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Corsi F.,Catholic University of the Sacred Heart | Corsi F.,University Pierre and Marie Curie | Lebreton G.,University Pierre and Marie Curie | Brechot N.,University Pierre and Marie Curie | And 9 more authors.
Critical Care | Year: 2017

Background: Despite quick implementation of reperfusion therapies, a few patients with high-risk, acute, massive, pulmonary embolism (PE) remain highly hemodynamically unstable. Others have absolute contraindication to receive reperfusion therapies. Venoarterial-extracorporeal membrane oxygenation (VA-ECMO) might lower their right ventricular overload, improve hemodynamic status, and restore tissue oxygenation. Methods: ECMO-related complications and 90-day mortality were analyzed for 17 highly unstable, ECMO-treated, massive PE patients admitted to a tertiary-care center (2006-2015). Hospital- discharge survivors were assessed for long-term health-related quality of life. A systematic review of this topic was also conducted. Results: Seventeen high-risk PE patients [median age 51 (range 18-70) years, Simplified Acute Physiology Score II (SAPS II) 78 (45-95)] were placed on VA-ECMO for 4 (1-12) days. Among 15 (82%) patients with pre-ECMO cardiac arrest, seven (41%) were cannulated during cardiopulmonary resuscitation, and eight (47%) underwent pre-ECMO thrombolysis. Pre-ECMO median blood pressure, pH, and blood lactate were, respectively: 42 (0-106) mmHg, 6.99 (6.54-7.37) and 13 (4-19) mmol/L. Ninety-day survival was 47%. Fifteen (88%) patients suffered in-ICU severe hemorrhages with no impact on survival. Like other ECMO-treated patients, ours reported limitations of all physical domains but preserved mental health 19 (4-69) months post-ICU discharge. Conclusions: VA-ECMO could be a lifesaving rescue therapy for patients with high-risk, acute, massive PE when thrombolytic therapy fails or the patient is too sick to benefit from surgical thrombectomy. Because heparin-induced clot dissolution and spontaneous fibrinolysis allows ECMO weaning within several days, future studies should investigate whether VA-ECMO should be the sole therapy or completed by additional mechanical clot-removal therapies in this setting. © 2017 The Author(s).


Orsoni A.,French Institute of Health and Medical Research | Orsoni A.,ICAN Institute of Cardiometabolism and Nutrition | Orsoni A.,University Pierre and Marie Curie | Villard E.F.,French Institute of Health and Medical Research | And 21 more authors.
Journal of Lipid Research | Year: 2012

In familial hypercholesterolemia (FH), low HDL cholesterol (HDL-C) levels are associated with functional alterations of HDL particles that reduce their capacity to mediate the reverse cholesterol transport (RCT) pathway. The objective of this study was to evaluate the consequences of LDL apheresis on the efficacy of the RCT pathway in FH patients. LDL apheresis markedly reduced abnormal accelerated cholesteryl ester transfer protein (CETP) -mediated cholesteryl ester (CE) transfer from HDL to LDL, thus reducing their CE content. Equally, we observed a major decrease (-53%; P < 0.0001) in pre-β1-HDL levels. The capacity of whole plasma to mediate free cholesterol efflux from human macrophages was reduced (-15%; P < 0.02) following LDL apheresis. Such reduction resulted from a marked decrease in the ABCA1-dependent efflux (-71%; P < 0.0001) in the scavenger receptor class B type I-dependent efflux (-21%; P < 0.0001) and in the ABCG1-dependent pathway (-15%; P < 0.04). However, HDL particles isolated from FH patients before and after LDL apheresis displayed a similar capacity to mediate cellular free cholesterol efflux or to deliver CE to hepatic cells. We demonstrate that rapid removal of circulating lipoprotein particles by LDL apheresis transitorily reduces RCT. However, LDL apheresis is without impact on the intrinsic ability of HDL particles to promote either cellular free cholesterol efflux from macrophages or to deliver CE to hepatic cells. Copyright © 2012 by the American Society for Biochemistry and Molecular Biology, Inc.


