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Background This study evaluated the effect of heparin on the platelet reactivity and the pharmacodynamic profile of abciximab. Methods and Results Ex vivo studies were performed on patients undergoing elective percutaneous coronary intervention (n = 26) who were at moderate to high risk of ischemic complications. Patients received a 12,000-U bolus of heparin followed by a 0.25-mg/kg bolus of abciximab. Before abciximab treatment, platelet aggregation responses to a variety of stimuli were assessed immediately before and 10 minutes after the heparin bolus. Heparin increased platelet aggregation to 2 and 5 μmol/L adenosine diphosphate (ADP) and 5 μg/ml collagen by 36%, 25%, and 46%, respectively ( P ≤ .001), but did not influence platelet reactivity to thrombin receptor-activating peptide or 20 μmol/L ADP and had no appreciable effect on platelet surface glycoprotein (GP) IIb/IIIa receptor numbers. To assess the impact of heparin on the pharmacodynamic profile of abciximab, GP IIb/IIIa receptor blockade and platelet aggregation inhibition estimates obtained after abciximab administration were calculated relative to the basal levels observed both before and after the heparin bolus. At 2 and 24 hours after the abciximab bolus, GP IIb/IIIa receptor blockade measurements normalized to either the preheparin or postheparin baseline determinations were equivalent. For all ADP concentrations tested, the 2-hour post-abciximab bolus platelet aggregation inhibition estimates based on the preheparin and postheparin baseline values were comparable. However, for 2 and 5 μmol/L ADP, the 24-hour post-abciximab platelet aggregation inhibition measurements based on preheparin baseline values were significantly lower than postheparin baseline determinations (both P ≤ .003). In vitro studies revealed that therapeutic heparin doses induced a concentration-dependent reduction in the extent of platelet inhibition produced by amounts of abciximab that elicit partial inhibition of platelet aggregation. However, at abciximab concentrations that achieved platelet aggregation blockade of >80%, the levels of inhibition of platelet aggregation in the presence and absence of heparin were equivalent. Conclusions The cumulative ex vivo and in vitro data indicate that for certain stimuli, heparin alters the platelet inhibitory profile of abciximab at concentrations of the agent that yield partial suppression of platelet function.

Background —Blockade of the platelet glycoprotein IIb/IIIa receptor with the monoclonal antibody fragment abciximab was shown in a placebo-controlled randomized trial to reduce the incidence of acute ischemic complications within 30 days among a broad spectrum of patients undergoing percutaneous coronary revascularization. The durability of clinical benefit in this setting has not been established. Methods and Results —A total of 2792 patients enrolled in the Evaluation in PTCA to Improve Long-term Outcome with abciximab GP IIb/IIIa blockade (EPILOG) trial were followed with maintenance of double-blinding for 1 year. Patients had been assigned at the time of their index coronary interventional procedure to receive placebo with standard-dose, weight-adjusted heparin (100 U/kg initial bolus), abciximab with standard-dose, weight-adjusted heparin, or abciximab with low-dose, weight-adjusted heparin (70 U/kg initial bolus). The primary outcome was the composite of death, myocardial infarction, or urgent repeat revascularization by 30 days; this composite end point and its individual components were also assessed at 6 months and 1 year. Rates of any repeat revascularization (urgent or elective), target vessel revascularization, and a composite of death, myocardial infarction, or any repeat revascularization were also reported. Follow-up at 1 year was 99% complete for survival status and 97% complete for other end points. By 1 year, the incidence of the primary composite end point was 16.1% in the placebo group, 9.6% in the abciximab with low-dose heparin group ( P P Conclusions —Acute reductions in ischemic events after percutaneous coronary intervention by abciximab are sustained over follow-up to at least 1 year. Early periprocedural myocardial infarctions suppressed by this therapy are associated with long-term mortality rates.

Background —The glycoprotein (GP) IIb/IIIa receptor antagonist abciximab is approved for use in high-risk percutaneous coronary interventions. The purpose of the present study was to establish the pharmacodynamic profile and platelet-bound life span of abciximab. Methods and Results —The pharmacodynamics of abciximab (inhibition of ex vivo platelet aggregation and GP IIb/IIIa receptor blockade) were measured in 41 individuals who were randomized to receive a 0.25-mg/kg bolus and a 12-hour infusion of either 10 μg/min (EPIC regimen) or 0.125 μg · kg −1 · min −1 (EPILOG regimen) of the antiplatelet agent. At extended times, the amount and distribution of platelet-bound abciximab were monitored by flow cytometry. The EPIC and EPILOG infusion regimens exhibited equivalent blockade of both GP IIb/IIIa receptors and platelet aggregation throughout the duration of abciximab treatment. Flow cytometry revealed a single, highly fluorescent platelet population during treatment, consistent with complete saturation and homogeneous distribution of abciximab on circulating platelets. For 15 days after treatment, the fluorescence histograms remained unimodal with gradually diminishing fluorescence intensity, indicating decreasing levels of platelet-bound abciximab. At 8 and 15 days, which exceeds the normal circulating life span of platelets, median relative fluorescence intensity corresponded to 29 100 (29% GP IIb/IIIa receptor blockade) and 13 300 (13% GP IIb/IIIa receptor blockade) abciximab molecules bound per platelet, respectively. Conclusions —These results are consistent with continuous reequilibration of abciximab among circulating platelets and may explain the gradual recovery of platelet function and long-term prevention of ischemic complications by abciximab after coronary intervention.

Objectives. We sought to evaluate the impact of angiographically visible thrombus on short- and long-term clinical outcomes after percutaneous transluminal coronary angioplasty (PTCA). Background. Intracoronary thrombus is frequently seen on angiography in patients with acute ischemic coronary syndromes or complex lesion morphology, or both, and is often considered to predict a higher rate of complications in patients undergoing PTCA. Methods. Prospectively collected data from 2,099 patients undergoing high risk PTCA in the Evaluation of IIb/IIIa Platelet Receptor Antagonist 7E3 in Preventing Ischemic Complications (EPIC) trial were analyzed. In addition to aspirin and heparin, patients were randomized to receive either abciximab bolus and infusion, abciximab bolus alone or placebo. Based on an angiographic core laboratory interpretation, patients were classified into three groups: thrombus absent, thrombus possible or thrombus present. The primary end point at 30 days was the composite of death, myocardial infarction or urgent revascularization. The 6-month end point was the composite of death, myocardial infarction or any revascularization. Results. Although abrupt closure was most common in patients with thrombus present compared with thrombus absent or possible (13%, 10.0% and 7.4%, respectively), neither the 30-day nor the 6-month clinical end points were different among the three groups (9%, 11% and 11.7%, respectively, and 30%, 34% and 31%, respectively). Most notably, the benefit of treatment with abciximab was present in all three thrombus groups, and the magnitude of benefit was not different among the thrombus groups. Conclusions. In high risk patients undergoing percutaneous coronary revascularization, features of thrombus on the preprocedure angiogram do not indicate an augmented risk of adverse clinical outcomes. Abciximab therapy reduces the rate of adverse outcomes regardless of the presence of thrombus and should therefore not necessarily be reserved for patients whose angiograms have features of intraluminal thrombus.

