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Stammet P.,Center Hospitalier | Goretti E.,Laboratory of Cardiovascular Research | Vausort M.,Laboratory of Cardiovascular Research | Zhang L.,Laboratory of Cardiovascular Research | And 3 more authors.
Critical Care Medicine | Year: 2012

Objective:: Prediction of clinical outcome after cardiac arrest is clinically important. While the potential of circulating microRNAs as biomarkers of acute coronary syndromes is an active field of investigation, it is unknown whether microRNAs are associated with outcome in cardiac arrest patients. DESIGN:: Prospective, single-center proof-of-concept study. SETTING:: Eighteen-bed adult general intensive care unit of an academic tertiary care hospital in Luxembourg. PATIENTS:: Twenty-eight patients with cardiac arrest treated by therapeutic hypothermia after cardiac resuscitation were enrolled. MEASUREMENTS AND MAIN Results:: Blood samples were obtained at 48 hrs after cardiac arrest for the determination of microRNA levels and neuron-specific enolase. Neurological outcome was determined by the cerebral performance category at discharge from the intensive care unit and at 6-month follow-up. Analysis of microRNA arrays and quantitative assessment by polymerase chain reaction identified two microRNAs, miR-122 and miR-21, overexpressed in patients with poor neurological outcome (cerebral performance category 3-5, n = 14) compared to patients with favorable neurological outcome (cerebral performance category 1-2, n = 14) (48-fold and three-fold, respectively). In vitro experiments showed that both miR-122 and miR-21 are produced by neuronal cells, indicating that the elevation of circulating levels of these microRNAs after cardiac arrest may reflect brain damage. miR-122 and miR-21 predicted neurological outcome with areas under the receiver operating characteristic curve of 0.73 and 0.77, respectively. Patients within the highest third of miR-122 or miR-21 values had elevated mortality rate (p = .02). Neuron-specific enolase was an accurate predictor of neurological outcome (areas under the receiver operating characteristic curve = 0.98) and mortality (p < .001). MicroRNA levels were not associated with myocardial damage or activation of inflammation. Conclusions:: As compared to neuron-specific enolase, circulating microRNAs are modest but significant predictors of neurological outcome and mortality in this small group of patients with cardiac arrest. This motivates assessing the prognostic value of microRNAs in larger cohorts of cardiac arrest patients. © 2012 by the Society of Critical Care Medicine and Lippincott Williams and Wilkins.


Goretti E.,Laboratory of Cardiovascular Research | Rolland-Turner M.,Laboratory of Cardiovascular Research | Leonard F.,Laboratory of Cardiovascular Research | Zhang L.,Laboratory of Cardiovascular Research | And 3 more authors.
Journal of Leukocyte Biology | Year: 2013

The capacity of EPCs to repair injured tissues is limited. The role of miRNAs in EPCs is largely unknown. We tested whether miRNAs may be useful to enhance the regenerative capacity of EPCs. Early EPCs were isolated from human PBMCs, and late EPCs were amplified from enriched human peripheral CD34+ cells. Expression profiles of miRNAs and mRNAs were obtained by microarrays. Among the miRNAs differentially expressed between early and late EPCs, five members of the miR-16 family (miR-15a/-15b/-16/-103/-107) were overexpressed in early EPCs. Web-accessible databases predicted 375 gene targets for these five miRNAs. Among these, two regulators of cell cycle progression (CCND1 and CCNE1) and one associated gene (CDK6) were less expressed in early EPCs. Administration of anti-miR-16 in early EPCs enhanced the expression of these three genes, and administration of premiR- 16 in late EPCs decreased their expression. In early EPCs, antagonism of miR-16 allowed for cell-cycle re-entry, stimulated differentiation, enhanced IL-8 secretion, and promoted the formation of capillary-like structures by HUVECs. In conclusion, miR-16 regulates key biological pathways in EPCs. This may have important implications to enhance the capacity of EPCs to repair injured tissues. © Society for Leukocyte Biology.


