RESUMO
Indications for TF-TAVI (transfemoral transcatheter aortic valve implantation) are rapidly changing according to increasing evidence from randomized controlled trials. Present trials document the non-inferiority or even superiority of TF-TAVI in intermediate-risk patients (STS-Score 4-8%) as well as in low-risk patients (STS-Score < 4%). However, risk scores exhibit limitations and, as a single criterion, are unable to establish an appropriate indication of TF-TAVI vs transapical TAVI vs SAVR (surgical aortic valve replacement). The ESC (European Society of Cardiology)/EACTS (European Association for Cardio-Thoracic Surgery) guidelines 2017 and the German DGK (Deutsche Gesellschaft für Kardiologie)/DGTHG (Deutsche Gesellschaft für Thorax-, Herz- und Gefäßchirurgie) commentary 2018 offer a framework for the selection of the best therapeutic method, but the individual decision is left to the discretion of the heart teams. An interdisciplinary TAVI consensus group of interventional cardiologists of the ALKK (Arbeitsgemeinschaft Leitende Kardiologische Krankenhausärzte e.V.) and cardiac surgeons has developed a detailed consensus on the indications for TF-TAVI to provide an up-to-date, evidence-based, comprehensive decision matrix for daily practice. The matrix of indication criteria includes age, risk scores, contraindications against SAVR (e.g., porcelain aorta), cardiovascular criteria pro TAVI, additional criteria pro TAVI (e.g., frailty, comorbidities, organ dysfunction), contraindications against TAVI (e.g., endocarditis) and cardiovascular criteria pro SAVR (e.g., bicuspid valve anatomy). This interdisciplinary consensus may provide orientation to heart teams for individual TAVI-indication decisions. Future adaptations according to evolving medical evidence are to be expected. Interdisciplinary consensus on indications for transfemoral transcatheter aortic valve implantation (TF-TAVI).
Assuntos
Estenose da Valva Aórtica/cirurgia , Substituição da Valva Aórtica Transcateter/métodos , Consenso , Artéria Femoral , Humanos , Seleção de Pacientes , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
BACKGROUND: The clinical benefits of heparin reach beyond its anticoagulative properties. Recently, it has been described that leukocytes adhere on immobilized heparin mediated by the integrin Mac-1 (CD11b/CD18, alphaMbeta2, or CR3). Because inhibition of this versatile adhesion molecule could explain various aspects of the beneficial clinical effects of heparin, we evaluated whether soluble heparin modulates Mac-1 function in vitro and in vivo. METHODS AND RESULTS: Binding of unfractionated heparin to Mac-1 on PMA-stimulated monocytes and granulocytes was directly demonstrated in flow cytometry, whereas no binding of heparin was detected on unstimulated leukocytes. Unfractionated heparin inhibited binding of the soluble ligands fibrinogen, factor X, and iC3b to Mac-1. Adhesion of the monocytic cell line THP-1 and of peripheral monocytes and granulocytes to immobilized ICAM-1 was impaired by unfractionated heparin, to the same extent as with inhibition of Mac-1 by monoclonal antibodies such as c7E3. Low-molecular-weight heparin also inhibits binding of fibrinogen to Mac-1. Additionally, flow cytometry of whole blood preparations of patients treated with unfractionated heparin revealed an inhibitory effect of heparin on the binding of fibrinogen to Mac-1 that correlates (n= 48, r=0.63, P<0.001) to the extent of prolongation of the activated partial thromboplastin time. CONCLUSIONS: We describe a pharmacologically relevant property of heparin that may contribute to its benefits in clinical use. The binding of heparin to Mac-1 and the resulting inhibition in binding of Mac-1 ligands may directly modulate coagulation, inflammation, and cell proliferation.
