CD14+CD16+ monocytes in coronary artery disease and their relationship to serum TNF-α levels

SummaryMonocytes play a central role in the inflammatory disease atherosclerosis. CD14+CD16+ monocytes are considered proinflammatory monocytes, as they have an increased capacity to produce proinflammatory cytokines, such as TNF-α, and are elevated in various inflammatory diseases. We hypothesized that patients with coronary artery disease (CAD) have increased levels of CD14+CD16+ monocytes, and that CD14+CD16+ monocytes are associated with inflammation markers. We investigated CD14+CD16+ monocytes in 247 patients with CAD and 61 control subjects using flow cytometry. In addition serum concentrations of TNF-α, IL-6, and Hs-CRP were assessed. Patients with CAD had higher levels of CD14+CD16…

PHOSPHODIESTERASE INHIBITORS PIROXIMONE AND ENOXIMONE INHIBIT PLATELET AGGREGATION IN VIVO AND IN VITRO

The phosphodiesterase type III inhibitors piroximone (PIR) and enoximone (ENO) exert positive inotropic and vasodilating effects in patients with severe heart failure. PIR and ENO raise cyclic AMP levels in cardiac and vascular smooth muscle cells. Platelet activity is also regulated by intracellular levels of cyclic AMP. In this study we have investigated the effects of PIR and ENO on platelet activity in vivo and in vitro. PIR and ENO inhibited ADP induced platelet aggregation in a time- and concentration-dependent manner with IC50-values of 67 +/- 14 mumol/l and 129 +/- 6 mumol/l, respectively. Coincubation of PIR with the adenylate cyclase activator iloprost resulted in a synergistic po…

Synergistic Platelet Inhibitory Effect of the Phosphodiesterase Inhibitor Piroximone and Iloprost

Platelet activity is regulated through synthesis and degradation of the intracellular second messengers cAMP or cGMP. The antiplatelet effect of the phosphodiesterase (PDE) III inhibitor Piroximone (PIR) was studied in vitro in platelet rich plasma. ADP induced aggregation was inhibited by PIR with an IC50 of 67 +/- 43 microM. The inhibitory effect was time and dose dependent. The antiaggregatory effects in vivo were studied in anaesthetised rats. Reduction of platelet count following injection of 100 micrograms/kg bw collagen was measured after bolus injection of PIR and vehicle. Piroximone bolus 2 mg/kg bw resulted in a 50% inhibition of platelet aggregation in rats. Cyclic AMP levels in …

Surgical procedure affects physiological parameters in rat myocardial ischemia: need for mechanical ventilation.

Several surgical approaches are being used to induce myocardial ischemia in rats. The present study investigated two different operative procedures in spontaneously breathing and mechanically ventilated rats under sham conditions. A snare around the left coronary artery (LCA) was achieved without occlusion. Left lateral thoracotomy was performed in spontaneously breathing and mechanically ventilated rats (tidal volume 8 ml/kg) with a respiratory rate of 90 strokes/min at different levels of O2 supplementation (room air and 30, 40, and 90% O2). All animals were observed for 60 min after thoracotomy. Rats operated with exteriorization of the heart through left lateral thoracotomy while breat…

The German CPU Registry: Comparison of troponin positive to troponin negative patients

Lars S. Maier ⁎, Harald Darius , Evangelos Giannitsis , Raimund Erbel , Michael Haude , Christian Hamm , Gerd Hasenfuss , Gerd Heusch , Harald Mudra , Thomas Munzel , Claus Schmitt , Burghard Schumacher , Jochen Senges , Thomas Voigtlander , Jan B. Schuttert a a Dept. of Cardiology & Pneumology/Heart Centre, Georg-August-University, Gottingen, Germany b Dept. of Cardiology, Angiology & Intensive Care Medicine, Vivantes Hospital Neukolln, Berlin, Germany c Dept. of Cardiology, Angiology & Pneumology, Ruprecht-Karls-University, Heidelberg, Germany d Dept. of Cardiology, West-German Heart Centre, University of Essen, Germany e Dept. of Cardiology & Nephrology, Lukas Hospital, Neuss, Germany f …

Elevated monocyte chemoattractant protein-1 serum levels in patients at risk for coronary artery disease.

Background Monocyte chemoattractant protein-1 (MCP-1) is involved in the recruitment of monocytes into the arterial vessel wall as one of the major events leading to atherosclerotic vascular diseases, such as coronary artery disease (CAD). Methods and Results The study group comprised 263 volunteers aged between 18 and 85 years who were admitted to hospital or clinic for scheduled invasive and non-invasive diagnostic procedures. MCP-1 serum levels were determined using a sandwich-enzyme-linked immunosorbent assay. In each patient, the coronary risk factors (CRF), such as hypertension, high cholesterol, diabetes mellitus, obesity, positive family history, and smoking were evaluated. Low-dens…

Prostacyclin inhibits adhesion of polymorphonuclear leukocytes to human vascular endothelial cells due to adhesion molecule independent regulatory mechanisms

Prostacyclin is an important endothelial mediator involved in the interaction of neutrophils (PMN) with the vessel wall. Many studies have shown the beneficial effects of prostacyclin in ischemia and reperfusion. However, no previous study has investigated the direct effects of the prostacyclin analogs iloprost (ILO) and alprostadil (PGE(1)) on the endothelial part of the adhesion process. Human umbilical vein endothelial cells (HUVECs) were grown to confluence, stimulated with 300 U/ml TNF-alpha and treated with increasing concentrations of ILO and PGE(1). The cells were washed to remove TNF and the inhibitors and adhesion of fluorescence-green labeled PMN was determined microscopically. I…

The presence of infection-related antiphospholipid antibodies in infective endocarditis determines a major risk factor for embolic events.