Background The glycoprotein (GP) IIb/IIIa receptor antagonist abciximab (c7E3 Fab, ReoPro) is approved for use in high-risk percutaneous transluminal coronary angioplasty (PTCA). At present, no “point of care” exists for measuring pharmacological GP IIb/IIIa blockade. To address this need, the Chrono-log Whole Blood Aggregometer, which measures platelet aggregation by electrical impedance, was adapted to test platelet function at the bedside. Methods and Results GP IIb/IIIa receptor blockade, impedance (5 μg/mL collagen), and turbidimetric aggregation (5 and 20 μmol/L ADP) measurements were obtained on 14 PTCA patients who received the standard bolus plus a 12-hour infusion of abciximab. During abciximab administration, mean GP IIb/IIIa receptor blockade was >91%, and both impedance and turbidimetric aggregation were inhibited by ≥90%. At 12 hours after abciximab treatment, the mean inhibition of turbidimetric platelet aggregation to 5 and 20 μmol/L ADP was 65±20% and 49±14%, respectively, and inhibition of impedance aggregation was 69±12%. GP IIb/IIIa receptor blockade was 67±8%. At 36 hours after abciximab treatment (n=8), the mean inhibition of turbidimetric platelet aggregation to 5 and 20 μmol/L ADP was 44±21% and 30±14%, respectively, whereas impedance aggregation was inhibited by 60±14%. GP IIb/IIIa receptor blockade was 57±7%. Conclusions During and at 12 hours after abciximab therapy, impedance and turbidimetric platelet aggregation to 5 μmol/L ADP were comparable and closely correlated with GP IIb/IIIa receptor blockade. However, at 36 hours after abciximab treatment, impedance platelet aggregation more closely paralleled GP IIb/IIIa receptor blockade and indicated a slower recovery of platelet function than turbidimetric aggregometry.

The platelet membrane glycoprotein (GP) IIb/IIIa integrin receptor is the final common pathway leading to platelet aggregation. Local aggregation commonly occurs following atherosclerotic plaque rupture or other injury to the vascular wall. When GP IIb/IIIa is activated, fibrinogen and von Willebrand factor bind to the receptor with high affinity, crosslinking platelets and locking them to the vessel surface and to each other. This process is central to arterial thrombus formation and consequent acute coronary syndromes, such as myocardial infarction (MI), unstable angina, and abrupt closure following revascularization procedures. Abciximab (c7E3 Fab; ReoPro) is a chimeric monoclonal antibody fragment developed specifically to inhibit GP IIb/IIIa receptor activity and thus prevent platelet aggregation and thrombosis. Abciximab has been evaluated in several clinical studies, the largest of which was the Evaluation of Abciximab for the Prevention of Ischemic Complications (EPIC) trial. This randomized, multicenter, placebo-controlled trial enrolled 2,099 patients at high risk for ischemic complications following coronary revascularization. The patients were randomized into three treatment groups: placebo, abciximab bolus (0.25 mg/kg), or abciximab bolus plus 12-h infusion (10 μg/min). Patients in the abciximab bolus plus infusion group had significant reductions, compared with placebo, in a composite end point of death, nonfatal MI, and urgent coronary intervention within 30 days. These positive, short-term findings were maintained at 6 months of follow-up. Bleeding complications and transfusions were significantly increased in abciximab patients, although there was no increase in bleeding-related death, stroke, or surgery. Retrospective secondary analyses suggested that many of the bleeding events observed in the EPIC trial may have been associated with concomitant high-dose heparin therapy, particularly in lighter weight patients. Subsequent clinical trials have shown that bleeding events can be reduced in patients treated with abciximab by using weight-adjusted heparin dosing without affecting the efficacy of the abciximab bolus plus infusion regimen. Examination of health economic data from the EPIC trial showed that abciximab bolus plus infusion is cost effective as well as clinically beneficial. These results confirm the importance of platelet GP IIb/IIIa receptor blockade in the treatment of acute thrombotic syndromes. Key Words: Platelet aggregation—GP IIb/IIIa receptor—Coronary revascularization— Ischemia.

Objectives. We sought to evaluate whether patients with unstable angina undergoing coronary intervention derive particular clinical benefit from potent platelet inhibition. Background. Plaque rupture and platelet aggregation are pathogenetic processes common to unstable angina and ischemic complications of percutaneous coronary intervention. Methods. Of the 2,099 patients undergoing a coronary intervention in the Evaluation of 7E3 in Preventing Ischemic Complications (EPIC) trial, 489 were enrolled with the diagnosis of unstable angina and randomized to receive placebo, an abciximab (c7E3) bolus immediately before the intervention or an abciximab bolus followed by a 12-h infusion. The primary end point was a composite of death, myocardial infarction (MI) or urgent repeat revascularization within 30 days of randomization. The occurrence of death, MI or any revascularization within 6 months was also assessed. Results. Compared with placebo, the bolus and infusion of abciximab resulted in a 62% reduction in the rate of the primary end point (12.8% vs. 4.8%, p = 0.012) among patients with unstable angina, due primarily to a reduction in the incidences of death (3.2% vs. 1.2%, p = 0.164) and MI (9% vs. 1.8%, p = 0.004). By 6 months, cumulative death and MI were further reduced by abciximab (6.6% vs. 1.8%, p = 0.018 and 11.1% vs. 2.4%, p = 0.002, respectively). The magnitude of the risk reduction with abciximab was greater among the patients with unstable angina than among other patients in the EPIC trial without unstable angina for the end points of death (interaction: p = 0.008 at 30 days, p = 0.002 at 6 months) and MI (interaction: p = 0.004 at 30 days, p = 0.003 at 6 months). Conclusions. The syndrome of unstable angina identifies patients who will experience particularly marked reductions in the risk of death and MI with abciximab during coronary intervention. (J Am Coll Cardiol 1997;30:149–56)

A large number of glycoprotein (GP) IIb/IIIa receptors are present on the surface of platelets. Studies to define precisely the number of GPIIb/IIIa receptors using specific monoclonal antibodies (MoAbs) or fibrinogen binding have, however, yielded varying estimates of receptor number. To refine the quantitative estimation of GPIIb/IIIa receptors on resting platelets, we have used the MoAb 7E3, which has high affinity for GPIIb/IIIa. Quantitative binding studies were performed using radiolabeled conjugates of 7E3 IgG, as well as fragments and derivatives of 7E3. For platelets obtained from any single individual, the numbers of 7E3 F(ab′)2 and IgG molecules bound per platelet were equivalent (approximately 40,000), whereas the number of Fab molecules bound per platelet was consistently approximately twofold higher (approximately 80,000). To investigate the basis of the quantitative disparity in binding of intact 7E3 and 7E3 F(ab′)2 versus 7E3 Fab, we studied the binding of a newly constructed, bispecific (Fab′)2 molecule containing only a single 7E3 combining site. Because this construct bound to the same extent as the Fab species, the larger size of the intact 7E3 and 7E3 F(ab′)2 molecules could not explain the reduced number of molecules that bound per platelet compared to the Fab fragment. Rather, it appears that the valency of the antibody is the critical factor determining the number of antibody molecules bound per platelet. Thus, we conclude that the binding of 7E3 Fab corresponds most closely with surface GPIIb/IIIa number and that the number of GPIIb/IIIa receptors is approximately 80,000 per platelet.

