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51. Paradoxical gastrointestinal effects of interleukin-17 blockers

Author: Nadine Petitpain, Djésia Arnone, Ferdinando D'Amico, Laurent Peyrin-Biroulet, Patrick Netter, Jean-Yves Jouzeau, David Moulin, Marine Fauny, Damien Loeuille, Service de Rhumatologie [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Ingénierie Moléculaire et Physiopathologie Articulaire (IMoPA), Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), Humanitas University [Milan] (Hunimed), Nutrition-Génétique et Exposition aux Risques Environnementaux (NGERE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Service de Pharmacologie Clinique et Toxicologie [CHRU Nancy], IMPACT GEENAGE, ANR-15-IDEX-0004,LUE,Isite LUE(2015), MOULIN, David, and ISITE - Isite LUE - - LUE2015 - ANR-15-IDEX-0004 - IDEX - VALID
Subjects: Adult, Male, 0301 basic medicine, Immunology, Brodalumab, Antibodies, Monoclonal, Humanized, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Psoriatic arthritis, 0302 clinical medicine, Crohn Disease, Rheumatology, Psoriasis, Humans, Immunology and Allergy, Medicine, Spondylitis, Ankylosing, Randomized Controlled Trials as Topic, 030203 arthritis & rheumatology, [SDV.MHEP.RSOA] Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, business.industry, Arthritis, Psoriatic, Interleukin-17, Interleukin, [SDV.IMM.IMM]Life Sciences [q-bio]/Immunology/Immunotherapy, Middle Aged, Inflammatory Bowel Diseases, medicine.disease, Ulcerative colitis, 3. Good health, Ixekizumab, Treatment Outcome, 030104 developmental biology, [SDV.MHEP.RSOA]Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, Antirheumatic Agents, Colitis, Ulcerative, Female, Secukinumab, Interleukin 17, [SDV.IMM.IMM] Life Sciences [q-bio]/Immunology/Immunotherapy, business
Abstract: International audience; Secukinumab, ixekizumab and brodalumab are monoclonal antibody therapies that inhibit interleukin (IL)-17 activity and are widely used for the treatment of psoriasis, psoriatic arthritis and ankylosing spondylitis. The promising efficacy results in dermatology and rheumatology prompted the evaluation of these drugs in Crohn's disease and ulcerative colitis, but the onset of paradoxical events (disease exacerbation after treatment with a theoretically curative drug) prevented their approval in patients with inflammatory bowel diseases (IBDs). To date, the pathophysiological mechanisms underlying these paradoxical effects are not well defined, and there are no clear guidelines for the management of patients with disease flare or new IBD onset after anti-IL-17 drug therapy. In this review, we summarise the literature on putative mechanisms, the clinical digestive effects after therapy with IL-17 inhibitors and provide guidance for the management of these paradoxical effects in clinical practice.
Published: 2020
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52. Longer Duration of Hypertension and MRI Microvascular Brain Alterations Are Associated with Lower Hippocampal Volumes in Older Individuals with Hypertension

Author: Triantafyllou, Areti, Ferreira, Joao Pedro, Kobayashi, Masatake, Micard, Emilien, Xie, Yu, Kearney-Schwartz, Anna, Hossu, Gabriela, Rossignol, Patrick, Bracard, Serge, Benetos, Athanase, DE CARVALHO, Philippe, Combattre l'insuffisance cardiaque - - FIGHT-HF2015 - ANR-15-RHUS-0004 - RHUS - VALID, ISITE - Isite LUE - - LUE2015 - ANR-15-IDEX-0004 - IDEX - VALID, Centres Mémoire de Ressources et de Recherche [CHRU Nancy] (CMRR de Lorraine), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Centre d'investigation clinique plurithématique Pierre Drouin [Nancy] (CIC-P), Centre d'investigation clinique [Nancy] (CIC), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Défaillance Cardiovasculaire Aiguë et Chronique (DCAC), Université de Lorraine (UL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Cardiovascular and Renal Clinical Trialists [Vandoeuvre-les-Nancy] (INI-CRCT), Institut Lorrain du Coeur et des Vaisseaux Louis Mathieu [Nancy], French-Clinical Research Infrastructure Network - F-CRIN [Paris] (Cardiovascular & Renal Clinical Trialists - CRCT ), Department of Physiology and Cardiothoracic Surgery, University of Porto, Centre d'Investigation Clinique - Innovation Technologique [Nancy] (CIC-IT), Imagerie Adaptative Diagnostique et Interventionnelle (IADI), Université de Lorraine (UL)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département de neuroradiologie diagnostique et thérapeutique [CHRU Nancy], This study was funded by grants from the Programme Hospitalier de Recherche Clinique (PHRC national, N◦2010-A01399-30). This work was supported by the 'Federation Hospitalo-Universitaire on Cardiac and Arterial Aging – FHU CARTAGE). AB, JPF and PR are partly supported by the French PIA projects: 'Lorraine Universite d’Excellence' (reference: ANR-15-IDEX-04-LUE) and RHU Fight-HF (reference: ANR-15-RHU-0004). Both public grants are overseen the French National Research Agency (ANR) as part of the second Investissementsd’Avenir' programme., IMPACT GEENAGE, ANR-15-RHUS-0004,FIGHT-HF,Combattre l'insuffisance cardiaque(2015), and ANR-15-IDEX-0004,LUE,Isite LUE(2015)
Subjects: Male, brain MRI, hypertension, Genotype, hippocampus, [SDV]Life Sciences [q-bio], Blood Pressure, Neuropsychological Tests, Body Mass Index, Cohort Studies, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Humans, Cognitive Dysfunction, Longitudinal Studies, Prospective Studies, Aged, Aged, 80 and over, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, white matter lesions, Aortic stiffness, Middle Aged, cognitive decline, Magnetic Resonance Imaging, White Matter, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, [SDV] Life Sciences [q-bio], macrovascular, Mental Recall, Microvessels, Female, Atrophy, microvascular, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Research Article, dementia
