Monocyte hyporesponsiveness and Toll-like receptor expression profiles in coronary artery bypass grafting and its clinical implications for postoperative inflammatory response and pneumonia: An observational cohort study.

BACKGROUND: Cardiac surgery with cardiopulmonary bypass has a major impact on the congenital immune response, in which Toll-like receptors (TLRs) are the first line of defence. Decreased surface expression of TLRs and impaired monocyte responsiveness to TLR ligands occur following surgery. However, the clinical implications of this altered immune response are not clear. OBJECTIVES: To study cardiac surgery induced changes in perioperative TLR expression and monocyte responsiveness, and the association with postoperative inflammatory complications. DESIGN: A prospective cohort study. SETTING: Single university hospital, enrolment March to December 2007. PATIENTS: Eighty-four out of 92 patients who underwent coronary artery bypass grafting (CABG) were followed up until hospital discharge. MAIN OUTCOME MEASURES: We assessed in-vivo TLR-2 and TLR-4 expression and ex-vivo monocyte responsiveness to TLR-2 and TLR-4 ligands, measured by Pam3Cys and lipopolysaccharide (LPS)-induced interleukin (IL)-6 and IL-8, and tumour necrosis factor alpha (TNF-α) secretion until 24 h after surgery. Patients were followed to identify adverse inflammatory and infectious outcomes. RESULTS: Monocyte TLR expression decreased during CABG but returned to baseline after 24 h [linear mixed effects (LME) over time P < 0.0001]. Monocyte responsiveness changed significantly over time, with marked postoperative hyporesponsiveness (LME P < 0.0001). Decreased monocyte responsiveness to LPS was associated with monocyte TLR-4 expression (LME for IL-6 P = 0.04, IL-8 P = 0.002, TNF-α P = 0.05). Intraoperative decrease of monocyte TLR-2 expression was associated with postoperative systemic inflammatory response syndrome (SIRS) and pneumonia [odds ratio (OR) 2.06, 95% confidence interval (95% CI) 1.14 to 3.72], but the perioperative decrease of monocyte TLR-4 expression was not (OR 1.10, 95% CI 0.80 to 1.52). CONCLUSION: CABG surgery induced a decrease in in-vivo monocyte TLR expression and also in ex-vivo monocyte responsiveness, with which monocyte TLR-4 expression and monocyte LPS responsiveness seemed to be associated. Decreased TLR-2 expression was associated with the occurrence of SIRS and pneumonia, suggesting a role in the cause of postoperative inflammatory conditions. REGISTRATION: Clinicaltrials.gov identifier: NCT00356746.

Temporal changes of soluble ST2 after cardiovascular interventions.

BACKGROUND: Soluble ST2 (sST2), a member of the IL-1 receptor family, has been proposed as a novel biomarker with predictive value for heart failure and mortality in patients suffering from cardiovascular diseases. The influence of clinical characteristics on variability of sST2 levels is relatively unexplored. Here, we studied the effect of cardiovascular interventions and clinical characteristics on plasma sST2 expression levels. MATERIAL AND METHODS: In the current study, sST2 levels were assessed in the plasma of patients scheduled for coronary artery bypass grafting (CABG) (n = 76), percutaneous coronary intervention (PCI) (n = 68) or peripheral vascular surgery (n = 27). RESULTS: Age was the only classical risk factor significantly correlating with sST2 levels. Soluble ST2 levels were significantly increased 1 h after CABG (48 [33-70] vs. 61 [42-89] pg/mL, P = 0·001) and increased even further after 24 h (1116 [578-13 666] pg/mL, P < 0·001). An average threefold increase in sST2 levels was also observed in patients 24 h after peripheral interventions (30 [21-41] vs. 98 [48-211] pg/mL, P < 0·001). Two months after PCI, we found that sST2 levels were significantly higher compared with baseline levels (41 [29-61] vs. 48 [31-80] pg/mL, P = 0·007, n = 52). In addition, we did not observe an association between sST2 and any inflammatory or cardiac-specific markers that were measured in this study. CONCLUSIONS: Soluble ST2 increases significantly following cardiovascular interventions. The notion of a recent cardiovascular intervention is a strong determinant of sST2 levels and therefore needs to be taken into account when exploring sST2 as predictor of future cardiovascular events.