Dubern B.,Nutrition et gastroenterologie pediatriques | Dubern B.,ICAN Institute of Cardiometabolism and Nutrition
Obesite | Year: 2014

Due to the increased frequency of extreme obesity in adolescents and the inefficiency of usual treatments, bariatric surgery is now largely discussed as novel therapeutic option. However, it is important to be cautious due the specificity of this age. In addition, until now, the type of surgery (adjustable gastric banding, sleeve gastrectomy or Roux-en-Y gastric bypass) is still largely discussed even if Roux-en-Y gastric bypass should be the better option due to its higher efficacy. © 2013 Springer-Verlag France.


El Khoury P.,French Institute of Health and Medical Research | El Khoury P.,Saint - Joseph University | Waldmann E.,Ludwig Maximilians University of Munich | Huby T.,French Institute of Health and Medical Research | And 16 more authors.
Arteriosclerosis, Thrombosis, and Vascular Biology | Year: 2016

Objectives-Postprandial atherogenic lipoproteins, characterizing high-risk patients, correlate positively with cardiovascular events. Although the effect of niacin on fasting lipids is well established, its impact on atheroprotective reverse cholesterol transport (RCT) pathway and on functional features of circulating lipoproteins during the postprandial state remains indeterminate. Approach and Results-We evaluated RCT pathway during postprandial phase in dyslipidemic patients displaying a low high-density lipoprotein (HDL) cholesterol phenotype. Ten subjects on stable statin therapy received 1 g/20 mg extended-release niacin/laropiprant (ERN/LRPT) for 4 weeks followed by 2 g/40 mg ERN/LRPT for additional 8 weeks. At each experimental period, postprandial hypertriglyceridemia and major steps of RCT, including cholesterol efflux from human macrophages, cholesteryl ester transfer protein-mediated cholesteryl ester transfer, and hepatic HDL-cholesteryl ester selective uptake were evaluated. Equally, the capacity of postprandial HDL particles isolated from patients before and after ERN/LRPT treatment to mediate RCT to feces was evaluated in vivo in human apolipoprotein B/cholesteryl ester transfer protein double transgenic mouse model. Compared with baseline, ERN/LRPT significantly reduced postprandial hypertriglyceridemia (incremental area under the curve-triglyceride:-53%; P=0.02). Postprandial increase in endogenous plasma cholesteryl ester transfer protein activity was completely abolished after ERN/LRPT treatment. Despite a slight reduction in plasma cholesterol efflux capacity from human THP-1 macrophages, evaluation of global RCT efficacy by combining both ex vivo and in vivo approaches indicate that postprandial HDL particles formed under ERN/LRPT therapy displayed a greater capacity for HDL-mediated RCT to feces. Conclusions-ERN/LRPT treatment efficiently attenuates atherogenic postprandial lipemia and stimulates HDL-mediated cholesterol return to the liver and elimination into feces during postprandial phase, thus maintaining an efficient removal of cholesterol from the body. © 2016 American Heart Association, Inc.


Rizkalla S.W.,University Pierre and Marie Curie | Rizkalla S.W.,Ican Institute Of Cardiometabolism And Nutrition | Cotillard A.,University Pierre and Marie Curie | Pelloux V.,University Pierre and Marie Curie | And 10 more authors.
American Journal of Clinical Nutrition | Year: 2012

Background: The most effective and safe dietary approach for weight loss and its impact on the metabolic functions and morphology of adipose tissue remain unclear. Objectives: We evaluated whether an energy-restricted high-protein diet with a low glycemic index and soluble fiber (LC-P-LGI) would be more effective than a low-calorie conventional diet (LC-CONV) on weight loss and related metabolic risk factors. We further determined factors that may influence adipocyte size during energy restriction. Design: Thirteen obese participants were randomly assigned in a crossover design to 2 periods of a 4-wk hypocaloric diet as either LC-P-LGI or LC-CONV, separated by 8-wk washout intervals. Results: In comparison with the LC-CONV diet, the main effect of the LC-P-LGI diet was a greater decrease in adipocyte diameter (P = 0.048), plasma plasminogen activator inhibitor protein-1 (P = 0.019), vascular endothelial growth factor (P = 0.032), and interferon-c inducible protein 10 (P = 0.010). Whereas fasting plasma glucose and high-sensitivity C-reactive protein decreased only after the LC-P-LGI diet, with no differences between diets, fasting plasma insulin and insulin resistance were lower after the LC-CONV diet. The diet results did not differ for body composition and lipid variables. Kinetic modifications in adipocyte diameter were associated with metabolic variables and genes implicated in adipocyte proliferation, apoptosis, and angiogenesis. Conclusions: In comparison with the LC-CONV diet, the LC-PLGI diet was associated with improvement in some cardiometabolic risk factors and greater reduction in adipocyte size. Profiles of genes involved in inhibiting adipogenesis and angiogenesis, but increasing apoptosis, were correlated with decreased adipocyte size. This study provides insight into the adipose tissue-remodeling changes that induce regulation of adipocyte size during dietary weight loss. This trial was registered at clinicaltrials.gov as NCT01312740. © 2012 American Society for Nutrition.


