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Background: Although aspirin is beneficial in patients with unstable angina, it is a relatively weak inhibitor of platelet aggregation. The effect of Integrelin, which inhibits the platelet fibrinogen receptor glycoprotein (GP) IIb/IIIa, on the frequency and duration of Holter ischemia was evaluated in 227 patients with unstable angina., Methods and Results: Patients received intravenous heparin and standard ischemic therapy and were randomized to receive oral aspirin and placebo Integrelin; placebo aspirin and low-dose Integrelin. 45 micrograms/kg bolus followed by a 0.5 microgram.kg-1. min-1 continuous infusion; or placebo aspirin and high-dose Integrelin, 90 micrograms/kg bolus followed by a 1.0-microgram.kg-1, min-1 constant infusion. Study drug was continued for 24 to 72 hours, and Holter monitoring was performed. Patients randomized to high-dose Integrelin experienced 0.24 +/- 0.11 ischemic episodes (mean +/- SEM) on Holter lasting 8.41 +/- 5.29 minutes over 24 hours of study drug infusion. Patients randomized to aspirin experienced a greater number (1.0 +/- 0.33, P < .05) and longer duration (26.2 +/- 9.8 minutes, P = .01) of ischemic episodes than the high-dose Integrelin group. There was no evidence of rebound ischemia after withdrawal of study drug. In 46 patients, platelet aggregation was rapidly inhibited by Integrelin in a dose-dependent fashion. The number of clinical events was small, and there were no bleeding differences in the three treatment arms., Conclusions: Intravenous Integrelin is well tolerated, is a potent reversible inhibitor of platelet aggregation, and added to full-dose heparin reduces the number and duration of Holter ischemic events in patients with unstable angina compared with aspirin.

Background: With the thrombogenic tendency and permanent implant nature of metallic stents, synthetic polymers have been proposed as candidate materials for stents and local drug delivery designs. We investigated the biocompatibility of several synthetic polymers after experimental placement in the coronary artery., Methods and Results: Five different biodegradable polymers (polyglycolic acid/polylactic acid [PGLA], polycaprolactone [PCL], polyhydroxybutyrate valerate [PHBV], polyorthoester [POE], and polyethyleneoxide/polybutylene terephthalate [PEO/ PBTP]) and three nonbiodegradable polymers (polyurethane [PUR], silicone [SIL], and polyethylene terephthalate [PETP]) were tested as strips deployed longitudinally across 90 degrees of the circumferential surface of coil wire stents. Appropriately sized polymer-loaded stents were implanted in porcine coronary arteries of 2.5- to 3.0-mm diameter. Four weeks after implantation, stent patency was assessed by angiography followed by microscopic examination of the coronary arteries. The biodegradable PCL, PHBV, and POE and the nonbiodegradable PUR and SIL evoked extensive inflammatory responses and fibrocellular proliferation (thickness of tissue response: 0.79 +/- 0.22, 1.12 +/- 0.01, 2.36 +/- 0.60, 1.24 +/- 0.36, and 1.43 +/- 0.15 mm, respectively). Less but still severe responses were observed for the biodegradable PGLA and PEO/PBTP (0.46 +/- 0.18 and 0.61 +/- 0.23 mm, respectively) and for the nonbiodegradable PETP (0.46 +/- 0.11 mm)., Conclusions: An array of both biodegradable and nonbiodegradable polymers has been demonstrated to induce a marked inflammatory reaction within the coronary artery with subsequent neointimal thickening, which was not expected on the basis of in vitro tests. The observed tissue response may be attributable to a combination of parent polymer compound, biodegradation products, and possibly implant geometry.

Background: Several perfusion balloon catheters are under investigation for local drug delivery; however, sustained tissue drug levels are difficult to achieve with these techniques. To overcome this problem, sustained-release, biodegradable nanoparticles represent a potential alternative for prolonged local delivery., Methods and Results: A biodegradable polylactic-polyglycolic acid (PLGA) copolymer was used to formulate nanoparticles. Fluorescent-labeled nanoparticles were intraluminally administered in a single, 180-second infusion after balloon injury in the rat carotid model. Localization and retention at different time points and biocompatibility of nanoparticles were evaluated. To evaluate the potential of the system in the prevention of neointimal formation, dexamethasone was incorporated into the particles and delivered locally as above. Nanoparticles were seen in the three layers of the artery at 3 hours and 24 hours. At 3 days, they were mainly present in the adventitial layer, decreasing at 7 days, with no fluorescent activity at 14 days. The PLGA nanoparticles appeared to be fully biocompatible. In the dexamethasone nanoparticle study, a significant amount of dexamethasone was present in the treated segment for up to 14 days after a single infusion, with no plasma levels detected after the first 3 hours. There was a 31% reduction in intima-media ratio in animals treated with local dexamethasone nanoparticles compared with control., Conclusions: Nanoparticles successfully penetrated into the vessel wall and persisted for up to 14 days after a short, single intraluminal infusion. Local administration of nanoparticles with incorporated dexamethasone significantly decreased neointimal formation. This methodology appears to have important potential for clinical applications in local drug delivery.

