BACKGROUND: Vascular endothelial growth factor (VEGF) inhibition is known to decrease capillary density. Decreased capillary density may be the basis for VEGF inhibitor-related side-effects. We... Show moreBACKGROUND: Vascular endothelial growth factor (VEGF) inhibition is known to decrease capillary density. Decreased capillary density may be the basis for VEGF inhibitor-related side-effects. We investigated whether the effects of bevacizumab on capillary density are reversible. PATIENTS AND METHODS: Capillary density, assessed by sidestream dark field imaging of the mucosal surface of the lip, was measured at baseline, after 6 weeks of bevacizumab treatment and >3 months after discontinuation. Additional measurements included blood pressure (BP) measurements, flow-mediated dilation (FMD), nitroglycerin-mediated dilation (NMD) and aortic pulse wave velocity (PWV). RESULTS: Fourteen patients were included. Seven patients completed measurements at all three predefined time points. Capillary density significantly decreased after 6 weeks of bevacizumab treatment and was reversible after discontinuation of bevacizumab (P = 0.00001 using a general linear model repeated measures test). BP, FMD and NMD remained unchanged. Mean PWV increased after 6 weeks of treatment (P = 0.027) and decreased after bevacizumab discontinuation. Among the six patients with the best response were the three patients showing the clearest decrease in capillary density after 6 weeks of bevacizumab treatment. CONCLUSIONS: Bevacizumab-induced decrease in capillary density is reversible. Noninvasive assessment of capillary density during treatment with antiangiogenic drugs may be useful as a marker of treatment efficacy. Show less
Patients and methods: Capillary density, assessed by sidestream dark field imaging of the mucosal surface of the lip, was measured at baseline, after 6 weeks of bevacizumab treatment and > 3... Show morePatients and methods: Capillary density, assessed by sidestream dark field imaging of the mucosal surface of the lip, was measured at baseline, after 6 weeks of bevacizumab treatment and > 3 months after discontinuation. Additional measurements included blood pressure (BP) measurements, flow-mediated dilation (FMD), nitroglycerin-mediated dilation (NMD) and aortic pulse wave velocity (PWV). Results: Fourteen patients were included. Seven patients completed measurements at all three predefined time points. Capillary density significantly decreased after 6 weeks of bevacizumab treatment and was reversible after discontinuation of bevacizumab (P = 0.00001 using a general linear model repeated measures test). BP, FMD and NMD remained unchanged. Mean PWV increased after 6 weeks of treatment (P = 0.027) and decreased after bevacizumab discontinuation. Among the six patients with the best response were the three patients showing the clearest decrease in capillary density after 6 weeks of bevacizumab treatment. Conclusions: Bevacizumab-induced decrease in capillary density is reversible. Noninvasive assessment of capillary density during treatment with antiangiogenic drugs may be useful as a marker of treatment efficacy. Show less
Background. Proteinuria predicts progressive renal failure. Next to being a progression marker, non-selective proteinuria itself is thought to be toxic to the tubulointerstitium. In proteinuric... Show moreBackground. Proteinuria predicts progressive renal failure. Next to being a progression marker, non-selective proteinuria itself is thought to be toxic to the tubulointerstitium. In proteinuric states, activation of filtered or locally produced complement is toxic for renal tubular cells and likely contributes to the progression of renal failure. Recent experimental evidence suggests an important role for properdin in promoting intrarenal complement activation. We measured properdin in proteinuric urine and assessed its relation with urinary SC5b-9 levels, the soluble form of the effector phase of complement activation. Methods. Seventy patients with renal disease of different origin but all with a protein excretion of at least 1 g/day were studied. Urinary properdin and SC5b-9 levels were measured using an ELISA technique. Results. Properdin was detectable in the urine of 37 patients (53%). These subjects had higher urinary SC5b-9 levels {median 0.50 U/ml [interquartile range (IQR) 0.13-1.81] versus 0.049 U/ml (IQR 0.024-0.089), P < 0.001}. When adjusted for proteinuria and renal function, properdin excretion was strongly associated with increased urinary SC5b-9 levels (odds ratio 16.2, 95% confidence interval 3.6-74.4). Properdin excretion was associated with worse renal function. Conclusion. Our results suggest that urinary properdin excretion enhances intrarenal complement activation and thus may contribute to the progression of renal damage in proteinuric states. Show less
OBJECTIVE - identification of asymptomatic patients with type 2 diabetes at increased risk for coronary artery disease (CAD) remains a challenge. We evaluated the Potential of carotid intima-media... Show moreOBJECTIVE - identification of asymptomatic patients with type 2 diabetes at increased risk for coronary artery disease (CAD) remains a challenge. We evaluated the Potential of carotid intima-media thickness (CIMT) for prediction of abnormal myocardial perfusion in this population. RESEARCH DESIGN AND METHODS- CIMT and SPECT myocardial perfusion imaging were assessed in 98 asymptomatic patients with type 2 diabetes. An increased CIMT was defined as >= 75th percentile of reference values. RESULTS - increased CIMT was an independent predictor of the extent of abnormal perfusion (P < 0.001). In patients with increased CIMT as compared with patients with normal CIMT, abnormal perfusion (75 vs. 9%) and severely abnormal perfusion (28 vs. 3%) were observed more frequently. CONCLUSIONS - increased CIMT was significantly related to the presence and extent of abnormal myocardial perfusion. Assessment of CIMT may be useful to identify asymptomatic patients with type 2 diabetes at higher risk for CAD. Show less
