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Background: A substantial group of patients with gallstone disease experience negative outcome after surgical removal of the gallbladder (cholecystectomy). Early identification of these patients is important.Purpose: The aim of the study is to identify predictors (clinical symptoms and trait anxiety) of negative symptomatic outcomes at 6 weeks after cholecystectomy.Methods: Consecutive patients (n = 133), 18-65 years, with symptomatic gallstone disease, completed symptom checklists and the state-trait anxiety inventory preoperatively and at 6 weeks after cholecystectomy.Results: High trait anxiety was the only predictor of persistence of biliary symptoms at 6 weeks after cholecystectomy (OR = 6.88).Conclusion: In addition to clinical symptoms, high trait anxiety is a predictor of negative symptomatic outcome at 6 weeks after cholecystectomy. Trait anxiety should be evaluated to aim at a patient-tailored approach in gallstone disease. [ABSTRACT FROM AUTHOR]

Aims: Diabetes accelerates progression of atherosclerotic disease, but data on associations between diabetes and advanced atherosclerotic plaque composition are scarce., Methods and Results: We used one of the largest biobanks, the Athero-Express study (n=1455) at carotid endarterectomy (CEA). All plaques were subjected to histological analysis to assess lipid core size, collagen, macrophages, smooth muscle cells, micro-vessel density and calcifications. In addition, within a subset of patients cytokines and chemokines were assessed. The 295 patients (20%) with type-2 diabetes showed a higher proportion of previous cardiovascular interventions and more stringent treatment for hypertension and hypercholesterolaemia compared with patients without type-2 diabetes. Surprisingly, no associations between diabetes and histological plaque characteristics were observed. In addition, no differences were observed in the expression of inflammatory chemokines, cytokines or advanced glycation end products in plaques of diabetic and non-diabetic patients., Conclusion: In patients suffering from significant carotid artery disease, diabetes does not appear to be associated with specific atherosclerotic plaque characteristics., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Matrix metalloproteinase-14 (MMP-14) promotes vulnerable plaque morphology in mice, whereas tissue inhibitor of metalloproteinases-3 (TIMP-3) overexpression is protective. MMP-14(hi) TIMP-3(lo) rabbit foam cells are more invasive and more prone to apoptosis than MMP-14(lo) TIMP-3(hi) cells. We investigated the implications of these findings for human atherosclerosis. In vitro generated macrophages and foam-cell macrophages, together with atherosclerotic plaques characterised as unstable or stable, were examined for expression of MMP-14, TIMP-3, and inflammatory markers. Proinflammatory stimuli increased MMP-14 and decreased TIMP-3 mRNA and protein expression in human macrophages. However, conversion to foam-cells with oxidized LDL increased MMP-14 and decreased TIMP-3 protein, independently of inflammatory mediators and partly through posttranscriptional mechanisms. Within atherosclerotic plaques, MMP-14 was prominent in foam-cells with either pro- or anti-inflammatory macrophage markers, whereas TIMP-3 was present in less foamy macrophages and colocalised with CD206. MMP-14 positive macrophages were more abundant whereas TIMP-3 positive macrophages were less abundant in plaques histologically designated as rupture prone. We conclude that foam-cells characterised by high MMP-14 and low TIMP-3 expression are prevalent in rupture-prone atherosclerotic plaques, independent of pro- or anti-inflammatory activation. Therefore reducing MMP-14 activity and increasing that of TIMP-3 could be valid therapeutic approaches to reduce plaque rupture and myocardial infarction.