Abstract: International audience; Background: Hippocampal atrophy is associated with cognitive decline. Determining the clinical features associated with hippocampal volume (HV)/atrophy may help in tailoring preventive strategies.Objective: This study was aimed to investigate the association between HV (at visit 2) and vascular status (both at visit 1 and visit 2) in a cohort of individuals aged 60+ with hypertension and without overt cognitive impairment at visit 1 (visit 1 and visit 2 were separated by approximately 8 years).Methods: Hippocampal volume was estimated in brain MRIs as HV both clinically with the Scheltens’ Medial Temporal Atrophy score, and automatically with the Free Surfer Software application. A detailed medical history, somatometric measurements, cognitive tests, leukoaraiosis severity (Fazekas score), vascular parameters including pulse wave velocity, central blood pressure, and carotid artery plaques, as well as several biochemical parameters were also measured.Results: 113 hypertensive patients, 47% male, aged 75.1 ± 5.6 years, participated in both visit 1 and visit 2 of the ADELAHYDE study. Age ( = –0.30) and hypertension duration ( = –0.20) at visit 1 were independently associated with smaller HV at visit 2 (p < 0.05 for all). In addition to these variables, low body mass index ( = 0.18), high MRI Fazekas score ( = –0.20), and low Grober-Buschke total recall ( ¨ = 0.27) were associated with smaller HV at visit 2 (p < 0.05 for all).Conclusion: In a cohort of older individuals without cognitive impairment at baseline, we described several factors associated with lower HV, of which hypertension duration can potentially be modified.
Published: 2020
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53. Étude intégrative des facteurs environnementaux, de la génétique et de l’épigénétique du patient atteint d’obésité avant et après la chirurgie bariatrique

Author: Antoine, Darlène, UL, Thèses, ISITE - Isite LUE - - LUE2015 - ANR-15-IDEX-0004 - IDEX - VALID, Nutrition-Génétique et Exposition aux Risques Environnementaux (NGERE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Université de Lorraine, Rosa-Maria Guéant-Rodriguez, David Meyre, IMPACT GEENAGE, and ANR-15-IDEX-0004,LUE (ISITE),Lorraine Université d'Excellence(2016)
Subjects: Bariatric surgery, DNA methylation, Vitamin B12, [SDV]Life Sciences [q-bio], Épigénétique, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Chirurgie bariatrique, [SDV.MHEP.HEG] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Rare genetic variants, [SDV] Life Sciences [q-bio], [SDV.AEN] Life Sciences [q-bio]/Food and Nutrition, Variants génétiques rares/basse fréquence, Epigenetics, Méthylation de l'ADN, Obesity, Obésité, Vitamine B12, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition
Abstract: Obesity is a complex and multifactorial disease, resulting from genetic and environmental influences. In 2016, obesity affected more than 1.9 billion people worldwide, and this disorder is associated with multiple co-morbidities. In France, few treatment options are available to manage obesity such as lifestyle and behavior changes with poor results. In contrast, bariatric surgery leads to significant weight loss, better quality of life and decreased mortality rate. However, it is associated with nutritional complications. We evaluated in a cohort of patients undergoing bariatric surgery (OBESEPI "severe and epigenetic obesity") nutritional, genetic and epigenetic factors at medium-term following surgery. First, we observed that the vitamin B12 concentration before surgery was the only predictor of vitamin B12 concentration at a period of time (e.g. 2 years) after surgery, and it was also associated with age and aspartate aminotransferase / platelet ratio score. Second, we studied 14 rare / uncommon coding variants in "OBESEPI" patients as cases, and in the French Exome (FREX) as controls. We constructed a risk score, or protective score based on 11 rare variants. The results showed that neither the risk score nor the protective score was associated with preoperative BMI in patients with obesity or having an effect on the change in BMI in response to a lifestyle /behavior modification. In contrast, rare protective variants (decreased BMI) were significantly less common in patients with severe obesity compared to healthy controls. Third, we compared DNA methylation profiles using genome-wide analysis in cases and controls from the OBESEPI and the Marseille Thrombosis Association (MARTHA). This study showed that DNA methylation profiles in people with obesity were similar between the whole blood and liver, but not the visceral adipose tissue. In conclusion, this integrative approach to this work provided evidence for the interaction between genetic and environmental exposures in the pathogenesis of the obese phenotype., L'obésité est une maladie complexe et multifactorielle, résultant d’influences génétiques et environnementales. En 2016, l'obésité touchait plus de 1,9 milliards de personnes dans le monde, et cette maladie est associée à de multiples comorbidités. En France, peu d’options thérapeutiques sont disponibles pour lutter contre l’obésité, telles que les modifications du mode de vie et du comportement, avec des résultats médiocres. En revanche, la chirurgie bariatrique entraîne une perte de poids significative, une meilleure qualité