Abstract OBJECTIVES The impact of infection-associated antiphospholipid antibodies (APA) on endothelial cell activation, blood coagulation and fibrinolysis was evaluated in patients with infective endocarditis with and without major embolic events. BACKGROUND An embolic event is a common and severe complication of infective endocarditis. Despite the fact that APAs are known to be associated with infectious diseases, their pathogenic role in infective endocarditis has not been clearly defined. METHODS The relationship among the occurrence of major embolic events, echocardiographic vegetation size, endothelial cell activation, thrombin generation, fibrinolysis and APA was examined in 91 patie…

A Functional Role of IκB-ε in Endothelial Cell Activation

Abstract The NF-κB inhibitor IκB-ε is a new member of the IκB protein family, but its functional role in regulating NF-κB-mediated induction of adhesion molecule expression is unknown. In vascular endothelial cells, IκB-ε associates predominantly with the NF-κB subunit Rel A and to a lesser extent with c-Rel, whereas IκB-α and IκB-β associate with Rel A only. Following stimulation with TNF-α, pyrrolidine dithiocarbamate (PDTC), N-acetylcysteine, and dexamethasone prevented IκB kinase-induced IκB-α, but not IκB-β or IκB-ε phosphorylation and degradation. Since the activation of NF-κB is required for the induction of adhesion molecule expression, we examined the role of IκB-ε in the transacti…

Recombinant growth hormone therapy in patients with ischemic cardiomyopathy : effects on hemodynamics, left ventricular function, and cardiopulmonary exercise capacity.

Background —We studied the effects of recombinant growth hormone (rhGH) on exercise capacity and cardiac function in patients with ischemic cardiomyopathy. Methods and Results —Seven patients (aged 55±9 years) with mild to moderate congestive heart failure (ejection fraction 31±4%) who were on standard therapy were included. The patients were studied at baseline, after 3 months of rhGH treatment, and 3 months after rhGH discontinuation. Cardiac function was assessed by exercise capacity, right heart catheterization at rest and after submaximal exercise, MRI, echocardiography, and Holter monitoring. When administered at a dose of 2 IU/d, rhGH doubled the serum concentration of insulin-like …

Intramural delivery of Sirolimus prevents vascular remodeling following balloon injury

Abstract Objective. Several studies have demonstrated that Sirolimus-eluting stents reduce restenosis in patients with coronary artery disease. Here, we tested whether direct delivery of Sirolimus into the vessel wall during balloon angioplasty can modify vascular remodeling over several weeks. Methods and Results. During angioplasty of the rabbit iliac artery we administered an intramural infusion of Sirolimus or its vehicle directly through a balloon catheter into the vessel wall. After 3 weeks neointimal formation was decreased (0.71 ± 0.1 vs. 1.4 ± 0.12 intima/media ratio), and this process was attributed to the inhibitory properties of Sirolimus on ECM deposition and smooth muscle cell…

Guideline-adherence regarding critical time intervals in the German Chest Pain Unit registry

Background: Since 2008, the German Cardiac Society certified 256 Chest Pain Units (CPUs). Little is known about adherence to recommended performance measures in patients with suspected acute coronary syndrome (ACS) presenting to CPUs. We investigated guideline-adherence regarding critical time intervals and selected performance measures in German Chest Pain Units. Methods: From 2008 to 2014, 23,804 consecutive patients with suspected ACS were prospectively enrolled in the Chest Pain Unit registry of the German Cardiac Society. Results: Median time from symptom onset to first medical contact was 2 h in patients with ST-elevation myocardial infarction (STEMI) and 4 h in patients with unstable…

Aktuelle Therapie der koronaren Herzkrankheit

In der vorliegenden Arbeit wird der gegenwartige Stand der Pravention und der medikamentosen Behandlung der koronaren Herzkrankheit aufgezeigt. Auf vielen verschiedenen Feldern konnten Erfolge erzielt und fruhere Ergebnisse durch experimentelle Forschung oder klinische Studien gesichert werden. Das gilt besonders fur den Einsatz von Azetylsalizylsaure zur Sekundarprophylaxe koronarer Ereignisse und kombiniert mit Fibrinolytika beim akuten Myokardinfarkt sowie kombiniert mit niedermolekularem Heparin beim akuten Koronarsyndrom. Direkte Thrombinantagonisten, Glykoprotein-Rezeptorantagonisten, Ticlopidin sowie neue und weiterentwickelte Fibrinolytika erbrachten grose Fortschritte. Der molekula…

Two‐dimensional analysis of myocardial protein expression following myocardial ischemia and reperfusion in rabbits

Myocardial ischemia and reperfusion injury (MI/R) can be related to leukocyte activation with subsequent release of cytokines and oxygen derived free radicals. Activation of the complement system has been implicated in the pathogenesis of myocardial ischemia and reperfusion injury. Inflammatory injury will subsequently result in cellular activation and protein synthesis. In the present study we analyzed the myocardial protein expression and its pattern following myocardial ischemia and reperfusion, with and without complement inhibition with the synthetic serine protease inhibitor Futhan/nafamstat mesilate (FUT-175) known to inhibit classical and alternative complement pathway in a rabbit m…

Receptor Binding Properties of the New and Specific Thromboxane Receptor Antagonist Bay U 3405

Human platelet membranes were used to characterize the receptor binding properties of the specific thromboxane receptor antagonist 3H-SQ 29548 and the displacement of 3H-SQ 29548 from its binding site by the new thromboxane receptor antagonist Bay u 3405. The specific binding of 3H-SQ 29548 was saturable with an association rate constant of 1 x 10(-11) mol-1 min-1 and a dissociation rate constant of 0.032 min-1. Nonspecific binding of 3H-SQ 29548 was below 10%. When Scatchard plot analysis was performed on equilibrium saturation binding the kD was 69 nmol/l and the Bmax was calculated as 3.9 pmol/mg membrane protein. 3H-SQ 29548 was dose dependently displaced from its binding site by additi…

Invasive treatment of NSTEMI patients in German Chest Pain Units - Evidence for a treatment paradox.

