Incidental finding of a giant intracardiac angioma infiltrating both ventricles in a 35-year-old woman: a case report.

BACKGROUND: Primary cardiac tumors are rare and often asymptomatic or present with unspecific symptoms. Benign cardiac tumors of vascular origin are especially rare, with only few existing data in the literature. CASE PRESENTATION: A 35-year-old Caucasian female patient presented to our department with an asymptomatic giant intracardiac angioma infiltrating both ventricles. Evaluation of this tumor involved electrocardiography, echocardiography, cardiac magnetic resonance imaging, coronary angiography, an open myocardial biopsy, and histological examination of the resected specimen. Because our patient was asymptomatic, she was managed conservatively with regular follow-up. We discuss the treatment options available in comparison with similar cases. CONCLUSION: Diagnosis and therapy of benign cardiac tumors, especially of asymptomatic lesions, can be a challenge. There is no evidence available to help in the management of such patients. An extensive evaluation is needed with different imaging modalities, and case-specific decisions should be made that involve experts in cardiology, cardio-oncology, and heart surgery.

Spiegelmer Inhibition of MCP-1/CCR2--Potential as an Adjunct Immunosuppressive Therapy in Transplantation.

The rejection process remains the key unsolved issue after transplantation of disparate tissue. The CC chemokine monocyte chemoattractant protein-1 (MCP-1/CCL2) has been reported to be involved in the process of alloimmune interaction. Spiegelmers are l-oligonucleotides that can be designed to bind to pharmacologically relevant target molecules. Here, we tested a high-affinity Spiegelmer-based MCP-1 inhibitor (mNOX-E36) in an allogeneic heart transplant model. Fully vascularized allogeneic heterotopic heart transplantations from BALB/c to C57BL/6 mice were performed. Mice were either treated with the anti-MCP-1-Spiegelmer (mNOX-E36) in monotherapy or in combination with subtherapeutic doses of cyclosporine A (CsA) (10 mg/kgBW/day) for 10 days. Controls received equivalent doses of a non-functional Spiegelmer (revmNOX-E36). Graft survival of allogeneic heart transplants was slightly but significantly prolonged under mNOX-E36 monotherapy (median graft survival 10 day ± 0.7) compared to revmNOX-E36 (median graft survival 7 day ± 0.3; P = 0.001). A synergistic beneficial effect could be seen when mNOX-E36 was administered in combination with subtherapeutic doses of CsA (18 day ± 2.8 versus 7 day ± 0.3; P < 0.0001). Levels of inflammatory cytokines and 'alarmins' were significantly reduced, and the number of F4/80(+) cells was lower under combination therapy (1.8% ± 1.3%; versus 14.6% ± 4.4%; P = 0.0002). This novel inhibitor of the MCP-1/CCR2 axis (mNOX-E36), which has already proven efficacy and tolerability in early clinical trials, alleviates acute rejection processes in allogeneic transplantation especially when combined with subtherapeutic doses of CsA. Thus, mNOX-E36 may have potential as an adjunct immunomodulatory agent.

HMGB1 is an independent predictor of death and heart transplantation in heart failure.