Toll-Like Receptor (TLR) -2 and -4 expression and TLR-induced cytokine response of inflammatory cells are related to atherogenesis and atherosclerotic plaque progression. We examined whether immediate TLR induced changes in CD11b and L-selectin (CD62L) expression are able to discriminate the presence and severity of atherosclerotic disease by exploring single dose whole blood TLR stimulation and detailed dose-response curves. Blood samples were obtained from 125 coronary artery disease (CAD) patients and 28 controls. CD11b and L-selectin expression on CD14+ monocytes was measured after whole blood stimulation with multiple concentrations of the TLR4 ligand LPS (0.01-10 ng/ml) and the TLR2 ligand P3C (0.5-500 ng/ml). Subsequently, dose-response curves were created and the following parameters were calculated: hillslope, EC50, area under the curve (AUC) and delta. These parameters provide information about the maximum response following activation, as well as the minimum trigger required to induce activation and the intensity of the response. CAD patients showed a significantly higher L-selectin, but not CD11b response to TLR ligation than controls after single dose stimulations as well as significant differences in the hillslope and EC50 of the dose-response curves. Within the CAD patient group, dose-response curves of L-selectin showed significant differences in the presence of hypertension, dyslipidemia, coronary occlusion and degree of stenosis, whereas CD11b expression had the strongest discriminating power after single dose stimulation. In conclusion, single dose stimulations and dose-response curves of CD11b and L-selectin expression after TLR stimulation provide diverse but limited information about atherosclerotic disease severity in stable angina patients. However, both single dose stimulation and dose-response curves of LPS-induced L-selectin expression can discriminate between controls and CAD patients.

Background: Matrix metalloproteinase-12 (MMP-12) promotes atherosclerosis in animal models. MMP-12 is expressed in only a subset of foam-cell macrophages (FCMs) in human plaques. We investigated whether the prevalence of this MMP-12-expressing subpopulation is a prognostic indicator of adverse outcome in patients after carotid endarterectomy (CEA)., Methods and Results: Serial sections of culprit lesions from 236 patients who underwent CEA and had undergone 3 years of clinical follow-up were stained immunocytochemically for MMP-12 and for CD68, and the MMP-12/CD68 ratio was used to quantify the MMP-12-expressing subpopulation. A high MMP-12/CD68 ratio correlated with a high content of lipid and total macrophages and a low content of vascular smooth muscle cells, as well as with MMP-8 (R=0.211, P=0.001), MMP-9 (R=0.251, P<0.001), and cleaved caspase-3 (R=0.142, P=0.036) activity measured in a neighboring segment. Dual immunohistochemical examination confirmed the location of MMP-12 in a subpopulation of MMP-8- and MMP-9-positive FCMs, whereas all apoptotic FCMs were MMP-12 positive. Patients who yielded plaques within the highest quartile compared with the lowest quartile of MMP-12/CD68 ratio had a 2.4-fold (hazard ratio, 2.4; 95% CI, 1.1- to 5.1-fold; adjusted P=0.027) increased risk of major adverse cardiovascular event and a 3.4-fold (3.4; 1.2- to 9.6-fold, P=0.024) increased risk for stroke., Conclusions: The prevalence of an MMP-12-positive subset of FCMs is a prognostic marker for adverse clinical outcome after CEA.

The innate immune response elicited by activation of TLRs (Toll-like receptors) plays an important role in the pathogenesis of atherosclerosis. We hypothesized that cardiovascular risk factors are associated with the activation status of the innate immune system. We therefore assessed the responsiveness of TLRs on circulating cells in two groups of patients with established atherosclerosis and related this to the presence of cardiovascular risk factors. TNF (tumour necrosis factor)-α release induced by TLR2 and TLR4 activation was measured in patients with established coronary [PCI (percutaneous coronary intervention) study, n=78] or carotid artery disease [CEA (carotid endarterectomy) study, n=104], by stimulating whole blood samples with lipopolysaccharide (TLR4 ligand) and Pam3CSK4 [tripalmitoylcysteinylseryl-(lysyl)4; TLR2 ligand]. As an early activation marker, CD11b expression was measured by flow cytometry on CD14+ cells. Obesity was the 'only' risk factor that correlated with the TLR response. In both studies, obese patients had significantly higher TNF-α levels after stimulation of TLR2 compared with non-obese patients [16.9 (7.7-49.4) compared with 7.5 (1.5-19.2) pg/ml (P=0.008) in coronary artery disease and 14.6 (8.1-28.4) compared with 9.5 (6.1-15.7) pg/ml (P=0.015) in carotid artery disease; values are medians (interquartile range)]. Similar results were obtained following TLR4 stimulation. The enhanced inflammatory state in obese patients was also confirmed by a significant increased expression of the activation marker CD11b on circulating monocytes. In conclusion, obesity is associated with an enhanced TLR response in patients suffering from established atherosclerotic disease.