de vie et une diminution du taux de mortalité. Cependant, elle est associée à des complications nutritionnelles. Nous avons évalué dans une cohorte de patients subissant une chirurgie bariatrique (OBESEPI « obésité sévère et épigénétique ») les facteurs nutritionnels, génétiques et épigénétiques qui peuvent jouer sur le statut nutritionnel et sur la perte de poids à moyen terme après chirurgie. Tout d’abord, nous avons observé que la concentration de vitamine B12 avant la chirurgie était le seul prédicteur de la concentration de vitamine B12 à une période (par exemple, 2ans) après la chirurgie, et qu’elle était également associée à l'âge et au score du rapport aspartate aminotransférase/plaquettes. Par la suite, nous avons étudié 14 des variants codants rares / peu fréquents chez les patients « OBESEPI » comme cas, et dans la cohorte d'Exome français (FREX) comme témoins. Nous avons construit un score, soit risque, soit protecteur, basé sur 11 variants rares. Les résultats ont montré que, ni le score à risque, ni le score protecteur, ne sont associés à l'IMC, avant l'intervention chez les patients atteints d’obésité ou ayant un effet sur la modification de l'IMC en réponse à une modification de style de vie/comportement. Par contre, les variants rares protecteurs (diminution de l'IMC), sont significativement moins fréquents chez les patients souffrant d'obésité sévère par rapport aux témoins sains. Pour terminer, nous avons comparé les profils de méthylation de l'ADN à l'aide d'une analyse à l'échelle du génome dans des cas et des contrôles de l'OBESEPI et de la Marseille Thrombosis Association (MARTHA). Cette étude a montré que les profils de méthylation de l'ADN des personnes atteintes d'obésité sont similaires entre le sang total et le foie, mais pas le tissu adipeux viscéral. En conclusion, cette approche intégrative de ce travail a fourni des preuves de l'interaction entre les expositions génétiques et environnementales dans la pathogenèse du phénotype obèse.
Published: 2020

54. Population and evolutionary genetics of the PAH locus to uncover overdominance and adaptive mechanisms in phenylketonuria: Results from a multiethnic study

Author: Oussalah, Abderrahim, Jeannesson-Thivisol, Elise, Chery, Céline, Perrin, Pascal, Rouyer, Pierre, Josse, Thomas, Cano, Aline, Barth, Magalie, Fouilhoux, Alain, Mention, Karine, Labarthe, François, Arnoux, Jean-Baptiste, Maillot, François, Lenaerts, Catherine, Dumesnil, Cécile, Wagner, Kathy, Terral, Daniel, Broue, Pierre, de Parscau, Loïc, Gay, Claire, Kuster, Alice, Bedu, Antoine, Besson, Gérard, Lamireau, Delphine, Odent, Sylvie, Masurel, Alice, Rodriguez-Guéant, Rosa-Maria, Feillet, François, Guéant, Jean-Louis, Namour, Fares, Nutrition-Génétique et Exposition aux Risques Environnementaux (NGERE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Centre de référence des maladies héréditaires du métabolisme (MaMEA Nancy-Brabois), Hôpital de la Timone [CHU - APHM] (TIMONE), Service de génétique [Angers], Université d'Angers (UA)-Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), Hôpital Jeanne de Flandres, Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Amiens-Picardie, CHU Rouen, Normandie Université (NU), Hôpitaux Pédiatriques de Nice Lenval (CHU-Lenval), Centre Hospitalier Universitaire de Nice (CHU Nice), Service de Pédiatrie Générale [CHU Clermont-Ferrand], CHU Estaing [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand, Hôpital des Enfants, CHU Toulouse [Toulouse], CHRU de Brest - Département de Pédiatrie (CHU BREST Pédiatrie), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Centre Hospitalier Universitaire de Saint-Etienne (CHU de Saint-Etienne), Centre hospitalier universitaire de Nantes (CHU Nantes), Service de Pédiatrie médicale - réanimation et néonatologie [CHU Limoges], CHU Limoges, Centre Hospitalier Universitaire [Grenoble] (CHU), Hôpital Pellegrin, CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, CHU Pontchaillou [Rennes], Service de génétique, CHU Dijon, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), IMPACT GEENAGE, ANR-15-IDEX-0004,LUE,Isite LUE(2015), Centre Hospitalier Régional Universitaire de Tours (CHRU TOURS), DE CARVALHO, Philippe, ISITE - Isite LUE - - LUE2015 - ANR-15-IDEX-0004 - IDEX - VALID, and Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)
Subjects: Male, Research paper, [SDV]Life Sciences [q-bio], lcsh:Medicine, Metabolic adaptation, Gene Frequency, Phenylketonurias, Overdominance, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Ethnicity, Humans, Phenylketonuria, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Exome, Genetic Association Studies, Phylogeny, Principal Component Analysis, lcsh:R5-920, Geography, lcsh:R, Phenylalanine Hydroxylase, Biological Evolution, [SDV] Life Sciences [q-bio], Balancing selection, Genetics, Population, Haplotypes, Genetic Loci, Population divergence, Female, France, lcsh:Medicine (General)
