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Background Elevated serum levels of growth differentiation factor-15 (GDF-15), is an established risk factor for a range of cardiovascular diseases. We aimed to evaluate the predictive value of plasma GDF-15 as a biomarker for secondary cardiovascular events (CVE) in patients with atherosclerosis undergoing carotid endarterectomy (CEA). Secondly, we determined whether plasma GDF-15 was associated with carotid plaque characteristics. Methods Circulating GDF-15 levels were determined by Luminex assay in a cohort of 1056 patients from the Athero-Express biobank. Composite endpoint was defined as major CVE, death and peripheral vascular interventions. Findings were validated in 473 patients from the independent Carotid Plaque Imaging Project biobank. Results GDF-15 levels did not associate with secondary CVE in the total cohort. However, following a significant interaction with sex, it was found to be strongly, independently predictive of secondary CVE in women but not men (quartile 4 vs. quartile 1: HR 3.04 [95% CI 1.35–6.86], p =0.007 in women vs. HR 0.96 [95% CI 0.66–1.40], p =0.845 in men). This was also observed in the validation cohort (women: HR 2.28 [95% CI 1.04–5.05], p =0.041), albeit dependent upon renal function. In addition, GDF-15 was associated with the presence of plaque smooth muscle cells and calcification. Conclusion High circulating GDF-15 levels are predictive of secondary CVE in women but not in men with carotid atherosclerotic disease undergoing CEA, suggesting a potential use for GDF-15 as a biomarker for secondary prevention in women. Sex differences in the role of GDF-15 in atherosclerotic disease deserve further interest.

Objectives . Recurrent stenosis is a drawback of carotid endarterectomy (CEA), and may lead to recurrent symptoms and reintervention. Restenosis can be detected by duplex ultrasound scanning (DUS) with cutoff values based on peak systolic velocity (PSV), which vary among vascular laboratories. On short term, histological carotid plaque characteristics have shown to predict DUS-based restenosis rates. Therefore, we aimed to analyze the association of both plaque and patient characteristics with continuous PSV values in the carotid artery at different timepoints during follow-up after CEA. Methods . 760 atherosclerotic plaques of 725 patients, who underwent CEA between 2003 and 2011, were analyzed for smooth muscle cells, collagen, macrophages, lipid core, plaque hemorrhage, and vessel density. Patients underwent DUS at 3 and 12 months follow-up and yearly thereafter. The association between plaque and patient characteristics and mean PSV was analyzed in a multivariable analysis, at 3 months and total (mid-term) follow-up. Results . Patients with a large lipid core in their plaque ( n = 170) had significantly lower PSVs at 3 months follow-up; 109 cm/s, 95% confidence interval (CI): 103–116 versus 118 cm/s, 95% CI: 114–122, ( P = 0.03) for no or small lipid core ( n = 454). After mid-term follow-up (median duration of 2.5 years, interquartile range 1.7–4.3), these PSV values were not significantly different (115 vs. 111 cm/s, P = 0.278). Presence of contralateral stenosis, female sex, and asymptomatic presentation in women were independently associated with higher PSVs at mid-term follow-up. Conclusions . Dissection of a lipid-poor plaque showed an independent association with higher PSVs in the internal carotid artery 3 months after CEA, not after mid-term follow-up. In women, significantly higher PSVs were found after midterm follow-up, especially if they were asymptomatic.

Objectives . Long-term age- and sex-specific mortality data in patients undergoing carotid endarterectomy (CEA) and iliac/femoral endarterectomy (FEA) are scarce. We examined long-term mortality in these patient groups, stratified by age and sex. Methods . Between 2002 and 2012, 1771 patients (1200 men, 571 women) treated by CEA, and 685 patients (495 men, 190 women) who underwent FEA, were included and linked to the national mortality registry of the Netherlands. Absolute mortality risks during follow-up were analyzed by life-table and Kaplan Meier survival analyses in two age groups and stratified by sex, and compared to a matched sample from the general population. In addition, multivariable Cox regression analyses were performed. Results . After CEA, with a median follow-up duration of 4.3 years (interquartile range 2.0–7.1), 298 all-cause deaths had occurred in men (25%) and 105 (18%) in women. As in the general population, cumulative survival after CEA was significantly better in women compared to men ( P = 0.002) and absolute CEA-associated mortality risk in women was similar to that of the general population. For FEA patients, mortality risk was worse than for CEA patients and the general population in both sexes and surprisingly, female sex did not have a favorable effect on survival. Following FEA, 130 men (26%) and 51 women (27%) died after a median follow-up time of 3.0 years (interquartile range 1.5–5.9). Stratifying by age, and adjusting for cardiovascular risk factors did not change these trends. Conclusions . Long-term mortality after CEA is higher in men than in women, and in women mortality risk is similar to the general population. After FEA, the benefit of women as seen after CEA is lost.