Assuntos
Anticoagulantes/farmacologia , Heparina/farmacologia , Antígeno de Macrófago 1/metabolismo , Animais , Fator X/metabolismo , Fibrinogênio/metabolismo , Granulócitos/metabolismo , Heparina/metabolismo , Humanos , Molécula 1 de Adesão Intercelular/metabolismo , Camundongos , Monócitos/metabolismo , Tempo de Tromboplastina Parcial , Acetato de Tetradecanoilforbol/farmacologiaRESUMO
BACKGROUND: Improvement of thrombolysis may be achieved by concomitant strong platelet inhibition. To monitor platelet function in patients with myocardial infarction (n=46) who were treated with the fibrinolytic agent reteplase, the glycoprotein (GP) IIb/IIIa blocker abciximab, and the ADP receptor antagonist ticlopidine, we developed a flow cytometric assay. METHODS AND RESULTS: Binding of abciximab to platelets was directly monitored as the percentage of platelets stained by a goat anti-mouse antibody. Blood drawn 10 minutes and 2 hours after the start of therapy with reteplase and abciximab and during the 12-hour infusion of abciximab demonstrated a maximal blockade of GP IIb/IIIa (10 minutes, 86.2+/-10.3%; 12 hours, 85.8+/-7.1%). Starting at 24 hours, abciximab binding gradually decreased (24 hours, 74.6+/-16.2%; 48 hours, 66.8+/-14.9%; 72 hours, 60.5+/-16.7%; 96 hours, 49.4+/-17.8%; 120 hours, 35.8+/-16. 4%; and 144 hours, 29.9+/-15.3%). Binding of a chicken anti-fibrinogen antibody to platelets, indicating the level of functional blockade of GP IIb/IIIa, was inversely correlated with the binding of abciximab (r=-0.72, P:<0.0001). In blood drawn at 10 minutes, platelet aggregation was maximally inhibited but recovered within 48 hours even if the majority of GP IIb/IIIa receptors were still blocked by abciximab. Reteplase did not influence abciximab binding and did not activate platelets, as measured by P-selectin expression, fibrinogen binding, and platelet aggregation. Platelet inhibition that was achieved during the first 24 hours by abciximab was directly maintained by additional treatment with ticlopidine. CONCLUSIONS: Flow cytometric monitoring of platelet function allows differentiation of the effects of reteplase, abciximab, and ticlopidine. The combination of abciximab and ticlopidine is an attractive therapeutic strategy that provides a fast and continuous platelet inhibition.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Plaquetas/efeitos dos fármacos , Fibrinolíticos/uso terapêutico , Fragmentos Fab das Imunoglobulinas/uso terapêutico , Infarto do Miocárdio/sangue , Infarto do Miocárdio/tratamento farmacológico , Inibidores da Agregação Plaquetária/uso terapêutico , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/efeitos dos fármacos , Proteínas Recombinantes/uso terapêutico , Ticlopidina/uso terapêutico , Ativador de Plasminogênio Tecidual/uso terapêutico , Abciximab , Idoso , Anticorpos Monoclonais/sangue , Plaquetas/fisiologia , Feminino , Fibrinolíticos/sangue , Citometria de Fluxo , Humanos , Fragmentos Fab das Imunoglobulinas/sangue , Masculino , Pessoa de Meia-Idade , Agregação Plaquetária/efeitos dos fármacos , Inibidores da Agregação Plaquetária/sangue , Proteínas Recombinantes/sangue , Ticlopidina/sangue , Fatores de Tempo , Ativador de Plasminogênio Tecidual/sangueRESUMO
BACKGROUND: Changes in platelet aggregation (PA) and platelet surface receptor expression induced by thrombolytic therapy for acute myocardial infarction may influence the rate of initial reperfusion and early reocclusion. METHODS AND RESULTS: In the RAPID-1 (Reteplase Angiographic Phase II International Dose-finding study), RAPID-2 (Reteplase vs Alteplase Patency Investigation During myocardial infarction), INJECT (INternational Joint Efficacy Comparison of Thrombolytics), and GUSTO-3 (Global Use of Strategies To Open occluded coronary arteries) trials, 126 patients were enrolled in a single center. Patients were treated with either conventional alteplase (100 mg/180 min; n=15), accelerated alteplase (100 mg/90 min; n=21), reteplase 10+10-U double bolus (n=50), reteplase 10+5-U double bolus (n=15), reteplase 15-U single bolus (n=15), or streptokinase (1.5 MU/60 min; n=10). PA (after stimulation with ADP), P-selectin expression and fibrinogen binding to glycoprotein (GP) IIb/IIIa (determined by flow cytometry with and without stimulation with ADP), and levels of soluble P-selectin, prothrombin fragments F1 and F2, thrombin-antithrombin complexes (TAT), and antithrombin III (ATIII) were determined. PA decreased significantly at 1 and 2 hours in patients treated by 10+10-U reteplase or by streptokinase. Fibrinogen binding to platelet GP IIb/IIIa followed a similar pattern. Significant thrombin generation and significantly elevated thrombin levels during thrombolysis were reflected by increased F1 and F2 fragments and TAT levels in all treatment groups. ATIII levels decreased significantly during thrombolytic therapy. CONCLUSIONS: A decrease in PA in patients treated by reteplase or streptokinase compared with alteplase could be observed in the early phase. Double bolus (10+10 U) reteplase and streptokinase resulted in lower PA at 1 and 2 hours than therapy with accelerated alteplase. Total fibrinogen and fibrinogen binding to GP IIb/IIIa tended to be lower during the first 2 hours after reteplase than after accelerated alteplase.