Inducible cardiac ischaemia is related to a decrease in the whole-blood Toll-like receptor 2 and 4 response.

TLR (Toll-like receptor) activation-induced inflammatory responses are important in the progression of atherosclerosis. We previously showed that TLR-dependent leucocyte responsiveness is acutely attenuated following percutaneous coronary intervention or vascular surgery. Furthermore, cytokine release following whole-blood TLR-2 and TLR-4 stimulation is negatively correlated with fractional flow reserve, suggesting that chronic ischaemia can elicit an enhanced inflammatory response. In the present study, we assessed the association between leucocyte TLR-2 and TLR-4 responsiveness and pre-existent and inducible ischaemia in patients undergoing SPECT (single-photon emission computed tomography)-MPI (myocardial perfusion imaging). TLR-2, TLR-4 and CD11b expression on monocytes were measured in blood samples that were obtained from 100 patients with suspected coronary artery disease before and after myocardial stress testing for SPECT-MPI. IL-8 (interleukin-8) levels were determined after whole-blood stimulation with Pam3Cys (TLR-2) and LPS (lipopolysaccharide; TLR-4). On the basis of SPECT-MPI, patients were categorized into three groups: reversible defect, irreversible defect and no defect. Myocardial stress induced a reduction in TLR-4 expression (2.46±0.21 compared with 2.17±0.16 arbitrary units, P=0.001) and CD11b expression (83.2±1.73 compared with 76.0±1.89 arbitrary units, P<0.001). TLR-induced IL-8 production before myocardial stress induction was not associated with the results of SPECT-MPI. However, a significant decrease in IL-8 production following TLR stimulation was observed after stress, which was more pronounced in patients with a reversible defect. In conclusion, inducible ischaemia is associated with a decrease in whole-blood TLR-2 and TLR-4 response. These results point to a regulating role of TLRs in order to prevent excessive inflammatory events known to occur during acute ischaemia.

Toll-like receptor 2 and 4 stimulation elicits an enhanced inflammatory response in human obese patients with atherosclerosis.

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.

Immune regulatory cells: circulating biomarker factories in cardiovascular disease.

TLRs (Toll-like receptors) are the first line of defence of the innate immune system. These receptors recognize not only exogenous but also endogenous ligands that are expressed following arterial injury and atherosclerotic disease. Expression of TLR2 and TLR4 is observed in macrophages and different vascular cells and is increased in atherosclerotic disease. It is suggested that TLR expression and functional responsiveness following ligation could serve as biomarkers for atherosclerotic disease progression. Recently published research papers support the concept that the TLRs are fast responders upon arterial injury. In the present issue of Clinical Science, Ishikawa and co-workers provide new evidence emerges that points to the potential prognostic properties of the TLRs.

[Carbapenem-resistant Klebsiella pneumoniae following foreign travel]. / Carbapenem-resistente Klebsiella pneumoniae na verblijf in het buitenland.

This is the first report of 3 patients in whom carbapenemase-producing Klebsiella pneumoniae was identified in the Netherlands following foreign travel. They were a 55-year-old man who had undergone chemotherapy for lung cancer metastases, a 66-year-old woman and a 30-year-old man. The first patient was transferred from a Greek hospital; his isolate belonged to an epidemic clone (multilocus sequence type 258) with a KPC-2 carbapenemase gene. The patient died from pneumonia. The other two patients, who had been travelling around in India, were found to be colonised in the gasto-intestinal tract with different multiresistant K. pneumoniae isolates containing a New Delhi metallo-carbapenemase gene (NDM-1). The rapid emergence and dissemination of Enterobacteriaceae resistant to carbapenems such as imipenem and meropenem poses a considerable threat to clinical patient care and public health. Carbapenemase-producing strains are characterized by resistance to nearly all available beta-lactam antibiotics including cephalosporins and carbapenems. These strains are often also resistant to other classes of antibiotics. Invasive infections by these strains are associated with high morbidity and mortality rates. Adequate microbiological laboratory detection and infection control measures in hospital are pivotal to preventing dissemination in the Dutch healthcare setting.