Cardiovascular disease is the leading cause of death in Western countries and current research is still focusing on optimizing therapeutic approaches in the battle against this multifactorial disease. Concepts regarding the pathogenesis of many cardiovascular diseases originate from observations of human atherosclerotic tissue obtained from autopsies or during vascular surgery. These observations have helped us to disentangle the pathophysiology of atherosclerosis. However, identifying vulnerable patients, those prone to developing cardiovascular complications, remains difficult. The search for predictive cardiovascular biomarkers continues and large, well organized biobanks are needed to discover or validate novel biomarkers. Biobanks are an extremely valuable resource that enables us to study the influence of both genetic and environmental factors on the development of multifactorial diseases such as atherosclerosis. This review will focus on the advantages and pitfalls in atherosclerotic biobanking.

Background: As many patients with gallstone disease do not benefit from cholecystectomy, preoperative recognition of such high-risk patients is important. The aim of the study is to identify predictors of persisting symptoms at 6 months after cholecystectomy for patients with different preoperative symptomatology., Method: Participants in this prospective study were consecutive patients (n = 172), age 18-65 years, with symptomatic cholelithiasis, undergoing a laparoscopic cholecystectomy. Predictors were identified using uni- and multivariate regression analyses., Results: At 6 months postcholecystectomy, patients with only preoperative biliary symptoms were most often free of symptoms (62.5%). Patients with only dyspeptic symptoms most often reported persistence of preexisting symptoms (63.2%). Preoperative non-specific symptoms predicted the report of postoperative biliary and/or dyspeptic symptoms (OR = 4.5-6.1). Persistence of preexisting pattern of symptoms was predicted by the use of psychotropic medication (OR = 5.3) and dyspeptic symptoms (OR = 4.5). Postoperative biliary symptoms were predicted by High Trait Anxiety (HTA) (OR = 10.6)., Conclusion: Surgeons should take account of individual risks of patients in the management of cholelithiasis. Instead of cholecystectomy, expectative management should be the first choice in patients with non-specific symptoms, with dyspeptic symptoms only, with HTA and in patients using psychotropic medication.

Objective: Many patients with symptomatic cholelithiasis report persisting symptoms after elective cholecystectomy. The current prospective follow-up study aims at the identification and valuation of risk factors for negative symptomatic outcome at 6 weeks., Methods: Consecutive patients (n = 183), age 18-65 years, indicated for elective cholecystectomy due to symptomatic cholelithiasis, completed a self-report questionnaire. At 6 weeks post-operatively, the same self-report questionnaires were completed (n = 129). Predictors of the persistence and emergence of biliary and dyspeptic symptoms at 6 weeks post-cholecystectomy were investigated using univariate and multivariate logistic regression., Results: At 6 weeks post-operatively, the report of post-operative biliary symptoms was independently predicted by pre-operative dyspeptic symptoms (OR = 6.60) and bad taste (OR = 3.55). Pre-operative flatulence was an independent predictor of the report of biliary and dyspeptic symptoms ((OR = 3.33) and (OR = 3.27), respectively) and persisting biliary symptoms (OR = 4.21). Predictors of symptomatic outcome were only identified in women, not in men., Conclusion: Patients with pre-operative dyspeptic symptoms, notably bad taste and flatulence, have an increased risk of negative post-cholecystectomy outcomes at 6 weeks. A symptom-specific approach should lead to optimalization of the indication of cholecystectomy and information of patients. Known risk factors for long-term outcomes might be valuable in female patients only.