Purpose: To review the current understanding of the clinical significance, detection, pathogenesis, and prevention of anthracycline-induced cardiotoxicity., Data Sources: A MEDLINE search of the English-language medical literature and a manual search of the bibliographies of relevant articles, including abstracts from national cardiology meetings., Study Selection: Pertinent clinical and experimental studies addressing the clinical relevance, pathogenesis, detection, and prevention of anthracycline cardiotoxicity were selected from peer-reviewed journals without judgments about study design. A total of 137 original studies and 9 other articles were chosen., Data Extraction: Data quality and validity were assessed by each author independently. Statistical analysis of combined data was inappropriate given the differences in patient selection, testing, and follow-up in the available studies., Data Synthesis: Anthracycline-induced cardiotoxicity limits effective cancer chemotherapy by causing early cardiomyopathy, and it can produce late-onset ventricular dysfunction years after treatment has ceased. Detection of subclinical anthracycline-induced cardiomyopathy through resting left ventricular ejection fraction or echocardiographic fractional shortening is suboptimal. Conventional doses of anthracycline often lead to permanent myocardial damage and reduced functional reserve. Underlying pathogenetic mechanisms may include free-radical-mediated myocyte damage, adrenergic dysfunction, intracellular calcium overload, and the release of cardiotoxic cytokines. Dexrazoxane is the only cardioprotectant clinically approved for use against anthracyclines, and it was only recently introduced for selected patients with breast cancer who are receiving anthracycline therapy., Conclusions: A rapidly growing number of persons, including an alarming fraction of the 150 000 or more adults in the United States who have survived childhood cancer, will have substantial morbidity and mortality because of anthracycline-related cardiac disease. The development of effective protection against anthracycline-induced cardiotoxicity will probably have a significant effect on the overall survival of these patients.

The main procedural drawback to percutaneous coronary angioplasty is restenosis of the treated site within 6 months. Despite advances in equipment, technique, and adjunctive therapies, restenosis has occurred in approximately one-third to one-half of all patients. The biology of restenosis can be divided into plaque persistence and recoil, thrombus formation and transformation, and cellular proliferation and vascular remodeling. Animal models of restenosis have helped to elucidate these mechanisms of restenosis and provide a means to test pharmacologic and mechanical strategies to reduce stenosis recurrence. While numerous agents have been tested in animal models, until recently none has translated into benefit in large-scale clinical trials. Two therapeutic "hopefuls" which have recently emerged in clinical practice are the potent platelet inhibitors, glycoprotein IIb/IIIa receptor antagonists, and intracoronary metallic stents. The IIb/IIIa receptor antagonists target thrombus formation at the angioplasty site, thereby minimizing abrupt vessel closure acutely and neointimal growth chronically, while intracoronary stents safely produce a large coronary arterial lumen acutely and prevent vessel recoil. Separately, these therapeutic strategies have been shown to reduce clinical restenosis 20-30% at 6-month follow-up. With these encouraging results, the future will certainly provide more pharmacologic and mechanical therapies targeting restenosis. With increased understanding of the restenotic process and continued refinement of effective treatments, it may be possible one day to prevent stenosis recurrence.

We studied the pharmacokinetic and pharmacodynamic properties of integrelin, a novel platelet glycoprotein IIb/IIIa receptor inhibitor, in patients undergoing elective percutaneous coronary intervention. Patients were randomized to placebo (n = 19) or to 1 of 4 integrelin dosing regimens (total n = 54) that were studied sequentially. All patients received aspirin and heparin. Patients were followed until discharge for the occurrence of adverse clinical events: death, myocardial infarction, coronary artery bypass surgery, repeat intervention, or recurrent ischemia. Bleeding was the primary safety end point. Frequent blood sampling was performed for adenosine diphosphate-induced platelet aggregations. Simplate bleeding times were performed. Adverse clinical events occurred less often in the integrelin-treated patients, although the overall numbers were too small to make a definitive statement as to clinical efficacy. There was no significant increase in serious bleeding among integrelin-treated patients. The 2 highest integrelin boluses (180 and 135 micrograms/kg) immediately (15 minutes after the bolus) provided > 80% inhibition of adenosine diphosphate-induced platelet aggregation in > 75% of treated patients. A constant integrelin infusion of 0.75 micrograms/kg/min maintained this marked antiplatelet effect, whereas an infusion of 0.50 micrograms/kg/min allowed gradual recovery of platelet function. Elective coronary intervention was performed safely and with no significant increase in serious bleeding events using integrelin with aspirin and heparin as an antithrombotic regimen. Integrelin provided rapid, intense, and persistent ex vivo platelet inhibition during coronary intervention. This new antiplatelet agent may be beneficial in reducing platelet-mediated ischemic complications of percutaneous coronary intervention.