Background: Patients with non ST-segment elevation myocardial infarction (NSTEMI) represent the largest fraction of patients with acute coronary syndrome in German Chest Pain units. Recent evidence on early vs. selective percutaneous coronary intervention (PCI) is ambiguous with respect to effects on mortality, myocardial infarction (MI) and recurrent angina. With the present study we sought to investigate the prognostic impact of PCI and its timing in German Chest Pain Unit (CPU) NSTEMI patients. Methods and results: Data from 1549 patients whose leading diagnosis was NSTEMI were retrieved from the German CPU registry for the interval between 3/2010 and 3/2014. Follow-up was available at m…

Increase in Endogenous Fibrinolysis and Platelet Activity during Exercise in Young Volunteers

Physicians at the Medical Clinic at the Johannes Gutenberg University in Mainz Germany compared data on 6 18-35 year old healthy women who took low-dose estrogen oral contraceptives (OCs) with data on 10 healthy women of same age who did not take OCs and with data on 12 18-35 year old males to examine gender differences of the coagulation system endogenous fibrinolytic activity and platelet aggregation under normal conditions and immediately after spiroergometric exercise beyond the anaerobic threshold. This type of exercise considerably boosted tissue plasminogen activator (t-PA) in both men and women (1.6-5.5 IU/ml and 1.8-5.3 IU/ml respectively; p < .005). The increase was not as high in…

MIC trial: metoprolol in patients with mild to moderate heart failure: effects on ventricular function and cardiopulmonary exercise testing

Beta-blocker therapy results in a functional benefit in patients with heart failure (CHF) due to idiopathic dilated cardiomyopathy (DCM). This study assessed if similar effects were observed in patients with ischemic heart disease (CAD), NYHA II–III after 6 months of therapy with metoprolol. Methods and results: Fifty-two patients with CHF secondary to DCM (26 patients) and CAD (26 patients) and a left ventricular ejection fraction (EF) < 40% were enrolled in the placebo-controlled study. The study medication was titrated over 6 weeks, the mean final dosage was 135 mg/day. Three patients died due to cardiogenic shock, two received placebo and one metoprolol. Eight patients did not complete …

Highly efficient liposome-mediated gene transfer of inducible nitric oxide synthase in vivo and in vitro in vascular smooth muscle cells.

Objective: The efficient introduction of regulatory genes into vascular smooth muscle cells (SMCs) is one of the most promising options for gene therapy of cardiovascular diseases. Cationic liposome-mediated gene transfer may become a favorable transfection technique with regard to patient’s safety for in vivo administration. However, this method until now has its limitation in a low transfection efficiency. Therefore, the present study was designed to improve cationic liposome-mediated transfection of rabbit vascular SMCs in vitro and in vivo, in order to enhance transfection efficiency and present an optimized system which may offer a potential therapeutic benefit for in vivo application.…

The German CPU Registry: Dyspnea independently predicts negative short-term outcome in patients admitted to German Chest Pain Units.

While dyspnea is a common symptom in patients admitted to Chest Pain Units (CPUs) little is known about the impact of dyspnea on their outcome. The purpose of this study was to evaluate the impact of dyspnea on the short-term outcome of CPU patients.We analyzed data from a total of 9169 patients admitted to one of the 38 participating CPUs in this registry between December 2008 and January 2013. Only patients who underwent coronary angiography for suspected ACS were included. 2601 patients (28.4%) presented with dyspnea.Patients with dyspnea at admission were older and frequently had a wide range of comorbidities compared to patients without dyspnea. Heart failure symptoms in particular wer…

Differential regulation of endothelial cell adhesion molecule expression by nitric oxide donors and antioxidants.

Although nitric oxide (NO) and antioxidants inhibit adhesion molecule expression, their inhibitory effects on nuclear factor kappaB (NF-kappaB) activation may differ. The NO donors, but not 8-bromo-cGMP, decreased tumor necrosis factor alpha (TNF-alpha)-induced VCAM-1, ICAM-1, and E-selectin expression by 11-70%. In contrast, NAC completely abolished VCAM-1 and E-selectin expression and decreased ICAM-1 expression by 56%. Gel shift assays demonstrate that NF-kappaB activation was inhibited by both NO and antioxidants. The activation of NF-kappaB involves the phosphorylation and degradation of its cytoplasmic inhibitor IkappaB-alpha by 26S proteasomes. The 26S proteasome inhibitor MG132 prev…

Effect of antibiotic treatment on vegetation size and complication rate in infective endocarditis

Background: Infective endocarditis is associated with significant morbidity and mortality, with valvular destruction, and with congestive heart failure. Embolic events are more common in patients with echocardiographically discernible vegetations, especially when vegetations are >10 mm in diameter. Hypothesis: The objective of the study was to follow vegetation morphology during native valve endocarditis, to compare it with the clinical course and antibiotic treatment chosen, and to evaluate whether the impact on vegetation size and complication rate of antibiotic regimens differed in patients with positive and negative blood cultures. Methods: The effect of different antibiotic regimes on …

Effects of Ciprostene on Restenosis Rate during Therapeutic Transluminal Coronary Angioplasty

Ciprostene, a chemically stable prostacyclin analog was studied for its effects on restenosis in patients with coronary artery disease undergoing therapeutic percutaneous transluminal coronary angioplasty (PTCA). In a double-blind, randomized trial 32 patients were randomized to receive either ciprostene or the respective placebo. The infusion started intracoronarily at a rate of 40 ng/kg/min 20 min before introduction of the balloon catheter into the coronary artery. Thereafter infusion was continued intravenously for 36 hours at a rate of 120 ng/kg/min and a tapering off period until 48 hours. The quantitative analyses of the degree of coronary artery stenoses on the angiographic films be…

Role of Nitrates for the Therapy of Coronary Artery Disease Patients in the Years beyond 2000

Vasodilator therapy with nitrates has been used for almost a century to bring relief to patients suffering from angina. The acute anti-ischemic effects of nitro-vasodilators for the treatment and prevention of anginal attacks is unquestioned. In addition, nitrates are administered in order to reduce symptomatic and silent ischemic episodes, in patients with proven coronary heart disease who exert ST segment alterations on Holter monitoring. The reduction in total ischemic burden may result in an improved prognosis with regard to infarct prevention and possible prevention of deterioration of left ventricular function due to repetitive episodes of myocardial ischemia. In patients with unstabl…

Staphylococcus aureus alpha toxin mediates polymorphonuclear leukocyte-induced vasocontraction and endothelial dysfunction.