Assuntos
Fibrinogênio/metabolismo , Infarto do Miocárdio/tratamento farmacológico , Ativação Plaquetária/efeitos dos fármacos , Agregação Plaquetária/efeitos dos fármacos , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/metabolismo , Terapia Trombolítica , Método Duplo-Cego , Humanos , Pessoa de Meia-Idade , Infarto do Miocárdio/sangue , Selectina-P/metabolismo , Ligação Proteica , Proteínas Recombinantes/uso terapêutico , Estreptoquinase/uso terapêutico , Ativador de Plasminogênio Tecidual/uso terapêuticoRESUMO
Patients with hyperinsulinemia, defined by increased concentrations of IRI in plasma, experience increased cardiovascular mortality. In type II diabetic patients, the increase in IRI may reflect, in part, not only insulin but also proinsulinemia as a result of impaired conversion of proinsulin to insulin by pancreatic beta-cells. High IRI is accompanied by attenuation of endogenous fibrinolytic activity and increased plasma PAI-1, the primary physiological inhibitor of t-PA. Concordant increases of plasma PAI-1 and plasma IRI appear to reflect direct effects of insulin and proinsulin on the synthesis and secretion of PAI-1 by endothelial and liver cells as judged from results of studies in vitro. Because attenuated fibrinolysis may predispose to thrombosis, the increased exposure of luminal surfaces of vessels to atherogenic, clot-associated mitogens and chemoattractants may activate macrophages and potentiate proliferation of vascular smooth muscle cells. Accordingly, increased concentrations of plasma IRI may contribute to macrovascular disease in diabetic patients by impairing endogenous fibrinolysis.
Assuntos
Arteriosclerose/fisiopatologia , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/fisiopatologia , Angiopatias Diabéticas/fisiopatologia , Fibrinólise , Arteriosclerose/epidemiologia , Angiopatias Diabéticas/epidemiologia , Humanos , Hiperinsulinismo/fisiopatologia , Resistência à Insulina , Inibidor 1 de Ativador de Plasminogênio/sangue , Fatores de RiscoRESUMO
In patients with non-insulin-dependent diabetes mellitus, concentrations in plasma of insulin and its precursors, proinsulin and split proinsulin, are increased. Because increased concentrations of plasminogen activator inhibitor type-1 (PAI-1) occur also, we hypothesized that proinsulin and split proinsulin may augment endothelial cell PAI-1 expression, thereby potentially attenuating endogenous fibrinolysis and accelerating atherosclerosis. Proinsulin increased PAI-1 activity in conditioned media of endothelial cells as did split proinsulin, paralleled by increased expression of PAI-1 mRNA. These effects of proinsulin were not dependent on its conversion to insulin nor on its interactions with the insulin receptor. The proinsulin stimulation of PAI-1 expression was not attenuated by either anti-insulin receptor antibodies or a 100-fold excess of insulin. Furthermore, proinsulin-mediated increases in PAI-1 expression were not inhibited by a 500-fold excess of insulinlike growth factor I. In addition, inhibition of tyrosine kinase, which mediates many of the diverse effects of insulin and insulinlike growth factor I, did not attenuate the effect of proinsulin. These results indicate that proinsulin augments PAI-1 expression, potentially contributing to vasculopathy in patients with non-insulin-dependent diabetes mellitus.
Assuntos
Endotélio Vascular/fisiologia , Inativadores de Plasminogênio/metabolismo , Proinsulina/farmacologia , RNA Mensageiro/metabolismo , Animais , Aorta , Células Cultivadas , Relação Dose-Resposta a Droga , Interações Medicamentosas , Endotélio Vascular/efeitos dos fármacos , Insulina/farmacologia , Fator de Crescimento Insulin-Like I/farmacologia , Cinética , Modelos Estatísticos , Análise Multivariada , RNA Mensageiro/genética , SuínosRESUMO
OBJECTIVE: Migration of smooth muscle cells into the neointima has been implicated in atherogenesis. Vitronectin, a serum factor that promotes cell spreading and attachment, accumulates in atherosclerotic human tissues. The aim of this study was to determine the role of vitronectin and its receptor (integrin alpha V beta 3) in migration of smooth muscle cells. METHODS: Human aortic smooth muscle cell migration was studied in modified Boyden chambers. Expression of vitronectin receptor was determined by northern blotting of receptor mRNA and immunoprecipitation of receptor protein. RESULTS: Vitronectin dose dependently increased smooth muscle cell migration by an amount comparable to that induced by platelet derived growth factor, (PDGF)-BB. Antiserum to alpha V beta 3 diminished vitronectin driven migration. Northern blot analysis showed low constitutive expression of alpha V and beta 3 mRNA by smooth muscle cell and rapid induction with transforming growth factor beta (TGF-beta) and thrombin. Immunoprecipitation confirmed increased synthesis of the alpha V beta 3 vitronectin receptor complex by TGF-beta or thrombin. Smooth muscle cells pretreated with TGF-beta or thrombin showed increased vitronectin driven migration. cAMP suppressed induction of migration, but inhibition of protein kinase C increased it. CONCLUSIONS: These results show that vitronectin-induced human aortic smooth muscle cell migration is mediated by alpha V beta 3 vitronectin receptor and expression of the receptor is induced by TGF-beta and thrombin, which in turn induce vitronectin driven, vitronectin receptor modulated smooth muscle cell migration.