Background: The relation among the coagulation cascade, its individual proteins, and the response to vascular injury is largely undefined. We have evaluated the effect of four probes that block specific levels of coagulation cascade on neointimal hyperplasia in the atherosclerotic rabbit arterial injury model., Methods and Results: Focal femoral atherosclerosis was induced by air-desiccation injury and hypercholesterolemic diet in 48 New Zealand White rabbits, followed by balloon angioplasty. Active-site inactivated factor VIIa (DEGR-VIIa), which blocks the binding of factor VIIa to tissue factor, was administered (n = 12 arteries) by intravenous bolus (1 mg/kg) at the time of balloon angioplasty and followed by infusion of 50 micrograms.kg-1.h-1 for 3 days; for the control (n = 13 arteries), 150 U heparin was injected as bolus and followed by infusion of saline at 50 microL.kg-1.min-1. Recombinant tissue factor pathway inhibitor (TFPI), which binds factor Xa and inhibits the tissue factor-factor VIIa complex and factor Xa, was given as a 1 mg/kg bolus followed by 15 micrograms.kg-1.min-1 infusion for 3 days (n = 17 arteries). Recombinant tick anticoagulant peptide (TAP; n = 15 arteries) and hirudin (n = 14 arteries), which block factor Xa and thrombin, respectively, were administered as a 1 mg/kg bolus followed by 5 micrograms.kg-1.min-1 infusion for 3 days. These three groups had their own controls (n = 14 arteries). There were no differences among treatment groups in preangioplasty and postangioplasty minimal luminal diameter (MLD) by angiography. The mean MLD 21 days after balloon angioplasty was significantly different between control and DEGR-VIIa-treated groups (0.74 +/- 0.25 and 1.24 +/- 0.27 mm, respectively; P = .0001) and between the TFPI-treated group and others (0.88 +/- 0.21 mm for control, 0.97 +/- 0.22 mm for hirudin-treated, 0.98 +/- 0.14 mm for TAP-treated, and 1.32 +/- 0.21 mm for TFPI-treated arteries; P = .0001 by ANOVA). By quantitative histological analysis, the ratio of neointimal cross-sectional area compared with the area of internal elastic lamina in the DEGR-VIIa-treated group was significantly less than control (0.48 +/- 0.12 versus 0.67 +/- 0.12, P = .0001), and the ratio of neointimal cross-sectional area to the area demarcated by the internal elastic lamina of the TFPI-treated group was significantly reduced compared with the other groups (0.46 +/- 0.20 for TFPI-treated, 0.67 +/- 0.15 for hirudin-treated, 0.61 +/- 0.15 for TAP-treated, and 0.64 +/- 0.13 for control groups; P = .003)., Conclusions: Treatment with DEGR-VIIa or TFPI for 3 days in this rabbit atherosclerotic injury model reduced angiographic restenosis and decreased neointimal hyperplasia compared with controls. These findings highlight the importance of early initiators of the extrinsic coagulation pathway, especially factor VII and tissue factor, in the response to arterial injury.

The Evaluation of 7E3 for the Prevention of Ischaemic Complications (EPIC) trial assessed the use of abciximab in the treatment of patients at high risk undergoing percutaneous revascularization procedures. Abciximab (c7E3) is a chimeric monoclonal antibody targeted to block the glycoprotein IIb/IIIa receptor on the surface of the platelet; this receptor is believed to be the final common pathway of platelet aggregation. Administered at the time of angioplasty or directional coronary atherectomy, abciximab had a beneficial effect in the population studied, which included patients considered to be at high risk from complications of the procedure, based on the presence of acute or recent myocardial infarction, severe unstable angina or adverse coronary morphological characteristics. Abciximab reduced the risk of the primary endpoint at 30 days (death, myocardial infarction, repeat angioplasty or bypass surgery for recurrent ischaemia, balloon pump or stent insertion for ischaemia) by 35%: from 12.8% in the placebo group to 8.3% in patients treated with abciximab bolus and infusion. This trend was observed as a whole and in each component of the primary endpoint. At 6 months follow-up, the effect of the treatment was modestly enhanced beyond 30 days. A variety of substudies have documented substantial evidence of treatment benefit in patients with acute myocardial infarction and unstable angina. Non-fatal infarction, observed as beyond that normally expected in other studies with directional coronary atherectomy, was not above normal in patients treated with abciximab, and there was evidence of a treatment benefit in the elderly, although more information would be helpful in patients over the age of 70. The substantial site-to-site variability indicates that standardization of percutaneous revascularization could enhance the benefit of abciximab, while reducing bleeding complications.

Aggregation of platelets leading to thrombosis is one of the hallmarks of unstable angina, acute myocardial infarction, and ischaemic complications following coronary angioplasty. Activated platelets bind to fibrinogen through the glycoprotein IIb/IIIa integrin receptor. New agents have been developed to bind this receptor and thus prevent aggregation of platelets. One such compound (integrelin) is a cyclical peptide that has been shown to be a potent inhibitor of the glycoprotein IIb/IIIa receptor in man. A number of phase I and phase II clinical trials have been completed to evaluate this agent for the indications of unstable angina, acute myocardial infarction, as well as an adjunct to coronary angioplasty. This article will focus on the clinical investigation of integrelin with particular emphasis on its use during angioplasty. It has been consistently shown across different trials that integrelin can inhibit between 70% and 95% of platelet aggregation responses to 20 mumols of ADP at a variety of dosages used in the phase II trials. Preliminaray data also suggest that a more clinically unstable patient may require a higher dose of integrelin to cause a near complete inhibition of the platelet aggregation response to ADP. Future studies will need to explore more definitely the relationship between dose of glycoprotein IIb/IIIa receptor blockers and clinical instability.

