epidermal-growth-factor and Coronary-Thrombosis

Several genes are expressed in aspirated coronary thrombi in acute myocardial infarction (AMI), exhibiting dynamic changes along ischemic time. Whether soluble biomarkers reflect the local gene environment and ischemic time is unclear. We explored whether circulating biomarkers were associated with corresponding coronary thrombi genes and total ischemic time.. In 33 AMI patients undergoing percutaneous coronary intervention (PCI), blood samples were collected within 6-24h for markers related to plaque rupture (metalloproteinase 9, tissue inhibitor of metalloproteinases 1), platelet and endothelial cell activation (P-selectin, CD40 ligand, PAR-1), hemostasis (tissue factor, tissue plasminogen activator, plasminogen activator inhibitor 1, free and total tissue factor pathway inhibitor, D-dimer, prothrombin fragment 1+2), inflammation (interleukin 8 and 18, fractalkine, monocyte chemoattractant protein 1 (MCP-1), CXCL1, pentraxin 3, myeloperoxidase) and galectin 3, caspase 8 and epidermal growth factor (EGF). Laboratory analyses were performed by Proximity Extension Assay (Proseek Multiplex CVD I(96 × 96)), ELISAs and RT-PCR.. Only circulating P-selectin correlated to the corresponding P-selectin gene expression in thrombi (r=0.530, p=0.002). Plasma galectin 3, fractalkine, MCP-1 and caspase 8 correlated inversely to ischemic time (r=-0.38-0.50, all p <0.05), while plasma MCP-1, galectin 3 and EGF were higher at short (≤ 4 h) vs. long (>4h) ischemic time (all p <0.05).. The dynamic changes in circulating mediators along ischemic time were not reflected in the profile of locally expressed genes. These observations indicate a locally confined milieu within the site of atherothrombosis, which may be important for selective therapy.

Topics: Adult; Aged; Biomarkers; Blood Platelets; Blood Proteins; Caspase 8; Chemokine CCL2; Chemokine CX3CL1; Cohort Studies; Coronary Thrombosis; Epidermal Growth Factor; Female; Galectin 3; Galectins; Gene Expression Regulation; Humans; Male; Middle Aged; Myocardial Infarction; P-Selectin; Percutaneous Coronary Intervention; Thrombosis; Time Factors

The aim of this study was to compare the effects of a novel modified tissue-type plasminogen activator (t-PA), E6010, to those of native t-PA and urokinase on reperfusion arrhythmias (premature ventricular complexes: PVC) and the mortality rate after coronary thrombolysis. The frequency of PVC and the mortality rate were evaluated in anesthetized dogs which had 1-, 3- or 6-h-old thrombi induced by a copper coil in the coronary artery. Thrombolytic treatment with a bolus intravenous (iv) injection of E6010 was compared with the continuous iv administration of native t-PA or urokinase. The frequency of PVC was significantly lower in the E6010 group than in the native t-PA and urokinase groups (P < 0.05). The mortality rate in the E6010 group (0.0%) tended to be lower than those in the native t-PA group (10.7%) and the urokinase group (7.1%). These results indicate that the bolus iv injection of E6010 reduced both PVC and the mortality rate, compared with the continuous iv administration of native t-PA or urokinase for coronary thrombolysis; Therefore, E6010 may have beneficial effects in prehospital thrombolysis.

Topics: Analysis of Variance; Animals; Chi-Square Distribution; Coronary Thrombosis; Dogs; Epidermal Growth Factor; Female; Fibrinolytic Agents; Male; Myocardial Reperfusion Injury; Plasminogen Activators; Thrombolytic Therapy; Tissue Plasminogen Activator; Urokinase-Type Plasminogen Activator; Ventricular Premature Complexes

Using the centerline method in a canine model, we compared left ventricular function after coronary thrombolysis induced by a novel modified recombinant tissue plasminogen activator (rt-PA) (E6010: 84Cys-->84Ser) to that induced by rt-PA or urokinase. Thirty minutes after occlusion, a bolus injection of E6010 (0.2 mg/kg) or a continuous infusion of either rt-PA (0.6 mg/kg over 1 h) or urokinase (0.38 mg/kg over 1 h) was administered intravenously. Animals with sustained copper coil-occlusion served as non-reperfused controls. Left ventricular ejection fraction and regional wall motion (expressed as the infarction chord number; ie, the number of chords < -2SD among chords 12-66) were 42 +/- 5%** and 5 +/- 3,** respectively, in the E6010 group, 31 +/- 8% and 16 +/- 12 in the rt-PA group, and 31 +/- 2% and 32 +/- 13 in the urokinase group 1 h after reperfusion, indicating earlier recovery of left ventricular function after thrombolysis in the E6010 group than in the rt-PA and urokinase groups (**p < 0.01 vs control). Coronary reperfusion with E6010 induced earlier recovery of left ventricular function than reperfusion with rt-PA or urokinase. These results suggest that E6010 may be of clinical value in the treatment of coronary occlusion.