Villard E.F.,French Institute of Health and Medical Research | Villard E.F.,University Pierre and Marie Curie | Villard E.F.,ICAN Institute of CardioMetabolism and Nutrition | Federspiel M.-C.,AP HP | And 20 more authors.
Atherosclerosis | Year: 2013

Objectives: To identify key determinants of plasma endogenous CETP activity and threshold value of plasma CETP activity associated with high cardiovascular risk. Methods: Endogenous plasma CETP activity was measured in a total of 1403 individuals. Results: Multivariate analysis revealed that 23.5% of endogenous CETP activity variability was explained by plasma LDL-C (12.0%), HDL-C (6.4%) and TG (4.4%) whereas sex and BMI accounted together for only 0.7% of its variability. Scoring patients for cardiovascular risk on the basis of their plasma lipid levels (TC, TG, LDL-C and HDL-C), revealed that patients with high cardiovascular risk (score ≥3) displayed a mean endogenous plasma CETP activity above 34%. Conclusion: Plasma CETP activity represents a potent indicator of cardiovascular risk in patients with metabolic disorders since it integrates major independent risk factors. © 2013 Elsevier Ireland Ltd.


Gautier E.L.,French Institute of Health and Medical Research | Gautier E.L.,University Pierre and Marie Curie | Gautier E.L.,ICAN Institute of CArdiometabolism and Nutrition | Yvan-Charvet L.,French Institute of Health and Medical Research
Immunological Reviews | Year: 2014

Macrophages are phagocytes characterized by high lysosomal activity and are involved in a wide range of biological processes. Consequently, macrophages have long been recognized for their critical roles in development as well as in healthy and pathological states. Our knowledge about macrophage biology has evolved greatly over the past several years. Significantly, it has now been demonstrated that monocytes are not direct precursors for most tissue-resident macrophages at the steady state. Only few tissue macrophage populations derive from monocytes during homeostasis; rather, monocytes give rise to inflammatory macrophages that infiltrate tissues during inflammation. Tissue-resident macrophages have recently been characterized at the transcriptional level, which provided the basis to uncover the molecular pathways controlling their functional diversity as well as to identify a core signature. Transcription factors controlling specific tissue-resident macrophage populations have been described, suggesting that diversity is under the control of specific regulatory programs. In this review, we discuss and summarize several of the new paradigms emerging in the field of macrophage biology. In particular, we emphasize new findings relevant to macrophage ontogeny, similarities and differences observed across macrophage populations, and gene regulatory programs controlling specialized aspects of tissue macrophage functions. © 2014 John Wiley & Sons A/S.


El Khoury P.,French Institute of Health and Medical Research | El Khoury P.,Saint - Joseph University | Plengpanich W.,Chulalongkorn University | Frisdal E.,French Institute of Health and Medical Research | And 5 more authors.
Atherosclerosis | Year: 2014

Objectives: CETP or HL deficiencies lead to a marked increase in HDL-C levels however the atheroprotective effect of this phenotype, in particular the ability of HDL particles to remove cholesterol from human macrophages, remains to be determined. Methods: We measured cholesterol efflux from human THP-1 macrophages to total plasma or to isolated HDL subfractions in patients with HALP carrying molecular defect in either the CETP or LIPC gene. Results: We demonstrate that HALP is associated with an increased plasma cholesterol efflux capacity from human macrophages. This observation is primarily related to a stimulation of both SR-BI and ABCA1 dependent efflux pathways as a result of quantitative elevation in HDL2 and enhanced intrinsic capacity of HDL3 subspecies, respectively. Conclusion: HDL particles from HALP patients with molecular defect within either CETP or LIPC gene are not dysfunctional and are efficient to stimulate cholesterol efflux from human macrophages. © 2014 Elsevier Ireland Ltd.