Objectives: We examined the results of the Coronary Angioplasty Versus Excisional Atherectomy Trial (CAVEAT) to determine the characteristics and consequences of creatine kinase (CK) and creatine kinase, MB myocardial isoenzyme fraction (CK-MB) elevations after percutaneous coronary intervention., Background: Enzyme elevations after interventional procedures have usually been thought to be without long-term clinical consequences. However, recent preliminary reports have suggested that there are important long-term clinical sequelae in patients with even mild enzyme elevations after coronary procedures., Methods: Patients with new native lesions undergoing coronary intervention at 35 clinical sites were randomized to undergo percutaneous coronary angioplasty (n = 500) or directional coronary atherectomy (n = 512). Cardiac enzyme levels were measured 12 and 24 h after the interventional procedure and when clinically indicated for recurrent myocardial ischemia. Enzyme profiles were analyzed using a ratio that compared the peak enzyme level and the local laboratory upper limit of normal. Standard 12-lead electrocardiograms (ECGs) recorded before and after the procedure were interpreted by two independent readers who had no knowledge of the randomization data. Postprocedural myocardial infarction was defined as the appearance of new Q waves on the ECG, CK-MB levels three or more times the upper limit of normal or a total CK concentration two or more times the upper limit of normal when CK-MB levels were unavailable. Regression models were used to evaluate the predictive significance of a postintervention myocardial infarction with respect to clinical outcomes at 30 days and 1 year., Results: There were 78 myocardial infarctions in the atherectomy group and 34 in the angioplasty group (15.2% vs. 6.8%, p = 0.001). Patients with a myocardial infarction more often had a repeat intervention or emergency coronary artery bypass surgery. Hospital length of stay was increased among patients with an infarction, as were mean hospital costs ($17,340.65 vs. $11,308.47, p = 0.0003). Postprocedural myocardial infarction was highly predictive of mortality, bypass surgery or repeat intervention within 30 days (p < 0.0001)., Conclusions: Myocardial infarction occurred commonly after coronary intervention in CAVEAT and was associated with a worse clinical outcome. Although the incidence of myocardial infarction was higher with atherectomy than with angioplasty, the baseline characteristics and consequences of the infarctions were similar between the treatments with regard to 30-day outcome. Myocardial enzyme elevations after an otherwise successful interventional procedure may identify a population at risk for a future cardiac event.

To determine whether pharmacologic reperfusion to Thrombolysis in Myocardial Infarction (TIMI) grade 2 flow during acute myocardial infarction confers the same clinical benefit as restoration of TIMI 3 flow, in-hospital clinical and angiographic outcomes in 1,229 patients prospectively enrolled in the Thrombolysis and Angioplasty in Myocardial Infarction trials were analyzed. Patients were treated with intravenous tissue plasminogen activator or urokinase, or both. Angiography of the infarct-related artery 90 minutes after initiation of thrombolytic therapy demonstrated TIMI grades 0, 1, 2, or 3 flow in 20%, 7%, 17%, and 55% of vessels, respectively. Rescue or adjunctive coronary angioplasty was performed in 80%, 27%, and 16% of patients with TIMI 0/1, 2, or 3 flow, respectively. Predischarge angiography was performed in 963 patients. A significant gradient of increasing mortality was seen in patients with lower TIMI flow (4.3%, 6.1%, and 10.1% with TIMI 3, 2, and 0/1 flow, respectively, p = 0.002). The incidence of congestive heart failure and recurrent ischemia was significantly higher in patients with TIMI 2 than with TIMI 3 perfusion (26% vs 19% for heart failure, p = 0.03; 23% vs 17% for recurrent ischemia, p = 0.05). Acute left ventricular ejection fraction and infarct zone regional wall motion were also significantly improved in patients with TIMI 3 than with TIMI 2 flow, with trends toward better improvement in global and regional function in the TIMI 3 group. These findings were not affected by the use of acute coronary angioplasty.(ABSTRACT TRUNCATED AT 250 WORDS)

Objectives: This study sought to ascertain whether early and 12-month clinical outcomes after percutaneous coronary revascularization have improved between 1986-1987 and 1991., Background: Since the mid-1980s, when the results of percutaneous revascularization were considered to be somewhat static, justifying large-scale clinical trials of percutaneous transluminal coronary angioplasty versus other modes of therapy, balloon technology has improved, and several new percutaneous revascularization techniques have become available. The clinical results of the current integrated approach to revascularization compared with those for coronary angioplasty alone in the late 1980s are not known., Methods: In this prospective case-control study, 200 consecutively treated patients with multivessel disease in 1991 were studied prospectively and compared with 400 consecutive patients from the same centers during 1986-1987. Patients from 1991 were matched with earlier patients on the basis of four previously described prognostic determinants (left ventricular ejection fraction, presence of unstable angina, diabetes and target lesion morphology score) and the treating institution and were assessed for treatment outcome (completeness of revascularization, procedural success and event-free survival [freedom from death, myocardial infarction and further revascularization])., Results: The 1991 cohort of patients was older (mean [+/- SD] age 62 +/- 11 vs. 58 +/- 11 years, p < 0.001) and tended to have slightly worse left ventricular function (ejection fraction 56 +/- 10% vs. 58 +/- 11%, p = 0.009) than the 1986-1987 cohort. Overall lesion morphology risk scores were similar. New devices (other than coronary angioplasty) were used in 26% of patients. The 1991 patient cohort had more frequent total revascularization (35% vs. 21%, p = 0.003), fewer emergency bypass operations (1.0% vs. 5.5%, p = 0.006) and an improved overall procedural success rate (90% vs. 84%, p = 0.04). In addition, at 12 months the event-free survival rate was superior in the 1991 cohort (73.3% vs. 63.6%, p = 0.02), although there was no difference in infarct-free survival rate (94.6% vs. 93.2%, p = NS)., Conclusions: Improved results with percutaneous revascularization in 1991 have important implications for patient care and interpretation of ongoing randomized trials enrolling patients in the late 1980s and intending to compare standard coronary angioplasty with other forms of therapy.