BACKGROUND: High-Mobility-Group Box 1 (HMGB1) has been established as an important mediator of myocardial inflammation and associated with progression of heart failure (HF). The aim of this study was to analyze the prognostic value of systemic HMGB1 levels in HF patients with ischemic and non-ischemic cardiomyopathy. METHODS AND RESULTS: We conducted an analysis (median follow-up time 2.5 years) of HMGB1 plasma concentration in 154 patients with systolic HF and correlated the results with disease severity and prognosis. HMGB1 in HF patients with severe symptoms (NYHA III/IV; 5.35 ng/ml; interquartile range (IQR) = 3.48-8.42 ng/ml) was significantly elevated compared with that in patients with mild symptoms (NYHA I/II; 3.37 ng/ml, IQR = 2.31-5.22 ng/ml, p < 0.0001) and with controls (3.25 ng/ml, IQR = 3.04-3.67 ng/ml, p < 0.0001). HMGB1 levels correlated with other markers of heart failure indicating an association of HMGB1 with disease severity in HF. In a univariate cox regression model for the combined endpoint of death and heart transplantation, HMGB1 proved to be a predictor at cut-off values based on HMGB1 terciles of either 3.4 or 6.1 ng/ml (p = 0.001 and p < 0.0001, respectively). In a multivariate cox regression model, which included NT-proBNP, creatinine, age, NYHA class, white blood cell count, anemia, and age, HMGB1 remained an independent predictor of the combined endpoint (hazard ratio (HR) = 2.48, 95% confidence interval (CI) = 1.06-5.83, p = 0.037 and HR = 2.48, 95% CI = 1.31-4.71, p = 0.005, respectively). CONCLUSION: Our findings demonstrate that HMGB1 plasma concentration is elevated in HF and correlates with disease severity and that is an independent predictor of the combined endpoint death and heart transplantation in HF patients.

HMGB1 as a predictor of infarct transmurality and functional recovery in patients with myocardial infarction.

OBJECTIVES: High-mobility group box 1 (HMGB1) protein is an innate danger signal for the initiation of host defence and tissue repair. The aim of this study was to analyse serum HMGB1 concentration and its correlation with infarct transmurality and functional recovery in patients with ST-elevation (STEMI) and non-ST-elevation myocardial infarction (NSTEMI). DESIGN: We prospectively examined patients with first-time STEMI (n = 46) or NSTEMI (n = 49), treated according to current guidelines. Contrast-enhanced cardiac magnetic resonance imaging was performed 2-4 days after infarction for the estimation of infarct transmurality and was repeated after 6 months for the estimation of residual left ventricular function. HMGB1 was measured 2-4 days after infarction. RESULTS: High-mobility group box 1 concentration was related to infarct size and to residual ejection fraction in patients with STEMI (r(2) = 0.81 and r(2) =0.40, respectively, P < 0.001 for both) and NSTEMI (r(2) = 0.74 and r(2) = 0.25, respectively, P < 0.001 for both). Receiver operating characteristic (ROC) curve-derived cut-off values of 6.2 and 5.9 ng mL(-1) for patients with STEMI and NSTEMI, respectively, were predictive of infarct transmurality greater than 75% (STEMI: area under the curve (AUC) = 0.93, standard error (SE) = 0.04, 95% confidence interval (CI) = 0.81-0.98; NSTEMI: AUC = 0.96, SE = 0.04, 95% CI = 0.86-0.99). HMGB1 cut-off values of 7.2 and 6.4 ng mL(-1) for patients with STEMI and NSTEMI, respectively, were predictive of residual ejection fraction 6 months after myocardial infarction (MI) (STEMI: AUC = 0.81, SE = 0.07, 95% CI = 0.66-0.91; NSTEMI: AUC = 0.81, SE = 0.09, 95% CI = 0.68-0.91). CONCLUSION: High-mobility group box 1 serum levels represent a highly valuable surrogate marker for infarct transmurality and for the prediction of residual left ventricular function after MI.

Radial artery thrombosis following transradial coronary angiography: incidence and rationale for treatment of symptomatic patients with low-molecular-weight heparins.