The effect of Staphylococcus aureus alpha toxin (alpha-toxin) on selectin-mediated neutrophil adhesion was investigated in polymorphonuclear leukocyte- (PMN) induced vasocontraction and endothelial dysfunction. Adherence of human PMNs to rat aortic endothelium increased significantly following stimulation of the endothelium with alpha-toxin (0.1, 0.5, and 1 microg/mL). This effect could be significantly attenuated by monoclonal antibodies directed against P-selectin or fucoidin, a carbohydrate known to block selectins. Unstimulated human PMNs (10(6)cells/mL) were added to organ chambers containing rat aortic rings stimulated with alpha-toxin (0.5 microg/mL). PMNs elicited a significant vaso…

Cardiomyocyte apoptosis is related to left ventricular dysfunction and remodelling in dilated cardiomyopathy, but is not affected by growth hormone treatment.

Background and aims Cardiomyocyte apoptosis (CA) is a common feature of end-stage heart failure. We examined whether CA is associated with cardiac dysfunction and remodelling in heart failure due to dilated cardiomyopathy and studied the effect of human growth hormone (hGH) on CA. Methods and results We studied 38 patients, included in a phase III multi-center, randomised, double-blind and placebo-controlled trial of biosynthetic hGH treatment in dilated cardiomyopathy, at baseline and after 14 weeks treatment. Twenty-six patients received hGH and 12 received placebo. CA was quantified in endomyocardial biopsies using the TUNEL assay. CA correlated with left ventricular size (r=0.43, p=0.00…

Herpesvirus DNA (Epstein-Barr virus, herpes simplex virus, cytomegalovirus) in circulating monocytes of patients with coronary artery disease

Background -The underlying mechanism of the chronic inflammatory process in atherosclerosis is still unknown. As a possible trigger, several studies in recent years have suggested that different viruses and bacteria are associated with atherosclerotic diseases. Methods - We applied polymerase chain reaction to analyse whether Epstein-Barr virus (EBV), herpes simplex virus (HSV), and cytomegalovirus (CMV) DNA could be detected in CD14 + cells from 184 patients with angiographically documented coronary artery disease (CAD) (74 patients with stable angina (SAP), 51 patients with unstable angina (UAP), and 59 patients with myocardial infarction (Ml)) and from 52 healthy controls. Results - In t…

Synergistic platelet antiaggregatory effects of the adenylate cyclase activator iloprost and the guanylate cyclase activating agent SIN-1 in vivo

The aim of our study was to evaluate the platelet antiaggregatory and hemodynamic effects of the stable prostacyclin analog iloprost and the NO-donor SIN-1, an active metabolite of molsidomine. The number of circulating platelets was determined in anesthetized male Wistar rats as a measure of in vivo platelet aggregation. Platelet count decreased from 648 +/- 25 to 476 +/- 15 x 10(3) platelets/microliter and from 578 +/- 36 to 411 +/- 40 (mean +/- SEM) in response to two repetitive injections of collagen (70 micrograms/kg body weight). Treatment with SIN-1 bolus injections (0.3 or 1 mg/kg bw) and/or continuous i.v. infusion of iloprost (0.2 or 0.4 micrograms/kg bw/min) was initiated 15 min …

TCT-350 Safety and Performance of the Resorbable Magnesium Scaffold, Magmaris in a Real World Setting - First 400 Subjects at 12-month Follow-up of the BIOSOLVE-IV Registry

The aim of this registry is to investigate the clinical performance and long-term safety of the Resorbable Magnesium Scaffold (Magmaris) (BIOTRONIK AG, Buelach, Switzerland) in a real-world setting. Up to 2,054 subjects in up to 120 clinical sites in Europe, Asia, and Asia-Pacific countries will

Synergistic interaction of adenylate cyclase activators and nitric oxide donor SIN-1 on platelet cyclic AMP

Abstract The molecular mechanism of the synergistic platelet inhibition by activators of adenylate cyclase and guanylate cyclase in human platelets was investigated. The adenylate cyclase activators iloprost and prostaglandin E 1 and the guanylate cyclase activator 3-morpholino-synonimine (SIN-1) dose-dependently inhibited thrombin-induced aggregation of washed human platelets. Furthermore, SIN-1 at a concentration inhibiting platelet aggregation by only 10% shifted the IC 50 values of iloprost and prostaglandin E 1 by one order of magnitude to the left, indicating a synergistic action of adenylate cyclase and guanylate cyclase activators. Iloprost and prostaglandin E 1 dose-dependently ele…

Intracoronary application of C1 esterase inhibitor improves cardiac function and reduces myocardial necrosis in an experimental model of ischemia and reperfusion.

Background Myocardial injury from ischemia can be aggravated by reperfusion of the jeopardized area. The precise underlying mechanisms have not been clearly defined, but proinflammatory events, including complement activation, leukocyte adhesion, and infiltration and release of diverse mediators, probably play important roles. The present study addresses the possibility of reducing reperfusion damage by the application of C1 esterase inhibitor (C1-INH). Methods and Results Cardioprotection by C1-INH 20 IU/kg IC was examined in a pig model with 60 minutes of coronary occlusion, followed by 120 minutes of reperfusion. C1-INH was administered during the first 5 minutes of coronary reperfusion…

Aprotinin inhibits leukocyte–endothelial cell interactions after hemorrhage and reperfusion

Background. The serine protease inhibitor aprotinin has been successfully used to reduce blood loss in patients undergoing cardiac operations. We studied aprotinin for its ability to modulate leukocyte– endothelial cell interactions after ischemia and reperfusion. Methods. The effects of aprotinin on leukocyte– endothelial cell interactions were observed by intravital microscopy in the rat mesenteric microcirculation and immunohistochemical analysis. The inflammatory cascade (leukocyte rolling, firm adherence, and transmigration) was studied after thrombin stimulation and after hemorrhage and reperfusion. Results. Intravenous bolus administration of aprotinin treatment (20,000 U/kg) signifi…

Spontaneous echo contrast imaging in infective endocarditis: a predictor of complications?