Azuaje F.,Laboratory of Cardiovascular Research | Devaux Y.,Laboratory of Cardiovascular Research | Wagner D.R.,Laboratory of Cardiovascular Research | Wagner D.R.,Center Hospitalier
BMC Systems Biology | Year: 2010

Background: The identification of potentially relevant biomarkers and a deeper understanding of molecular mechanisms related to heart failure (HF) development can be enhanced by the implementation of biological network-based analyses. To support these efforts, here we report a global network of protein-protein interactions (PPIs) relevant to HF, which was characterized through integrative bioinformatic analyses of multiple sources of "omic" information.Results: We found that the structural and functional architecture of this PPI network is highly modular. These network modules can be assigned to specialized processes, specific cellular regions and their functional roles tend to partially overlap. Our results suggest that HF biomarkers may be defined as key coordinators of intra- and inter-module communication. Putative biomarkers can, in general, be distinguished as "information traffic" mediators within this network. The top high traffic proteins are encoded by genes that are not highly differentially expressed across HF and non-HF patients. Nevertheless, we present evidence that the integration of expression patterns from high traffic genes may support accurate prediction of HF. We quantitatively demonstrate that intra- and inter-module functional activity may be controlled by a family of transcription factors known to be associated with the prevention of hypertrophy.Conclusion: The systems-driven analysis reported here provides the basis for the identification of potentially novel biomarkers and understanding HF-related mechanisms in a more comprehensive and integrated way. © 2010 Azuaje et al; licensee BioMed Central Ltd.


Devaux Y.,Laboratory of Cardiovascular Research | Vausort M.,Laboratory of Cardiovascular Research | McCann G.P.,University of Leicester | Zangrando J.,Laboratory of Cardiovascular Research | And 7 more authors.
Circulation: Cardiovascular Genetics | Year: 2013

Background-Left ventricular (LV) remodeling after acute myocardial infarction is associated with adverse prognosis. MicroRNAs (miRNAs) regulate the expression of several genes involved in LV remodeling. Our aim was to identify miRNAs associated with LV remodeling after acute myocardial infarction. Methods and Results-We studied 90 patients after first ST-segment-elevation acute myocardial infarction. A derivation cohort consisted of 60 patients characterized by echocardiography predischarge and at 6-month follow-up. Thirty patients characterized by magnetic resonance imaging predischarge and at 4-month follow-up were the validation cohort. Remodeling was defined as an increase in LV end-diastolic volume (ΔEDV>0) between discharge and follow-up. Circulating miRNAs were measured by microarrays and polymerase chain reaction. Using a systems-based approach, we identified several miRNAs potentially involved in LV remodeling. In the derivation cohort, one of these miRNAs, miR-150, was downregulated in patients with remodeling (ΔEDV>0) compared with patients without remodeling (ΔEDV≤0). In the validation cohort, patients with remodeling had 2-fold lower levels of miR-150 than those without (P=0.03). miR-150 outperformed N-terminal pro-brain natriuretic peptide to predict remodeling (area under the receiver-operating characteristic curve of 0.74 and 0.60, respectively). miR-150 reclassified 54% (95% confidence interval, 5-102; P=0.03) of patients misclassified by N-terminal pro-brain natriuretic peptide and 59% (95% confidence interval, 9-108; P=0.02) of patients misclassified by a multiparameter clinical model, including age, sex, and admission levels of troponin I, creatine kinase, and N-terminal pro-brain natriuretic peptide. Conclusions-Low circulating levels of miR-150 are associated with LV remodeling after first ST-segment-elevation acute myocardial infarction. miR-150 has potential as a novel biomarker in this setting. © 2013 American Heart Association, Inc.


Emeus I.,Laboratory of Cardiovascular Research | Bonsquenaud M.,Laboratory of Cardiovascular Research | Lenoir B.,Laboratory of Cardiovascular Research | Devaux Y.,Laboratory of Cardiovascular Research | And 2 more authors.
Journal of Leukocyte Biology | Year: 2015

Increase of blood capillary density at the interface between normal and ischemic tissue after acute Ml reduces infarct size and improves cardiac function. Cardiac injury triggers the production of the matricellular component TSP-1, but its role in angiogenesis is not clear, as both anti- and proangiogenic properties have been reported. It is unknown whether TSP-1 is modulated by other factors released during cardiac injury. Among these, Ado is a well-known promoter of angiogenesis. This study determined whether Ado modulates TSP-1 expression and the implication on angiogenesis. Ado dose dependently increased the production of TSP-1 by human macrophages. With the use of agonists and antagonists of AdoRs, coupled to RNA interference, we observed that this effect is mediated via A2AR and A2BR. The Ado effect was reproduced by cholera toxin (Gs protein activator) and forskolin (adenylate cyclase activator) and blocked by the PKA inhibitor H89. Conditioned medium from Ado-treated macrophages stimulated microvessel outgrowth from aortic ring explants by 400%, and induced vessel formation in matrigel plugs, Microvessel outgrowth and vessel formation were blocked completely by addition of anti-TSP-1 antibodies to conditioned medium. Chronic administration of Ado to rats after Ml maintained long-term expression of TSP-1 in the infarct border zone, and this was associated with enhanced border-zone vascularization. Ado up-regulates TSP-1 production by macrophages, resulting in stimulation of angiogenesis. The mechanism Involves A2AR and A2BR and is mediated through the CAMP/PKA pathway. This information may be important when designing Ado-based therapies of angiogenesis. © Society for Leukocyte Biology.