Objectives.This study sought to describe in detail the pharmacokinetics and pharmacodynamics of chimeric monoclonal 7E3 Fab (c7E3 Fab) and to compare platelet responses to adenosine diphosphate (ADP) and the 11-amino acid thrombin receptor-activating peptide (TRAP [SFLLRNPNDKY-NH2]) in patients undergoing elective coronary angioplasty.Background.Inhibition of platelet aggregation with monoclonal antibody c7E3 Fab directed against glycoprotein (GP) IIb/IIIa has been shown to reduce ischemic complications after angioplasty and is being considered for treatment of other acute ischemic syndromes.Methods.Patients undergoing elective coronary angioplasty received aspirin (325 mg orally), heparin (12,000 U intravenously) and a bolus of c7E3 Fab (0.25 mg/kg body weight). Surface GPIIb/IIIa receptor blockade and aggregation in response to 20 μmol/liter ADP, 5 μg/ml collagen and 7.5 and 15 μmol/liter TRAP were assessed.Results.Surface GPIIb/IIIa receptor blockade by c7E3 Fab was 80% 2 h after injection and decreased to 50% at 24 h. Platelet aggregation in response to 20 μmol/liter ADP was inhibited by 73% at 2 h, and this inhibition decreased to 27% at 24 h. Platelet aggregation in response to 7.5 μmol/liter TRAP was inhibited by 53% at 2 h and 30% at 24 h. In contrast, aggregation in response to 15 μmol/liter TRAP was inhibited only 37% at 2 h and 10% at 24 h (p < 0.001 and p = 0.006, respectively vs. 20 μmol/liter ADP). Addition of exogenous c7E3 Fab to platelet-rich plasma led to more complete inhibition of 7.5 μmol/liter TRAP-induced aggregation.Conclusions.After c7E3 Fab treatment, inhibition of platelet aggregation depends on the agonist and can be overcome by increased thrombin activity but is restored if additional c7E3 Fab is added to block additional GPIIb/IIIa receptors. This phenomenon may be related to an internal pool of GPIIb/IIIa receptors joining the surface membrane and has implications concerning the duration of therapy with c7E3 Fab for patients with unstable angina or acute myocardial infarction.

Background The potential for novel antiplatelet and antithrombin agents to contribute to periprocedural bleeding complications of percutaneous coronary revascularization is poorly defined. In the Evaluation of c7E3 Fab in Preventing Ischemic Complications of High-Risk Angioplasty (EPIC) trial, the periprocedural use of aspirin, heparin, and a chimeric antibody to the platelet glycoprotein IIb/IIIa integrin c7E3 Fab in 2099 patients significantly reduced postprocedural ischemic complications and 6-month clinical restenosis but was associated with increased procedural bleeding complications. We review these complications and describe clinical and procedural variables associated with increased bleeding complications in the EPIC trial. Methods and Results Patients with high-risk clinical or lesion morphological characteristics were randomized to receive placebo bolus plus placebo infusion, c7E3 Fab bolus plus placebo infusion, or c7E3 Fab bolus plus c7E3 Fab infusion. Patients received periprocedural aspirin and intravenous heparin continued for a minimum of 12 hours after the procedure. Outcomes reflecting bleeding complications were measured: transfusions, decreased hemoglobin, and an index including both parameters. Major bleeding complications unrelated to bypass surgery occurred in 3.3%, 8.6%, and 10.6%, and blood product transfusions were used in 7.5%, 14.0%, and 16.8% of patients treated with placebo, bolus c7E3 Fab, and bolus plus infusion c7E3 Fab, respectively (both P P =.38 and P =.14, respectively). Conclusions Bleeding complications unrelated to bypass surgery were two to three times more frequent in patients receiving c7E3 Fab than in those receiving placebo, but most were transient and well tolerated. Risk-factor analysis and modification of concomitant antithrombotic and antiplatelet treatment strategies may aid in reducing bleeding complications and enhancing clinical benefit in patients receiving c7E3 Fab during percutaneous coronary revascularization.

The activated clotting time (ACT) has been used during percutaneous transluminal coronary angioplasty (PTCA) to monitor the extent of thrombin inhibition and anti-coagulation from heparin in an attempt to minimize untoward thrombotic events and hemorrhagic complications. With the introduction of potent platelet inhibitors, such as the chimeric monoclonal antibody c7E3, to interventional cardiology, the utility of measuring and regulating procedural ACT has not been examined. To investigate the possible influence of platelet IIb/IIIa antagonism on procedural ACT, we reviewed data from the Evaluation of c7E3 Fab in the Prevention of Ischemic Complications (EPIC) trial. In the EPIC trial, 2,099 patients undergoing PTCA with a high risk of abrupt vessel closure were randomized to receive placebo (n = 696) or the IIb/IIIa platelet receptor antagonist c7E3 Fab (n = 1,403). Despite receiving less procedural heparin, and fewer patients receiving very high heparin doses (> 14,000 U) than the placebo group, those receiving c7E3 had a higher mean (401 vs 367 seconds, p < 0.001) ACT when corrected for body weight. The ACT is increased approximately 35 seconds by the platelet IIb/IIIa receptor antagonist c7E3 Fab. This has important implications for dosing conjunctive heparin therapy and performing PTCA or directional coronary atherectomy in the setting of IIb/IIIa-directed therapy.

The GPIIb/IIIa (α IIb β 3 ) receptor plays a crucial role in platelet aggregation and platelet thrombus formation. Inhibition of GPIIb/IIIa with the Fab fragment of the mouse/human chimeric monoclonal antibody 7E3, snake venom peptides containing the arginine-glycine-aspartic acid (RGD) sequence, or peptides or peptidomimetics based on the RGD sequence results in abolition of platelet aggregation and platelet thrombus formation. This results in profound inhibition of thrombotic occlusions in animal models. The Phase III EPIC study demonstrated that c7E3 Fab, given as bolus followed by a 12 h infusion, reduced the risk of acute ischemic complications after coronary angioplasty by ∼35 % in patients at high risk of suffering such complications. Treated patients had an ∼2-fold increased risk of major bleeding, but no increase in cerebral hemorrhage or lethal bleeding. Treatment with c7E3 Fab may have had a beneficial effect on clinical restenosis at 6 months, but this needs to be confirmed. A possible anticoagulant effect of c7E3 Fab was also identified in EPIC, and in vitro studies support this possibility. With the approval of c7E3 Fab (abciximab ; ReoPro) for patients undergoing high-risk angioplasty in the US and several European and Scandinavian countries, GPIIb/IIIa inhibition joins the armamentarium of antithrombotic agents.