Assuntos
Arteriosclerose/patologia , Proteínas da Matriz Extracelular/farmacologia , Glicoproteínas/farmacologia , Músculo Liso Vascular/efeitos dos fármacos , Northern Blotting , Movimento Celular/efeitos dos fármacos , Células Cultivadas , Relação Dose-Resposta a Droga , Humanos , Integrinas/análise , Músculo Liso Vascular/química , Músculo Liso Vascular/patologia , Receptores de Citoadesina/análise , Receptores de Vitronectina , Estimulação Química , Trombina/farmacologia , Fator de Crescimento Transformador beta/farmacologia , VitronectinaRESUMO
Troglitazone, a novel oral insulin sensitizer, normalizes increased plasma activity of plasminogen activator inhibitor type 1 (PAI-1) in hyperinsulinemic patients such as women with polycystic ovary syndrome and patients with type 2 diabetes mellitus. However, underlying mechanisms have not yet been fully elucidated. Human hepatic and vascular cells, the main sources of circulating PAI-1, were studied in cell culture. In human hepatic cells, PAI-1 accumulated in conditioned medium by 23% within 24 h after exposure to 3 microg/mL troglitazone (P = 0.001). The accumulation depended on the concentration of troglitazone, but not that of insulin (known to stimulate PAI-1 synthesis). By contrast, in human aortic smooth muscle cells, 3 microg/mL troglitazone decreased basal PAI-1 expression by 23% (P = 0.037) and decreased transforming growth factor-beta-induced expression by 34% (P = 0.026). Concomitant insulin had no effect. Tissue-type plasminogen activator was decreased by 38% (P = 0.002). In human endothelial cells, PAI-1 was diminished by 32% (P < 0.001), whereas tissue-type plasminogen activator was unaffected. The results suggest that the reduction in plasma activity of PAI-1 induced by troglitazone in patients may reflect both directly mediated diminution of its elaboration from vessel walls and indirectly mediated reduction of its hepatic synthesis secondary to attenuation of hyperinsulinemia (known to increase the hepatic synthesis of PAI-1).
Assuntos
Cromanos/farmacologia , Endotélio Vascular/efeitos dos fármacos , Hipoglicemiantes/farmacologia , Fígado/efeitos dos fármacos , Músculo Liso Vascular/efeitos dos fármacos , Inibidor 1 de Ativador de Plasminogênio/metabolismo , Tiazóis/farmacologia , Tiazolidinedionas , Aorta , Carcinoma Hepatocelular , Células Cultivadas , Meios de Cultivo Condicionados , Endotélio Vascular/metabolismo , Humanos , Cinética , Fígado/metabolismo , Neoplasias Hepáticas , Músculo Liso Vascular/metabolismo , Troglitazona , Células Tumorais Cultivadas , Veias Umbilicais , Ativador de Plasminogênio Tipo Uroquinase/metabolismoRESUMO
To examine the influence of coingestion of fat and protein in a mixed meal on carbohydrate metabolism, subjects with non-insulin-dependent diabetes mellitus (NIDDM) received three different breakfasts varying in the amount of fat and protein (group 1) or only in the amount of fat (group 2). Compared with the changes after a standard breakfast, insulin increased after the protein-rich meal and decreased after the fat-rich meal in group 1. Glucose and gastric inhibitory polypeptide (GIP) remained constant. In contrast, only GIP showed a significant increase after a high-fat meal in group 2. Thus, in NIDDM subjects, glucose and insulin responses to different mixed meals do not appear to be exclusively mediated by GIP. Protein was confirmed as a potent stimulator of insulin secretion. Other factors, such as an altered beta-cell response in diabetics to GIP or other incretions, must be considered to explain the reported results.
