Positron Emission Tomography/Computed Tomography Imaging in Device Infective Endocarditis: Ready for Prime Time
Lancellotti, Patrizio ; ; Oury, Cécile et al
in Circulation (2015), 132
Over the last decade there has been a remarkable increase in prosthetic heart valve replacement and cardiac implantable electronic device utilization. Although capable of improving the quality and ... [more ▼]
Over the last decade there has been a remarkable increase in prosthetic heart valve replacement and cardiac implantable electronic device utilization. Although capable of improving the quality and quantity of life of patients suffering from severe valvular heart disease or rhythm disorders, they are both subject to potentially life-threatening infection involving the endocardium, referred to as device infective endocarditis (DIE)1,2. The rate of prosthetic valve endocarditis (PVE) ranges from 1-6% to 15%, being higher in revision surgery1. The infection usually involves the junction between the sewing ring and the annulus, leading to perivalvular abscess, dehiscence, pseudo-aneurysms, and fistulae, or the leaflets of the prosthesis, leading to vegetations, cusp rupture, and perforation. Cardiac device-related infective endocarditis (CDRIE), to be distinguished from local device infection (pocket/generator), is defined as an infection involving the electrode leads, cardiac valve leaflets, or endocardial surface. An incidence of 1.4 per 1000 device-years of definite CDRIE has been reported3. DIE may occur at anytime, being related to surgery only in early cases. [less ▲]Detailed reference viewed: 51 (25 ULg)
Elevated Plasma Soluble ST2 Is Associated with Heart Failure Symptoms and Outcome in Aortic Stenosis.
LANCELLOTTI, Patrizio ; DULGHERU, Raluca Elena ; et al
in PloS one (2015), 10(9), 0138940
B-type natriuretic peptide (BNP) is often used as a complementary finding in the diagnostic work-up of patients with aortic stenosis (AS). Whether soluble ST2, a new biomarker of cardiac stretch, is ... [more ▼]
B-type natriuretic peptide (BNP) is often used as a complementary finding in the diagnostic work-up of patients with aortic stenosis (AS). Whether soluble ST2, a new biomarker of cardiac stretch, is associated with symptomatic status and outcome in asymptomatic AS is unknown. sST2 and BNP levels were measured in 86 patients (74+/-13 years; 59 asymptomatic, 69%) with AS (<1.5 cm2) and preserved left ventricular ejection fraction who were followed-up for 26+/-16 months. Both BNP and sST2 were associated with NYHA class but sST2 (>23 ng/mL, AUC = 0.68, p<0.01) was more accurate to identify asymptomatic patients or those who developed symptoms during follow-up. sST2 was independently related to left atrial index (p<0.0001) and aortic valve area (p = 0.004; model R2 = 0.32). A modest correlation was found with BNP (r = 0.4, p<0.01). During follow-up, 29 asymptomatic patients (34%) developed heart failure symptoms. With multivariable analysis, peak aortic jet velocity (HR = 2.7, p = 0.007) and sST2 level (HR = 1.04, p = 0.03) were independent predictors of cardiovascular events. In AS, sST2 levels could provide complementary information regarding symptomatic status, new onset heart failure symptoms and outcome. It might become a promising biomarker in these patients. [less ▲]Detailed reference viewed: 43 (11 ULg)
Biological Effects of Cardiac Magnetic Resonance on Human Blood Cells.