BACKGROUND Thrombosis has been implicated as central to the clinical complications of coronary angioplasty (PTCA). Chimeric monoclonal 7E3 Fab (c7E3 Fab) is the first of a new class of antiplatelet drugs directed at the platelet glycoprotein IIb/IIIa integrin. This study was performed to determine the pharmacodynamics of c7E3 Fab administration during PTCA and to gain an initial clinical experience with this novel agent. METHODS AND RESULTS The study was a multicenter, open-label, dose-escalation study conducted in two stages. Enrollment included 56 patients scheduled for elective PTCA who were estimated to be at moderate to high risk of sustaining ischemic complications. All patients were given aspirin and heparin. The study drug was given at least 10 minutes before PTCA. In stage 1, increasing bolus doses of c7E3 Fab were given to 15 patients; a bolus dose of 0.25 mg/kg was found to result in blockade of > 80% of the receptors and reduce platelet aggregation to < 20% compared with baseline, establishing this dose as that necessary to sufficiently suppress platelet activity. In stage 2, additional c7E3 Fab was administered by continuous infusion to 32 patients for progressively longer periods of time (up to 24 hours) to confirm that platelet inhibition could be maintained with prolonged drug infusion. Also, 9 patients otherwise meeting entry criteria were given placebo. There were no thrombotic events among patients receiving c7E3 Fab. Overall procedural and clinical success and complication rates as well as rates of bleeding were statistically similar among groups. However, minor bleeding was more frequent with administration of the active drug. CONCLUSIONS The novel antiplatelet agent c7E3 Fab can be administered during PTCA in combination with aspirin and heparin. Suppression of platelet activity is dose dependent and can be maintained for up to 24 hours. Further evaluation will be required to determine the extent of improvement in ischemic complication and restenosis rates and to provide additional insight into the safety profile of this potent monoclonal platelet antibody.

Restenosis after coronary angioplasty occurs in at least 30% of patients in the first six months and, as yet, there is no known treatment to decrease this event. We tested a monoclonal antibody Fab fragment (c7E3) directed against the platelet glycoprotein IIb/IIIa integrin, the receptor mediating the final common pathway of platelet aggregation, to see whether it reduced the frequency of clinical restenosis. Patients who had unstable angina, recent or evolving myocardial infarction, or high-risk angiographic morphology, were randomised to receive c7E3 bolus and a 12 hour infusion of c7E3 (708 patients), c7E3 bolus and placebo infusion (695 patients), or placebo bolus and placebo infusion (696 patients). With maintenance of the double-blind state, patients were followed-up for at least 6 months to determine the need for repeat angioplasty or surgical coronary revascularisation and the occurrence of ischaemic events. By 30 days, 12·8% of placebo bolus/placebo infusion patients had had a major ischaemic event (death, myocardial infarcton, urgent revascularisation), compared with 8·3% of c7E3 bolus/c7E3 infusion patients, yielding a 4·5% difference (35% reduction, p=0·008). At 6 months, the absolute difference in patients with a major ischaemic event or elective revascularisation was 8·1% between placebo bolus/ placebo infusion and c7E3 bolus/c7E3 infusion patients (35·1% vs 27·0%; 23% reduction p=0·001). The favourable long-term effect was mainly due to less need for bypass surgery or repeat angioplasty in patients with an initial successful procedure, since need for repeat target vessel revascularisation was 26% less for c7E3 bolus/c7E3 infusion than for placebo treatment (16·5% vs 22·3%; p=0·007). The c7E3 bolus/placebo infusion group had an intermediate outcome which was not significantly better than that of the placebo bolus/placebo infusion group. These results extend the benefit of c7E3 bolus/c7E3 infusion from reducing abrupt closure and acute-phase adverse outcomes to a diminished need for subsequent coronary revascularisation procedures. Because this therapy carries a risk of bleeding complications and has been studied only in high-risk angioplasty patients, further evaluation is needed before it can be applied to other patient groups.

The remarkable progress in immunologic techniques in the development of monoclonal antibodies offers the potential for powerful new tools for the detection of cardiovascular disorders, such as acute myocardial necrosis and acute deep venous thrombosis, in an accurate, safe, and noninvasive manner. Historically the use of monoclonal antibodies has been viewed as a tool dominated by the field of oncology. However, because of the relative ease of identifying and characterizing well-defined, unique antigens on necrotic cells, blood clots, and cellular components of the circulatory system, the chance for success in developing a clinically useful diagnostic product is significantly enhanced. In addition to being unique, these antigenic sites are also virtually universal in their expression by the targeted tissues or cells in the human population. Also, the epitope for these antibodies is less prone to "shedding" than many of the tumor markers present on the surface of malignant cells. This review describes the clinical experience with two immunoscintigraphic diagnostic agents specifically designed for the assessment of cardiovascular disorders resulting in the death of myocytes and the formation of acute blood clots indium-111 antimyosin-Fab-diethylenetriamine pentaacetic acid for the detection of myocardial necrosis and technetium-99m antifibrin Fab' (T2G1s) for the detection of acute venous thrombosis.

Despite many advances since its inception in humans in 1977, coronary angioplasty continues to be limited by the problems of abrupt arterial closure and late restenosis. Excessive platelet deposition at the site of angioplasty undoubtedly plays an important role in the pathophysiology of both of these problems. Monoclonal antibodies and snake venom-derived or synthetic peptides directed against a common protein recognition sequence on the platelet glycoprotein IIb/IIIa receptor are currently in the early stages of preclinical and clinical testing and hold promise of preventing abrupt closure and restenosis by inhibiting platelet function. Whether any of these agents will eventually be commonly used in clinical practice will depend on their effects on the complex pathophysiology of these problems and on their safety profile when administered to patients who are likely to receive other antithrombotic medications and who are instrumented for coronary angioplasty.

Recent imaging studies suggest that technetium-99m (Tc-99m) pyrophosphate yields a considerably larger estimate of myocardial infarct size than does indium-111 (In-111) monoclonal antimyosin antibody. To determine whether Tc-99m pyrophosphate may be taken up by reversibly injured myocytes, particularly in the setting of coronary reperfusion, the tissue localization of Tc-99m pyrophosphate and antimyosin antibody was compared in 11 dogs 24 to 68 h after anterior descending coronary artery occlusion (4 dogs with permanent occlusion, 7 with reperfusion). Technetium-99m pyrophosphate and In-111 antimyosin antibody content was determined in serial 2 to 3 mm wide endocardial and epicardial samples taken through the infarct zone in multiple short-axis left ventricular slices. The number of samples with increased In-111 antimyosin antibody (defined as ≧ mean + 2 SD of normal) was not significantly different from that with increased Tc-99m pyrophosphate. This was true in both reperfused and nonreperfused infarcts. However, the intensity of uptake of Tc-99m pyrophosphate exceeded that of In-111 antimyosin antibody, particularly in the border zones of reperfused infarcts, and the area with moderate to marked increase in tracer uptake (≥2 times normal) was significantly larger with Tc-99m pyrophosphate than In-111 antimyosin antibody (p Thus, the spatial extent of In-111 antimyosin antibody and Tc-99m pyrophosphate uptake was identical in myocardial infarction as measured by ex vivo tissue counting. Larger scintigraphic estimates of infarct size with Tc-99m pyrophosphate are probably due to more intense uptake of Tc-99m pyrophosphate in necrotic myocytes, particularly those located at the infarct boundary, rather than uptake in injured viable tissue.