To date, six families of cell adhesion molecules are known. These are cell surface receptors that mediate adhesion of cells to each other or to components of the extracellular matrix and include integrins, selectins, the immunoglobulin superfamily, cadherins, proteoglycans and mucins. These cell adhesion molecules play a key role in cell-cell interaction (such as among endothelium, monocytes, smooth muscle cells and platelets) and cell-extracellular matrix interaction (such as between leukocytes, platelets or fibroblasts and the extracellular matrix). The importance of these interactions has recently been demonstrated in clinical trials with the use of an antibody fragment directed against the platelet alpha IIb beta IIIa integrin, with reduction of arterial thrombosis and restenosis after percutaneous coronary interventions. A fundamental role for cell adhesion molecules has been suggested for several other relevant disease processes, including atherosclerosis, acute coronary syndromes, reperfusion injury and allograft vasculopathy. This review focuses on providing the clinically relevant biology of these families of adhesion molecules, setting the foundation for delineation of their emerging role in cardiovascular therapeutics.

Background: Patients who have suffered acute myocardial infarction (AMI) and have been treated with intravenous thrombolytic agents resulting in early 'patent' [Thrombolysis in Myocardial Infarction (TIMI) 2-3 flow grade] arteries have been shown not to benefit from early percutaneous transluminal coronary angioplasty (PTCA). Recent data, however, suggest that the clinical outcome of patients with early TIMI 2 flow is decidedly inferior to that of patients with TIMI 3 flow, raising the question whether early PTCA might be beneficial for patients with TIMI 2 flow. The clinical utility of PTCA for this particular subset of patients has never been assessed., Methods: We analyzed left ventricular ejection fraction (LVEF) recovery by contrast ventriculography and clinical outcome in Thrombolysis and Angioplasty in Myocardial Infarction Phase I (TAMI-I) study patients with initial TIMI 2 flow grade, determined by blinded core laboratory analysis., Results: No differences were observed between baseline demographic data for the 49 patients randomly assigned to undergo early PTCA compared with that from the 59 patients randomly assigned to receive early medical therapy. Patients were 56 +/- 11 years of age (mean +/- SD), 80% were men, the time from onset of chest pain to catheterization was 268 +/- 71 min, 42% had anterior AMI, and 42% had multivessel disease. Ninety minute baseline LVEF to prehospital discharge LVEF was minimally better in the group randomly assigned to undergo PTCA (51 +/- 12 to 52 +/- 11% versus 55 +/- 10 to 53 +/- 12%, P = 0.06). This contrasted with findings in patients with TIMI 3 flow grade at baseline, which showed a relative benefit for patients randomly assigned to receive early medical therapy (54 +/- 10 to 54 +/- 8% for PTCA, versus 55 +/- 10 to 58 +/- 8% for medical therapy, P = 0.01). Among patients with TIMI 2 flow grade there were no differences in in-hospital death or congestive heart failure (6.1 versus 1.7%, P = 0.25 and 18.4 versus 23.7%, P = 0.50, PTCA versus medical therapy, respectively)., Conclusion: We conclude that (1) PTCA of infarct-related arteries with TIMI 2 flow grade may modestly improve recovery of left ventricular function, and (2) widespread application of PTCA in this setting should be deferred, pending demonstration that this benefit outweighs the risks of PTCA.

The identification of the factors which predict increased risk for procedural complications in patients undergoing percutaneous revascularization allows a prospective stratification and evaluation of the risk benefit ratio in the individual patient. Such stratification may allow choice of other management options, such as medical therapy or bypass surgery, but probably more importantly allows the selective application of adjunctive pharmacotherapy or mechanical support techniques. It is important to recognize the limitations of all pre-procedural risk assessment however in that overall these criteria still have relatively low predictive value and to a great extent closure remains unforeseeable. Additionally, high risk characteristics are frequently encountered in clinical practice, and for many high risk patients the best option for revascularization may still be the percutaneous one.