Toll-like receptor 2 and 4 response and expression on monocytes decrease rapidly in patients undergoing arterial surgery and are related to preoperative smoking.

Previously, we have shown that small arterial trauma is accompanied by a decreased capability of both toll-like receptors (TLRs) 2 and 4 to respond to stimulation with their respective ligands Pam3Cys and LPS. In this study, we assessed whether surgical arterial trauma induces a decrease in the TLR response and investigated the time course of the altered responsiveness. In addition, TLR responsiveness was related to baseline patient characteristics. Patients undergoing arterial surgery were included in the study. Patients undergoing pacemaker replacement served as control. Blood samples were drawn before, during, and immediately after vascular surgery and 24 h postoperatively. In all samples, we measured TLR-2 and TLR-4 expression using flow cytometry. Whole-blood samples were incubated with 5, 50, and 500 ng/mL Pam3Cys and with 1, 10, and 100 ng/mL LPS. Toll-like receptor response was assessed by measuring TNF-alpha in the supernatant with an enzyme-linked immune fluorescent assay. We observed a dose-dependent response in TNF-alpha production after stimulation with both LPS and Pam3Cys (P < 0.001). The TLR response decreased significantly after arterial trauma (P = 0.022). This effect on TLR response persisted in the 24-h postoperative period, whereas no such effect was observed in the control group. Toll-like receptor 2 expression decreased significantly immediately after surgery (P = 0.005) but increased 24 h after surgery (P < 0.001). Furthermore, an inverse relation between the TLR response and smoking was observed (P = 0.026). Toll-like receptor 2 and 4 response declines rapidly after arterial trauma in patients undergoing vascular surgery. These results point to a significant role for TLRs in the induction of postoperative immune tolerance. Furthermore, smoking is negatively related to baseline TLR response.

Clinical impact of abciximab on long-term outcome after complex coronary angioplasty.

Glycoprotein IIb/IIIa receptor antagonists, such as abciximab, are used to reduce major adverse cardiac events (MACEs) in patients undergoing percutaneous transluminal coronary angioplasty. The goal of this study was to evaluate the administration of abciximab in relation to lesion complexity and periprocedural complications. A total of 357 patients with 435 de novo lesions were included in this study. Lesions were divided into simple (type A and type B1) and complex (type B2 and type C) lesions according to the American College of Cardiology/American Heart Association Task Force lesion complexity system. Abciximab was given to unstable complex lesions and simple lesions with a periprocedural unstable complicated course. The overall incidence of MACE during the 9-month follow-up period was 17.0%. Patients treated with abciximab had a higher lesion complexity (P < 0.001), dissections (P = 0.014), stents (P < 0.001), and vessels involved (P < 0.001). in addition, the abciximab group was characterized by a higher angina NYHA class (P = 0.005), lower TIMI flow prior to stenting (P = 0.01), and a longer total inflation time (P = 0.006). Despite these clinical differences, the occurrence of MACE within the abciximab group was slightly less than in the group without abciximab (16.2% and 17.3%, respectively). Lesion complexity was directly related to MACE in the group that did not receive abciximab (simple and stable complex lesions; P = 0.04). On the other hand, in subjects treated with abciximab, lesion complexity was not related to a higher incidence of MACE (P = 0.76). The use of abciximab equalizes the difference in outcome between simple and complex lesions. Therefore, abciximab should be advocated especially in unstable and complex percutaneous coronary interventions.