Abstract: Background: Phenylketonuria (PKU) is the most common inborn error of amino acid metabolism in Europe. The reasons underlying the high prevalence of heterozygous carriers are not clearly understood. We aimed to look for pathogenic PAH variant enrichment according to geographical areas and patients’ ethnicity using a multiethnic nationwide cohort of patients with PKU in France. We subsequently appraised the population differentiation, balancing selection and the molecular evolutionary history of the PAH locus. Methods: The French nationwide PKU study included patients who have been referred at the national level to the University Hospital of Nancy, and for whom a molecular diagnosis of phenylketonuria was made by Sanger sequencing. We performed enrichment analyses by comparing alternative allele frequencies using Fisher's exact test with Bonferroni adjustment. We estimated the amount of genetic differentiation among populations using Wright's fixation index (Fst). To estimate the molecular evolutionary history of the PAH gene, we performed phylogenetic and evolutionary analyses using whole-genome and exome-sequencing data from healthy individuals and non-PKU patients, respectively. Finally, we used exome-wide association study to decipher potential genetic loci associated with population divergence on PAH. Findings: The study included 696 patients and revealed 132 pathogenic PAH variants. Three geographical areas showed significant enrichment for a pathogenic PAH variant: North of France (p.Arg243Leu), North-West of France (p.Leu348Val), and Mediterranean coast (p.Ala403Val). One PAH variant (p.Glu280Gln) was significantly enriched among North-Africans (OR = 23·23; 95% CI: 9·75–55·38). PAH variants exhibiting a strong genetic differentiation were significantly enriched in the ‘Biopterin_H’ domain (OR = 6·45; 95% CI: 1·99–20·84), suggesting a balancing selection pressure on the biopterin function of PAH. Phylogenetic and timetree analyses were consistent with population differentiation events on European-, African-, and Asian-ancestry populations. The five PAH variants most strongly associated with a high selection pressure were phylogenetically close and were located within the biopterin domain coding region of PAH or in its vicinity. Among the non-PAH loci potentially associated with population divergence, two reached exome-wide significance: SSPO (SCO-spondin) and DBH (dopamine beta-hydroxylase), involved in neuroprotection and metabolic adaptation, respectively. Interpretation: Our data provide evidence on the combination of evolutionary and adaptive events in populations with distinct ancestries, which may explain the overdominance of some genetic variants on PAH. Funding: French National Institute of Health and Medical Research (INSERM) UMR_S 1256. Keywords: Phenylketonuria, Balancing selection, Population divergence, Overdominance, Metabolic adaptation
Published: 2020
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55. Cardiovascular and Non-Cardiovascular death distinction: the utility of Troponin beyond NT-proBNP. Findings from the BIOSTAT-CHF study

Author: Ferreira, Joao Pedro, Ouwerkerk, Wouter, Tromp, Jasper, Ng, Leong, Dickstein, Kenneth, Anker, Stefan, Filippatos, Gerasimos, Cleland, John, Metra, Marco, Veldhuisen, Dirk, Voors, Adriaan, Zannad, Faiez, Centre d'investigation clinique plurithématique Pierre Drouin [Nancy] (CIC-P), Centre d'investigation clinique [Nancy] (CIC), Université de Lorraine (UL)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM), Défaillance Cardiovasculaire Aiguë et Chronique (DCAC), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Cardiovascular and Renal Clinical Trialists [Vandoeuvre-les-Nancy] (INI-CRCT), Institut Lorrain du Coeur et des Vaisseaux Louis Mathieu [Nancy], French-Clinical Research Infrastructure Network - F-CRIN [Paris] (Cardiovascular & Renal Clinical Trialists - CRCT ), National Heart Centre Singapore (NHCS), University of Amsterdam [Amsterdam] (UvA), University Medical Center Groningen [Groningen] (UMCG), University of Leicester, Stavanger University Hospital, Berlin-Brandenburg Center for Regenerative Therapies [Berlin, Germany], Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], University General Hospital ' Attikon ' [Athens, Greece], University of Cyprus (UCY), Robertson Centre for Biostatistics and Clinical Trials, University of Glasgow and National Heart & Lung Institute, National Heart and Lung Institute [London] (NHLI), Imperial College London-Royal Brompton and Harefield NHS Foundation Trust, Università degli Studi di Brescia [Brescia], Contrat de Plan Etat Région Lorraine and FEDER IT2MP, IMPACT GEENAGE, ANR-15-RHUS-0004,FIGHT-HF,Combattre l'insuffisance cardiaque(2015), ANR-15-IDEX-0004,LUE,Isite LUE(2015), European Project: 242209,EC:FP7:HEALTH,FP7-HEALTH-2009-single-stage,BIOSTAT-CHF(2010), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), University of Cyprus [Nicosia] (UCY), Università degli Studi di Brescia = University of Brescia (UniBs), DE CARVALHO, Philippe, Combattre l'insuffisance cardiaque - - FIGHT-HF2015 - ANR-15-RHUS-0004 - RHUS - VALID, ISITE - Isite LUE - - LUE2015 - ANR-15-IDEX-0004 - IDEX - VALID, and A systems BIOlogy Study to TAilored Treatment in Chronic Heart Failure - BIOSTAT-CHF - - EC:FP7:HEALTH2010-04-01 - 2015-03-31 - 242209 - VALID
Subjects: [SDV] Life Sciences [q-bio], Risk, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, [SDV]Life Sciences [q-bio], Events, Cardiovascular death, Heart failure, Natriuretic peptides, Non-cardiovascular death, Troponin, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system