LANCELLOTTI, Patrizio ; NCHIMI LONGANG, Alain ; Delierneux, Céline et al
in Circulation. Cardiovascular imaging (2015), 8(9),
BACKGROUND: Cardiac magnetic resonance (CMR) is increasingly used for the diagnosis and management of cardiac diseases. Recent studies have reported immediate post-CMR DNA double-strand breaks in T ... [more ▼]
BACKGROUND: Cardiac magnetic resonance (CMR) is increasingly used for the diagnosis and management of cardiac diseases. Recent studies have reported immediate post-CMR DNA double-strand breaks in T lymphocytes. We sought to evaluate CMR-induced DNA damage in lymphocytes, alterations of blood cells, and their temporal persistence. METHODS AND RESULTS: In 20 prospectively enrolled healthy men (31.4+/-7.9 years), blood was drawn before and after (1-2 hours, 2 days, 1 month, and 1 year) unenhanced 1.5T CMR. Blood cell counts, cell death, and activation status of lymphocytes, monocytes, neutrophils, and platelets were evaluated. The first 2-hour post-CMR were characterized by a small increase of lymphocyte B and neutrophil counts and a transient drop of total lymphocytes because of a decrease in natural killer cells. Among blood cells, only neutrophils and monocytes displayed slight and transient activation. DNA double-strand breaks in lymphocytes were quantified through flow cytometric analysis of H2AX phosphorylation (gamma-H2AX). gamma-H2AX intensity in T lymphocytes did not change early after CMR but increased significantly at day 2 </=1 month before returning to baseline levels of 1-year post-CMR. CONCLUSIONS: Unenhanced CMR is associated with minor but significant immediate blood cell alterations or activations figuring inflammatory response, as well as DNA damage in T lymphocytes observed from day 2 until the first month but disappearing at 1-year follow-up. Although further studies are required to definitely state whether CMR can be used safely, our findings already call for caution when it comes to repeat this examination within a month. [less ▲]Detailed reference viewed: 54 (8 ULg)
In vitro study of the specific interaction between poly (2-dimethylamino ethylmethacrylate) based polymers with platelets and red blood cells.
Flebus, Luca ; Lombart, François ; et al
in International Journal of Pharmaceutics (2015), 492
Poly(2-dimethylamino)ethyl methacrylate (PDMAEMA) is an attractive polycation frequently proposed as a non-viral vector for gene therapy. As expected for other cationic carriers, intravenous ... [more ▼]
Poly(2-dimethylamino)ethyl methacrylate (PDMAEMA) is an attractive polycation frequently proposed as a non-viral vector for gene therapy. As expected for other cationic carriers, intravenous administration of PDMAEMA can result in its ionic complexation with various negatively charged domains found within the blood. To gain more insight into this polycation hemoreactivity, we followed the binding kinetics of a free form (FF) of fluorescein labelled PDMAEMA (below 15 kDa) in normal human blood using flow cytometry. This in vitro study highlighted that platelets display higher affinity for this polycation compared to red blood cells (RBCs), with an adsorption isotherm characteristics of a specific saturable binding site. PDMAEMA (1-20μg/mL) exerted a concentration dependent proaggregant effect with a biphasic aggregation of washed platelets. Activation of platelets was also noticed in whole blood with the expression of P-selectin and fibrinogen on platelet surface. Although additional studies would be needed in order to elucidate the mechanism of PDMAEMA mediated activation of platelets, our manuscript provides important information on the hemoreactivity of FF PDMAEMA. [less ▲]Detailed reference viewed: 32 (15 ULg)
Erratum: Elevated basal levels of circulating activated platelets predict ICU-acquired sepsis and mortality: a prospective study.
; Delierneux, Céline ; et al
in Critical care (London, England) (2015), 19(1), 301Detailed reference viewed: 29 (2 ULg)
Erratum: Prospective immune profiling in critically ill adults: before, during and after severe sepsis and septic shock.
; GOSSET, Christian ; Delierneux, Céline et al
in Critical care (London, England) (2015), 19(1), 300Detailed reference viewed: 25 (5 ULg)
Poster session 6: Saturday 6 December 2014, 08:30-12:30Location: Poster area.
; DULGHERU, Raluca Elena ; et al
Poster (2014, December)Detailed reference viewed: 13 (2 ULg)
Poster session 5: Friday 5 December 2014, 14:00-18:00Location: Poster area.
; DULGHERU, Raluca Elena ; et al
Poster (2014, December)Detailed reference viewed: 30 (10 ULg)
Platelets contribute to colitis-associated carcinogenesis : evidence from a mouse model.