Background— Time-dependent trends in the incidence of cardiovascular disease have been reported in high-income countries. Because atherosclerosis underlies the majority of cardiovascular diseases, we investigated temporal changes in the composition of atherosclerotic plaques removed from patients undergoing carotid endarterectomy. Methods and Results— The Athero-Express study is an ongoing, longitudinal, vascular biobank study that includes the collection of atherosclerotic plaques of patients undergoing primary carotid endarterectomy in the province of Utrecht from 2002 to 2011. Histopathologic features of plaques of 1583 patients were analyzed in intervals of 2 years. The analysis included quantification of collagen, calcifications, lipid cores, plaque thrombosis, macrophages, smooth muscle cells, and microvessels. Large atheroma, plaque thrombosis, macrophages, and calcifications were less frequently observed over time, with adjusted odds ratios of 0.72 (95% confidence interval, 0.650-0.789), 0.62 (95% confidence interval, 0.569-0.679), 0.87 (95% confidence interval, 0.800-0.940), and 0.75 (95% confidence interval, 0.692-0.816) per 2-year increase in time, respectively. These changes in plaque characteristics were consistently observed in patient subgroups presenting with stroke, transient ischemic attack, ocular symptoms, and asymptomatic patients. Concomitantly, risk factor management and secondary prevention strategies among vascular patients scheduled for carotid endarterectomy significantly improved over the past decade. Conclusions— In conclusion, over the past decade, atherosclerotic plaques harvested during carotid endarterectomy show a time-dependent change in plaque composition characterized by a decrease in features currently believed to be causal for plaque instability. This appears to go hand in hand with improvements in risk factor management.

Background: In patients with established cardiovascular disease, high levels of the extracellular vesicle (EV)-derived proteins cystatin C, CD14, and a2-antiplasmin predict recurrent cardiovascular events. We examined whether these proteins are associated with the extent of vascular disease. Methods: In 1062 patients from the SMART (Secondary Manifestations in ARTerial disease) study, EVs were isolated from plasma at baseline. Cystatin C, CD14, and a2-antiplasmin were measured in these vesicles using a multiplex assay. The extent of vascular disease burden was determined by a sum score that incorporates history and current presence of clinically manifest coronary, cerebrovascular, peripheral arterial, and abdominal aneurysm disease, and parameters of atherosclerosis that were assessed during the SMART screening protocol (ankle-brachial index, common carotid intima- media thickness, carotid stenosis, and aorta diameter). The relation between EV protein levels and extent of vascular disease was evaluated using ordinal multivariable regression models. Results: EV-derived CD14 was significantly associated with the number of affected vascular territories (OR 2.4, 95% CI 1.4-4.1) as represented by the sum score, independently of cardiovascular risk factors. Cystatin C and a2-antiplasmin EV levels did not show an independent association with vascular disease extent. When investigating parameters of the sum score separately, we did not observe a strong association between any of the EV-derived proteins and the markers of atherosclerosis. Conclusions: EV-derived CD14 levels are strongly correlated to the extent of vascular disease, but not specifically to markers that reflect atherosclerosis burden, in patients with manifest cardiovascular disease.