Abstract: International audience; AIMS:Heart failure (HF) patients are at high-risk of cardiovascular (CV) events, including CV death. Nonetheless, a substantial proportion of these patients die from non-CV causes. Identifying patients at higher risk for each individual event may help selecting patients for clinical trials and tailoring cardiovascular therapies. The aims of the present study are to: (i) characterize patients according to CV vs. non-CV death; (ii) develop models for the prediction of the respective events; (iii) assess the models' performance to differentiate CV from non-CV death.METHODS AND RESULTS:This study included 2309 patients with HF from the BIOSTAT-CHF (a systems BIOlogy Study to TAilored Treatment in Chronic Heart Failure) study. Competing-risk models were used to assess the best combination of variables associated with each cause-specific death. Results were validated in an independent cohort of 1738 HF patients. The best model to predict CV death included low blood pressure, estimated glomerular filtration rate ≤ 60 mL/min, peripheral oedema, previous HF hospitalization, ischaemic HF, chronic obstructive pulmonary disease, elevated N-terminal pro-B-type natriuretic peptide (NT-proBNP), and troponin (c-index = 0.73). The non-CV death model incorporated age > 75 years, anaemia and elevated NT-proBNP (c-index = 0.71). Both CV and non-CV death rose by quintiles of the risk scores; yet these models allowed the identification of patients in whom absolute CV death rates clearly outweigh non-CV death ones. These findings were externally replicated, but performed worse in a less severely diseased population.CONCLUSIONS:Risk models for predicting CV and non-CV death allowed the identification of patients at higher absolute risk of dying from CV causes (vs. non-CV ones). Troponin helped in predicting CV death only, whereas NT-proBNP helped in the prediction of both CV and non-CV death. These findings can be useful both for tailoring therapies and for patient selection in HF trials in order to attain CV event enrichment.
Published: 2019
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56. Management of hyperkalemia in the acutely ill patient

Author: W. Frank Peacock, Zubaid Rafique, Kathleen D. Liu, Patrick Rossignol, Matthieu Legrand, François Dépret, Service d'Anesthésie-Réanimation [AP-HP Hôpitaux Saint-Louis Lariboisière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Biomarqueurs CArdioNeuroVASCulaires (BioCANVAS), Université Paris 13 (UP13)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Baylor College of Medicine (BCM), Baylor University, Department of Medicine [San Francisco], University of California [San Francisco] (UCSF), University of California-University of California, French-Clinical Research Infrastructure Network - F-CRIN [Paris] (Cardiovascular & Renal Clinical Trialists - CRCT ), Défaillance Cardiovasculaire Aiguë et Chronique (DCAC), Université de Lorraine (UL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Centre d'investigation clinique [Nancy] (CIC), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), IMPACT GEENAGE, ANR-15-IDEX-0004,LUE,Isite LUE(2015), ANR-15-RHUS-0004,FIGHT-HF,Combattre l'insuffisance cardiaque(2015), F-CRIN, INICRCT network, Paris, CIC-Nancy, Institut Lorrain du Coeur et des Vaisseaux Louis Mathieu [Nancy]-Institut National de la Santé et de la Recherche Médicale (INSERM), Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), ANR-15-IDEX-04-LUE,LUE,Lorraine Université d'Excellence(2016), and ANR: ANR-15-RHU-0004,Programme Investissement d'Avenir ANR-15-RHU-0004
Subjects: medicine.medical_specialty, Kidney Disease, Hyperkalemia, medicine.medical_treatment, [SDV]Life Sciences [q-bio], Clinical Sciences, Renal and urogenital, Review, 030204 cardiovascular system & hematology, Cardiovascular, Critical Care and Intensive Care Medicine, [SDV.MHEP.UN]Life Sciences [q-bio]/Human health and pathology/Urology and Nephrology, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Anesthesiology, Intensive care, medicine, 030212 general & internal medicine, Renal replacement therapy, Intensive care medicine, Dialysis, Sodium bicarbonate, business.industry, Insulin, lcsh:Medical emergencies. Critical care. Intensive care. First aid, Acute kidney injury, Evaluation of treatments and therapeutic interventions, lcsh:RC86-88.9, medicine.disease, 3. Good health, Heart Disease, chemistry, 6.1 Pharmaceuticals, Emergency, Public Health and Health Services, medicine.symptom, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: Purpose To review the mechanisms of action, expected efficacy and side effects of strategies to control hyperkalemia in acutely ill patients. Methods We searched MEDLINE and EMBASE for relevant papers published in English between Jan 1, 1938, and July 1, 2018, in accordance with the PRISMA Statement using the following terms: “hyperkalemia,” “intensive care,” “acute kidney injury,” “acute kidney failure,” “hyperkalemia treatment,” “renal replacement therapy,” “dialysis,” “sodium bicarbonate,” “emergency,” “acute.” Reports from within the past 10 years were selected preferentially, together with highly relevant older publications. Results Hyperkalemia is a potentially life-threatening electrolyte abnormality and may cause cardiac electrophysiological disturbances in the acutely ill patient. Frequently used therapies for hyperkalemia may, however, also be associated with morbidity. Therapeutics may include the simultaneous administration of insulin and glucose (associated with frequent dysglycemic complications), β-2 agonists (associated with potential cardiac ischemia and arrhythmias), hypertonic sodium bicarbonate infusion in the acidotic patient (representing a large hypertonic sodium load) and renal replacement therapy (effective but invasive). Potassium-lowering drugs can cause rapid decrease in serum potassium level leading to cardiac hyperexcitability and rhythm disorders. Conclusions Treatment of hyperkalemia should not only focus on the ability of specific therapies to lower serum potassium level but also on their potential side effects. Tailoring treatment to the patient condition and situation may limit the risks. Electronic supplementary material The online version of this article (10.1186/s13613-019-0509-8) contains supplementary material, which is available to authorized users.