BACKGROUND: Transradial access for diagnostic and therapeutic coronary angiography gains more and more popularity because of its advantages over the femoral approach, enhancing patient comfort, reducing bleeding complications and duration of hospital stay. However, these benefits are overshadowed by an increased rate of radial artery (RA) occlusion. There are little data regarding the exact incidence, potential predictors and outcome of post-procedural RA occlusions. Furthermore, there is no clear evidence for the optimal treatment of this complication. METHODS: In a single-centre prospective observational study, 488 consecutive patients were evaluated by ultrasound the day after transradial cardiac catheterization for signs of RA occlusion. Symptomatic patients with sonographically identified radial artery thrombosis underwent treatment with low-molecular-weight heparin (LMWH) for 4 weeks. Asymptomatic patients did not receive anticoagulation therapy. The primary endpoint was the patency rate of the radial artery at 4 weeks of follow-up. RESULTS: Radial artery thrombosis was found in 51 of 488 (10.5%) patients 1 day after transradial cardiac catheterization. 30 (58.8%) patients showed symptoms on access site, whereas 21 (41.2%) did not show any symptoms. After 4 weeks, 26 (86.7%) of the symptomatic patients showed a partial or complete recanalization of the radial artery after treatment with LMWH, compared with 4 (19.1%) of the asymptomatic patients without anticoagulation (P < 0.001). CONCLUSION: Radial artery thrombosis is a frequent complication after transradial coronary angiography. Incidence of RA occlusion is underestimated due to the often asymptomatic clinical course. Treatment of symptomatic RA occlusion with low-molecular-weight heparins significantly increases patency rates after 4 weeks.

Telmisartan improves absolute walking distance and endothelial function in patients with peripheral artery disease.

BACKGROUND: Peripheral artery disease (PAD) is associated with high cardiovascular mortality and a poor quality of life. The AT1-receptor blocker telmisartan has been shown to have pleiotropic effects and it may also improve endothelial function. The aim of this study was to analyze the effects of telmisartan on absolute walking distance (WD) and endothelial function in patients with PAD. METHODS: In a single centre, single-blinded, prospective study, 36 patients with PAD at stage Fontaine II or higher and mild to moderate arterial hypertension were treated with telmisartan 40/80 mg once daily or placebo for 12 months. Primary endpoint was the improvement of the absolute treadmill WD. Flow-mediated vasodilation (FMD), carotid intima-media thickness (IMT), ankle-brachial index (ABI) and disease-related quality of life (DRQL) were examined as well. RESULTS: After 12 months, maximum WD increased by 26% in the telmisartan group (P < 0.001). However, in the placebo group it was comparable to baseline. FMD rose by 40% in the telmisartan group while it deteriorated in the placebo group (P < 0.001). IMT and ABI were comparable in both groups at baseline and did not change considerably after 12 months. In non-diabetic patients (72.2%), the ABI did not change in the placebo group, whereas it increased by 11% in the telmisartan group (P < 0.001). While the DRQL remained stable in the telmisartan group, placebo treatment was associated with a marked deterioration (P < 0.01). CONCLUSION: Telmisartan improves WD and endothelial function, the ABI in non-diabetic patients and it may prevent further loss of quality of life in patients with advanced PAD.

Glucose control with insulin results in reduction of NF-kappaB-binding activity in mononuclear blood cells of patients with recently manifested type 1 diabetes.

AIM: Chronic elevated blood glucose levels are associated with the formation of advanced glycation end products (AGEs). Hyperglycaemia and AGEs have been shown to induce activation of the redox-sensitive transcription factor nuclear factor-kappaB (NF-kappaB). To validate the hypothesis that the maintenance of normal glucose levels results in the reduction of NF-kappaB-binding activity in vivo, the redox-sensitive transcription factor NF-kappaB was used as marker of hyperglycaemia-induced mononuclear cell activation in patients who recently developed type 1 diabetes. METHODS: Twelve patients with recently manifested type 1 diabetes mellitus were examined in our study. After sampling blood for determination of baseline glucose values, the 12 patients were treated with insulin, and blood samples were taken 4 and 12 weeks later. Mononuclear cells were isolated and assayed in a tissue culture-independent electrophoretic mobility shift assay (EMSA)-based detection system for NF-kappaB-binding activity. Western blot analysis was used to determine nuclear and cytoplasmic localization of NF-kappaB-p65 and cytoplasmic content of inhibitor of kappa B-alpha (IkappaB-alpha). In addition, we determined the concentration of heme oxygenase-1 (HO-1) from cytoplasmic extract as a marker of oxidative stress. RESULTS: Normalization of blood glucose levels resulted in a highly significant reduction of NF-kappaB activation in EMSA. Before and after glucose normalization, there were no differences in binding by the members of the NF-kappaB family to the NF-kappaB consensus sequence oligonucleotide. Similar data were obtained by Western blot analysis showing NF-kappaB-p65 localization in the nucleus, while p65 levels increased in the cytoplasm. IkappaB-alpha increased in the cytoplasm after glucose normalization. HO-1 antigen consistently decreased, as expected from the decrease in NF-kappaB activation. CONCLUSION: Thus, we conclude that normalization of blood glucose levels results in the reduction of NF-kappaB activation and gene products controlled by this transcription factor.