Servais, Laurence ; ; Jacques, Sophie et al
Poster (2014, November)Detailed reference viewed: 8 (0 ULg)
P2X1 expressed on polymorphonuclear neutrophils and platelets is required for thrombosis in mice
; Delierneux, Céline ; et al
in Blood (2014), 124
Adenosine Triphosphate (ATP) and its metabolite, adenosine, are key regulators of polymorphonuclear neutrophils (PMNs) functions. PMNs have recently been implicated in the initiation of thrombosis. We ... [more ▼]
Adenosine Triphosphate (ATP) and its metabolite, adenosine, are key regulators of polymorphonuclear neutrophils (PMNs) functions. PMNs have recently been implicated in the initiation of thrombosis. We investigated the role of ATP and adenosine in PMN activation and recruitment at the site of endothelial injury. Following binding to the injured vessel wall, PMNs are activated and release elastase. The recruitment of PMNs and the subsequent fibrin generation and thrombus formation are strongly affected in mice deficient in the P2X1-ATP receptor and in wild-type mice treated with CGS 21680, an agonist of the A2A adenosine receptor or NF449 a P2X1 antagonist. Infusion of wild-type PMNs into P2X1-deficient mice increases fibrin generation but not thrombus formation. Restoration of thrombosis requires infusion of both platelets and PMNs from wild-type mice. In vitro, ATP activates PMNs, whereas CGS 21680 prevents their binding to activated endothelial cells. These data indicate that ATP contributes to PMN activation leading to their adhesion at the site of laser-induced endothelial injury, a necessary step leading to the generation of fibrin and subsequent platelet-dependent thrombus formation. Altogether, our study identifies previously unknown mechanisms by which ATP and adenosine are key molecules involved in thrombosis by regulating the activation state of PMNs. [less ▲]Detailed reference viewed: 40 (8 ULg)
Rasa3 Controls Megakaryocyte Rap1 Activation, Integrin Signaling and Differentiation into Proplatelet
Molina Ortiz, Patricia ; ; Ramery, Eve et al
in PLoS Genetics (2014), 10(6), 1004420
Rasa3 is a GTPase activating protein of the GAP1 family which targets Ras and Rap1. Ubiquitous Rasa3 catalytic inactivation in mouse results in early embryonic lethality. Here, we show that Rasa3 ... [more ▼]
Rasa3 is a GTPase activating protein of the GAP1 family which targets Ras and Rap1. Ubiquitous Rasa3 catalytic inactivation in mouse results in early embryonic lethality. Here, we show that Rasa3 catalytic inactivation in mouse hematopoietic cells results in a lethal syndrome characterized by severe defects during megakaryopoiesis, thrombocytopenia and a predisposition to develop preleukemia. The main objective of this study was to define the cellular and the molecular mechanisms of terminal megakaryopoiesis alterations. We found that Rasa3 catalytic inactivation altered megakaryocyte development, adherence, migration, actin cytoskeleton organization and differentiation into proplatelet forming megakaryocytes. These megakaryocyte alterations were associated with an increased active Rap1 level and a constitutive integrin activation. Thus, these mice presented a severe thrombocytopenia, bleeding and anemia associated with an increased percentage of megakaryocytes in the bone marrow, bone marrow fibrosis, extramedular hematopoiesis, splenomegaly and premature death. Altogether, our results indicate that Rasa3 catalytic activity controls Rap1 activation and integrin signaling during megakaryocyte differentiation in mouse. [less ▲]Detailed reference viewed: 335 (12 ULg)
CAMKKβ/AMPK-α1 pathway regulates phosphorylation of cytoskeletal targets in thrombin-stimulated human platelets
; Oury, Cécile ; et al
in Journal of Thrombosis and Haemostasis (2014), 12(6), 973-986
Background. Platelet activation requires sweeping morphological changes, supported by contraction and remodelling of platelet actin cytoskeleton. In various other cell types, AMP-activated protein kinase ... [more ▼]
