no contraindication exists. In patients surviving malignant ventricular arrhythmias, defibrillator implantation is beneficial in elderly patients with heart failure. Prognosis and treatment of nonsustained arrhythmias depends on the presence of underlying cardiac abnormalities. In the healthy elderly population, treatment is not indicated. In patients with coronary artery disease, decreased ejection fraction, and nonsustained ventricular tachycardia, electrophysiology can further stratify risk, and defibrillator implantation can improve survival if arrhythmias are induced. This benefit is as great in elderly patients as in younger patients. Symptomatic bradycardias are increasingly common with advancing age. Symptoms are improved with pacing, with maximum benefit from physiologic rather than ventricular pacing. Although the elderly population poses a unique challenge when faced with arrhythmias, an active approach not only saves lives but also reduces morbidity.

Age Factors↗
PubMed2000

Clinical implication of antiembolic trials in atrial fibrillation and role of transesophageal echocardiography in atrial fibrillation.

Risk for stroke in patients with atrial fibrillation (AF) is highly heterogeneous. Increasing age, history of diabetes, hypertension, previous transient ischemic attack or stroke, and poor ventricular function are independent risk factors for stroke in patients with AF. Accordingly, some groups of patients with AF have low risk and some have high risk. In general, patients at high risk benefit most from anticoagulation therapy with warfarin. In general, if a patient is younger than 65 years of age and has none of the defined risk factors, the stroke rate without prophylaxis (aspirin or warfarin) is low. In patients 65 to 75 years of age with no risk factors, the risk for stroke is low with either aspirin or warfarin therapy; the choice is left to the caretaking physician. All patients older than 75 years and all patients of any age who have risk factors obtain striking benefit from the use of anticoagulation with warfarin. This benefit far outweighs any risk for major hemorrhage.

Age Factors↗
PubMed1999

Preventing stroke in patients with atrial fibrillation.

CONTEXT: Atrial fibrillation, a common disorder that affects nearly one sixth of the population aged 75 years and older, is a major risk factor for stroke. OBJECTIVES: To review and evaluate the evidence supporting the use of warfarin and/or aspirin for stroke prevention in patients with atrial fibrillation. DATA SOURCES: Prospective, randomized trials of patients with atrial fibrillation evaluating either warfarin or aspirin or both, from MEDLINE from January 1, 1966, to February 23, 1999. STUDY SELECTION: Five primary prevention placebo-controlled studies, which had been formally pooled, 1 study evaluating secondary prevention of stroke, 1 study comparing warfarin with aspirin, and 3 studies of warfarin in combination with aspirin were identified. DATA SYNTHESIS: The risk of developing stroke is heterogeneous and increases with each decade above 65 years; history of high blood pressure, diabetes mellitus, previous transient ischemic attack, or stroke; poor ventricular function; and in women older than 75 years. For patients younger than 65 years, without risk factors, and not receiving antithrombotic therapy, the risk of stroke is 1%/y; those without risk factors between the ages of 65 and 75 years have a risk of 1.1%/y if taking warfarin and 1.4%/y if taking aspirin. For all other patients, stroke risk is reduced from an untreated rate of between 4.3%/y and more than 12%/y to a rate of 1.2%/y to 4%/y with warfarin use. CONCLUSION: The protection afforded by warfarin is most pronounced in patients at the highest risk for stroke, while aspirin treatment seems adequate in low-risk populations.

Adult↗
PubMed1998

Enhanced monocyte tissue factor response after experimental balloon angioplasty in hypercholesterolemic rabbit: inhibition with dietary L-arginine.

BACKGROUND: There is evidence that tissue factor (TF) is a major contributor to the thrombogenicity of a ruptured atherosclerotic plaque. Nitric oxide (NO) has antiatherogenic and antithrombotic properties. We investigated whether L-arginine (L-arg), the endogenous precursor of NO, might affect the ability of monocytes to produce TF. METHODS AND RESULTS: We studied TF expression in 18 rabbits with atherosclerosis induced by bilateral iliac damage and 10 weeks of a 2% cholesterol diet. Six weeks after the initiation of the diet, an angioplasty was performed. After angioplasty, the surviving rabbits (n=15) were randomized to receive L-arg (2.25%) supplementation in drinking water (L-arg group, n=8) or no treatment (untreated group, n=7). TF expression was evaluated in mononuclear cells from arterial blood in the presence and absence of endotoxin stimulation. Monocyte TF expression, as assessed with an amidolytic assay, did not differ significantly before or after the induction of atherosclerotic lesions (87+/-15 versus 70+/-12 mU of TF/1000 monocytes, P=NS). Endotoxin-stimulated TF activity increased significantly 4 weeks after angioplasty (138+/-22 versus 70+/-12 mU of TF/1000 monocytes, P=0.02). This increase was blunted by L-arg (43+/-16 mU of TF/1000 monocytes, P=0.01). CONCLUSIONS: This study demonstrates that angioplasty-induced plaque rupture is associated with a marked increase in monocyte TF response that is blunted by the oral administration of L-arg. This suggests that the documented antithrombotic properties of NO may be related in part to an inhibitory effect on monocyte TF response.

Angioplasty, Balloon↗
PubMed1998

Rationale and design of the Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) study that evaluates atorvastatin in unstable angina pectoris and in non-Q-wave acute myocardial infarction.

The goal of the Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) study is to determine whether early, rapid, and profound cholesterol lowering therapy with atorvastatin can reduce early recurrent ischemic events in patients with unstable angina or non-Q-wave acute myocardial infarction. Within 1 to 4 days of hospitalization for one of these conditions, 2,100 patients will be randomly assigned to receive atorvastatin, 80 mg/day, or placebo in a double-blind design. Both groups receive dietary counseling. Over a 16-week follow-up period, the primary outcome measure is the time to occurrence of an ischemic event, defined as death, nonfatal acute myocardial infarction, cardiac arrest with resuscitation, or recurrent symptomatic myocardial ischemia requiring emergency rehospitalization. Secondary outcome measures are the time to occurrence and incidence of each of the primary outcome components, as well as nonfatal stroke, worsening angina, congestive heart failure requiring hospitalization, and need for coronary revascularization not anticipated before randomization. The sample size of 1,050 patients in each group is expected to provide 95% power to detect a 30% reduction in the primary outcome measure with a 5% level of significance. The results of the MIRACL study will determine the utility of profound cholesterol lowering as an early intervention in acute coronary syndromes.

Angina, Unstable↗