The BCR/ABL1 inhibitor Nilotinib is increasingly used to treat patients with chronic myeloid leukemia (CML). Although otherwise well-tolerated, Nilotinib has been associated with the occurrence of ...progressive arterial occlusive disease (AOD). Our objective was to determine the exact frequency of AOD and examine in vitro and in vivo effects of Nilotinib and Imatinib on endothelial cells to explain AOD-development. In contrast to Imatinib, Nilotinib was found to upregulate pro-atherogenic adhesion-proteins (ICAM-1, E-selectin, VCAM-1) on human endothelial cells. Nilotinib also suppressed endothelial cell proliferation, migration and tube-formation and bound to a distinct set of target-kinases, relevant to angiogenesis and atherosclerosis, including angiopoietin receptor-1 TEK, ABL-2, JAK1 and MAP-kinases. Nilotinib and siRNA against ABL-2 also suppressed KDR expression. In addition, Nilotinib augmented atherosclerosis in ApoE-/- mice and blocked reperfusion and angiogenesis in a hindlimb-ischemia model of arterial occlusion, whereas Imatinib showed no comparable effects. Clinically overt AOD-events were found to accumulate over time in Nilotinib-treated patients. After a median observation-time of 2.0 years, the AOD-frequency was higher in these patients (29.4%) compared to risk factor- and age-matched controls (<5%). Together, Nilotinib exerts direct pro-atherogenic and anti-angiogenic effects on vascular endothelial cells, which may contribute to development of AOD in patients with CML.
Background: Patients with morbid obesity (MO; body mass index > 40 kg m−2) suffer from an increased risk of cardiovascular disease, stroke, venous thromboembolism and all‐cause mortality. Objectives: ...Because weight loss by bariatric surgery reduces cardiovascular and all‐cause mortality, we hypothesized that the plasmatic clotting system might be involved in cardiovascular risk. Patients/Methods: Thirty‐six MO patients mean age 42 (±13) years; 29 female) were investigated before and 2 years after bariatric surgery. Thrombin generation was measured with a commercially available assay (Technothrombin‐TGA,Technoclone). Metabolic parameters and parameters of the hemostatic system, such as tissue factor (TF), TF pathway inhibitor (TFPI), plasminogen activator inhibitor‐1 (PAI‐1) and prothrombinfragment 1.2 (F1.2), were determined. To investigate associations of changing parameters, deltas were calculated. Results: Metabolic parameters improved with a mean weight loss of 41 (±19) kg. Postoperatively, the lag phase was significantly extended compared with preoperative values median (25th–75th percentile), 7 (4–12) vs. 12 (7–19) min, P = 0.005. Peak thrombin decreased after weight loss from 345 (232–455) to 282 (111–388) nm (P = 0.015) and the area under the curve from 3962 (3432–5023) to 3227 (2202–4030) nm thrombin (P < 0.001). TF, PAI‐1 and F1.2 significantly decreased after weight loss. Analyses of the deltas showed a significant correlation between peak thrombin and total cholesterol (r = 0.50), triglycerides (r = 0.46) and HbA1c (r = 0.55). Moreover, an inverse correlation was found between insulin resistance and the lag phase (r = −0.46). Conclusion: Thrombin generation, a marker of the overall coagulation potential, decreased significantly with weight reduction. This might, at least in part, explain the decreased risk of cardiovascular disease after bariatric surgery.
Background CD33 (Siglec‐3) is becoming increasingly important as a target of antibody‐mediated therapy in acute myeloid leukaemia (AML). In normal myelopoiesis, expression of CD33 is restricted to ...advanced stages of differentiation, whereas primitive stem cells do not express CD33. In the present study, we asked whether leukaemic stem cells in patients with AML express CD33.
Materials and methods A multicolour‐staining technique was applied in 11 patients with AML, and leukaemic progenitors defined as CD34+/CD38−/CD123+ cells. AML stem cells were purified by cell sorting and were examined for expression of CD33 mRNA by reverse transcriptase–polymerase chain reaction (RT–PCR).
Results In all patients in whom the majority of myeloblasts expressed CD33 (n = 8), AML progenitors reacted with the CD33 antibody P67·6. Repopulation experiments utilizing irradiated NOD/SCID mice confirmed that AML stem cells in these patients reside within the CD33+ subpopulation of the leukaemic clone. Moreover, highly purified AML stem cells (> 98% purity) from patients with CD33+ AML were found to express CD33 mRNA in RT–PCR analyses. CD33 was neither detectable on CD34+/CD38− cells in normal bone marrow nor on leukaemic stem cells in patients with CD33‐negative AML.
Conclusions Leukaemic stem cells in patients with CD33+ AML express CD33. This observation is in favour of novel treatment concepts employing CD33‐targeting antibodies in AML.
The increased cardiovascular (CV) disease risk in patients with morbid obesity (MO) cannot be fully explained by traditional CV risk factors. Activation of the receptor of Advanced Glycation ...Endproducts (RAGE) leads to inflammation via the NF κβ (nuclear factor κβ) pathway. The soluble form of RAGE (sRAGE), which is present in plasma, can bind to ligands of RAGE and avoids interaction of RAGE with proinflammatory ligands. We investigated sRAGE levels in patients with MO and compared them with healthy lean controls (CO), before and after bariatric surgery.