Infective endocarditis is associated with significant morbidity and mortality. Valvular destruction and congestive heart failure are more common in patients with echocardiographically detectable vegetations. In addition, spontaneous platelet aggregation is increased when vegetations are present on cardiac valves. The aim of the study was to assess the prognostic value of spontaneous echo contrast (SEC) imaging, as SEC is supposed to reflect red blood cell aggregates stimulated by platelet activity. We studied 293 patients with clinical signs of infective endocarditis. Vegetations, attached to the aortic or mitral valve, were found in 130 patients (44.4%) who were followed for a mean period …

Führt hochdosiertes Dipyridamol in der sekundären Schlaganfallprävention zu kardialen Ereignissen?

In einer post-hoc Analyse der European Stroke Prevention Study 2 (ESPS2) wurde untersucht, ob die Gabe von Dipyridamol als Thrombozytenfunktionshemmer bei Patienten mit TIA oder Schlaganfallen das Risiko kardialer Ereignisse erhoht. ESPS2 war eine Sekundarpraventionsstudie an 6602 Patienten nach TIA oder ischamischem Insult, die in vier Armen Acetylsalicylsaure (ASS, 2×25 mg), retardiertes Dipyridamol (DP, 2×200 mg), die Kombination aus ASS plus DP oder Placebo verglich. Es ergaben sich keine Anhaltspunkte dafur, dass DP zu vermehrten kardialen Ereignissen (Angina pectoris, Myokardinfarkt, Tod) fuhrt. Die Kombination aus ASS und DP war allerdings in der Schlaganfallpravention deutlich wirks…

Tissue classification by texture and spectral analysis of intracoronary ultrasound radio-frequency data

Imaging of vascular structures by intracoronary ultrasound allows in principal the recognition of different lesion types due to the echomorphology in the B-mode image. The subjective visual diagnosis is often difficult, especially the differentiation between thrombi and non-calcified plaque. The aim of this study was the extraction of features from the ultrasound radio-frequency signal for an objective characterization of coronary tissue. Methods of texture analysis and frequency analysis were used to differentiate red and white thrombi in vitro. Eight texture parameters of first and second order significantly differentiated red and white thrombi. The backscatter transfer function of red th…

Increased Platelet Sensitivity toward Platelet Inhibitors during Physical Exercise in Patients with Coronary Artery Disease

Generalized atherosclerosis and coronary artery disease (CAD) are associated with endothelial dysfunction and during acute myocardial ischemia platelet activation has been reported. Activated platelets exert activated fibrinogen receptors (GP IIb/IIIa) and express CD 62p being regarded as reliable marker for platelet activation. Patients with angiographically proven CAD performed a bicycle exercise test until the onset of angina or ST-segment depression. We studied the ischemia-induced alterations in fibrinogen binding to activated platelet GP IIb/IIIa receptors and CD 62p expression. Therefore, the basal fibrinogen binding to GP IIb/IIIa and CD 62p expression and the thrombin-concentration…

Simvastatin Inhibits Inflammatory Properties ofStaphylococcus aureusα-Toxin

Background—Simvastatin, a 3-hydroxy-methylglutaryl coenzyme A reductase inhibitor, has been shown to lower serum cholesterol levels in clinical use. Moreover, statins exert beneficial effects in vascular diseases by inhibition of leukocyte rolling, adherence, and transmigration. The aim of this study was to determine if pretreatment with simvastatin attenuatesStaphylococcus aureusα-toxin–induced increase in leukocyte-endothelial interactions during exotoxemia.Methods and Results—The effects of simvastatin on leukocyte-endothelial cell interactions were observed by intravital microscopy in the rat mesenteric microcirculation. Simvastatin (50 or 100 μg/kg) was administered 18 hours before the…

Novel Small Molecule Inhibitor of C1s Exerts Cardioprotective Effects in Ischemia-Reperfusion Injury in Rabbits

Abstract Myocardial ischemia-reperfusion injury can be related to complement activation with generation of chemotactic agents, adhesion molecule expression, release of cytokines and oxygen-derived free radicals, and subsequent neutrophil accumulation. In the present study the cardioprotective effects of a novel highly selective small molecule C1s inhibitor (C1s-INH-248, Knoll) were examined in a rabbit model of myocardial ischemia (I) and reperfusion (R; i.e., 60 min I + 180 min R). In in vitro tests (enzyme activity and SRBC lysis) C1s-INH-248 demonstrated profound inhibitory potency. In vivo C1s-INH-248 (1 mg/kg body weight) administered 5 min before reperfusion significantly attenuated m…

Involvement of PKC and NF-κB in Nitric Oxide Induced Apoptosis in Human Coronary Artery Smooth Muscle Cells

Apoptosis of vascular smooth muscle cells is critically involved in progression of atherosclerosis and may prevent intimal hyperplasia in restenosis and vascular remodeling. Nitric oxide (NO) is known to induce apoptosis, but the signaling pathways still remain unclear. We investigated p53 accumulation, protein kinase C (PKC) activation and nuclear transcription factor (NF-kappaB) binding activity as possible signaling mechanisms of NO-induced apoptosis. Apoptosis was induced dose-dependently with the NO-donors sodiumnitroprusside (SNP: 232+/-48%) and SIN-1 (241+/-90% of actinomycin D induced apoptosis; means +/- SEM, *por =0.05 vs. control) in HSMC. Inhibition of PKC significantly attenuat…

NO Reduces PMN Adhesion to Human Vascular Endothelial Cells Due to Downregulation of ICAM-1 mRNA and Surface Expression

Reperfusion damage is largely due to the adherence of polymorphonuclear leukocytes to the endothelium initiated by adhesion molecule upregulation. The reduced endothelial nitric oxide release during ischemia may be involved in the upregulation of intercellular adhesion molecule 1. In this study, we tested if nitric oxide donors suppress polymorphonuclear leukocyte adherence to activated endothelial cells by inhibition of the intercellular adhesion molecule 1 surface expression. Confluent human umbilical vein endothelial cells were stimulated with tumor necrosis factor alpha (300 U/mL) after preincubation with increasing concentrations of the nitric oxide donors CAS 1609 (0.005-5 mM/L) and 3…

Comparison of ReoPro((R)) (abciximab) versus intracoronary thrombolysis for early coronary stent thrombosis.