We analyzed the results of exercise testing performed in the absence of all antiarrhythmic drugs in 11 case patients with newly documented polymorphic ventricular tachycardia in response to type Ia antiarrhythmic agents. These results were compared with those found in 11 control patients matched for age, sex, and heart disease to determine whether the response of the QT interval to exercise testing was abnormal in patients who developed worsening of arrhythmia while taking antiarrhythmic drugs. QT, RR, and QTc intervals (by Bazett's method) were evaluated at rest and at 3 minutes of exercise in both groups. At rest, there was no significant difference in the QT interval (410 +/- 13 vs. 386 +/- 11 msec), RR interval (890 +/- 56 vs. 781 +/- 43 msec), or corrected QT interval (438 +/- 10 vs. 438 +/- 4 msec) in the case patients and the control patients. Both groups demonstrated a similar chronotropic response to exercise. The QT interval shortened in both groups with exercise (p less than 0.001), but the degree of shortening tended to be greater in the control patients (to 310 +/- 9 msec) than in the case patients (to 357 +/- 11 msec) (p = 0.06). Thus, there was a paradoxical increase in the QTc interval in the patients who experienced a proarrhythmic effect of type Ia drugs but not in the control patients (to 482 +/- 8 vs. 431 +/- 5 msec; p less than 0.001). Ten of 11 case patients but only one of 11 control patients had an increase in QTc interval of more than 10 msec with exercise (p less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Platelet aggregation plays a crucial role in the development of the life-threatening thrombosis responsible for such acute coronary syndromes as myocardial infarction and unstable angina pectoris. Although aspirin has traditionally been the mainstay of antiplatelet therapy, it is neither potent nor specific enough to provide adequate protection against thrombosis. The identification of glycoprotein (GP) IIb/IIIa as the key platelet receptor in the final common pathway of platelet aggregation and the development of therapeutic agents that block this receptor have opened up an entirely new dimension in cardiovascular medicine.

The platelet GPIIb/IIIa receptor mediates platelet aggregation induced by all physiologic agonists. Blockade of the receptor, either by monoclonal antibodies or small molecules patterned after the arginine glycine-aspartic acid (RGD) cell recognition domain, prevents arterial thrombosis in animal models much better than does aspirin. c7E3 Fab, the Fab fragment of the mouse/human chimeric antibody 7E3 (abciximab: ReoProTM), was shown to reduce ischemic events after angioplasty when given in conjunction with heparin and aspirin to patients at high risk in the EPIC study, but its was associated with an increase in bleeding. Preliminary data from the subsequent EPILOG study, in which a lower dose of heparin was used, demonstrated efficacy in low risk as well as high risk patients and no significant increase in major bleeding. Preliminary data from the CAPTURE study support the use of c7E3 Fab in patients with unstable angina who are candidates for PTC A within 24 hours. Positive trends toward decreased thrombotic events have also been observed in patients treated with small molecule inhibitors of GPIIb/IIIa receptors. This new class of agents thus holds promise for improving the therapy of angioplasty as well as perhaps other thrombotic phenomena.

Percutaneous transluminal coronary angioplasty (PTCA) for acute myocardial infarction is an attractive alternative to thrombolysis, but is still limited by recurrent ischemia and restenosis. We determined whether adjunctive platelet glycoprotein IIb/IIIa receptor blockade improved outcomes in patients undergoing direct and rescue PTCA in the Evaluation of c7E3 for Prevention of Ischemic Complications (EPIC) trial. Of the 2,099 patients undergoing percutaneous intervention who randomly received chimeric 7E3 Fab (c7E3) as a bolus, a bolus and 12-hour infusion, or placebo, 42 underwent direct PTCA for acute myocardial infarction and 22 patients had rescue PTCA after failed thrombolysis. The primary composite end point comprised death, reinfarction, repeat intervention, or bypass surgery. Outcomes were assessed at 30 days and 6 months. Baseline characteristics were similar in direct and rescue PTCA patients. Pooling the 2 groups, c7E3 bolus and infusion reduced the primary composite end point by 83% (26.1% placebo vs 4.5% c7E3 bolus and infusion, p = 0.06). No reinfarctions or repeat urgent interventions occurred in c7E3 bolus and infusion patients at 30 days, although there was a trend toward more deaths in c7E3-treated patients. Major bleeding was increased with c7E3 (24% vs 13%, p = 0.28). At 6 months, ischemic events were reduced from 47.8% with placebo to 4.5% with c7E3 bolus and infusion (p = 0.002), particularly reinfarction (p = 0.05) and repeat revascularization (p = 0.002). We conclude that adjunctive c7E3 therapy during direct and rescue PTCA decreased acute ischemic events and clinical restenosis in the EPIC trial. These data provide initial evidence of benefit for glycoprotein IIb/IIIa receptor blockade during PTCA for acute myocardial infarction.

A murine monoclonal antibody (7E3) directed against the platelet glycoprotein IIb/IIIa was engineered to reduce immunogenicity by substituting human for murine constant regions. The chimeric antibody is functionally identical to the murine antibody in vitro. Results from clinical trials with 7E3 Fab antibody fragments, however, show that the 7E3 variable region, which elicits the vast majority of the immune response to murine 7E3 Fab, is rendered dramatically less immunogenic (incidence reduced from 17% to 1%) when the identical variable region is linked to human rather than murine constant regions. Neither murine nor human constant regions were highly immunogenic themselves. We conclude that the constant regions of the Fab fragments are critical in modulating the immune response elicited by the linked 7E3 variable region. Because naturally occurring anti-human Fab fragment antibodies are prevalent both in the normal human population and in the patient population studied here, murine 7E3 Fab and chimeric 7E3 Fab may be fundamentally different in their interactions with the human immune system. This difference may be related to the dramatic difference in immunogenicity observed between murine 7E3 Fab and chimeric 7E3 Fab.

The platelet glycoprotein (GP) IIb/IIIa receptor can bind fibrinogen, von Willebrand factor, and other adhesive ligands; this binding is the final common pathway mediating platelet aggregation. The purpose of this study was to evaluate the safety and platelet inhibitory characteristics of the Fab fragment of the murine monoclonal anti-GPII/IIIa 7E3 antibody (m7E3 Fab) when administered intravenously as a single bolus dose, as a single and repeat bolus dose, and as a single bolus dose followed by continuous infusions of varying duration. Various dosage regimens of m7E3 Fab were studied in 74 patients with stable angina. Dosage regimens included single doses of m7E3 Fab from 0.1 to 0.3 mg/kg, a single dose of 0.20-0.30 mg/kg, and a repeat dose of 0.05 mg/kg, or a loading dose followed by a continuous infusion of m7E3 Fab for up to 36 hours. To assess the effect of m7E3 Fab on platelet function, quantitative blockade of GPIIb/IIIa receptors, inhibition of ex vivo platelet aggregation, and template bleeding time were measured in all patients. Dose-dependent inhibition of platelet function was evident in response to escalating bolus doses of m7E3 Fab, with maximum inhibition observed at 0.25-0.30 mg/kg body weight; at the 0.30 mg/kg dose, mean (+/- SE) GPIIb/IIIa receptor blockade was 81 +/- 3%, ex vivo platelet aggregation in response to 20 microM ADP was 14 +/- 6% of baseline, and the median bleeding time was20 minutes. Although platelet function gradually recovered following a single bolus injection, platelet inhibition could be sustained by continuous, low-dose infusion of the antibody. Platelet inhibition occurred within minutes, but m7E3 Fab that did not bind to platelets cleared rapidly from circulation. Sixteen percent of the m7E3 Fab-injected subjects exhibited low titer, human anti-murine antibody responses. No significant bleeding or allergic reactions were observed in any patients. One of the 74 patients developed transient thrombocytopenia soon after receiving m7E3 Fab. These studies establish that m7E3 Fab can be administered safely at doses that cause profound inhibition of platelet function.