Azuaje F.,Laboratory of Cardiovascular Research | Devaux Y.,Laboratory of Cardiovascular Research | Wagner D.R.,Laboratory of Cardiovascular Research | Wagner D.R.,Center Hospitalier
PLoS ONE | Year: 2010

Background: A significant proportion of myocardial infarction (MI) patients undergo complex, coordinated perturbations at the molecular level that may eventually drive the occurrence of ventricular dysfunction and heart failure. Despite advances in the elucidation of key processes implicated in this condition, traditional methods relying on gene expression data and the identification of individual biomarkers in isolation pose major limitations not only for improving prediction power, but also for model interpretability. Mechanisms underlying clinical responses after MI remain elusive and there is no biomarker with the capacity to accurately predict ventricular dysfunction after MI. This calls for the exploration of system-level modeling of ventricular dysfunction in post-MI patients. Within this discovery framework key perturbations and predictive patterns are characterized by the integrated biological activity levels observed in pathways, rather than in individual genes. Methodology/Principal Findings: Here we report an integrative approach to identifying pathways related with ventricular dysfunction post MI with potential prognostic and therapeutic value. We found that a diversity of pathway-level perturbations can be profiled in samples of patients with ventricular dysfunction post MI, most of which represent major reductions of gene expression. Highly perturbed pathways included those implicated in antigen-dependent B-cell activation and the synthesis of leucine. By analyzing patient-specific samples encoded with information derived from highly-perturbed pathways, it is possible to visualize differential prognostic patterns and to perform computational classification of patients with areas under the receiver operating characteristic curve above 0.75. We also demonstrate how the integration of the outcomes generated by different pathway-based analysis models may improve ventricular dysfunction prediction performance. Significance: This research offers an alternative, comprehensive view of key relationships and perturbations that may trigger the emergence or prevention of ventricular dysfunction post-MI. © 2010 Azuaje et al.


Stammet P.,Center Hospitalier | Wagner D.R.,Center Hospitalier | Wagner D.R.,Laboratory of Cardiovascular Research | Gilson G.,Center Hospitalier | Devaux Y.,Laboratory of Cardiovascular Research
Journal of the American College of Cardiology | Year: 2013

Objectives This study was designed to evaluate multimodal prognostication in patients after cardiac arrest (CA). Background Accurate methods to predict outcome after CA are lacking. Methods Seventy-five patients with CA treated with therapeutic hypothermia after cardiac resuscitation were enrolled in this prospective observational study. Serum levels of neuron-specific enolase (NSE) and neuron-enriched S100 beta (S100β) were measured 48 h after CA. Bispectral index (BIS) was continuously monitored during the first 48 h after CA. The primary endpoint was neurological outcome, as defined by the cerebral performance category (CPC) at 6-month follow-up: scores 1 or 2 indicated good outcome, and scores 3 to 5, poor outcome. The secondary endpoint was survival. Results A total of 46 (61%) patients survived at 6 months and 41 (55%) patients had CPC 1 or 2. Levels of NSE and S100β were higher in patients with poor outcomes compared with patients with good outcomes (4-fold and 10-fold, respectively; p < 0.001). BIS was lower in patients with poor outcomes (10-fold; p < 0.001). NSE, S100β, or BIS alone predicted neurological outcome, with areas under the receiver-operating characteristic curve (AUC) above 0.80. Combined determination of S100β and BIS had an incremental predictive value (AUC: 0.95). S100β improved discriminations based on BIS (p = 0.0008), and BIS improved discriminations based on S100β (p < 10-5). Patients with S100β level above 0.03 μg/l and BIS below 5.5 had a 3.6-fold higher risk of poor neurological outcome (p < 0.0001). S100β and BIS predicted 6-month mortality (log-rank statistic: 50.41; p < 0.001). Conclusions Combined determination of serum level of S100β and BIS monitoring accurately predicts outcome after CA. © 2013 by the American College of Cardiology Foundation Published by Elsevier Inc.