AIMS: This study evaluated the treatment of early coronary stent thrombosis with intracoronary urokinase or the platelet glycoprotein IIb/IIIa receptor inhibitor ReoPro (abciximab). METHODS AND RESULTS: Seventy-four patients (126 stents) were treated immediately after identification of early (0-30 days) coronary stent thrombosis. Twenty-nine patients were treated with intracoronary urokinase (UK) (UK alone in 19; UK and additional balloon angioplasty in 10) and another 45 patients were given ReoPro((R)) (abciximab) (0.25 mg/kg as a bolus alone in 26, abciximab with additional balloon angioplasty in 19) within 30 days of stent implantation. TIMI grade 3 flow was obtained in 23 patients (79%)…

Taprostene (CG-4203)

Clinical and morphological characteristics in Streptococcus bovis endocarditis: a comparison with other causative microorganisms in 177 cases

Aim—To compare the clinical and morphological characteristics of patients with Streptococcus bovis endocarditis with those of patients with endocarditis caused by other microorganisms. Methods—177 consecutive patients (Streptococcus bovis, 22; other streptococci, 94; staphylococci, 44; other, 17) with definite infective endocarditis according to the Duke criteria were included. All patients underwent transthoracic and transoesophageal echocardiography. In 88 patients, findings from surgery/necropsy were obtained. Results—S bovis endocarditis was associated with older patients, with a higher mortality (p = 0.04), and with a higher rate of cardiac surgery (p < 0.001) than other microorganisms…

Cardioprotective effects of the serine protease inhibitor aprotinin after regional ischemia and reperfusion on the beating heart.

AbstractObjective: Early coronary reperfusion of the ischemic myocardium is a desired therapeutic goal to preserve myocardium. However, reperfusion itself contributes to an additional myocardial injury (ie, reperfusion injury), which has been attributed to neutrophil infiltration with subsequent release of proteases and oxygen-derived radicals. We studied the effects of the serine protease inhibitor aprotinin (Trasylol) on myocardial ischemia and reperfusion in a rat model. Methods: The effects of aprotinin (5000 and 20,000 U/kg) were examined in vivo in a rat model of regional myocardial ischemia (20 minutes) and long-term reperfusion (24 hours). Cardioprotecive effects were determined by …

Antithrombotic Therapy in Patients with Atrial Fibrillation and Acute Coronary Syndrome Treated Medically or with Percutaneous Coronary Intervention or Undergoing Elective Percutaneous Coronary Intervention: Insights from the AUGUSTUS Trial.

Background: The safety and efficacy of antithrombotic regimens may differ between patients with atrial fibrillation who have acute coronary syndromes (ACS), treated medically or with percutaneous coronary intervention (PCI), and those undergoing elective PCI. Methods: Using a 2×2 factorial design, we compared apixaban with vitamin K antagonists and aspirin with placebo in patients with atrial fibrillation who had ACS or were undergoing PCI and were receiving a P2Y 12 inhibitor. We explored bleeding, death and hospitalization, as well as death and ischemic events, by antithrombotic strategy in 3 prespecified subgroups: patients with ACS treated medically, patients with ACS treated with PCI,…

Effest of Molsidomine on t-PA and PAI Activity in Man: A Double Blind, Placebo Controlled Study

Oral Glycoprotein IIb/IIa Antagonists for Unstable Angina — Is There Still a Chance for the Oral Substances?

The intravenous glycoprotein IIb/IIIa antagonists abciximab, tirofiban and eptifibatide are well accepted for the therapy of patients with unstable angina and/or as concomitant medication during coronary interventions. Despite the fact that these drugs are not used in all patients presenting with unstable angina during coronary interventions, the scientific evidence is overwhelming including the substantial reduction in mortality 3 years after utilisation of abciximab for coronary interventions in patients with unstable angina. In addition to these two indications, intravenous glycoprotein IIb/IIIa antagonists are currently being investigated for use in patients undergoing carotid artery in…

Diagnosis of culture-negative endocarditis: The role of the Duke criteria and the impact of transesophageal echocardiography

Abstract Background The Duke criteria have been shown to be more sensitive than the von Reyn criteria in the diagnosis of culture-positive endocarditis but to date have not been fully validated for culture-negative endocarditis (CNE). The aim of this study was (1) to compare the diagnostic accuracy of the Duke criteria versus clinical judgment and the von Reyn criteria in CNE and (2) to assess the diagnostic impact of transesophageal echocardiography (TEE) on the Duke criteria in CNE. Methods The study group consisted of 49 patients with suspected CNE in whom the presence (n = 32) or absence (n = 17) of endocarditis was confirmed by surgery, autopsy, or both. All patients underwent transtho…

Substantial Reduction of Platelet Adhesion by Heparin-Coated Stents

Although optimized antiplatelet medication has improved the clinical outcome after coronary stenting, vessel occlusion and restenosis still remain a relevant clinical problem. Platelets play a key role in this process. Therefore, the authors compared the platelet adhesion on different stent surface modifications (electropolished without coating or coated with carbon, carbon and additional heparin, silicon carbide, or heparin alone) to investigate their role in reducing platelet adhesion. All stents and additional stainless steel plates were incubated in heparinized whole blood with radiolabeled platelets. After washing the stents and plates four times, radioactivity caused by the adhesion o…