Perovanovic J.,Center for Genetic Medicine Research | Perovanovic J.,George Washington University | Dell'Orso S.,U.S. National Institutes of Health | Gnochi V.F.,Center for Genetic Medicine Research | And 13 more authors.
Science Translational Medicine | Year: 2016

The nuclear envelope protein lamin A is encoded by the lamin A/C (LMNA) gene, which can contain missense mutations that cause Emery-Dreifuss muscular dystrophy (EDMD) (p.R453W). We fused mutated forms of the lamin A protein to bacterial DNA adenine methyltransferase (Dam) to define euchromatic-heterochromatin (epigenomic) transitions at the nuclear envelope during myogenesis (using DamID-seq). Lamin A missense mutations disrupted appropriate formation of lamin A-associated heterochromatin domains in an allele-specific manner-findings that were confirmed by chromatin immunoprecipitation-DNA sequencing (ChIP-seq) in murine H2K cells and DNA methylation studies in fibroblasts from muscular dystrophy patient who carried a distinct LMNA mutation (p.H222P). Observed perturbations of the epigenomic transitions included exit from pluripotency and cell cycle programs [euchromatin (open, transcribed) to heterochromatin (closed, silent)], as well as induction of myogenic loci (heterochromatin to euchromatin). In muscle biopsies from patients with either a gain- or change-of-function LMNA gene mutation or a loss-of-function mutation in the emerin gene, both of which cause EDMD, we observed inappropriate loss of heterochromatin formation at the Sox2 pluripotency locus, which was associated with persistent mRNA expression of Sox2. Overexpression of Sox2 inhibited myogenic differentiation in human immortalized myoblasts. Our findings suggest that nuclear envelopathies are disorders of developmental epigenetic programming that result from altered formation of lamina-associated domains.


Villard E.F.,French Institute of Health and Medical Research | Villard E.F.,University Pierre and Marie Curie | Villard E.F.,ICAN Institute of CardioMetabolism and Nutrition | Ei Khoury P.,French Institute of Health and Medical Research | And 20 more authors.
Arteriosclerosis, Thrombosis, and Vascular Biology | Year: 2013

OBJECTIVE: We investigated the impact of several genetic variants located in genes encoding for proteins involved in biogenesis, maturation, and intravascular remodeling of high density lipoprotein (HDL) particles on plasma efflux capacity. APPROACH AND RESULTS: The capacity of whole-plasma to mediate cholesterol efflux from cholesterol-loaded human THP-1 macrophages was measured in 846 individuals (450 men and 396 women). We demonstrated that rs17231506 (CETP c.-1337 C>T), rs2230806 (ABCA1 p.R219K), rs1799837 (APOA1 c.-75 G>A), rs5086 (APOAII c.-265 T>C), and rs1800588 (LIPC c.-514 C>T) single nucleotide polymorphisms (SNPs) significantly modulate the capacity of whole-plasma to mediate cholesterol efflux from human macrophages in a sex-dependent manner. Such associations were independent of circulating plasma lipid levels (HDL-cholesterol, triglyceride, low density lipoprotein- cholesterol). In women, we identified the APOA1 c.-75 G>A and the LIPC c.-514 C>T variants as major contributors of interindividual variability of plasma efflux capacity, whereas the ABCA1 p.R219K and the APOAII c.-265 T>C SNPs mostly contribute to total variance of plasma efflux capacity in men. Multiple regression analyses revealed that the 7 SNPs tested accounted together for approximately 6% of total plasma efflux capacity. We demonstrated that genetically determined plasma efflux capacity represents a better predictor of macrophage cholesterol removal, as compared with plasma HDL-cholesterol levels. CONCLUSIONS: Genetic variants located within genes encoding proteins involved in HDL metabolism significantly impact plasma efflux capacity independently of variation in plasma HDL-cholesterol levels. © 2013 American Heart Association, Inc.

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