Assuntos
Carboidratos/sangue , Diabetes Mellitus Tipo 2/sangue , Dieta para Diabéticos , Idoso , Análise de Variância , Glicemia/metabolismo , Peptídeo C/sangue , Diabetes Mellitus Tipo 2/dietoterapia , Gorduras na Dieta/administração & dosagem , Proteínas Alimentares/administração & dosagem , Feminino , Polipeptídeo Inibidor Gástrico/sangue , Glucagon/sangue , Humanos , Insulina/sangue , Masculino , Triglicerídeos/sangueRESUMO
BACKGROUND: Targeting of plasminogen activators to the fibrin component of a thrombus by antibodies directed against human fibrin can enhance their thrombolytic potency and clot specificity. OBJECTIVES: To overcome the disadvantages of chemical conjugation, we investigated whether the recombinant fusion of a single-chain antibody and a plasminogen activator results in an active bifunctional molecule that might be useful as a therapeutic agent. METHODS: The cDNA of low-molecular-weight single-chain urokinase-type plasminogen activator, comprising amino acids Leu144-Leu411 (scuPA(LMW)), was cloned from human endothelial cells and fused to a single-chain antibody specific for the 7 N-terminal amino acids (beta(15-22)) in the beta-chain of human fibrin (scFv(59D8)). The fusion protein was purified using affinity chromatography with the beta(15-22)-peptide of human fibrin. RESULTS: Purified scFv(59D8)-scuPA(LMW) migrated as a 60-kDa band, which is consistent with a molecule composed of one scFv(59D8) and one scuPA(LMW) moiety. Both functions of the fusion molecule, fibrin-specific binding and plasminogen activation, were fully preserved. In human plasma clots, thrombolysis by scFv(59D8)-scuPA(LMW) is significantly faster and more potent compared with the clinically used urokinase. CONCLUSIONS: ScFv(59D8)-scuPA(LMW) constitutes a new recombinant chimeric plasminogen activator with a significantly enhanced thrombolytic potency and relative fibrin selectivity, that can be produced with modern methods at low cost, large quantities and reproducible activity in Escherichia coli.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Sistemas de Liberação de Medicamentos/métodos , Fibrina/imunologia , Ativadores de Plasminogênio/administração & dosagem , Engenharia de Proteínas/métodos , Ativador de Plasminogênio Tipo Uroquinase/administração & dosagem , Anticorpos Monoclonais/genética , Clonagem Molecular , Fibrinólise/efeitos dos fármacos , Fibrinolíticos/administração & dosagem , Humanos , Cinética , Ativadores de Plasminogênio/genética , Ligação Proteica , Proteínas Recombinantes de Fusão , Ativador de Plasminogênio Tipo Uroquinase/genéticaRESUMO
Cardiovascular disease is responsible for approximately 50% of total mortality in Europe, the USA and Japan. Established risk factors including smoking, hypercholesterolemia, and hypertension explain about half of the incidence of cardiovascular disease only. Reduced endogenous fibrinolytic activity secondary to increased plasma activity of plasminogen activator inhibitor type-1 (PAI-1) is now considered as a new cardiovascular risk factor. In this review, evidence is gathered for the notion that PAI-1 constitutes a predictor of cardiovascular disease and also contributes to the development of cardiovascular disease as a pathogenetic factor. The review will focus on experimental studies modulating PAI-1 activity and clinical studies addressing coronary heart disease, myocardial infarction, restenosis after coronary angioplasty, and graft occlusion after coronary artery bypass grafting.
Assuntos
Doenças Cardiovasculares , Inibidor 1 de Ativador de Plasminogênio/fisiologia , Animais , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/fisiopatologia , HumanosRESUMO
An increasing number of descriptive reports on soluble adhesion molecules and association with various diseases are published. Throughout these reports soluble adhesion molecules are identified as markers of inflammation. Since atherosclerosis demonstrates features of a chronic inflammatory disease, a potential association of soluble adhesion molecules with atherosclerosis has been postulated. However, conflicting results have been reported. One reason for this might be the differing definitions of atherosclerosis and patient groups. Besides the definition of atherosclerosis based on clinical symptoms, few reports use a direct quantification of atherosclerosis in their search for a marker of atherosclerosis. In those reports that quantify atherosclerosis, sVCAM-1 seems to be more specific for atherosclerosis than other markers. The serum level of sVCAM-1 appears to correlate with the extent of atherosclerosis and might allow for the detection of early stages of atherosclerosis. Large scale prospective studies will have to prove that sVCAM-1 can be used as a diagnostic tool for the detection of early stages of asymptomatic atherosclerosis and whether an early therapeutic intervention based on this approach is able to prevent progression and manifestation of the clinical sequelae of atherosclerosis.
Assuntos
Arteriosclerose/metabolismo , Molécula 1 de Adesão de Célula Vascular/metabolismo , Animais , Arteriosclerose/fisiopatologia , Biomarcadores , HumanosRESUMO
In acute myocardial infarction rapid, complete, and sustained reperfusion of the infarct-related coronary artery is the most important therapeutic principle. Lanoteplase or n-PA, a third-generation plasminogen activator consisting of a deletion and point mutant of tissue-type plasminogen activator (t-PA), is a promising agent to approach this therapeutic goal. The molecule exhibits an increased plasma half-life allowing single-bolus administration. In this article, after characterizing the n-PA molecule, the currently available pharmacokinetic and pharmacodynamic data including the results of the InTIME study are reviewed.