Published: 2019
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57. MRAs in Elderly HF Patients: Individual Patient-Data Meta-Analysis of RALES, EMPHASIS-HF, and TOPCAT

Author: Ferreira, João Pedro, Rossello, Xavier, Eschalier, Romain, McMurray, John J. V., Pocock, Stuart J., Girerd, Nicolas, Rossignol, Patrick, Pitt, Bertram, Zannad, Faiez, Centre d'investigation clinique plurithématique Pierre Drouin [Nancy] (CIC-P), Centre d'investigation clinique [Nancy] (CIC), Université de Lorraine (UL)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Lorraine (UL)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM), BHF Glasgow Cardiovascular Research Centre, University of Glasgow, London School of Hygiene and Tropical Medicine (LSHTM), Center for Molecular and Vascular Biology, Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), University of Michigan [Ann Arbor], University of Michigan System, Contrat de Plan Etat Région Lorraine, and FEDER grant IT2MP, SEC-CNIC CARDIOJOVEN fellowship program, IMPACT GEENAGE, ANR-15-IDEX-0004,LUE (ISITE),Lorraine Université d'Excellence(2016), ANR-15-RHUS-0004,FIGHT-HF,Combattre l'insuffisance cardiaque(2015), CCSD, Accord Elsevier, ISITE - Isite LUE - - LUE2015 - ANR-15-IDEX-0004 - IDEX - VALID, Combattre l'insuffisance cardiaque - - FIGHT-HF2015 - ANR-15-RHUS-0004 - RHUS - VALID, Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), ANR-15-IDEX-0004,LUE,Isite LUE(2015), Centre d'investigation clinique plurithématique Pierre Drouin (CIC-P), CIC-Nancy, Institut Lorrain du Coeur et des Vaisseaux Louis Mathieu [Nancy]-Institut National de la Santé et de la Recherche Médicale (INSERM), ANR-15-IDEX-04-LUE,LUE,Lorraine Université d'Excellence(2016), and ANR-15-RHU-0004,FIGHT-HF ,Fighting Heart Failure
Subjects: [SDV] Life Sciences [q-bio], [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, [SDV]Life Sciences [q-bio], mineralocorticoid receptor antagonists, treatment effects, elderly, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system
Abstract: International audience; OBJECTIVES:This study sought to assess the effect of MRA treatment (vs. placebo) in older patients (≥75 years of age) compared with younger patients (
Published: 2019
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58. A PRDX1 mutant allele causes a MMACHC secondary epimutation in cblC patients

Author: Guéant, Jean-Louis, Chéry, Céline, Oussalah, Abderrahim, Nadaf, Javad, Coelho, David, Josse, Thomas, Flayac, Justine, Robert, Aurélie, Koscinski, Isabelle, Gastin, Isabelle, Filhine-Tresarrieu, Pierre, Pupavac, Mihaela, Brebner, Alison, Watkins, David, Pastinen, Tomi, Montpetit, Alexandre, Hariri, Fadi, Tregouët, David, Raby, Benjamin A, Chung, Wendy K., Morange, Pierre-Emmanuel, Froese, D. Sean, Baumgartner, Matthias R., Benoist, Jean-François, Ficicioglu, Can, Marchand, Virginie, Motorin, Yuri, Bonnemains, Chrystèle, Feillet, François, Majewski, Jacek, Rosenblatt, David S., GONNET, JULIE, ISITE - Isite LUE - - LUE2015 - ANR-15-IDEX-0004 - IDEX - VALID, Nutrition-Génétique et Exposition aux Risques Environnementaux (NGERE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), McGill University = Université McGill [Montréal, Canada], Institut de Cancérologie de Lorraine - Alexis Vautrin [Nancy] (UNICANCER/ICL), UNICANCER, Génétique épidémiologique et moléculaire des pathologies cardiovasculaires, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR14-Institut National de la Santé et de la Recherche Médicale (INSERM), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Harvard Medical School [Boston] (HMS), University of Missouri [Columbia] (Mizzou), University of Missouri System, Nutrition, obésité et risque thrombotique (NORT), Institut National de la Recherche Agronomique (INRA)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Aix Marseille Université (AMU), Centre recherche en CardioVasculaire et Nutrition = Center for CardioVascular and Nutrition research (C2VN), University hospital of Zurich [Zurich], Hôpital Robert Debré, Hôpital Robert Debré-Centre Hospitalier Universitaire de Reims (CHU Reims), Perelman School of Medicine, University of Pennsylvania, Children’s Hospital of Philadelphia (CHOP ), Ingénierie Moléculaire et Physiopathologie Articulaire (IMoPA), Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), Ingénierie, Biologie et Santé en Lorraine (IBSLor), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), IMPACT GEENAGE, ANR-15-IDEX-0004,LUE,Isite LUE(2015), McGill University, Institut de Cancérologie de Lorraine - Alexis Vautrin (ICL), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [APHP], University of Missouri [Columbia], Aix Marseille Université (AMU)-Institut National de la Recherche Agronomique (INRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre recherche en CardioVasculaire et Nutrition (C2VN), University of Pennsylvania [Philadelphia], Université de Lorraine (UL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), ANR-15-IDEX-04-LUE,LUE,Lorraine Université d'Excellence(2016), and Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)