We conducted a cross-sectional study and a 24-month longitudinal study.
We included 85 patients (mean age: 41 ± 12 years; mean body mass index (BMI): 45.4 ± 7.9 kg m(-2)) with MO in comparison with 40 CO (mean age: 42 ± 13 years; mean BMI: 26.0 ± 5.5 kg m(-2)). All patients were investigated before and 2 years after bariatric surgery. Apart from weight and CV risk markers (blood pressure, lipids), a glucose tolerance test (75 g), renal and inflammation parameters were assessed. sRAGE levels were assessed by a commercial ELISA. To investigate the associations of the observed reductions of values, delta (Δ) of parameters were calculated.
Patients with MO had significant lower sRAGE levels than CO: 1010 ± 514 vs 1501 ± 674 pg ml(-1); P<0.001. In the longitudinal study, sRAGE levels increased significantly after bariatric surgery from 1010 ± 514 to 1261 ± 710 pg ml(-1); P=0.008. In the correlation analysis, ΔsRAGE levels were associated with Δ1-h and Δ2-h postprandial glucose, Δfasting insulin, Δ2-h postprandial insulin, ΔHOMA (homeostatic model assessment)-insulin resistance (ΔHOMA-IR), Δγ-glutamyl transferase and Δtriglycerides. In a multivariate model, Δ1-h and Δ2-h postprandial glucose, Δ2-h postprandial insulin and ΔHOMA-IR predicted ΔsRAGE.
Patients with MO have significantly lower sRAGE levels compared with non-obese CO, but sRAGE levels increase significantly after weight loss induced by bariatric surgery. As high sRAGE levels inhibit the activation of inflammatory pathways, our results might help understand the beneficial effects of bariatric surgery regarding CV morbidity and mortality.
Prevention of cardiovascular morbidity and mortality remains the key factor in the treatment of type 2 diabetes (T2DM). In the early phase of T2DM, multifactorial intervention is mandatory and ...glucose levels should be near normal, in particular in younger patients presenting with the highest cardiovascular risk. Anti-diabetic drugs without any risk for hypoglycaemia should be preferred in order to reduce clinical inertia and increase the long-term adherence to the treatment. In patients already presenting with cardiovascular disease, the best outcome may be expected with the triple oral therapy of metformin, pioglitazone, and empagliflozin, although a controlled prospective study versus insulin therapy is needed to confirm the expectation.
Tissue factor (TF) is the main in vivo initiator of the blood coagulation cascade. Active circulating TF was detected on small, negatively charged membrane vesicles, the so-called microvesicles ...(MVs), which are released upon cell activation and apoptosis from a variety of cells. Increased coagulation activation was found in morbidly obese patients, and elevated levels of TF-bearing MVs may contribute to the prothrombotic state in these patients.
To determine MV-associated TF activity levels in morbidly obese patients before and after weight loss due to bariatric surgery.
MV-TF activity was measured with a factor Xa generation assay in morbidly obese patients before and 2 years after bariatric surgery. In addition, clinical parameters were determined.
Seventy-four morbidly obese patients (mean age: 42 (±11) years; 61 females) were included in this study. After bariatric surgery, the body mass index decreased from (median, 25-75th percentile) 45.5 (42.3-50.2) to 30.5 (28.0-34.4 kg m(-2); P<0.001), and a significant improvement in metabolic parameters was observed. Preoperative MV-TF activity correlated with C-reactive protein levels (r=0.3; P=0.02). Postoperatively, the mean MV-TF activity decreased significantly from 0.20 pg ml(-1) (0.18-0.47) to 0.02 (0.00-0.28; P<0.01).
We could demonstrate a significant decrease in MV-TF activity after weight loss in morbidly obese patients. Decreased MV-TF activity might contribute to an improved coagulation profile in these patients after weight loss.
Aims/hypothesis Pregnancy is characterised by temporarily increased insulin resistance. Gestational diabetes occurs when pancreatic beta cell function is unable to compensate for this insulin ...resistance. Retinol-binding protein 4 (RBP4) could be related to insulin resistance. We hypothesised that RBP4 is elevated in gestational diabetes. Methods Serum RBP4, transthyretin and retinol were cross-sectionally measured in 42 women with gestational diabetes and 45 pregnant controls. Of these, 20 women with and 22 without gestational diabetes were included in an additional longitudinal study. RBP4 was determined by enzyme immunometric assay (EIA) and western blot. Results Women with gestational diabetes had lower RBP4 EIA and western blot levels than controls (median 6.8 interquartile range, 3.9-14.3 vs 11.3 7.8-19.9 μg/ml, p < 0.001 and 25.1 21.7-29.6 vs 26.6 23.5-32.2 μg/ml, p = 0.026). Transthyretin and the RBP4:transthyretin molar ratio were comparable between the groups. Serum retinol was lower (p < 0.001) and the RBP4 Western blot level: retinol molar ratio was higher in women with gestational diabetes (p = 0.044). RBP4 was not associated with the glucose or homeostasis model assessment of insulin resistance (HOMA-IR), but in gestational diabetes the RBP4:retinol molar ratio correlated with blood glucose and negatively with 2 h post-load insulin. The RBP4:transthyretin ratio correlated with HOMA-IR and fasting insulin in controls. In women with gestational diabetes RBP4 EIA and western blot levels increased after delivery. Retinol increased in both groups, while transthyretin and the RBP4:transthyretin ratio were not altered after parturition. Conclusions/interpretation RBP4 measured by two different techniques is not elevated, but the RBP4:retinol molar ratio is higher and correlates with fasting blood glucose in women with gestational diabetes. Thus, the RBP4:retinol ratio and the RBP4:transthyretin ratio are more informative than RBP4 levels alone when assessing insulin-glucose homeostasis during pregnancy.