Assuntos
Fibrinolíticos/farmacocinética , Infarto do Miocárdio/tratamento farmacológico , Ativador de Plasminogênio Tecidual/farmacocinética , Animais , Fibrinolíticos/uso terapêutico , Humanos , Infarto do Miocárdio/fisiopatologia , Ativador de Plasminogênio Tecidual/uso terapêuticoRESUMO
Thrombolysis is well established in the treatment of acute myocardial infarction. However, clinical application of thrombolytic agents has limitations with respect to efficacy and specificity. To achieve highly effective and at the same time clot-selective plasminogen activation urokinase was coupled to a bispecific antibody consisting of the monovalent Fab' from the antifibrin monoclonal antibody 59D8 and the monovalent Fab' from the anti-glycoprotein GPIIb/IIIa monoclonal antibody 7E3. The bispecific antifibrin-antiplatelet urokinase conjugate (BAAUC) was synthesized and characterized. Assays with either immobilized platelets, GPIIb/IIIa or fibrin showed an increase in plasminogen activation compared to uncoupled urokinase by 10-fold, 58-fold and 13-fold, respectivley (p < 0.0001 each). In vitro clot lysis was performed on platelet-rich and fibrin-rich clots and revealed an up to 5-fold higher potency of BAAUC compared to uncoupled urokinase (p < 0.0001). In vitro platelet aggregation was effectively inhibited by the hybrid molecule, whereas urokinase had no effect. BAAUC and two monospecific urokinase-conjugates, UK-59D8-IgG and UK-7E3-(Fab')2 were compared with each other with regard to similar tests. In vitro clot assays with platelet-rich and platelet-poor clots were performed. BAAUC achieved a significantly higher plasminogen activation compared to each of the monospecific conjugates (p < 0.05, respectively). We conclude that BAAUC, a bispecific plasminogen activator with antifibrin and antiplatelet properties has the potency to lyse both fibrin-rich and platelet-rich thrombi with high efficacy and to effectively inhibit platelet aggregation.
Assuntos
Anticorpos Biespecíficos/farmacologia , Coagulação Sanguínea/efeitos dos fármacos , Imunoconjugados/farmacologia , Agregação Plaquetária/efeitos dos fármacos , Plaquetas/imunologia , Fibrina/imunologia , Humanos , Imunoconjugados/química , Imunoconjugados/imunologia , Fragmentos Fc das Imunoglobulinas/imunologia , Fragmentos Fc das Imunoglobulinas/farmacologia , Ativador de Plasminogênio Tipo Uroquinase/química , Ativador de Plasminogênio Tipo Uroquinase/imunologia , Ativador de Plasminogênio Tipo Uroquinase/farmacologiaRESUMO
RATIONALE: Reocclusion after thrombolysis diminishes the benefits of early reperfusion after acute myocardial infarction (AMI). No clinical or laboratory variables have been identified as predictors for reocclusion yet. METHODS AND RESULTS: To evaluate hemostatic variables as potential risk determinants platelet aggregation (PA, representing platelet activity), thrombin/antithrombin complexes (TAT, representing thrombin generation), and plasminogen activator inhibitor type 1 (PAI-1, representing endogenous fibrinolysis) were determined in 31 patients with AMI at 0, 1, 2. and 12 h after the start of thrombolysis as well as at hospital discharge. Reocclusion (defined as reinfarction or angiographically confirmed, clinically silent coronary reocclusion) occurred in 5 patients within 5-14 days and in 8 patients within 1 year. TAT plasma concentrations were lower in patients with reocclusion than in those without (9.9+/-5.7 vs. 22.9+/-22.2 ng/ml at 2 h, 6.5+/-3.1 vs. 1 1.2+/-6.4 ng/ml at 12 h, means+/-SD, p <0.05 each). Neither concentration nor activity of PAI-1 in plasma differed between both patient groups. However, both slope and maximum of PA (induced by 2 micromol/l ADP) were augmented in patients with reocclusion (slope: 39.4+/-1.7 vs. 32.5+/-7.4 at 2 h, p <0.001; 42.6+/-2.6 vs. 36.6+/-8.9 at 12 h, p <0.01). Results were independent of the thrombolytic agent used (alteplase or reteplase). A PA slope at 2 h higher than the average slope before thrombolysis (37.2+/-5.7) could be identified as best predictor for early (within 5-14 d, p=0.017, sensitivity 1.00, specificity 0.69) and late reocclusion (within 1 y, p=0.009, 0.88 and 0.74, respectively). CONCLUSIONS: Increased PA following coronary thrombolysis appears to be associated with early and late reocclusion. This marker could be useful in identifying patients who may benefit from more aggressive antiplatelet (such as GP IIb/IIIa receptor antagonists), interventional, or both strategies.