Devaux Y.,Laboratory of Cardiovascular Research | Azuaje F.,Laboratory of Cardiovascular Research | Vausort M.,Laboratory of Cardiovascular Research | Yvorra C.,Laboratory of Cardiovascular Research | Wagner D.R.,Center Hospitalier
Functional and Integrative Genomics | Year: 2010

A significant proportion of patients develop left ventricular (LV) dysfunction and heart failure (HF) after acute myocardial infarction (MI). Existing biomarkers of HF provide limited information after MI. To identify new prognostic biomarkers in MI patients, we designed an approach combining protein interaction networks and microarray analysis of blood cells. Blood samples for RNA and protein analysis were taken from 127 acute MI patients. Echocardiography was performed at one month. Assuming that angiogenesis is related to cardiac repair after MI, a protein-protein interaction network of angiogenesis was constructed and analyzed. Among the 556 proteins and 686 interactions of this network, a cluster of 53 proteins highly specialized in regulation of cell growth was identified. Of these 53 proteins, 38 were found differentially expressed by microarrays between low (≤40%) and high (>40%) LV ejection fraction (EF) patients (n=32). Among these 38 genes, prediction analysis identified a set of three genes able to predict significant LV dysfunction (EF≤40%) with an area under the receiver operating characteristic curve (AUC) of 0.82. These three genes-vascular endothelial growth factor B, thrombospondin-1 and placental growth factor-had a stronger predictive value than brain natriuretic peptide and troponin T (AUC of 0.63). Independent validations on protein expression and quantitative PCR datasets confirmed the results. In conclusion, a new strategy is described that allows identifying new potential biomarkers. The three specific biomarkers described here remain to be validated in a larger patient population. © 2010 Springer-Verlag.


Bousquenaud M.,Laboratory of Cardiovascular Research | Schwartz C.,Laboratory of Cardiovascular Research | Lonard F.,Laboratory of Cardiovascular Research | Rolland-Turner M.,Laboratory of Cardiovascular Research | And 3 more authors.
Cardiovascular Research | Year: 2012

Aims Circulating angiogenic cells (CAC) participate in cardiac repair. CAC recruitment to the ischaemic heart is mainly induced by the chemokine (CXC motif) receptor 4 (CXCR4)/stromal-cell derived factor-1α axis. However, CAC mobilization is only partly prevented by CXCR4 blockade, indicating that other mechanisms are involved. Since the expression of monocyte chemotactic protein 3 (MCP3) is increased in ischaemic hearts, we hypothesized that it may participate in CAC mobilization. Methods and resultsCAC were obtained from peripheral blood mononuclear cells of healthy volunteers. In vitro migration of CAC was concentration-dependently increased by recombinant MCP3 (one-fold increase, P 0.001), and this effect was inhibited by antibodies neutralizing the chemokine (CC motif) receptor 1 (CCR1). CCR1 expression at the surface of CAC was confirmed by flow cytometry. Conditioned medium from heparan sulfate-activated macrophages, which contained MCP3, induced the migration of CAC (one-fold increase, P 0.01). This increase was partly inhibited by CCR1 antibodies. The migration of CAC was also stimulated by macrophage inflammatory protein 3β. This effect was blocked by CCR7 antibodies and was of lower magnitude than that of MCP3. MCP3 induced the formation of blood vessels in Matrigel plugs implanted in mice (1.5-fold increase, P< 0.001). This effect was abrogated by anti-CCR1 antibodies. Conclusion This study shows that MCP3 stimulates the migration of CAC and angiogenesis, suggesting that MCP3 may be useful to improve cardiac repair. © 2012 The Author.


Azuajeu F.,Laboratory of Cardiovascular Research
Briefings in Bioinformatics | Year: 2011

Tissue growth and regeneration are fundamental processes underpinning crucial physiological and pathological conditions: ranging from normal blood vessel network development, response to stem cells therapy and cancers. Modelling of such biological phenomena has been addressed through mathematical and algorithmic approaches. The former implements continuous representations based on differential equations. The latter exploit operational descriptions in the form of computing programs to represent and execute the models. Within this area, models that define the cell as the fundamental unit of model development, as well as discrete representations of different model entities, are important to plan in vitro experiments and to generate new testable hypotheses. This article reviews the application of algorithmic discrete models, with a focus on tissue growth and regeneration phenomena in the context of health and disease. The review begins with an overview of basic concepts, problems and approaches of computational discrete models. This will include a discussion of basic assumptions and design principles. An overview of key cell-driven approaches and examples of applications in tissue growth and regeneration is provided. The specification, implementation and analysis of a model are illustrated with a hypothetical example, which mimics the branching and sprouting patterns observed in blood vessel network development. The article concludes with a discussion of current challenges and recommendations. © The Author 2010. Published by Oxford University Press.

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