Background. Platelet activation requires sweeping morphological changes, supported by contraction and remodelling of platelet actin cytoskeleton. In various other cell types, AMP-activated protein kinase (AMPK) controls the phosphorylation state of cytoskeletal targets. Objective. We hypothesized that AMPK is activated during platelet aggregation and contributes to the control of cytoskeletal targets. Results. We found that AMPK-α1 was mainly activated by thrombin and not by other platelet agonists in purified human platelets. Thrombin activated AMPK-α1 ex vivo via a Ca2+/calmodulin-dependent kinase kinase β (CAMKKβ)-dependent pathway. Pharmacological inhibition of CAMKKβ blocked thrombin-induced platelet aggregation and counteracted thrombin-induced phosphorylation of several cytoskeletal proteins, namely, regulatory myosin light chains (MLC), cofilin and vasodilator-stimulated phosphoprotein (VASP), three key elements involved in actin cytoskeleton contraction and polymerization. Platelets isolated from mice lacking AMPK-α1 exhibited reduced aggregation in response to thrombin, associated with a defect in MLC, cofilin and VASP phosphorylation and actin polymerization. More importantly, we show for the first time that AMPK pathway was activated in platelets of patients undergoing major cardiac surgery, in a heparin-sensitive manner. Conclusion. AMPK-α1 is activated by thrombin in human platelets. It controls phosphorylation of key cytoskeletal targets and actin cytoskeleton remodelling during platelet aggregation. [less ▲]Detailed reference viewed: 50 (2 ULg)
Epithelial-to-Mesenchymal Transitions modulate interactions between Circulating Tumor Cells and the coagulation system: implication for the metastatic spread.
Bourcy, Morgane ; Suarez-Carmona, Meggy ; Francart, Marie-Emilie et al
Poster (2014, May)Detailed reference viewed: 31 (3 ULg)
Assessing the contribution of platelets to colorectal tumor growth in a mouse model of colitis-associated cancer
Servais, Laurence ; ; Jacques, Sophie et al
Poster (2014, May)Detailed reference viewed: 10 (1 ULg)
Combined use of GWAS and eQTL information to identify genes controlling platelet biology
Gori, Ann-Stephan ; LECUT, Christelle ; Theatre, Emilie et al
Poster (2014, April 24)
Genome Wide Association Studies (GWAS) have identified at least 68 loci involved in megakaryopoiesis and platelet formation. As for all GWAS, identified risk loci span hundreds of kilobases encompassing ... [more ▼]
Genome Wide Association Studies (GWAS) have identified at least 68 loci involved in megakaryopoiesis and platelet formation. As for all GWAS, identified risk loci span hundreds of kilobases encompassing multiple genes, such that causative variants and genes remain largely unknown. To aid in the identification of causative genes underlying GWAS hits for platelet function (as well as other phenotypes including common complex diseases), we have generated a dataset (" CEDAR ") comprising genome-wide SNP and transcriptome data on nine primary cell types, including platelets, for 330 healthy Caucasian individuals. In addition, we have measured platelet counts and volume, as well as platelet reactivity to ADP, collagen and thrombin-related peptide for all these individuals. After extensive quality control, the ensuing data set has been used to identify (i) QTL influencing platelet count, volume and reactivity, and (ii) cis-and transacting eQTL operating in platelets. To aid in the identification of genes underlying platelet biology, we are applying a recently developed method to search for correlations between association patterns with platelet phenotypes and eQTL association patterns. Such findings would strongly incriminate the corresponding genes (affected by the eQTL) as being causally involved in determining the cognate platelet phenotype. Latest results will be presented. [less ▲]Detailed reference viewed: 125 (19 ULg)
Usefulness of Serial B-type Natriuretic Peptide Assessment in Asymptomatic Aortic Stenosis.