Objectives: The goal of this study was to investigate whether female gender portends an adverse prognosis independent of the severity of the underlying disease after acute myocardial infarction treated by thrombolysis. A total of 348 women were compared with 1,271 men enrolled in the Thrombolysis and Angioplasty in Myocardial Infarction (TAMI) trials., Background: The reasons for gender differences in the management and prognosis of acute coronary artery syndromes remain poorly defined. The extent to which gender itself explains observed differences in outcome and use of diagnostic procedures remains unclear because confounding factors have not been specified., Methods: Patients < 76 years of age presenting within 6 h of onset of ischemic symptoms with electrocardiographic ST segment elevation and without contraindications to thrombolysis, previous infarction in the same distribution or cardiogenic shock were prospectively enrolled in Phases 1 to 3, 5 and 7 of the TAMI trials. All patients received recombinant tissue-type plasminogen activator, urokinase or a combination of both agents. Protocol-mandated cardiac catheterization was performed during the hospital period. Rescue coronary angioplasty was carried out for reperfusion failure at angiography 90 min after initiation of thrombolytic therapy. Coronary artery bypass grafting or coronary angioplasty was performed for clinical indications., Results: Women were older than men (61.0 +/- 9.7 vs. 55.8 +/- 10.1 years, mean +/- SD) and had a higher incidence of many risk factors for adverse outcome after myocardial infarction. There were no differences in baseline hemodynamic variables or time to thrombolytic treatment. Rates of acute and predischarge infarct-related artery patency and global and regional left ventricular function were similar in the two groups. Rates of in-hospital coronary angioplasty (52.6% and 54.1%) and bypass graft surgery (20.4% and 22.0%) were comparable in women and men, respectively. Women had higher unadjusted rates of mortality (9.2% vs. 5.4%, p = 0.014), reinfarction (6.4% vs. 2.6%, p = 0.005) and hemorrhagic stroke (2.0% vs. 0.55%, p = 0.017) than did men during the hospital period. When adjusted for clinical and angiographic variables, differences in mortality and hemorrhagic stroke did not reach statistical significance, and the risk of reinfarction was only marginally associated with gender., Conclusions: In selected patients undergoing thrombolytic therapy and cardiac catheterization for acute myocardial infarction, adjusted mortality rates and utilization of postlysis revascularization are similar in women and men. However, women may be at increased risk for reinfarction.

Turkey poults fed furazolidone (Fz) in high concentrations (700 ppm) develop dilated cardiomyopathy (Fz-DCM). We tested whether five cardioactive agents were cardioprotective in this model of heart failure, ie, whether they prevented dilatation and wall thinning and improved contractile performance. We compared the effects of chronic administration of a beta 1-selective and a nonselective beta-receptor antagonist, an alpha-receptor antagonist, and two Ca2+ channel antagonists in the presence of Fz administration. The greatest cardioprotection was found with treatment with either propranolol or nifedipine. At the gross morphological level, the effect of propranolol (a nonselective beta-adrenergic antagonist) was greater than the effect of atenolol (a selective beta 1-adrenergic antagonist), and the effect of nifedipine was greater than that of verapamil (Ca2+ channel antagonists), with all agents more cardioprotective than phenoxybenzamine (an alpha 1-adrenergic > alpha 2-adrenergic antagonist). Differences in cardioprotective efficacy of each agent increased with increased concentration. These data indicate that the dose and choice of a specific type of Ca2+ channel antagonist or beta-receptor antagonist might be important in the treatment of dilated cardiomyopathy. All agents that were cardioprotective caused similar functional improvements at both the whole heart and isolated muscle levels. Compared with control animals, Fz-DCM animals showed a significant reduction in peak left ventricular (LV) developed pressure (92 +/- 17 versus 143 +/- 24 mm Hg, P < .05), +dP/dt (1151 +/- 219 versus 2454 +/- 549 mm Hg/s), and -dP/dt (1128 +/- 291 versus 1875 +/- 396 mm Hg/s), with a significant increase in LV end-diastolic volumes (2.8 +/- 0.7 versus 0.16 +/- 0.1 mL for control animals, P < .05). In contradistinction, LV + dP/dt and -dP/dt values for animals receiving Fz plus a cardioactive agent that demonstrated cardioprotection were not significantly different from control values. Peak LV developed pressures were also similar for Fz animals receiving an agent that demonstrated cardioprotection and control animals not receiving any pharmacologic agent. Isolated muscles from Fz-DCM animals as well as animals receiving Fz plus cardioprotective pharmacologic agents responded normally with regard to increasing extracellular Ca2+ concentrations. Peak twitch forces were greater for animals receiving cardioprotective agents plus Fz than control animals not receiving any pharmacologic agents or Fz alone. At higher stimulation rates, Fz-DCM muscles demonstrated a significantly reduced peak twitch force (4 +/- 0.5 versus 1.5 +/- 0.4 g/mm2 for control muscles versus Fz-DCM muscles, respectively).(ABSTRACT TRUNCATED AT 400 WORDS)