Postprandial mononuclear NF-kappaB activation is independent of the AGE-content of a single meal.

OBJECTIVE: Dietary uptake of Advanced Glycation Endproducts (AGE) is supposed to potentially contribute to inflammatory reactions linked to vascular dysfunction and late diabetic complications. One mechanism by which dietary AGE might exert these effects is by activation of the proinflammatory transcription factor NF-kappa-B. The aim of this study was to analyze the postprandial effects of a casein meal with low or high AGE content on postprandial NF-kappaB activation in peripheral blood mononuclear cells (pBMC) of healthy volunteers. RESEARCH DESIGN AND METHODS: Casein was heated for 40 h at 50 degrees C in the presence of sorbitol or glucose, resulting in either minimal (Sorbitol [S]-casein) or large (glucose [G]-casein) amounts of AGE-modified casein. Nine healthy volunteers ate 250 g of both types of casein, whereas both meals were separated at least by 2 weeks. Plasma and pBMC were taken before and 2 h after each meal. Thereafter, the defined AGE carboxymethyllysine (CML) was determined by ELISA and Western blot. NF-kappaB activation in pBMC was assayed using Electrophoretic Mobility Shift Assays (EMSA) and Western blot analysis. RESULTS: S-casein contained only minor amounts of CML and no pentosidine, while G-casein contained large amounts of both. 2 h after ingestion, the S-casein or the G-casein-meal, both, resulted in a non-significant increase in plasma CML and in the intracellular CML-content of pBMC. This was paralleled by a highly significant increase in postprandial mononuclear NF-kappaB-binding activity. Remarkably, neither the extent of NF-kappaB induction (178% for S-casein, 188% for G-casein), nor composition of the NF-kappaB heterodimer (mainly consisting of NF-kappaB p50/p65) were significantly different after intake of S-casein or G-casein. Consistently, Western blots confirmed an increased NF-kappaBp65 nuclear translocation and a decrease of NF-kappaBp65 in the cytoplasm, while no difference in postprandial NF-kappaB nuclear translocation was observed following intake of S-casein or G-casein. CONCLUSION: Postprandial mononuclear NF-kappaB activation after a single meal is independent of the AGE-content of the ingested protein.

A 63bp deletion in the promoter of rage correlates with a decreased risk for nephropathy in patients with type 2 diabetes.

Several polymorphisms have been identified in the RAGE-promoter region that might modulate the outcome of disease. Here we analyse the association of a 63bp deletion (delta63) spanning from bp - 407 to bp - 345 with diabetic nephropathy. The deletion was determined using the polymerase chain reaction (PCR) in a cross-sectional study with 1087 patients with type 1 diabetes (n = 559) and type 2 diabetes (n = 528). 475 patients with osteoporosis served as disease independent control. The prevalence of the heterozygous genotype did not significantly differ between the three groups (type 1: 2.15 %, type 2: 2.27 %, controls: 1.47 %), indicating that heterozygous delta63 is not related to the manifestation of diabetes. Homozygous carriers were not identified in this study. The heterozygous delta63 genotype, was associated with a reduced prevalence of diabetic nephropathy in patients with type 2 diabetes (OR = 0.06; 95 % CI: [0.05, 0.07]), but not in patients with type 1 (OR = 1.49; 95 % CI: [1.14, 1.94]). We conclude, that patients with type 2 diabetes and the 63bp deletion in the promoter of RAGE seem to be protected from diabetic nephropathy. The observed difference between type 1 and type 2 diabetes might point to diverse pathomechanisms of nephropathy in both types of diabetes.