Assuntos
Infarto do Miocárdio/sangue , Ativadores de Plasminogênio/uso terapêutico , Agregação Plaquetária , Terapia Trombolítica , Ativador de Plasminogênio Tecidual/uso terapêutico , Difosfato de Adenosina/farmacologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticoagulantes/administração & dosagem , Anticoagulantes/uso terapêutico , Antitrombina III/análise , Aspirina/administração & dosagem , Aspirina/uso terapêutico , Vasos Coronários/patologia , Diabetes Mellitus/epidemiologia , Quimioterapia Combinada , Feminino , Fibrinólise , Heparina/administração & dosagem , Heparina/uso terapêutico , Humanos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/tratamento farmacológico , Infarto do Miocárdio/epidemiologia , Obesidade/epidemiologia , Fragmentos de Peptídeos , Peptídeo Hidrolases/análise , Inibidor 1 de Ativador de Plasminogênio/análise , Agregação Plaquetária/efeitos dos fármacos , Valor Preditivo dos Testes , Protrombina , Proteínas Recombinantes/uso terapêutico , Recidiva , Fatores de Risco , Fumar/epidemiologia , Grau de Desobstrução VascularRESUMO
The initiating event of atherogenesis is thought to be an injury to the vessel wall resulting in endothelial dysfunction. This is followed by key features of atherosclerotic plaque formation such as inflammatory responses, cell proliferation and remodeling of the vasculature, finally leading to vascular lesion formation, plaque rupture, thrombosis and tissue infarction. A causative relationship exists between these events and oxidative stress in the vessel wall. Besides leukocytes, vascular cells are a potent source of oxygen-derived free radicals. Oxidants exert mitogenic effects that are partially mediated through generation of growth factors. Mitogens, on the other hand, are potent stimulators of oxidant generation, indicating a putative self-perpetuating mechanism of atherogenesis. Oxidants influence the balance of the coagulation system towards platelet aggregation and thrombus formation. Therapeutic approaches by means of antioxidants are promising in both experimental and clinical designs. However, additional clinical trials are necessary to assess the role of antioxidants in cardiovascular disease.
Assuntos
Arteriosclerose , Animais , Antioxidantes/uso terapêutico , Arteriosclerose/complicações , Arteriosclerose/tratamento farmacológico , Arteriosclerose/metabolismo , Arteriosclerose/fisiopatologia , Substâncias de Crescimento/fisiologia , Humanos , Estresse Oxidativo , Estresse Mecânico , Trombose/etiologia , Trombose/fisiopatologiaRESUMO
Human atherosclerotic lesions exhibit increased expression of plasminogen activator inhibitor type-1 (PAI-1) that has been implicated in atherogenesis. Although vascular smooth muscle cells are a predominant source of PAI-1 expression potentially favorable modulation of PAI-1 expression by fibrates has not yet been characterized in these cells. Human aortic smooth muscle cells were exposed to selected growth factors. PAI-1 expression was stimulated most powerfully by TGF-beta (EC50 = 0.2 ng/ml, up to 12-fold increase). Gemfibrozil inhibited basal PAI-1 expression by 23% (p = ns) and TGF-beta-induced PAI-1 expression by 52% (p = 0.017) whereas t-PA and total protein synthesis was not affected. Changes in PAI-1 protein accumulation reflected PAI-1 gene expression attributable to modulation of half-life of PAI-1 mRNA by gemfibrozil. Inhibition by other fibrates was less. Gemfibrozil specifically attenuates TGF-beta-induced PAI-1 expression in human arterial smooth muscle cells. Thus, fibrates are promising agents for normalizing increased PAI-1 expression in arterial walls in patients in whom PAI-1 expression is increased.
Assuntos
Genfibrozila/farmacologia , Músculo Liso Vascular/metabolismo , Inibidor 1 de Ativador de Plasminogênio/metabolismo , Aorta/citologia , Células Cultivadas , Interações Medicamentosas , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Músculo Liso Vascular/citologia , Inibidor 1 de Ativador de Plasminogênio/genética , Estabilidade de RNA/efeitos dos fármacos , RNA Mensageiro/efeitos dos fármacos , RNA Mensageiro/metabolismo , Fator de Crescimento Transformador beta/farmacologiaRESUMO
Lipoprotein (a) [Lp(a)] and plasminogen share a high degree of homology as recently evidenced by amino acid and deoxyribonucleic acid analysis. As Lp(a) is enzymatically inactive, it has been suggested that high levels of Lp(a) may suppress the profibrinolytic activity at the cell surface and increase the risk for arteriosclerosis and thrombosis by competitive inhibition of plasminogen. The present study evaluated whether high levels of Lp(a) influence thrombolytic therapy in patients with acute myocardial infarction. Forty-one patients with acute myocardial infarction received a combination low-dose thrombolytic therapy with recombinant tissue-type plasminogen activator (rt-PA) and human single-chain urokinase-type plasminogen activator (scu-PA). This regimen did not induce plasminemia or a lytic state as indicated by well-maintained levels of fibrinogen. Coronary patency was assessed angiographically 90 minutes after initiation of treatment. Thrombolysis was successful in 30 and unsuccessful in 11 patients. Patients with high Lp(a) levels (greater than or equal to 25 mg/dl) (n = 9) responded equally well to thrombolytic therapy (8 of 9, patency 89%) as did patients with normal or low levels of Lp(a) (22 of 32, patency 70%, difference greater than 0.1). Lp(a) levels did not differ significantly between patients with successful and unsuccessful thrombolysis. Our results demonstrate that high levels of Lp(a) do not affect thrombolysis in patients with acute myocardial infarction when low-dose pharmacologic concentrations of rt-PA and scu-PA are applied in combination.
