http://repub.eur.nl/res/aut/12399/ List of Publications en http://repub.eur.nl/static-eur/img/logo.png http://repub.eur.nl http://repub.eur.nl/res/pub/33656/ 2011-07-01T00:00:00Z Aims There is an increasing need for translational studies identifying molecular targets contributing to atherosclerotic plaque destabilization. Local molecular plaque markers that are related to plaque vulnerability may hold predictive value to identify patients who are at increased risk to suffer from cardiovascular events. Animal studies revealed that adipocyte fatty acid binding protein (FABP4) is associated with the progression of atherosclerosis; however, FABP4 expression studies in human atherosclerotic plaques are lacking. We investigated FABP4 expression in carotid atherosclerotic lesions in relation to plaque composition and future cardiovascular events. Methods and results therosclerotic plaques were obtained from 561 patients undergoing carotid endarterectomy (CEA). Plaques were analysed for the presence of macrophages, lipid core, smooth-muscle cells, collagen, calcification, and intraplaque haemorrhage. Patients were followed for 3 years after CEA. The primary outcome was defined as the composite of vascular death, vascular event, and surgical or percutaneous vascular intervention. Fatty acid binding protein levels correlated with unstable plaque characteristics and symptomatic lesions. Patients with increased FABP4 plaque levels showed a two-fold increased risk [HR 1.99, 95 confidence interval (95% CI) (1.30-3.04)] (P=0.005) to reach the primary outcome during follow-up. Increased FABP4 levels related to primary outcome, independent from general cardiovascular risk factors [HR 1.33, 95 CI (1.081.65)] (P = 0.008). Conclusion FABP4 levels in atherosclerotic lesions are associated with an unstable plaque phenotype and an increased risk for cardiovascular events during follow-up. Besides risk stratification for adverse future cardiovascular events, the outcome of the present study supports the relevance of exploring FABP4 antagonists as a potential pharmaceutical intervention to treat atherosclerotic disease progression. Published on behalf of the European Society of Cardiology. http://repub.eur.nl/res/pub/19914/ 2010-03-01T00:00:00Z Objective-Atherosclerotic cardiovascular disease is a major burden to health care. Because atherosclerosis is considered a systemic disease, we hypothesized that one single atherosclerotic plaque contains ample molecular information that predicts future cardiovascular events in all vascular territories. Methods and Results-AtheroExpress is a biobank collecting atherosclerotic lesions during surgery, with a 3-year follow-up. The composite primary outcome encompasses all cardiovascular events and interventions, eg, cardiovascular death, myocardial infarction, stroke, and endovascular interventions. A proteomics search identified osteopontin as a potential plaque biomarker. Patients undergoing carotid surgery (n=574) served as the cohort in which plaque osteopontin levels were examined in relation to their outcome during follow-up and was validated in a cohort of patients undergoing femoral endarterectomy (n=151). Comparing the highest quartile of carotid plaque osteopontin levels with quartile 1 showed a hazard ratio for the primary outcome of 3.8 (95% confidence interval, 2.6-5.9). The outcome did not change after adjustment for plaque characteristics and traditional risk factors (hazard ratio, 3.5; 95% confidence interval, 2.0-5.9). The femoral validation cohort showed a hazard ratio of 3.8 (95% confidence interval 2.0 to 7.4) comparing osteopontin levels in quartile 4 with quartile 1. Conclusion-Plaque osteopontin levels in single lesions are predictive for cardiovascular events in other vascular territories. Local atherosclerotic plaques are a source of prognostic biomarkers with a high predictive value for secondary manifestations of atherosclerotic disease. http://repub.eur.nl/res/pub/28924/ 2008-03-01T00:00:00Z Background: Toll like receptors (TLR) have been recognized for their role in atherosclerotic lesion development and progression. Endogenous TLR ligands that are also expressed in atherosclerotic tissues have been shown to promote atherosclerosis in mice. Since repetitive stimulation of TLR induces an attenuated inflammatory response, we hypothesized that the TLR response is altered during atherosclerosis development, due to chronic exposure to endogenous ligands. Methods and Results: We examined five groups of both ApoE-/- and C57Bl/6 mice aged 5, 10, 15, 25 and 40 weeks. In ApoE-/- mice with advanced stages of atherosclerosis, levels of mRNA encoding TLR2 and TLR4, the endogenous TLR ligands EDA and hsp60 as well as intracellular TLR-regulating mediators, like IRAK-M, were increased. Systemic TLR cell surface expression on circulating monocytes and EDA plasma levels were significantly increased in ApoE-/- mice with advanced atherosclerosis. We also observed that the endogenous TLR ligand EDA was capable of activating the TLR-signaling pathway in white blood cells. During the plaque progression stage however, stimulation of TLR2 and TLR4 in blood samples attenuated MIP-1α and RANTES release in atherosclerotic mice. Conclusion: During atherosclerotic lesion development, TLR2 and TLR4 expression increases in atherosclerotic plaques and on circulating blood cells. However, with advanced stages of atherosclerotic disease, circulating blood cells become less responsive to TLR ligation, which may be due to chronic TLR engagement by endogenous EDA.