Glimepiride reduces mononuclear activation of the redox-sensitive transcription factor nuclear factor-kappa B.

AIMS: Glimepiride has the lowest ratio of insulin release to glucose decrease compared with other sulphonylureas. This prompted us to study in vitro and in vivo in a placebo-controlled study the effect of glimepiride on the redox-sensitive transcription factor nuclear factor-kappa B (NF-kappaB). METHODS: Fifteen patients with type 2 diabetes on glibenclamide with a stable HbA1c over the last 6 months were included. After sampling for determination of baseline values, 10 patients were changed to an equivalent dose of glimepiride, while the placebo group was maintained at glibenclamide plus placebo. The glimepiride dose in these patients was adjusted so that no change in glucose control occurred, allowing for direct comparison. The others were kept on glibenclamide and received additional placebo. After 4 weeks of glimepiride or glibenclamide plus placebo, a second blood sample was taken. Mononuclear cells were isolated and assayed in a tissue-culture-independent electrophoretic mobility shift assay (EMSA)-based detection system for NF-kappaB binding activity, and by Western Blot for nuclear localization of NF-kappaB-p65, the cytoplasmic content of IkappaBalpha and the NF-kappaB-controlled haemoxygenase-1. Glimepiride dose-dependent inhibition of carboxymethyllysin (CML) albumin or tumour necrosis factor alpha (TNFalpha)- and H2O2-induced activation of NF-kappaB binding were determined, using isolated peripheral blood mononuclear cells from healthy volunteers, and transcriptional activity of bovine aortic endothelial cells either left untreated or induced with CML albumin incubated with or without glimepiride. Furthermore, in-vitro studies were implemented to demonstrate radical quenching properties of glimepiride in the cell-free 2,2'-azo-bis(2-aminopropane)-dihydrochloride system. RESULTS: Baseline glucose and HbA1c remained stable in the patients switched from glibenclamide to a corresponding dose of glimepiride or kept on glibenclamide plus placebo. While in the group of patients only taking glibenclamide plus placebo the NF-kappaB binding activity did not change significantly (p = 0.58), the NF-kappaB binding activity in the group of patients taking glimepiride was reduced from 19.3 relative NF-kappaB-p65-equivalents to 15.5 relative NF-kappaB-p65-equivalents (p = 0.04). The nuclear translocation of NF-kappaB-p65 was reduced from 100% at baseline to 58% after 4 weeks (p = 0.04); the cytoplasmic localization of NF-kappaB-p65 increased from 100% to 129% (p = 0.03) and the cytoplasmic content of IkappaBalpha increased from 100% to 109% (p = 0.06). The redox-sensitive haemoxygenase-1 antigen was reduced from 100% to 82% (p = 0.04). To prove directly that glimepiride reduces NF-kappaB activation, we isolated peripheral blood mononuclear cells (PBMC) from healthy volunteers. In vitro, glimepiride reduced TNFalpha-(1 nmol/l) and CML albumin (800 nmol/l)-induced NF-kappaB activation dose dependently, being half maximal at 120 micromol/l. H2O2-mediated NF-kappaB activation was only partially reduced. In addition, glimepiride reduced NF-kappaB-dependent gene expression using a NF-kappaB-driven luciferase reporter system. Finally, a cell-free detection system showed that glimepiride has radical quenching properties. CONCLUSION: Glimepiride can affect the activation of the redox-sensitive transcription factor NF-kappaB in vitro and in vivo.

Erythropoietin-mediated decrease of the redox-sensitive transcription factor NF-kappaB is inversely correlated with the hemoglobin level.