Background. Solitary fibrous tumors (SFTs) are rare mesenchymal tumors, and data regarding outcome and prognostic factors are scarce. We report the outcome and analysis of prognostic factors of a retrospective multicenter cohort study for patients treated for SFTs. Methods. Retrospective analysis was performed of patients treated for SFTs between 1995 and 2012. Clinical and histopathological features were analyzed for prognostic value. Endpoints were set at local recurrence, metastasis formation, or death. Survival was analyzed using Kaplan-Meier and Cox proportional hazards analyses. Results. A total of 81 patients underwent surgical resection of a SFT with curative intent. During follow-up, 21 patients developed distant metastases, while 18 patients developed local recurrence. The 5-year overall survival was 84 %. The local recurrence rate and the metastasis rate at 5 years were 29 and 34 %, respectively. Of all factors analyzed, positive resection margin significantly correlated with local recurrence [hazard ratio (HR) 4.8; 95 % confidence interval (95 % CI) 1.5-14.9]. Tum Conclusions. A substantial portion of patients with a SFT developed local recurrence or metastases. Local recurrence is significantly higher in patients with positive resection margins; metastasis frequency is significantly higher in patients with tumors [10 cm and tumors with a high mitosis rate.

Cardiovascular disease is a major public health problem worldwide. Its growing burden is particularly ominous in Asia, due to increasing rates of major risk factors such as diabetes, obesity and smoking. There is an urgent need for early identification and treatment of individuals at risk of adverse cardiovascular events. Plasma extracellular vesicle proteins are novel biomarkers that have been shown to be useful in the diagnosis, risk stratification and prognostication of patients with cardiovascular disease. Ongoing parallel biobank initiatives in European (the Netherlands) and Asian (Singapore) populations offer a unique opportunity to validate these biomarkers in diverse ethnic groups. Published version

Objective The management of small popliteal artery aneurysms remains a matter of debate. The goal of this study was to gain additional knowledge about this pathology, focusing specifically on popliteal arteries smaller than 20 mm in diameter. Furthermore, the need for surveillance of the contralateral popliteal artery in patients with a small aneurysm was studied. Methods A retrospective follow-up study was conducted in 2 Dutch hospitals. From 1998 until 2011, data were collected through a search in the hospital patient databases. A small aneurysm (which was defined as a popliteal artery diameter of 10–20 mm) was identified and evaluated in 73 patients. These patients were monitored, whereby symptoms, complications, and survival were recorded. In addition, the contralateral popliteal artery was analyzed in all 73 patients. Results Of 73 small aneurysms, 58% were asymptomatic, of which 24% developed an indication for surgical repair during follow-up. Furthermore, 32% were symptomatic and 11% completely thrombosed. Results of surgically treated aneurysms were good, with a secondary patency of 90% after a median follow-up of 30 months. A contralateral popliteal artery exceeding 10 mm was present in 49 patients (67%), of whom 59% had an indication for surgery. Conclusion This study found that small popliteal artery aneurysms show a considerable risk of becoming symptomatic. In all patients with a known popliteal artery aneurysm, investigation of the contralateral popliteal artery is advised.

Background: Following carotid endarterectomy (CEA), cerebrovascular hemodynamic may be hampered by ipsilateral restenosis or development of contralateral stenosis. It remains to be clarified if these patients need follow-up for identifying development of contralateral stenosis. Identification of risk factors contributing to development of contralateral stenosis could allow more specific follow-up. In this current study, we assessed clinical risk factors and plaque characteristics of patients undergoing CEA with development of new contralateral stenosis during mid-term follow-up. Methods: Seven hundred and sixty patients undergoing CEA between 2003 and 2011 at UMC Utrecht were included. Atherosclerotic plaques were excised and analyzed for smooth muscle cells (SMCs), collagen, macrophages, lipid core, plaque hemorrhage and vessel density. Patients underwent clinical and duplex ultrasound follow-up at 3 and 12 months and yearly thereafter. Association between plaque- and patient characteristics with development of contralateral stenosis ≥50% was assessed with univariate and multivariate analysis. Clinical outcome during follow-up was associated with development of new contralateral stenosis. Results: After a median follow-up time of 2.5 years, development of contralateral stenosis was observed in 108 patients (20%). Presence of high collagen (p = 0.025) and high SMC (p = 0.027) was associated with development of new contralateral stenosis, whereas large lipid core was negatively associated with new development of contralateral stenosis (p = 0.034). The same plaque characteristics were related to contralateral occlusion. History of coronary artery disease (p = 0.031) and asymptomatic presentation (p = 0.000) were univariably associated with development of contralateral stenosis. Multiple regression analysis indicated that asymptomatic status was independently associated with contralateral stenosis (p = 0.001). Patients with new development of contralateral stenosis more often showed symptoms during follow-up (p = 0.049). Conclusion: Dissection of a lipid-poor, collagen-rich or SMC-rich plaque yielded an association with development of new contralateral stenosis during mid-term follow-up after CEA. Asymptomatic patients had a significantly higher risk for development of contralateral stenosis. New contralateral stenosis was related to the presence of new cerebral symptoms. These findings may help to develop individual treatment algorithms for patients with cerebrovascular atherosclerotic burden.