; ; DULGHERU, Raluca Elena et al
in The American journal of cardiology (2014)
B-type natriuretic peptide (BNP) level may be a useful prognostic marker for the management of asymptomatic patients with aortic stenosis (AS). The aim of this study was to identify the echocardiographic ... [more ▼]
B-type natriuretic peptide (BNP) level may be a useful prognostic marker for the management of asymptomatic patients with aortic stenosis (AS). The aim of this study was to identify the echocardiographic determinants of BNP changes during follow-up in AS. We studied 61 asymptomatic patients with greater than moderate AS and preserved left ventricular (LV) ejection fraction who underwent rest and exercise Doppler echocardiography with concomitant BNP level measurement at baseline. BNP measurement was repeated after inclusion every 6 months. Patients were divided into 2 groups according to the median of BNP changes during follow-up. According to parameters at rest, patients in the high BNP changes group had significantly higher E/e' ratio. Statistically significant correlations were found between BNP changes and E/e' ratio and indexed left atrial area. According to exercise parameters, patients in the high BNP changes group had significantly lower exercise-induced increase in LV ejection fraction. Statistically significant correlations were found between BNP changes and exercise-induced changes in LV ejection fraction. After adjustment for age, mean aortic pressure gradient, and BNP level at baseline, multivariate analysis identified indexed left atrial area, E/e' at rest, and exercise-induced increase in ejection fraction as independent determinants of BNP changes during follow-up. In conclusion, this study shows that, in asymptomatic patients with preserved LV function and moderate AS, serial BNP measurements may widely vary. Subclinical LV diastolic and systolic dysfunctions are frequently present in patients with higher serial BNP changes. [less ▲]Detailed reference viewed: 41 (14 ULg)
Identification of a microRNA landscape targeting the PI3K/Akt signaling pathway in inflammation-induced colorectal carcinogenesis
JOSSE, Claire ; Bouznad, Nassim ; Geurts, Pierre et al
in American Journal of Physiology - Gastrointestinal and Liver Physiology (2014), 306
Inflammation can contribute to tumor formation; however, markers that predict progression are still lacking. In the present study, the well-established azoxymethane (AOM)/dextran sulfate sodium (DSS ... [more ▼]
Inflammation can contribute to tumor formation; however, markers that predict progression are still lacking. In the present study, the well-established azoxymethane (AOM)/dextran sulfate sodium (DSS)-induced mouse model of colitis-associated cancer was used to analyze microRNA (miRNA) modulation accompanying inflammation-induced tumor development and to determine whether inflammation-triggered miRNA alterations affect the expression of genes or pathways involved in cancer. A miRNA microarray experiment was performed to establish miRNA expression profiles in mouse colon at early and late time points during inflammation and/or tumor growth. Chronic inflammation and carcinogenesis were associated with distinct changes in miRNA expression. Nevertheless, prediction algorithms of miRNA-mRNA interactions and computational analyses based on ranked miRNA lists consistently identified putative target genes that play essential roles in tumor growth or that belong to key carcinogenesis-related signaling pathways. We identified PI3K/Akt and the insulin growth factor-1 (IGF-1) as major pathways being affected in the AOM/DSS model. DSS-induced chronic inflammation downregulates miR-133a and miR-143/145, which is reportedly associated with human colorectal cancer and PI3K/Akt activation. Accordingly, conditioned medium from inflammatory cells decreases the expression of these miRNA in colorectal adenocarcinoma Caco-2 cells. Overexpression of miR-223, one of the main miRNA showing strong upregulation during AOM/DSS tumor growth, inhibited Akt phosphorylation and IGF-1R expression in these cells. Cell sorting from mouse colons delineated distinct miRNA expression patterns in epithelial and myeloid cells during the periods preceding and spanning tumor growth. Hence, cell-type-specific miRNA dysregulation and subsequent PI3K/Akt activation may be involved in the transition from intestinal inflammation to cancer. [less ▲]Detailed reference viewed: 111 (21 ULg)