The aim of this study was to determine the effect of rh-EPO on the redox-sensitive transcription factor (NF-kappaB) in vivo and in vitro. Ten patients (7 female, 3 male), mean age 69.2 +/- 11 years, with end-stage renal failure and anemia prior to initiation of regular hemodialysis were enrolled and divided into 2 groups (group A "good responder", 7 patients and group B "poor responder", 3 patients) in accordance to the response to rh-EPO therapy. Nuclear binding activity of NF-kappaB was determined in ex vivo isolated mononuclear cells before, 4 and 8 weeks after onset of regular hemodialysis and rh-EPO therapy by electrophoretic mobility shift assays (EMSA). In group A, a reduction of NF-KB binding activity from 100% to 56 +/- 6% was observed within the first four weeks of rh-EPO treatment, while mean hemoglobin rose from 8.2 +/- 0.4 g/dl to 11.1 +/- 0.2 g/dl. However, this effect was abrogated after another 4 weeks of treatment when NF-kappaB signal increased back to 85.2 +/- 10.6% despite consistent mean hemoglobin level of 11.3 +/- 0.4 g/dl. Group B demonstrated a slight increase of NF-kappaB signal from 100% to 129 +/- 18.5%, while mean hemoglobin only moderately rose from 7.6 +/- 0.3 g/dl to 8.3 +/- 0.1 g/dl within the first 4 weeks, and it further rose to 180 +/- 45% after 8 weeks of treatment, while mean hemoglobin (9.5 +/- 0.1 g/dl) remained low. The NF-kappaB binding activity differed significantly when comparing both groups (p = 0.007). Binding activity of Oct-1, serving as control, did not change notably in either group (p = 0.34). In vitro studies showed that rh-EPO did not directly affect NF-KB binding activity in THP-1 cells. However, coincubation of THP-1 cells with erythrocytes led to a reduction of NF-kappaB binding activity only in THP-1 cells with a hemoglobin level adjusted to 11 g/dl compared to 8 g/dl in the presence of rh-EPO. In vivo and in vitro data implicate a complex interaction between rh-EPO, stimulated RBC and the redox-sensitive transcription factor NF-kappaB in mononuclear cells.

Diabetes-associated sustained activation of the transcription factor nuclear factor-kappaB.

Activation of the transcription factor nuclear factor-kappaB (NF-kappaB) has been suggested to participate in chronic disorders, such as diabetes and its complications. In contrast to the short and transient activation of NF-kappaB in vitro, we observed a long-lasting sustained activation of NF-kappaB in the absence of decreased IkappaBalpha in mononuclear cells from patients with type 1 diabetes. This was associated with increased transcription of NF-kappaBp65. A comparable increase in NF-kappaBp65 antigen and mRNA was also observed in vascular endothelial cells of diabetic rats. As a mechanism, we propose that binding of ligands such as advanced glycosylation end products (AGEs), members of the S100 family, or amyloid-beta peptide (Abeta) to the transmembrane receptor for AGE (RAGE) results in protein synthesis-dependent sustained activation of NF-kappaB both in vitro and in vivo. Infusion of AGE-albumin into mice bearing a beta-globin reporter transgene under control of NF-kappaB also resulted in prolonged expression of the reporter transgene. In vitro studies showed that RAGE-expressing cells induced sustained translocation of NF-kappaB (p50/p65) from the cytoplasm into the nucleus for >1 week. Sustained NF-kappaB activation by ligands of RAGE was mediated by initial degradation of IkappaB proteins followed by new synthesis of NF-kappaBp65 mRNA and protein in the presence of newly synthesized IkappaBalpha and IkappaBbeta. These data demonstrate that ligands of RAGE can induce sustained activation of NF-kappaB as a result of increased levels of de novo synthesized NF-kappaBp65 overriding endogenous negative feedback mechanisms and thus might contribute to the persistent NF-kappaB activation observed in hyperglycemia and possibly other chronic diseases.

Tissue factor--a receptor involved in the control of cellular properties, including angiogenesis.