Lokale Medikamentengabe und Gentherapie

Eines der wichtigsten Probleme der klinischen Kardiologie, die Entwickung einer Restenose nach koronarer Ballonangioplastie, ist bisher noch nicht befriedigend gelöst. Die pathophysiologischen Erkenntnisse über die Mechanismen der Neointimabildung sind noch unvollständig, und zahlreiche Therapiestudien mit systemisch applizierten Pharmaka mit unterschiedlichem Wirkungsmechanismus sind fehlgeschlagen. Mögliche innovative Therapieansätze betreffen die hochdosierte lokale Substanzapplikation an der Dilatationsstelle und lokale gentherapeutische Eingriffe zur Verhinderung der Neointimabildung durch Proliferationshemmung der glatten Gefäßmuskelzellen. Zahlreiche Kathetermodelle sind entwickelt w…

Spontaneous echo contrast caused by platelet and leukocyte aggregates?

Background and Purpose —Spontaneous echocardiographic contrast (SEC) is correlated to clinical thromboembolic events. We sought to determine the origin of SEC by utilizing direct analysis of left atrial blood. Methods —We examined the blood of 13 patients with and 19 without SEC. Blood samples were taken from the femoral vein and artery and from the right and left atria after transseptal puncture. Samples were incubated with fluorescence-labeled antibodies directed against the platelet (CD41a-PE, CD42b-PE, and CD62p-FITC) and leukocyte membrane epitopes (CD45-APC and CD14-FITC). The expressed epitopes were analyzed by dual laser flow cytometry immediately after blood withdrawal. Results —I…

Platelet-activating factor type activity in plasma from patients with septicemia and other diseases

The purpose of the present study was to determine whether increased levels of platelet-activating factor (PAF) type activity can be detected in plasma from patients with septicemia and other diseases. A level of PAF below 0.5 ng/mL of plasma was considered normal. We found that plasma from a patient with adverse anaphylactoidic reaction to intravenous analgetics contained 2.1 ng PAF/mL. In seven patients with septicemia, including urosepsis, endocarditis and peritonitis, and with positive blood culture, increased plasma PAF levels (1-20 ng PAF/mL) were observed. Other patients with clinical indications of septicemia had negative blood cultures and/or increased levels of C-reactive protein (…

Nonradical oxidants of the phagocyte type induce the activation of plasmatic single chain- urokinase

Single chain- urokinase (scu-PA) is the proenzyme of the plasminogen activator urokinase (tcu-PA). In human blood scu-PA is of great stability. Activated phagocytes generate large amounts of single chain- urokinase and of reactive oxidants (chloramines and HOCl). Since these cells participate in physiologic fibrinolysis, we were interested in the interaction between plasmatic scu-PA and chloramines. The oxidants dose dependently induce the activation of plasmatic scu-PA. Optimal activation of scu-PA occurs at about 3-5 mmol/l of chloramine-T. The findings suggest a control mechanism of scu-PA stability/activity by oxidatively modifiable plasma proteins, such as alpha-2-antiplasmin. The oxid…

In vitro Analysis of Synergistic Effects of Fibrinolytic Agents and Prostacyclin Analogues

We investigated the in vitro thrombolytic effects of streptoki-nase, urokinase, alteplase and saruplase, alone or in combination, with the prostacyclin analogues, iloprost and taprostene. Human platelet-rich plasma was stimulated with collagen (1 μg/ml) to generate thrombi containing platelets and fibrin. Following treatment with fibrinolytic agents, lysis was allowed to proceed for 30 min and was then terminated with aprotinin (2,000 ClU/ml). To evaluate the combinatory effects of fibrinolytic agents and prostacyclin analogues, we used concentrations of fibrinolytic agents which reduced thrombi weight by less than 50%. Neither iloprost nor taprostene alone demonstrated any thrombolytic eff…

Diminished Inhibition of Adhesion Molecule Expression in Prostacyclin Receptor Desensitized Human Platelets

Long-term exposure of platelets to prostacyclin or iloprost (100nM, 3hr) results in receptor desensitization measured as decrease in 3H-iloprost binding sites by 47 +/- 14%. Desensitized platelets respond with an increased adhesion to endothelial cells. The mechanism of increased adhesiveness was studied by measuring the expression of the adhesion molecule CD62p (p-selectin; GMP140) on washed human platelets by flowcytometry. In thrombin stimulated platelets CD62p expression was dose-dependently reduced by iloprost. In receptor desensitized platelets IC50 for iloprost inhibition of thrombin-induced CD62p expression increased from 0.48 +/- 0.10 to 2.4 +/- 0.7 nM.

Mechanism of reperfusion damage after thrombolysis and ‘direct PTCA’

Summary There is general agreement between cardiologists, that reperfusion of the infarct related coronary artery (PTCA) is the method of choice for the treatment of an acute myocardial infarction. However, the method utilized for inducing a rapid and complete reperfusion is still discussed. Even if thrombolysis will remain the method of choice for the major part of the population, part of the patient cohort with acute infarction will be treated by direct PTCA. Rapid reperfusion of ischemic myocardium reduces infarct size by limiting infarct extension into the entire area at risk, although a reperfusion damage is induced in the core ischemic area. This reperfusion damage has been convincing…

Characterization and referral patterns of ST-elevation myocardial infarction patients admitted to chest pain units rather than directly to catherization laboratories : Data from the German Chest Pain Unit Registry

Abstract Background Direct transfer to the catheterization laboratory for primary percutaneous coronary intervention (PCI) is standard of care for patients with ST-segment elevation myocardial infarction (STEMI). Nevertheless, a significant number of STEMI-patients are initially treated in chest pain units (CPUs) of admitting hospitals. Thus, it is important to characterize these patients and to define why an important deviation from recommended clinical pathways occurs and in particular to quantify the impact of deviation on critical time intervals. Methods and results 1679 STEMI patients admitted to a CPU in the period from 2010 to 2015 were enrolled in the German CPU registry (8.5% of 19…

Comparison of antiplatelet effects of aspirin, ticlopidine, or their combination after stent implantation.