Thrombolytic therapy significantly improves the natural history of acute myocardial infarction, but recent data suggest that current reperfusion strategies have yet to realize the maximum potential for reduction of mortality and salvage of ventricular function. Coronary patency rates as high as 85% assessed by angiography 90 minutes after initiation of treatment greatly overestimate the efficacy of thrombolytic regimens, as this conventional angiographic "snapshot" view does not satisfactorily reflect the dynamic processes of coronary artery recanalization and reocclusion or the adequacy of myocardial perfusion. In fact, only the unusual patient appears to achieve optimal reperfusion for acute myocardial infarction, with a substantial deterioration of benefit in many patients due to insufficiently early or rapid recanalization, incomplete patency with TIMI grade 2 flow or critical residual coronary stenoses, absence of myocardial tissue reflow despite epicardial artery patency, intermittent coronary patency, subsequent reocclusion, or reperfusion injury. Recently developed techniques to critically assess the quality of reperfusion, coupled with the introduction of novel pharmacological agents and an improved understanding of the roles and mechanisms of existing thrombolytic and adjunctive drugs, have provided the opportunity to overcome many of the present limitations of reperfusion therapy. Emerging strategies to achieve optimal reperfusion are directed at enhancement of the velocity and quality of thrombolysis, amelioration of the adverse effects of reperfusion, and use of alternative pathways to myocardial salvage.

Objectives: A case-control analysis was performed to compare clinical outcome after intracoronary stenting with that after conventional therapy for abrupt vessel closure., Background: Previous studies have demonstrated that stenting after abrupt vessel closure results in marked angiographic improvement and preservation of coronary flow, leading to the anticipation of similar improvement in clinical outcome., Methods: Sixty-one of 92 consecutive patients treated at two clinical sites by intracoronary stenting for abrupt vessel closure were matched, according to angiographic features of closure and estimated left ventricular mass threatened by ischemia, with patients treated conventionally during the 18 months before stent availability. In 33 pairs of matched patients, vessel closure was established; in 28 pairs, it was threatened (coronary dissection or worsening stenosis with preservation of normal anterograde flow). Baseline clinical and angiographic characteristics were comparable in the two matched groups. Patients with indeterminate mechanisms of total occlusion (31%) or dissections < 15 mm long (43%) predominated; patients with visible thrombus (8%) or dissections > 15 mm long (18%) were infrequently represented. Stents were successfully deployed in 60 of 61 patients at a median of 52 min (range 3 to 269) after the onset of closure., Results: When compared with conventional treatment, stenting resulted in less residual stenosis (26% vs. 49% diameter stenosis, p < 0.001), a greater likelihood of restoration of Thrombolysis in Myocardial Infarction (TIMI) grade 3 blood flow (97% vs. 72%, p < 0.001) and a reduction in the need for emergency bypass surgery (4.9% vs. 18%, p = 0.02). However, the incidence of Q wave myocardial infarction was nearly the same in the two groups (32% vs. 20%, respectively, p = NS). In the group with stenting, peak creatine kinase level and the frequency of Q wave infarction after established vessel closure increased with the time to stent placement (p = 0.001 and 0.054, respectively); the incidence of procedure-related Q wave infarction in patients who underwent stenting within 45 min of closure was very low (3.9%). In-hospital death occurred in 3.3% of patients in each treatment group. At a mean of 6.3 months of follow-up after hospital discharge, survival free from late cardiac death, myocardial infarction, bypass surgery or coronary angioplasty was 74.9% and 81.3% in the stent and the control treatment group, respectively (p = NS)., Conclusions: Although early treatment of established vessel closure by intracoronary stenting was associated with a low incidence of both myocardial infarction and emergency bypass surgery, the likelihood or severity of infarction was not reduced among those in whom stents were implanted later. Patients with threatened vessel closure could not be shown to benefit from stent treatment. These data provide preliminary indications for stent placement in the acute period to be validated in larger randomized studies.

To assess the clinical, angiographic and procedural correlates of outcome after abrupt vessel closure during coronary angioplasty, results were analyzed of 109 patients (8.3%) who had abrupt vessel closure during 1,319 consecutive coronary angioplasty procedures performed between July 1, 1988 and June 30, 1990. These 109 patients had a mean age of 59 +/- 11 years; 63% were male, 57% had had a prior myocardial infarction and 61% had multivessel disease. Coronary angioplasty was performed in the settings of acute myocardial infarction (14%), recent myocardial infarction (36%), unstable angina (34%) and stable ischemia (29%). Abrupt vessel closure occurred at a median of 27 min (range 0 min to 5 days) from the first balloon inflation. By angiographic criteria, thrombus or coronary dissection was identified in 20% and 28% of cases, respectively; both thrombus and dissection were present in 7% of closures, and 45% were due to indeterminate mechanisms. Successful reversal of abrupt vessel closure, defined as restoration of normal Thrombolysis In Myocardial Infarction (TIMI) grade 3 flow without resultant Q wave myocardial infarction, emergency bypass surgery or death, was achieved in 47 patients (43%). By hierarchal analysis, the incidence of death, emergency coronary bypass surgery, Q wave and non-Q wave myocardial infarction was 8%, 20%, 9% and 11%, respectively. Univariate analysis using 23 clinical, morphologic and procedural variables demonstrated that successful outcome after abrupt closure was associated with prolonged balloon inflations (greater than 120 s) (odds ratio = 6.87, p less than 0.001), unstable angina (odds ratio = 2.37, p = 0.034) and placement of an intracoronary stent (odds ratio = 5.33, p = 0.062). By multivariate analysis, independent correlates of successful outcome were prolonged balloon inflations (odds ratio = 5.11, p = 0.001) and intracoronary stenting (odds ratio = 4.37, p = 0.049). Thus, although prolonged balloon inflations and intracoronary stents may improve outcome after abrupt vessel closure, the cumulative risk of morbidity or mortality remains significant and mandates investigation into improved strategies for its prevention and treatment.