Objectives. We tested the hypothesis that cyclic alterations in coronary artery blood flow that occurred after coronary angioplasty could he attenuated or abolished by a monoclonal antibody to the platelet surface membrane GP IIb/IIIa receptor. Background. Coronary artery cyclic flow variations may occur after coronary angioplasty in experimental animal models and humans. In animal models of coronary thrombosis, cyclic alterations in flow often have preceded thrombotic occlusion or reocclusion. Several agents that inhibit platelet function have been shown to attenuate or eliminate cyclic flow variations in these models. Methods. We monitored coronary artery flow in 27 patients for 30 min after coronary angioplasty, using 0.018-in. (0.046 cm) coronary guide wires with pulsed wave Doppler ultrasound transducers on the distal tips. Clinical data were collected and quantitative analyses performed on coronary arteriograms made before and after the angioplasty procedures. We compared findings in patients with and without cyclic flow variations detected. Results. There were 20 men and 7 women. Mean age was 58 years, and 63% had unstable angina. They received standard doses of nitrates, aspirin, heparin, calcium channel antagonists and other medications clinically indicated. Nevertheless, we detected cyclic flow variations in five patients (19%). Four of these patients had stable flow restored with intravenous injection of 0.25 mg/kg normal body weight of monoclonal antibody c7E3 Fab to the platelet GP Ilb/IIIa receptor. In one patient, stable flow was restored by repeat dilation when an immediate angtogram revealed renarrowing. Patients developing cyclic alterations in flow had longer lesions (18.7 ± 7.5 mm vs. 13.1 ± 5.7 mm, p < 0.05) that had responded less well to angioplasty (stenosis postangioplasty 47 ± 13% vs. 33 ± 15%, p < 0.05). Conclusions. Cyclic alterations in coronary artery blood flow may occur in some patients after coronary angioplasty, despite the use of standard antiplotelet, antithrombotic and antivasospastic medications. We found that they could be eliminated by this monoclonal antibody that blocks the final common event of platelet aggregation.

BACKGROUND Reperfusion of acutely infarcted myocardium may be beneficial in limiting infarct expansion and ventricular remodeling even if established after the time that salvage of ischemic myocardium is possible. METHODS AND RESULTS To examine the permanency, time course, and mechanism of this effect of late reperfusion, 200 rats were randomized into one of four groups: (1) infarction with reperfusion after 1 to 2 hours, (2) infarction with reperfusion after 6 to 8 hours, (3) infarction without reperfusion, and (4) sham operation. Surviving rats were killed at either 7 days, when infarct expansion has plateaued, or 21 days, when infarct healing is complete. In both 7- and 21-day analyses, late reperfusion did not reduce infarct size or degree of transmural necrosis but significantly limited infarct expansion, as measured by an index based on infarct endocardial segment lengthening and infarct wall thinning (expansion index at 7 days: no reperfusion, 2.73 +/- 0.25, n = 13; reperfusion after 1 to 2 hours, 1.56 +/- 0.13, n = 23, P < .001; reperfusion after 6 to 8 hours, 1.78 +/- 0.15, n = 16, P = .002; at 21 days: no reperfusion, 3.45 +/- 0.39, n = 13; reperfusion after 1 to 2 hours, 2.21 +/- 0.24, n = 15, P = .01; reperfusion after 6 to 8 hours, 2.02 +/- 0.20, n = 9, P = .01). Reperfusion after 6 to 8 hours was equally effective in limiting expansion as reperfusion after 1 to 2 hours. Late reperfusion also significantly reduced ventricular remodeling at 21 days, as measured by an index based on left ventricular cavity dilatation and noninfarcted myocardial hypertrophy (remodeling index at 21 days: no reperfusion, 2.67 +/- 0.15, n = 13; reperfusion after 1 to 2 hours, 2.20 +/- 0.15, n = 15, P = .035; reperfusion after 6 to 8 hours, 2.12 +/- 0.10, n = 9, P = .012). Histological examination revealed that reperfusion accelerated the clearance of residual dead myofibrils, suggesting an increase in the rate of healing, and increased the degree of myocytolysis but did not change the final degree of infarct healing, tissue density, or viable subepicardial cells. CONCLUSIONS Late reperfusion causes a permanent reduction in postinfarction expansion that is present even after complete infarct healing. The time after coronary occlusion in which reperfusion is of benefit in reducing subsequent expansion and remodeling is substantially longer than previously established. The mechanism by which late reperfusion limits expansion may involve changing the rate of healing and the nature of myocardial necrosis but does not involve preserving subepicardial cells.

BACKGROUND To evaluate the in vivo safety, biodistribution, and diagnostic accuracy of a monoclonal Fab' antibody (S12) that is specific for the platelet membrane glycoprotein (GMP-140) expressed during platelet activation at vascular injury sites, 11 peripheral percutaneous transluminal angioplasty (PTA) patients (age, 61 +/- 8 years) with severe vascular disease had serial 99mTcS12 radionuclide imaging at 5 and 90 minutes, 4-6 hours, and 20-24 hours after a total of 23 angiographically successful PTA procedures. No acute allergic reactions or hematologic toxicity occurred. METHODS AND RESULTS The average PTA percent angiographic diameter stenosis (DS) at all 23 sites decreased from 85 +/- 12% to 12 +/- 11%, with a mean before-to-after-PTA change of 73 +/- 14% (p less than 0.01). The mean radionuclide image-derived ratio of 99mTc S12 activity in PTA versus contralateral non-PTA arterial segments for all angioplasty sites was 1.6 +/- 0.5. Vascular 99mTc S12 antibody activity was qualitatively evident in the majority (78%) of PTA sites at 4-6 hours after injection. 99mTc S12 target-to-background (muscle) ratio equaled 2.3 +/- 0.6 at PTA sites. Nine PTA sites (39%) had residual 99mTc S12 activity at 24 hours after injection (mean PTA site-to-contralateral artery ratio, 1.5 +/- 0.4). The mean vascular 99mTc S12 activity ratios in 10 procedurally complicated (defined as extensive dilation [greater than 2 cm] or grade I or greater arterial dissection) and 13 uncomplicated PTA segments were 1.9 +/- 0.5 versus 1.2 +/- 0.1, respectively (p less than 0.01). The associated before-to-after-PTA angiographic improvement was significantly less in procedurally complicated PTA sites (66 +/- 12% versus 80 +/- 12% DS; p less than 0.01). CONCLUSIONS 99mTc S12 activity is significantly increased at angiographically patent PTA sites that are procedurally complicated and are associated with less significant before-to-after-PTA angiographic improvement. 99mTc S12 monoclonal Fab' antibody imaging permits noninvasive identification of local vascular platelet activation resulting from angioplasty balloon injury in humans.