Background —This study was performed to analyze the influence of either aspirin, ticlopidine, or their combination on platelet activation and aggregation parameters after stent implantation. Methods and Results —Sixty-one patients with successful implantation of a single Palmaz-Schatz stent in a native coronary artery were randomly assigned to either group A (aspirin 300 mg/d+ticlopidine 2×250 mg/d), group B (ticlopidine 2×250 mg/d), or group C (aspirin 300 mg/d). Platelet activation was evaluated on days 1, 7, and 14 by flow cytometry measurement of expression of CD62p (p-selectin) and the binding of fibrinogen to the platelet surface glycoprotein IIb/IIIa receptor. Platelet aggregation w…

Potent low dose platelet inhibitory effects of clopidogrel and aspirin on coronary thrombus formation in an animal model of acute unstable angina

SummaryApplication of clopidogrel before percutaneous coronary intervention in patients with acute coronary syndrome reduces the risk of cardiac events. Clopidogrel administration before surgery increases bleeding complications after CABG. Therefore, the antithrombotic effect of the low-dose combination of clopidogrel and aspirin was investigated in an in vivo pig model of coronary artery thrombus formation with cyclic flow reductions. The platelet inhibitory effect was determined by platelet aggregation and CFR, according to the methodology described by Folts. CFR were initiated by endothelial damage and placement of a constrictor around the LAD. 30 min after CFR were established, clopidog…

Application of C1-Esterase Inhibitor During Reperfusion of Ischemic Myocardium

Background—Complement activation during reperfusion of ischemic myocardium augments myocardial injury, and complement inhibition with C1-esterase inhibitor (C1-INH) at the time of reperfusion exerts marked cardioprotective effects in experimental studies. Application of C1-INH in newborns, however, was recently reported to have dangerous and even lethal side effects. This study addresses the essential role of dosage in studies using C1-INH.Methods and Results—Cardioprotection by C1-INH was examined in a pig model with 60 minutes of coronary occlusion followed by 120 minutes of reperfusion. C1-INH was administered intravenously 5 to 10 minutes before coronary reperfusion without heparin at a…

Changes of neurohumoral parameters and endothelin-1 in response to exercise in patients with mild to moderate congestive heart failure

Plasma endothelin levels are increased in patients with moderate and severe CHF. Conflicting data exist about the endothelin-1 (ET) level in patients with mild to moderate CHF and the effect of maximal exercise on plasma ET levels.We determined the plasma levels of ET and various neurohumoral parameters in 93 patients with CHF in functional class II and III of the NYHA classification at rest and after maximal bicycle exercise. Baseline ET level was increased compared to an age-matched healthy volunteer group (6.95+/-0.31 vs 3.29+/-0.17 pg/ml, mean+/-S.E.M., P0.05), without significant differences between NYHA class II and III patients. Maximal exercise did not increase the ET level. In cont…

Guideline-adherence and perspectives in the acute management of unstable angina - Initial results from the German chest pain unit registry.

Abstract Background We investigated the current management of unstable angina pectoris (UAP) in certified chest pain units (CPUs) in Germany and focused on the European Society of Cardiology (ESC) guideline-adherence in the timing of invasive strategies or choice of conservative treatment options. More specifically, we analyzed differences in clinical outcome with respect to guideline-adherence. Method Prospective data from 1400 UAP patients were collected. Analyses of high-risk criteria with indication for invasive management and 3-month clinical outcome data were performed. Guideline-adherence was tested for a primarily conservative strategy as well as for percutaneous coronary interventi…

The effects of the nitric oxide donors molsidomine and SIN-1 on human polymorphonuclear leucocyte functionin vitro andex vivo

The nitrovasodilator and nitric oxide donor molsidomine and its metabolite SIN-I dilate vascular smooth muscle and inhibit platelet activation by increasing intracellular concentrations of cyclic GMP We have therefore studied the effects of molsidomine and SIN-I on isolated human polymorphonuclear leucocytes (PMN)in vitro andex vivo. In vitro molsidomine dose-dependently reducedβ-glucuronidase release and the generation of superoxide anions from non-activated and from FMLP- or PAF-stimulated human PMNs. SIN-1 was equally effective in reducing (β-glucuronidase release and totally inhibited oxygen radical generation at a concentration of 580 μmol · l−1. In a double-blind, placebo-controlled, …

Prostacyclin receptor desensitization is a reversible phenomenon in human platelets.

Background Long-term exposure of platelets to endogenous or exogenous prostacyclin or its analogues might result in desensitization of the platelet prostacyclin receptor in vitro and in vivo accompanied by a loss in receptor density on the platelet surface and a reduced sensitivity toward the inhibitory effects of prostacyclins. However, the reversibility of this process in platelets has not yet been investigated. Methods and Results Human platelets desensitized by the chemically stable prostacyclin analogue iloprost showed a significant reduction in [ 3 H]-iloprost binding sites that was reversed by saponin permeabilization. This indicates functionally active internalized prostacyclin rec…

Anti-inflammatory properties of simvastatin on leukocyte-endothelial cell interactions following hemorrhagic shock

Background Hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) have been shown to lower serum cholesterol levels. Recent studies reported that statins have vasculoprotective effects independent of their cholesterol-lowering properties. We studied simvastatin for its ability to modulate leukocyte-endothelial cell interactions under acute inflammation following hemorrhage and reperfusion. Methods The effects of simvastatin on leukocyte-endothelial cell interactions were observed by intravital microscopy in the rat mesenteric microcirculation and by immunohistochemical analyzes. Simvastatin (50 μg/kg or 100 μg/kg) was administrated intraperitoneally 18 h before study. Inf…