Subjects: MESH: Mutation, MESH: Metabolism, Inborn Errors, MESH: Pedigree, Science, MESH: Azacitidine, MESH: Peroxiredoxins, MESH: Carrier Proteins, MESH: Base Sequence, [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Article, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], MESH: Epistasis, Genetic, lcsh:Science, MESH: Heterozygote, MESH: Humans, MESH: Alleles, nutritional and metabolic diseases, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, MESH: Male, MESH: Vitamin B 12, MESH: Enzyme Inhibitors, MESH: Fibroblasts, MESH: Family Health, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], lcsh:Q, MESH: Whole Genome Sequencing, MESH: Female
Abstract: To date, epimutations reported in man have been somatic and erased in germlines. Here, we identify a cause of the autosomal recessive cblC class of inborn errors of vitamin B12 metabolism that we name “epi-cblC”. The subjects are compound heterozygotes for a genetic mutation and for a promoter epimutation, detected in blood, fibroblasts, and sperm, at the MMACHC locus; 5-azacytidine restores the expression of MMACHC in fibroblasts. MMACHC is flanked by CCDC163P and PRDX1, which are in the opposite orientation. The epimutation is present in three generations and results from PRDX1 mutations that force antisense transcription of MMACHC thereby possibly generating a H3K36me3 mark. The silencing of PRDX1 transcription leads to partial hypomethylation of the epiallele and restores the expression of MMACHC. This example of epi-cblC demonstrates the need to search for compound epigenetic-genetic heterozygosity in patients with typical disease manifestation and genetic heterozygosity in disease-causing genes located in other gene trios., Inborn errors of vitamin B12 metabolism of the cblC class are caused by mutations in the MMACHC gene. Here, Guéant et al. report epi-cblC, a class of cblC in which patients are compound heterozygous for a genetic mutation and a secondary epimutation at the MMACHC locus.
Published: 2018
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59. Telomeres: New players in immune-mediated inflammatory diseases?

Author: Laurent Peyrin-Biroulet, Anne-Charlotte Heba, Simon Toupance, Ndeye Coumba Ndiaye, Anthanase Benetos, Djésia Arnone, Nutrition-Génétique et Exposition aux Risques Environnementaux (NGERE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Défaillance Cardiovasculaire Aiguë et Chronique (DCAC), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Service d'Hépato-gastro-entérologie [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), CHRU-Nancy, Pôle 'Maladies du Vieillissement, Gérontologie et Soins Palliatif, Doctoral Fellowship from 'Reseau Lorrain des Maladies inflammatoires chroniques intestinales' MICILOR and Association des chefs de service from CHRU de Nancy to ACH. Research award 2020 from 'Societe Francophone de Nutrition Clinique et Métabolisme' SFNCM [GRANT_NUMBER: SFNCM2020] to DA. This work was supported by the French PIA project « Lorraine Université d’Excellence », reference ANR-15-IDEX-04-LUE and the Investments for the Future program under grant agreement No. ANR-15-RHU-0004., IMPACT GEENAGE, ANR-15-RHUS-0004,FIGHT-HF,Combattre l'insuffisance cardiaque(2015), and ANR-15-IDEX-0004,LUE,Isite LUE(2015)
Subjects: Immune-mediated inflammatory diseases, [SDV]Life Sciences [q-bio], Immunology, Inflammation, Biology, Bioinformatics, medicine.disease_cause, Inflammatory bowel disease, Arthritis, Rheumatoid, Uveitis, 03 medical and health sciences, 0302 clinical medicine, Chromosome instability, Psoriasis, Spondylarthritis, medicine, Humans, Immunology and Allergy, 030304 developmental biology, 0303 health sciences, Telomere, Inflammatory Bowel Diseases, medicine.disease, Dynamics, 3. Good health, Rheumatoid arthritis, medicine.symptom, 030217 neurology & neurosurgery, Oxidative stress
Abstract: International audience; Telomeres are repetitive DNA sequences located at the ends of linear chromosomes that preserve the integrity and stability of the genome. Telomere dysfunctions due to short telomeres or altered telomere structures can ultimately lead to replicative cellular senescence and chromosomal instability, both mechanisms being hallmarks of ageing. Chronic inflammation, oxidative stress and finally telomere length (TL) dynamics have been shown to be involved in various age-related non-communicable diseases (NCDs). Immune-mediated inflammatory diseases (IMIDs), including affections such as inflammatory bowel disease, psoriasis, rheumatoid arthritis, spondyloarthritis and uveitis belong to this group of age-related NCDs. Although in recent years, we have witnessed the emergence of studies in the literature linking these IMIDs to TL dynamics, the causality between these diseases and telomere attrition is still unclear and controversial. In this review, we provide an overview of available studies on telomere dynamics and discuss the utility of TL measurements in immune-mediated inflammatory diseases.