Amiodarone and its pharmacologically active metabolite desethylamiodarone have a sodium channel blocking action that explains some of their antiarrhythmic efficacy. However, the well-documented depression of the calcium channel-dependent sinus node and atrioventricular node function that occurs with amiodarone therapy suggests that amiodarone also blocks calcium influx through voltage-dependent calcium channels. Recent electrophysiologic data support the notion that amiodarone, but not desethylamiodarone, acts as a calcium channel antagonist. In this study, the effects of amiodarone and desethylamiodarone on calcium antagonist receptors associated with the voltage-dependent calcium channels were characterized. Amiodarone, but not its active metabolite desethylamiodarone, was a potent competitor at dihydropyridine and phenylalkylamine (verapamil-like) calcium antagonist binding sites in rat heart, brain, and skeletal and smooth muscles. Substantial inhibition of calcium antagonist binding was retained even after extensive washing of membranes and 2 days after in vivo treatment of rats with amiodarone. The pattern of inhibition of calcium antagonist binding suggests that amiodarone acts at phenylalkylamine binding sites. It is suggested that the acute effects of amiodarone--sinus and atrioventricular node inhibition, vasodilatation, and negative inotropic actions--may reflect calcium antagonist influences of amiodarone itself. Chronic effects of drug therapy, such as inhibition of ventricular conduction by sodium channel blockade, may selectively involve desethylamiodarone.

The EPIC Trial tested the efficacy of the c7E3 monoclonal antibody to the platelet GP IIbIIIa receptor in preventing ischemic events during “high-risk” PTCA or atherectomy by randomizing 2099 pts to receive placebo (PL), c7E3 bolus (BO), or c7E3 bolus + 12 hr infusion (BO + IN). BO + IN of c7E3 produced a 35% reduction in the 30-day composite primary endpoint (death, MI, urgent CABG, or re-PTCA) from 12.8% to 8.3% (p = 0.009) compared with placebo. Although c7E3 would not be expected to prevent the mechanical complication of coronary dissection, this agent may limit subsequent thrombus formation at dissection sites and thereby prevent progression to overt closure, embolization, or ischemic clinical events. The influence of c7E3 on adverse sequelae among pts who sustained dissection during EPIC was therefore investigated. Moderate (2–10 mm) or long (g 10 mm) dissections, as determined by Angiographic Core Laboratory analysis, occurred in 40.1%, 39,3%, and 42.5% of pts randomized to PL, BO, or BO + IN, respectively. Event PL (N = 278) BO IN = 273) BO + IN (N = 301) p-value Abrupt Closure 13% 7% 10% 0.080 Embolization l 1% 1% 1% 0.693 Primary Composite Endpoint 17% 12% 10% 0.025 Death 3% 1% 1% 0.510 Myocardial Infarction 12% 6% 7% 0.013 Emergency Re-PTCA 6% 5% 1% 0.002 Emergency CABG 5% 3% 3% 0.350 Although c7E3 did not significantly diminish the risk of abrupt closure or embolization among pts with moderate or long coronary dissections, potent reduction in the incidences of MI and emergency repeat revascularization may reflect ultimate stabilization of disrupted vascular segments during the post-procedural period. Further study is warranted to investigate a strategy of administration of c7E3 after coronary dissection has occurred.

Context. —Avciximab,lonal antibody fragment against the platelet receptor αllbβ3integrin, prevents platelet aggregation. A randomized, placebo-controlled study showed that abciximab improves outcomes for patients undergoing percutaneous coronary angioplasty at 30 days and at 6 months. Objective. —to determine whether abciximab improves outcomes 3 years after coronary angioplasty. Design. —Double-blind, placebo-controlled, randomized trial. Setting. —A total of 56 academic and community hospitals in the United States. Patients. —A total of 2099 high-risk patients undergoing coronary angioplasty were randomized. Sufficient time elapsed for 2.5 years of follow-up among 2001 patients and for 3 years of follow-up among 1599 patients. Intervention. —Abciximab bolus of 0.25 mg/kg followed by infusion at 10 μg/min for 12 hours; abciximab bolus of 0.25 mg/kg followed by placebo infusion; or placebo bolus followed by placebo infusion. Main Outcomes Measures. —The primary outcome was the composite of death, myocardial infarction, or coronary revascularization. Secondary outcomes were death, myocardial infarction, or coronary revascularization individually. Subgroups having refractory unstable angina or evolving myocardial infarction and having different elevations of creatine kinase during initial angioplasty were analyzed. Results. —At 3 years, composite end points occurred in 41.1% of those receiving abciximab bolus plus infusion; 47.4% of those receiving abciximab bolus only; and 47.2% of those receiving placebo only (for abciximab bolus plus infusion vs placebo,P=.009). Death occurred in 6.8%, 8.0%, and 8.6%, respectively (for abciximab bolus plus infusion vs placebo,P=.20); myocardial infarction in 10.7%, 12.2%, and 13.6%, respectively (for abciximab bolus plus infusion vs placebo,P=.08); and revascularization in 34.8%, 38.6%, and 40.1%, respectively (for abciximab bolus plus infusion vs placebo,P=.02). Among those with refractory unstable angina or evolving myocardial infarction, death occurred in 5.1%, 9.2%, and 12.7%, respectively (for abciximab bolus plus infusion vs placebo,P=.01). Death rates increased as periprocedural creatine kinase levels increased. Conclusions. —Adciximab bolus with infusion given at the time of coronary angioplasty improves outcomes as long as 3 years after the procedure.

Impaired energy production has been proposed as one mechanism to explain the contractile abnormality in post-ischemic "stunned" myocardium. If energy production were impaired, administration of inotropic agents should result in a deterioration of cellular energy stores because of an inability of ATP synthesis to match the rate of increased utilization. In this study we correlated changes in myocardial high energy phosphates, measured by 31P-NMR spectroscopy, with changes in left ventricular function and energy requirement in buffer perfused rabbit hearts following ischemia and reperfusion, and during stimulation with isoproterenol. Hearts were stunned by 20 min of zero flow global ischemia at room temperature. After reperfusion, isovolumic developed pressure returned to 77.8 +/- 2.2% of baseline and ATP content was reduced to 80.9 +/- 4.1% of baseline. Isoproterenol (5 x 10(-8) M for 10 min) caused increases in developed pressure and rate-pressure product (to 134.1 +/- 12.6% and 195.0 +/- 21.4% of baseline, respectively) without a decrease in ATP or phosphocreatine (PCr) content (80.0 +/- 7.1% and 103.0 +/- 3.8% of preischemia, respectively), and without functional or metabolic deterioration of the hearts after discontinuation of the drug. Control hearts not subjected to ischemia showed similar functional and metabolic responses to isoproterenol. The phosphocreatine/inorganic phosphate (PCr/Pi) ratio, an index of the balance between energy production and utilization, was higher (not lower) than baseline in stunned hearts, thus confirming that energy production was not intrinsically impaired. Together these data indicate that despite reduced myocardial ATP content, mitochondrial function in stunned hearts is capable of sustaining a large increase in function and energetic requirements.