Topics: Animals; Coronary Thrombosis; Cricetinae; Disease Models, Animal; Dogs; Epidermal Growth Factor; Female; Heart Diseases; Male; Mesocricetus; Recombinant Fusion Proteins; Reperfusion; Stroke Volume; Time; Tissue Plasminogen Activator; Ventricular Function, Left

In a canine copper coil-induced coronary thrombosis model, the differences in frequency of reperfusion arrhythmias (premature ventricular complexes: PVC) and mortality rate after thrombolysis by intravenous bolus injection of a novel modified tissue-type plasminogen activator (t-PA), E6010, and by continuous intravenous infusion of native t-PA or urokinase were evaluated. Rapid coronary occlusion and reperfusion were produced with a balloon catheter in another group of dogs, and the findings were compared with those in the thrombolysis groups. Reperfusion occurred gradually after the administration of E6010, but was significantly more rapid after administration of native t-PA and urokinase (P < 0.05). PVC were observed more frequently in native t-PA, urokinase and balloon occlusion-reperfusion groups than in the E6010 group. The mortality rate due to ventricular fibrillation was 0.0% in the E6010 group, 50.0% in the native t-PA and balloon occlusion-reperfusion groups, and 33.3% in the urokinase group. These results suggest that the more gradual reperfusion of the coronary artery at an earlier period after drug administration led to the lower frequency of reperfusion arrhythmias and low mortality rate in the E6010 group than in the native t-PA, urokinase and balloon occlusion-reperfusion groups.

Topics: Animals; Cardiac Complexes, Premature; Catheterization; Coronary Circulation; Coronary Thrombosis; Dogs; Epidermal Growth Factor; Female; Fibrinolytic Agents; Male; Myocardial Reperfusion Injury; Tissue Plasminogen Activator; Urokinase-Type Plasminogen Activator; Ventricular Fibrillation

We examined the thrombolytic properties of a novel modified human tissue plasminogen activator (PA) (E6010), in which cysteine 84 is replaced by serine, and which has a prolonged biologic half-life (t1/2). We compared the thrombolytic efficacy of continuous intracoronary (i.c.) infusion of E6010 with that of recombinant human tissue PA (rt-PA) in a canine model with copper coil-induced 1-h-old coronary artery thrombi and also compared the relation between thrombolytic efficacy and plasma clearance represented by pharmacokinetic parameters of i.c.-infused E6010 and rt-PA. Sixty-minute E6010 and rt-PA i.c. infusions were compared. The thrombolytic effects of i.c.-infused E6010 and rt-PA, represented by time to reperfusion (TR), reperfusion rate at 60 min (RR), and reocclusion rates at 60 min after reperfusion (OR) were as follows. E6010: Dose 0.06, 0.15, 0.3 (mg/kg/h); TR 25 +/- 10, 15 +/- 10, 13 +/- 5 (min); RR 100, 100, 100 (%); and OR 0, 0, 17 (%), respectively. Recombinant t-PA: Dose 0.06, 0.15, 0.3 (mg/kg/h); TR 47 +/- 12, 18 +/- 17, 14 +/- 4 (min); RR 50, 75, 100 (%); and OR 100, 33, 33 (%), respectively. These findings indicate that E6010 has more potent thrombolytic activity than rt-PA.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: alpha-2-Antiplasmin; Animals; Antibodies, Monoclonal; Coronary Thrombosis; Disease Models, Animal; Dogs; Dose-Response Relationship, Drug; Epidermal Growth Factor; Fibrinogen; Fibrinolytic Agents; Half-Life; Humans; Infusions, Intra-Arterial; Plasminogen; Recombinant Proteins; Reperfusion Injury; Tissue Plasminogen Activator

This study was conducted to compare the thrombolytic effect of a novel modified tissue plasminogen activator, E6010, with that of recombinant human tissue plasminogen activator (t-PA), administered by single intravenous bolus injection in pigs with occlusive coronary thrombosis. Thrombosis was induced by electrical stimulation of the intimal surface of the left circumflex coronary artery. Coronary blood flow velocity and hemodynamic parameters were observed for 1 hr after complete cessation of coronary flow. Ten minutes after heparin injection (300 U/kg), E6010, t-PA or placebo was intravenously administered as a bolus. E6010 at 0.2 and 0.4 mg/kg caused recanalization of the occluded coronary artery in 1 of 6 and 5 of 5 pigs, respectively. The time to recanalization after 0.4 mg/kg of E6010 was 22 +/- 11 min (mean +/- S.E.M.). t-PA (0.4 mg/kg) caused recanalization in only 1 of 5 pigs. Recanalization did not occur in any of the 6 animals administered placebo. Plasma clearance of E6010 was smaller than that of t-PA (4.9 +/- 0.3 vs. 9.4 +/- 3.8 ml/min/kg). There were no significant differences in plasma levels of fibrinogen, alpha 2-plasmin inhibitor and plasminogen among the placebo, E6010 and t-PA groups. These results suggest that the slower clearance of E6010 from plasma contributes to the effective thrombolytic action of E6010 following single intravenous bolus injection.

Topics: Animals; Coronary Thrombosis; Epidermal Growth Factor; Female; Fibrinolytic Agents; Hemodynamics; Hemostasis; Male; Swine; Tissue Plasminogen Activator