Zonneveld, A.J. van; Boer, H.C. de; Veer, E.P. van der; Rabelink, T.J. 2010
The systemic pro-inflammatory state present in patients with rheumatoid arthritis (RA) accelerates the progression of atherosclerosis through chronic endothelial activation. Uncoupling of... Show moreThe systemic pro-inflammatory state present in patients with rheumatoid arthritis (RA) accelerates the progression of atherosclerosis through chronic endothelial activation. Uncoupling of endothelial nitric oxide synthase plays a central role in the amplification of oxidative signalling pathways that chronically activate and, ultimately, injure the endothelium. Recent studies indicate that the resultant loss of endothelial integrity in patients with RA may also involve defects in the vascular regenerative potential provided by circulating endothelial progenitor cells (EPC). This is most likely the consequence of endothelial cell dysfunction in the bone marrow stroma, which hampers the mobilisation of these EPC to the circulation. In addition, mediators of systemic inflammation in RA can affect a second pathway of vascular regeneration. Under normal circumstances, myeloid CD14+ cells can adopt a pro-angiogenic phenotype that plays a key role in vascular remodelling and collateral formation. However, the chronic systemic inflammation observed in patients with RA may skew the differentiation of bone marrow and circulating CD14+ cells in such a way that these cells lose their capacity to support collateral formation, increasing the risk of cardiovascular disease. Taken together, in patients with RA, the impaired capacity of circulating cells to support vascular regeneration may comprise a novel pathway in the development of premature atherosclerosis. Show less
Zonneveld, A.J. van; Boer, H.C. de; Veer, E.P. van der; Rabelink, T.J. 2010
The systemic pro-inflammatory state present in patients with rheumatoid arthritis (RA) accelerates the progression of atherosclerosis through chronic endothelial activation. Uncoupling of... Show moreThe systemic pro-inflammatory state present in patients with rheumatoid arthritis (RA) accelerates the progression of atherosclerosis through chronic endothelial activation. Uncoupling of endothelial nitric oxide synthase plays a central role in the amplification of oxidative signalling pathways that chronically activate and, ultimately, injure the endothelium. Recent studies indicate that the resultant loss of endothelial integrity in patients with RA may also involve defects in the vascular regenerative potential provided by circulating endothelial progenitor cells (EPC). This is most likely the consequence of endothelial cell dysfunction in the bone marrow stroma, which hampers the mobilisation of these EPC to the circulation. In addition, mediators of systemic inflammation in RA can affect a second pathway of vascular regeneration. Under normal circumstances, myeloid CD14+ cells can adopt a pro-angiogenic phenotype that plays a key role in vascular remodelling and collateral formation. However, the chronic systemic inflammation observed in patients with RA may skew the differentiation of bone marrow and circulating CD14+ cells in such a way that these cells lose their capacity to support collateral formation, increasing the risk of cardiovascular disease. Taken together, in patients with RA, the impaired capacity of circulating cells to support vascular regeneration may comprise a novel pathway in the development of premature atherosclerosis. Show less
Reinders, M.E.J.; Fibbe, W.E.; Rabelink, T.J. 2010
Cell therapies aim at differentiation of stem cells into the specific cell type required to repair damaged or destroyed cells or tissues. Over recent years, cell therapy has been introduced in a... Show moreCell therapies aim at differentiation of stem cells into the specific cell type required to repair damaged or destroyed cells or tissues. Over recent years, cell therapy has been introduced in a variety of application areas, including cardiovascular repair, diabetes, musculoskeletal disorders and renal repair. Multipotent mesenchymal stromal cells (MSCs), often referred to as mesenchymal stem cells, are of particular interest as a cell therapy model, as this is one of the few cell types that are on the brink of entering the clinical arena in different areas of application. MSCs can be differentiated in vitro and in vivo into various cell types of mesenchymal origin such as bone, fat and cartilage. They have important effects on the innate and adaptive immune system and possess striking anti-inflammatory properties that make them attractive for potential use in diseases characterized by autoimmunity and inflammation. In addition, MSCs have been shown to migrate to sites of tissue injury and to enhance repair by secreting anti-fibrotic and pro-angiogenic factors. In this review, evidence for the renoprotective mechanisms of MSCs as well as their therapeutic possibilities and potential hazards in acute and chronic renal disease and allograft rejection is summarized. Show less