Objective Myocardial infarction (MI) is a frequent complication of carotid endarterectomy (CEA), yet most events are silent. Routine post-operative monitoring of cardiac troponin was implemented to facilitate timely recognition of MI and stratify high risk patients. The aim was to evaluate the incidence of troponin elevation after CEA and its association with adverse cardiovascular events. Methods This analysis included patients ≥60 years old who underwent CEA, whose troponin-I levels were routinely monitored post-operatively and were included in a cohort study that assessed clinical outcomes. A clinical troponin cutoff of 60 ng/L was used. The primary endpoint was the composite of MI, stroke, and cardiovascular death. Secondary endpoints were MI, stroke, coronary intervention, cardiovascular death, and all cause death. Results 225 consecutive patients were included in the analysis. Troponin elevation occurred in 34 patients (15%) and a post-operative MI was diagnosed in eight patients. After a median follow up of 1.8 years (IQR 1.0–2.6), the primary endpoint occurred in 29% of patients with troponin elevation versus 6.3% without (HR 5.6, 95% CI 2.4–13), MI in 24% versus 1.6% (HR 18.0, 95% CI 4.7–68), stroke in 5.9% versus 4.2% (HR 1.4, 95% CI 0.3–6.7), coronary intervention in 5.9% versus 2.6% (HR 2.7, 95% CI 0.5–14), cardiovascular death in 5.9% versus 0.5% (HR 11.8, 95% CI 1.1–131), and all cause death in 15% versus 5.8% (HR 3.0, 95% CI 1.0–8.7), respectively. Incidences of the primary endpoint and all cause mortality in patients with a post-operative MI versus “troponin only” were 25% versus 7.7% and 25% versus 12%, respectively. Conclusion Troponin elevation after CEA occurred in 15% of patients. The incidence of adverse cardiovascular events was significantly higher in patients with troponin elevation, which was mainly attributable to silent non-ST segment elevation MIs that occurred in the early post-operative phase.

Enterococcus faecium is a commensal of the gastrointestinal tract of humans and animals. Since the 1990s, it has also emerged as a nosocomial pathogen. Little is known about carbon metabolism of E. faecium even though the ability to utilize different sugars could be an important factor in adapting to different ecological niches. In this study we identify an E. faecium gene cluster that is responsible for the metabolism of the α-galactoside sugar raffinose. Phenotypic testing of seven E. faecium isolates of which the genomes were previously sequenced showed that one isolate (strain E980) could grow on raffinose. Genome analysis identified a gene cluster containing two genes encoding α-galactosidases (termed agaA and agaB) that was uniquely present in E980. The agaA and agaB genes were significantly more frequently found in strains that are phylogenetically related to E980 and were more prevalent in surveillance isolates from hospital and community sources than in isolates from clinical infections. Disruption of the α-galactosidase gene agaB, but not of agaA, disabled growth on raffinose in strain E980. In all strains agaA and agaB are carried on megaplasmids that are between 150 and 300 kb in size. Filter-mating experiments showed that the megaplasmid of E980 can be transferred to a plasmidless recipient which then gains the ability to grow on raffinose. The observation that raffinose utilization by E. faecium is a trait carried by megaplasmids indicates that these megaplasmids can have important roles in shaping the competitive fitness of E. faecium in the environment, for example by expanding the metabolic repertoire of this organism.