Mast cells (MC) are multipotent effector cells of the immune system. They contain an array of biologically active mediator substances in their granules. MC also express a number of functionally ...important cell surface antigens, including stem cell factor receptor (SCFR=kit=CD117), high affinity IgER (FcεRI), or C5aR (CD88). Respective ligands can induce or promote degranulation, migration, or cytokine production. Other integral surface molecules can mediate adhesion or cell aggregation. Recent data suggest that a number of critical molecules are variably expressed on the surface of human MC. In fact, depending on the environment (organ), stage of cell maturation, type of disease, and other factors, MC express variable amounts of activation‐linked antigens (CD25, CD63, CD69, CD88), cell recognition molecules (CD2, CD11, CD18, CD50, CD54), or cytokine receptors. At present, however, little is known about the mechanisms and regulation of expression of such antigens. The present article gives an overview of MC phenotypes in health and disease, and attempts to provide explanations for the phenotypic variability of MC.
This study was supported by Fonds zur Förderung der Wissenschaftlichen Forschung in Österreich – FWF grants # P12517 and # P14031, Fondo de Investigaciones Sanitarias de la Seguridad Social (FIS 98/1345), and Fundación Oftalmológica J. Cortés.
Background Morbid obesity is associated with increased cardiovascular morbidity and mortality. Recent studies suggest that soluble CD40 Ligand (sCD40L) may play a pathogenetic role in ...atherothrombotic complications in cardiovascular disease as well as in inflammation and thrombosis. As morbid obesity is closely associated with chronic inflammation and insulin resistance (IR), it was of interest to study sCD40L in patients with morbid obesity before and after massive weight loss induced by bariatric surgery.
Patients and methods A total of 34 patients (mean age 40 ± 12 years) with morbid obesity were studied before and 27·2 months after bariatric surgery. High sensitivity assays were used to measure concentrations of fasting sCD40L, monocyte‐chemoattractant‐protein‐1 (MCP‐1) and high‐sensitive C‐reactive protein (hsCRP). To investigate the associations of concentration changes of the parameters studied, differences between pre‐ and post‐operative data were assessed and tested by univariate and multivariate linear regression analysis.
Results After a mean weight loss of 33·1 ± 18·4 kg, circulating sCD40L decreased significantly from (3·7 ± 1·5) ng mL−1 to (2·2 ± 0·7) ng mL−1, (P < 0·001). The decline in sCD40L after weight loss correlated significantly with the decrease in fasting insulin, 2‐h insulin, HOMA insulin resistance (HOMA‐IR), triglycerides, and the inflammatory biomarkers MCP‐1 and hsCRP.
Conclusions We have shown a marked decrease in circulating sCD40L in association with an improvement of both insulin resistance and chronic inflammation in morbidly obese patients after bariatric surgery. As high sCD40L was shown to predict cardiovascular death and myocardial infarction in several prospective studies, the observed marked lowering of sCD40L might be of clinical relevance in morbidly obese patients.
Growth hormone (GH) and insulin-like growth factor 1 (IGF-1) are increasingly recognised for their role in cardiovascular (CV) physiology. The GH-IGF-1 axis plays an essential role in the development ...of the CV system as well as in the complex molecular network that regulates cardiac and endothelial structure and function. A considerable correlation between GH levels and CV mortality exists even among individuals in the general population without a notable deviation in the GHIGF- 1 axis functioning. In addition, over the last decades, evidence has demonstrated that pathologic conditions involving the GH-IGF-1 axis, as seen in GH excess to GH deficiency, are associated with an increased risk for CV morbidity and mortality. A significant part of that risk can be attributed to several accompanying comorbidities. In both conditions, disease control is associated with a consistent improvement of CV risk factors, reduction of CV mortality, and achievement of standardised mortality ratio similar to that of the general population. Data on the prevalence of peripheral arterial disease in patients with acromegaly or growth hormone deficiency and the effects of GH and IGF-1 levels on the disease progression is limited. In this review, we will consider the pivotal role of the GH-IGF-1 axis on CV system function, as well as the far-reaching consequences that arise when disorders within this axis occur, particularly in relation to the atherosclerosis process.
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