Indications for coronary angioplasty have expanded to include patients with unstable acute ischemic syndromes, severe multivessel coronary artery disease and impaired left ventricular function. Several mechanical approaches have been developed as adjuncts to high risk coronary angioplasty to improve patient tolerance of coronary balloon occlusion and maintain hemodynamic stability in the event of complications. These percutaneous techniques include intraaortic balloon counterpulsation, anterograde transcatheter coronary perfusion, coronary sinus retroperfusion, cardiopulmonary bypass, Hemopump left ventricular assistance and partial left heart bypass. The intraaortic balloon pump provides hemodynamic support and ameliorates ischemia by decreasing myocardial work; it may be inserted for periprocedural complications or before angioplasty in patients with ischemia or hypotension. Anterograde distal coronary artery perfusion may be accomplished passively through an autoperfusion catheter or by active pumping of oxygenated blood or fluorocarbons through the central lumen of an angioplasty catheter. Synchronized coronary sinus retroperfusion produces pulsatile blood flow via the cardiac veins to the coronary bed distal to a stenosis. Both perfusion techniques limit development of ischemic chest pain and myocardial dysfunction in patients undergoing prolonged balloon inflations. Percutaneous cardiopulmonary bypass provides complete systemic hemodynamic support which is independent of intrinsic cardiac function or rhythm and has been employed prophylactically in very high risk patients before coronary angioplasty or emergently for abrupt closure. These and newer support devices, while associated with significant complications, may ultimately improve the safety of coronary angioplasty and allow its application to those who would otherwise not be candidates for revascularization.

Experimental data of the radial incorporation of labeled cholesterol [14C-4] into the artery wall is regressed against a mathematical model that predicts macromolecular transport in this biological system. Data is obtained using excised canine carotid arteries that are perfused in vitro under pulsatile hemodynamic conditions for 2 hr. Vessels are exposed to either normotensive hemodynamics, hypertensive hemodynamics, or simulations in which the rate of flow or vessel compliance is deliberately altered. Several arteries are studied under normotensive conditions following balloon catheter deendothelialization. Transmural concentration profiles of [14C-4] activity are determined by microcryotomy of longitudinal sections of perfused vessels. Nonlinear Marquardt regression on 12 experimental cases yields parameter estimates of effective diffusivity, D and solute filtration velocity, V. Results of this experimental investigation support our hypothesis that hemodynamics and the endothelial lining influence wall flux in intact vessels. Exposure to altered (vs normotensive) hemodynamics is associated with increased incorporation of labeled cholesterol. A similar observation is made for deendothelialized vessels (e.g. a greater accumulation of label and a rise in convective flux). Based upon our companion measurements of vessel wall forces and endothelial cellular morphology accompanying hemodynamic simulations, we suggest that hemodynamically induced alterations to endothelial structures lead to the increased permeability, convection and incorporation that we observe in this work.

A mathematical model of transcapillary exchange has been developed which considers in detail the contribution of Taylor dispersion (i.e., non-uniform velocity and inequalities in radial concentration) to the uptake and wash-out of multiple tracers from single capillaries. A numerical solution to the two-dimensional unsteady-state species continuity equation for a single capillary is obtained (by the use of an array processor) which simulates the convective dispersion of labelled indicators in permeable capillaries. Particular attention is directed toward an analysis of the roles of capillary permeability, transport regime as characterised by the Peclet number, velocity profile and the length of the exchange region on the development of time-concentration profiles and on the importance of convective dispersion. For the physiologic range of parameters consistent with pulmonary capillary transport of multiple indicators (e.g., labelled urea, albumin, etc.), we find that the magnitude of convective dispersion is insufficient to markedly affect the shapes of simulated tracer concentration profiles. The implication in these circumstances is that the use of one-dimensional models, which do not account for Taylor dispersion, does not lead to significant errors in parameter estimates derived from data of multiple indicator dilution.

A mathematical model of transcapillary exchange has been developed that considers in detail the role of axial diffusion in the extravascular tissue region on estimates of such physiological parameters as lung water (VE) and pulmonary capillary permeability-surface area products (PS), obtained from multiple indicator dilution studies. The experimental cases considered correspond to two animal models of pulmonary oedema in which the integrity of the pulmonary capillary membrane is disrupted and the effects of extravascular axial diffusion may be important. A novel feature of the computational scheme is the use of an Array Processor in the solution of the governing equations, initial and boundary conditions. Computer time is reduced to 2-3 min for parameter identification, thereby allowing a wide range of values for extravascular axial diffusion coefficients (D'/L2) to be studied at little computational expense. The results indicate that diffusion in the extravascular region does not influence parameter estimates for PS to urea. A statistical correlation is suggested between values for VE, PS to water, and D'/L2.