Assuntos
Fibrinolíticos/uso terapêutico , Lipoproteínas/sangue , Infarto do Miocárdio/tratamento farmacológico , Ativadores de Plasminogênio/uso terapêutico , Terapia Trombolítica , Ativador de Plasminogênio Tecidual/uso terapêutico , Ativador de Plasminogênio Tipo Uroquinase/uso terapêutico , Idoso , Angiografia Coronária , Quimioterapia Combinada , Fibrinogênio/metabolismo , Humanos , Lipoproteína(a) , Pessoa de Meia-Idade , Infarto do Miocárdio/metabolismoRESUMO
Thrombolytic therapy has been shown to reduce mortality and morbidity after acute myocardial infarction. Therapeutic benefit seems to be directly correlated with completeness of reperfusion (Thrombolysis in Myocardial Infarction [TIMI] grade 3 flow) of the infarct-related coronary artery, as well as the timeliness of reperfusion. To determine which regimen of reteplase (r-PA), a deletion mutant of wild-type tissue plasminogen activator (t-PA), is most effective for clinical thrombolysis, several reteplase regimens were compared with the most successful standard regimens of recombinant t-PA (alteplase) in 2 large-scale, randomized studies. All patients received aspirin and intravenous heparin. In the Reteplase Angiographic Phase II International Dose Finding Trial (RAPID-1), results in 606 randomized patients showed that a 10 + 10 U double bolus of reteplase was more effective than a 15 U single bolus, a 10 + 5 double bolus, or conventional alteplase (100 mg over 3 hours). In the Reteplase versus Alteplase Patency Investigation During Acute Myocardial Infarction (RAPID-2) trial, results in 324 patients showed that significantly more patients achieved patency of the infarct-related artery (TIMI grade 2 or 3 flow) at 90 minutes with reteplase (10 + 10 U double bolus) than with accelerated alteplase (100 mg over 90 minutes): 83.4% versus 73.3%, respectively (p = 0.03). The incidence of complete patency (TIMI grade 3 flow) at 90 minutes was likewise greater with reteplase than with accelerated alteplase (59.9% vs 45.2%, respectively; p = 0.01). At 60 minutes, the incidence of TIMI grade 2 or 3 flow was also significantly higher with reteplase than with alteplase (81.8% vs 66.1%, respectively; p = 0.01), as was the incidence of TIMI grade 3 flow (51.2% vs 37.4%, respectively; p < 0.031). The 35-day mortality rate was 4.1% for reteplase and 8.4% for alteplase (p = not significant). Reteplase and alteplase did not differ significantly with regard to the occurrence of severe bleeding (12.4% vs 9.7%, respectively) or hemorrhagic stroke (1.2% vs 1.9%, respectively). The results of these trials show that reteplase, given as a 10 + 10 U double bolus, achieves significantly higher rates of early reperfusion of the infarct-related coronary artery and is associated with significantly fewer acute coronary interventions when compared with front-loaded alteplase. The benefits of reteplase are achieved without any apparent increased risk of complications.
Assuntos
Fibrinolíticos/uso terapêutico , Ativadores de Plasminogênio/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto , Terapia Trombolítica , Hemorragia Cerebral/induzido quimicamente , Ensaios Clínicos Fase II como Assunto , Circulação Coronária , Vasos Coronários/efeitos dos fármacos , Vasos Coronários/patologia , Esquema de Medicação , Fibrinolíticos/administração & dosagem , Fibrinolíticos/efeitos adversos , Hemorragia/induzido quimicamente , Humanos , Incidência , Infarto do Miocárdio/tratamento farmacológico , Infarto do Miocárdio/patologia , Ativadores de Plasminogênio/administração & dosagem , Ativadores de Plasminogênio/efeitos adversos , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/efeitos adversos , Proteínas Recombinantes/uso terapêutico , Taxa de Sobrevida , Ativador de Plasminogênio Tecidual/administração & dosagem , Ativador de Plasminogênio Tecidual/efeitos adversos , Ativador de Plasminogênio Tecidual/uso terapêutico , Resultado do Tratamento , Grau de Desobstrução Vascular/efeitos dos fármacosRESUMO
Increased expression of plasminogen activator inhibitor type 1 (PAI-1) is now considered as an independent risk factor for cardiovascular disease. Numerous biochemical factors have been found to regulate the expression of PAI-1 gene and the synthesis of PAI-1 protein. In the recent past, polymorphisms in the PAI-1 gene have been identified and their impact on PAI-1 expression has been characterized. This article will review the current knowledge of these PAI-1 gene polymorphisms (in cell culture epidemiological, and clinical studies) and their role in the development of cardiovascular disease.