OBJECTIVE: Platelet reactivity, platelet binding to monocytes and monocyte infiltration play a detrimental role in atherosclerotic plaque progression. We investigated whether platelet reactivity was associated with levels of circulating platelet-monocyte complexes (PMCs) and macrophages in human atherosclerotic carotid plaques. METHODS: Platelet reactivity was determined by measuring platelet P-selectin expression after platelet stimulation with increasing concentrations of adenosine diphosphate (ADP), in two independent cohorts: the Circulating Cells cohort (n = 244) and the Athero-Express cohort (n = 91). Levels of PMCs were assessed by flow cytometry in blood samples of patients who were scheduled for percutaneous coronary intervention (Circulating Cells cohort). Monocyte infiltration was semi-quantitatively determined by histological examination of atherosclerotic carotid plaques collected during carotid endarterectomy (Athero-Express cohort). RESULTS: We found increased platelet reactivity in patients with high PMCs as compared to patients with low PMCs (median (interquartile range): 4153 (1585-11267) area under the curve (AUC) vs. 9633 (3580-21565) AUC, P

Background and Purpose— Plaque hemorrhage (PH) may lead to accelerated progression of atherosclerotic disease. The presence of local PH in the carotid plaque predicts future cardiovascular events in any vascular territory. We investigated the prevalence of local PH and the predictive value of PH for the occurrence of cardiovascular events in men and women separately. Methods— Atherosclerotic plaques from 1422 patients (969 men, 453 women) who underwent carotid endarterectomy were analyzed histologically for the presence of PH. Patients were monitored for 3 years for cardiovascular events (nonfatal stroke, nonfatal myocardial infarction, vascular death, and vascular intervention). Results— Plaques from men showed a significantly higher prevalence of PH compared with women (67% versus 54%; P Conclusions— Atherosclerotic carotid plaques obtained from men reveal a higher prevalence of PH compared with women. Local PH is strongly related to secondary manifestations of cardiovascular disease in men but not in women.

Objectives: After exclusion of popliteal artery aneurysms (PAAs) through bypass surgery, there is a risk of persistent flow through collaterals and growth of the excluded aneurysmal sac. This study was conducted to evaluate this risk at long-term follow-up. Methods: Sixty-five PAAs treated by proximal and distal ligation and bypass grafting with reversed autologous vein in 52 patients (1998-2010) were retrospectively reviewed. Results: Mean follow-up was 41 months (range, 1-144 months). Five aneurysms showed residual flow (8%). One of these aneurysms had increased in size, 36 months postoperatively. This aneurysm underwent an embolization procedure after which no flow or further enlargement was demonstrated. Conclusion: In this study, the risk of persistent flow in a PAA excluded by proximal and distal ligation and bypass is low. Still, considering this risk and its possible complications, follow-up by duplex ultrasound in all patients until up to more than 10 years postoperatively is recommended.

Background The Gram-positive bacterium Enterococcus faecium is an important cause of nosocomial infections in immunocompromized patients. Results We present a pyrosequencing-based comparative genome analysis of seven E. faecium strains that were isolated from various sources. In the genomes of clinical isolates several antibiotic resistance genes were identified, including the vanA transposon that confers resistance to vancomycin in two strains. A functional comparison between E. faecium and the related opportunistic pathogen E. faecalis based on differences in the presence of protein families, revealed divergence in plant carbohydrate metabolic pathways and oxidative stress defense mechanisms. The E. faecium pan-genome was estimated to be essentially unlimited in size, indicating that E. faecium can efficiently acquire and incorporate exogenous DNA in its gene pool. One of the most prominent sources of genomic diversity consists of bacteriophages that have integrated in the genome. The CRISPR-Cas system, which contributes to immunity against bacteriophage infection in prokaryotes, is not present in the sequenced strains. Three sequenced isolates carry the esp gene, which is involved in urinary tract infections and biofilm formation. The esp gene is located on a large pathogenicity island (PAI), which is between 64 and 104 kb in size. Conjugation experiments showed that the entire esp PAI can be transferred horizontally and inserts in a site-specific manner. Conclusions Genes involved in environmental persistence, colonization and virulence can easily be aquired by E. faecium. This will make the development of successful treatment strategies targeted against this organism a challenge for years to come.