In the early 20th century, hamsters performed acrobatics instreetside circuses in China (I). Scientists found these Chinesehamsters useful as hosts for some infectious diseases, butthe strain could not be successfully bred in captivity. Oneofthe hamster'sMiddle Eastern cousins, the Syrian hamster,was successfully raised in the laboratory and has become awidely used species for study of a variety ofhuman diseases.In 1962, Homburgeret al. (2), at the Bio-ResearchInstitutein Cambridge, Massachusetts, described muscular dystro­phy (a hereditary muscle disease that is transmitted in anautosomal recessive manner) in a strain of Syrian hamsters(Bio 1.5). Since then, the Bio 14.6 and its descendant lineshave become the most intensively studied strain. In additionto skeletal muscle involvement, these myopathic hamstershave progressive cardiac failure. Heart involvement is themost prominent feature ofthe disease, and premature deathoccurs in most animals from congestive heart failure. Atautopsy, the animals have anasarca, pulmonary congestionand dilated hearts. This Syrian cardiomyopathic hamster hasbecome widely accepted as a model for cardiomyopathyleading to congestive heart failure.Syrian hamster cardiomyopathy. The cardiac diseasecan be divided into four phases (3). During the first orprenecrotic phase, the animals appear well and there is nopathologic evidence of disease. The second phase beginswhen the animals are about 30 days of age, and is char­acterized by the appearance of focal myocardial necroticlesions. During this phase the animals still appear well andthere is almost no mortality. However, electrocardiographic(ECG) abnormalities can be seen (4). At about 90 to 120

Reperfusion of ischemic myocardium may accelerate necrosis of injured myocytes. To determine the role of neutrophil leukocytes in this process, we examined whether neutrophil depletion during reperfusion could modify infarct size in anesthetized dogs. The proximal circumflex coronary artery was occluded for 90 minutes and then reperfused for 2 hours via an extracorporeal circuit with either whole blood (n = 11) or with blood depleted of neutrophils by leukocyte filters (n = 11). The leukocyte filters caused near-total neutropenia in blood reperfusing the ischemic myocardium (7 +/- 7 neutrophils/microliters compared with 2,551 +/- 317/microliters in controls, mean +/- SEM; p less than 0.001. Infarct size was measured by planimetry of myocardial slices stained with triphenyltetrazolium chloride (TTC), and the accuracy of TTC for identifying necrotic myocardium was verified by electron microscopy. The size of the ischemic risk region was the same in the control (41.6 +/- 1.0%) and neutropenic (41.8 +/- 2.1%) groups. Collateral blood flow to the risk region was the same in control (0.15 +/- 0.03 ml/min/g) and neutropenic (0.13 +/- 0.03 ml/min/g) groups. Among dogs with collateral flow less than 0.2 ml/min/g, infarct size was reduced in the neutropenic group (27.7 +/- 6.7% of risk region, n = 8), compared with control dogs (52.5 +/- 5.7%; n = 7; p = 0.02). Multiple linear regression described the relation between infarct size, risk region size, and collateral flow in the control group, and the same regression relation was used to predict infarct size for the neutropenic group. Mean predicted infarct size in the neutropenic group (n = 11) was 16.8 +/- 3.4% of left ventricle, whereas mean observed infarct size was 9.6 +/- 3.1% (p less than 0.01). The extent of the no-reflow zone (absence of thioflavin-S-fluorescence) was also less in the neutropenic than the control group (2.2 +/- 0.8% vs. 8.1 +/- 2.7% of the risk region, p less than 0.05). Neutropenia limited to the reperfusion period is associated with significant reductions in the extent of the infarct and no-reflow zones after 90 minutes of ischemia. These findings support the hypothesis that reperfusion necrosis occurs after prolonged myocardial ischemia and indicate that neutrophil leukocytes are important mediators of such reperfusion injury.

High-energy electrical ablation is a new experimental approach to control arrhythmias. In this study, the cellular electrophysiologic effects of high-energy shocks (5 to 40 J) delivered in vitro to 14 epicardial tissues from 11 dogs were studied in an attempt to understand the nature and extent of injury as well as potential arrhythmogenic mechanisms. In addition, this preparation was used to test the importance of cathode-anode configuration, current density, and fiber orientation in the induction of tissue injury in vitro. Electrophysiologic abnormalities were noted up to 10 mm from the electrode wall, and their extent was determined in part by current density and the cathode-anode orientation. A decrease in resting membrane potential, action potential amplitude, and dV/dT occurred in all tissues after high-energy shocks, which was worst nearest the cathode and of graded severity at increasing distances from the cathode. The most severe effects were noted with high current densities and in tissues located between the cathode and anode. In addition, impaired impulse conduction and abnormal repolarization were documented. Histologic study demonstrated contraction band necrosis immediately after delivery of high-energy shocks. The extent and distribution of the contraction bands was in part dependent on the energy delivered and the cathode-anode configuration. These findings suggest potential mechanisms for arrhythmogenesis and altered regional hemodynamic abnormalities that occur in vivo.

Dehydroepiandrosterone (DHEA) is an endogenous steroid that blocks carcinogenesis, retards aging, and exerts antiproliferative properties. In vitro, it is a potent inhibitor of glucose-6-phosphate dehydrogenase, the first committed step of the pentose phosphate pathway. In man, serum levels of DHEA and its sulfate peak in early adulthood and drop markedly with age. Epidemiologic evidence indicates that low levels of DHEA or its sulfate conjugate are linked to an increased risk of developing cancer or of death from cardiovascular disease. Like cancer, atherosclerosis is a proliferative process characterized by both initiation and promotion phases. This similarity provided a framework in which to study the antiatherogenic effects of DHEA. Rabbits were randomly assigned to four groups. Two groups of rabbits received aortic endothelial injury by balloon catheter and were fed a 2% cholesterol diet for 12 wk. DHEA, 0.5%, was incorporated into the diet of one group receiving the 2% cholesterol diet and endothelial injury and also into the diet of one of the control groups. Animals were killed after 12 wk and aortas, hearts, and livers were studied. Plasma samples were analyzed for total cholesterol, VLDL, LDL, HDL, triglycerides, DHEA, and DHEA-sulfate levels. The atherogenic insult resulted in severe atherosclerosis in animals not treated with DHEA. In those receiving DHEA there was an almost 50% reduction in plaque size (P = 0.006), inversely related to the serum level of DHEA attained. Fatty infiltration of the heart and liver were also markedly reduced. These beneficial actions were not attributable to differences in body weight gain, food intake, total plasma cholesterol or distribution of cholesterol among the VLDL, LDL, or HDL fractions. The results show that high levels of plasma DHEA inhibit the development of atherosclerosis and they provide an important experimental link to the epidemiologic studies correlating low DHEA-sulfate plasma levels with an enhanced risk of cardiovascular mortality.