Tissue factor (TF), the major initiator of blood coagulation, serves as a regulator of angiogenesis, tumor growth and metastasis. In several models, TF expression mediates upregulation of the proangiogenic vasular endothelial growth factor (VEGF) that can directly act on endothelial cells to promote vessel formation. This occurs through ligand binding, activation of signaling cascades, signal transduction and alteration of growth factor expression and is mediated by both, coagulation-dependent and -independent pathways. Depending on the cell type and the biological settings, TF seems to affect cellular properties through (i) factor VIIa (FVIIa)-dependent proteolysis of factor Xa (FXa) and thrombin and subsequent activation of proteinase activated receptor (PAR) -1 and PAR-2, (ii) through direct FVIIa signaling and mitogen activated protein (MAP) kinase activation, that is conferred by a not yet identified receptor, (iii) through interaction of FVII(a) proteolytic activity and signaling of the cytoplasmic domain and (iv) through cytoplasmic signaling independent of ligand binding. The role of phosphorylation of the cytoplasmic domain and the pathways controlling phosphorylation of TF remain poorly understood.

Regulation of monocyte procoagulant activity in acute myocardial infarction: role of tissue factor and tissue factor pathway inhibitor-1.

In acute myocardial infarction (AMI), monocyte procoagulant activity is increased and may contribute to the risk for recurrence and other thrombotic events. This study sought to investigate the role tissue factor (TF) and tissue factor pathway inhibitor-1 (TFPI-1) in the regulation of monocyte procoagulant activity in AMI. Serial venous blood samples were obtained from 40 patients with AMI undergoing revascularization by stent placement. Twenty patients with elective stenting for stable angina served as control subjects. TF proteolytic activity was measured with spectrozyme factor Xa (FXa), TF and TFPI-1 surface expression on monocytes by flow cytometry, RNA expression in whole blood by reverse transcription-polymerase chain reaction, and concentrations of plasma prothrombin fragments F(1 + 2) by immunoassay. Forty-eight hours after AMI, an increase was found in TF RNA, followed by an increase in TF surface expression by 24% +/- 4% and in plasma concentration of F(1 + 2) by 103% +/- 17% (P <.05). These changes could not be attributed to the intervention because they did not occur in the control group. TFPI-1 RNA and binding to the monocyte surface remained unchanged. FXa generation by monocytes of patients with AMI increased 53.6% +/- 9% in the presence of polyclonal antibodies to TFPI-1, indicating that cell-associated TFPI-1 inhibits monocyte TF activity. The increased monocyte procoagulant activity in AMI was caused by an up-regulation of TF that was partially inhibited by surface-bound TFPI-1. Anticoagulant therapy by direct inhibition of TF activity may, thus, be particularly effective in AMI. (Blood. 2001;97:3721-3726)

Endothelial dysfunction in diabetes mellitus.

Diabetes mellitus and impaired glucose tolerance are linked to increased cardiovascular morbidity and mortality. Vascular disease is directly associated with plasma glucose levels, and reduction of these levels forestalls to a certain extent the vascular complications of diabetes, such as myocardial infarction, nephropathies, and retinopathies. In addition to hyperglycemia, there are other risk factors that play a prominent role, such as hypertension, hyperlipidemia, and genetic factors. Endothelial dysfunction is one of the major factors in the development of cardiovascular disease. The vascular endothelium regulates the blood flow by tightly controlling the coagulation system, cell-cell interaction, and vascular tone. These functions are disturbed in diabetic patients. In diabetics, endothelin-1 levels are increased, leading to vasoconstriction. Endothelin levels are directly related to plasma glucose levels. In addition, the endothelial cell-NO axis is disturbed. NO release and function are impaired. This seems to be dependent upon hyperglycemia and genetic factors. Impaired NO function also results in vasoconstriction. Furthermore, enhanced vascular permeability is seen in diabetics. This appears to be related to impaired endothelial cell relaxation and reactive oxygen species as well as advanced glycosylated end products (AGEs). The complex changes seen in diabetes and even prediabetes are therefore related to numerous derailments related to endothelial dysfunction, and no single therapeutic approach is likely to solve the problem of vascular complications.