CD36: linking lipids to the NLRP3 inflammasome, atherogenesis and atherothrombosis
in Cellular & Molecular Immunology (2014), 11
Uptake of the atherogenic lipid mediator oxLDL by CD36 results in the formation of intracellular cholesterol crystals that caused lyso¬somal destabilization and NLRP3 activation. oxLDL not only primes ... [more ▼]
Uptake of the atherogenic lipid mediator oxLDL by CD36 results in the formation of intracellular cholesterol crystals that caused lyso¬somal destabilization and NLRP3 activation. oxLDL not only primes, via a NF-κB-dependent pathway, but also activates NLRP3. CD36-mediated inflammasome activation provides an early pathogenic pathway that links cholesterol accumulation to the chronic inflammatory process of atherosclerosis. During atherogenesis, activated or injured endothelial cells, leucocytes and platelets release ATP that acts in a paracrine manner to transduce sterile inflammatory signals. Among these signals, P2X7 receptors mediate K+ efflux leading to NLRP3 activation. Since ATP assembles ASC complexes in oxLDL-treated macrophages, P2X7 receptors and CD36 may cooperate in vivo to activate NLRP3 inflammasome, contributing to plaque formation. Besides macrophages, CD36 is expressed on platelets where it mediates oxLDL-dependent platelet activation and potentially further IL-1β release. P2X7 receptors contributes to protein disulfide isomerase (PDI) tissue factor-dependent thrombosis. Consequently, both CD36 and P2X7 receptors may be involved in atherothrombosis upon plaque rupture. [less ▲]Detailed reference viewed: 55 (2 ULg)
Connection between cardiac vascular permeability, myocardial oedema and inflammation during sepsis: role of the alpha1AMPK isoform
; ; et al
in Critical Care Medicine (2013), 41(12), 411-22
Objective: Since AMP-activated protein kinase (AMPK) both controls cytoskeletonorganization in endothelial cells (ECs) and exerts anti-inflammatory effects, we here postulated that it could influence ... [more ▼]
Objective: Since AMP-activated protein kinase (AMPK) both controls cytoskeletonorganization in endothelial cells (ECs) and exerts anti-inflammatory effects, we here postulated that it could influence vascular permeability and inflammation, thereby counteracting cardiac wall oedema during sepsis. Design: Controlled animal study Settings: University research laboratory Subjects: C57BL/6J, α1AMPK-/- and α1AMPK+/+ mice Intervention: Sepsis was triggered in vivo using a sub-lethal injection of lipopolysaccharide (LPS, O55B5, 10 mg.kg-1), inducing systolic left ventricular (LV) dysfunction. LV function, oedema, vascular permeability and inflammation were assessed in vivo in both wild type (WT) mice (α1AMPK+/+) and α1AMPK-deficient mice (α1AMPK-/-). 5-Aminoimidazole-4-carboxamide riboside (AICAr) served to study the impact of AMPK activation on vascular permeability in vivo. The integrity of EC monolayers was also examined in vitro after LPS challenge in the presence of AICAr and/or after α1AMPK silencing. Measurements and main results: α1AMPK-deficiency dramatically impaired tolerance to LPS challenge. Indeed, α1AMPK-/- exhibited heightened cardiac vascular permeability after LPS challenge compared to α1AMPK+/+. Consequently, an increase in LV mass corresponding to exaggerated wall oedema occurred in α1AMPK-/-, without any further decrease in systolic function. Mechanistically, the LPS-induced α1AMPK-/- cardiac phenotype could not be attributed to major changes in the systemic inflammatory response, but was due to an increased disruption of interendothelial tight junctions. Accordingly, AMPK activation by AICAr counteracted LPS-induced hyperpermeability in WT mice in vivo as well as in ECs in vitro. This effect was associated with a potent protection of ZO-1 linear border pattern in ECs. Conclusions: Our results demonstrate, for the first time the involvement of a signalling pathway in the control of LV wall oedema during sepsis. AMPK exerts a protective action through the preservation of interendothelial tight junctions. Interestingly, exaggerated LV wall oedema was not coupled with aggravated systolic dysfunction. However, it could contribute to diastolic dysfunction in septic patients. [less ▲]Detailed reference viewed: 77 (17 ULg)