Published: 2021
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60. Renin-angiotensin-aldosterone system and kidney interactions in heart failure

Author: Patrick Rossignol, João Pedro Ferreira, Faiez Zannad, Centre d'investigation clinique plurithématique Pierre Drouin (CIC-P), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Center for Molecular and Vascular Biology, Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), CIC-Nancy, Institut Lorrain du Coeur et des Vaisseaux Louis Mathieu [Nancy]-Institut National de la Santé et de la Recherche Médicale (INSERM), IMPACT GEENAGE, ANR-15-IDEX-04-LUE,LUE,Lorraine Université d'Excellence(2016), ANR-15-RHU-0004,FIGHT-HF ,Fighting Heart Failure, Centre d'investigation clinique plurithématique Pierre Drouin [Nancy] (CIC-P), Centre d'investigation clinique [Nancy] (CIC), Université de Lorraine (UL)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Lorraine (UL)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM), ANR-15-IDEX-0004,LUE (ISITE),Lorraine Université d'Excellence(2016), ANR-15-RHUS-0004,FIGHT-HF,Combattre l'insuffisance cardiaque(2015), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Défaillance Cardiovasculaire Aiguë et Chronique (DCAC), Cardiovascular and Renal Clinical Trialists [Vandoeuvre-les-Nancy] (INI-CRCT), Institut Lorrain du Coeur et des Vaisseaux Louis Mathieu [Nancy], French-Clinical Research Infrastructure Network - F-CRIN [Paris] (Cardiovascular & Renal Clinical Trialists - CRCT ), ANR-15-IDEX-0004,LUE,Isite LUE(2015), DE CARVALHO, Philippe, ISITE - Isite LUE - - LUE2015 - ANR-15-IDEX-0004 - IDEX - VALID, and Combattre l'insuffisance cardiaque - - FIGHT-HF2015 - ANR-15-RHUS-0004 - RHUS - VALID
Subjects: medicine.medical_specialty, Medicine (General), Hyperkalemia, [SDV]Life Sciences [q-bio], Heart failure, Cardiorenal syndrome, 030204 cardiovascular system & hematology, [SDV.MHEP.UN]Life Sciences [q-bio]/Human health and pathology/Urology and Nephrology, Renin-Angiotensin System, 03 medical and health sciences, 0302 clinical medicine, Endocrinology, R5-920, Internal medicine, Renin–angiotensin system, Internal Medicine, medicine, Humans, 030212 general & internal medicine, Renal Insufficiency, Chronic, ComputingMilieux_MISCELLANEOUS, cardiorenal syndrome, Kidney, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, business.industry, medicine.disease, hyperkalemia, [SDV.MHEP.UN] Life Sciences [q-bio]/Human health and pathology/Urology and Nephrology, 3. Good health, [SDV] Life Sciences [q-bio], medicine.anatomical_structure, Cardiology, Commentary, medicine.symptom, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: International audience
Published: 2019
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61. Beta-blockers in heart failure patients with severe chronic kidney disease—time for a randomized controlled trial?

Author: Patrick Rossignol, Rajiv Agarwal, Center for Molecular and Vascular Biology, Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Contrat de Plan Etat Région Lorraine IT2M and FEDER Lorraine, NIH (5R01-HL126903) and VA (I01-CX001753), IMPACT GEENAGE, ANR-15-IDEX-04-LUE,LUE,Lorraine Université d'Excellence(2016), ANR-15-RHU-0004,FIGHT-HF ,Fighting Heart Failure, Indiana University School of Medicine, Indiana University System, Défaillance Cardiovasculaire Aiguë et Chronique (DCAC), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Centre d'investigation clinique plurithématique Pierre Drouin [Nancy] (CIC-P), Centre d'investigation clinique [Nancy] (CIC), Université de Lorraine (UL)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM), Cardiovascular and Renal Clinical Trialists [Vandoeuvre-les-Nancy] (INI-CRCT), Institut Lorrain du Coeur et des Vaisseaux Louis Mathieu [Nancy], French-Clinical Research Infrastructure Network - F-CRIN [Paris] (Cardiovascular & Renal Clinical Trialists - CRCT ), ANR-15-IDEX-0004,LUE,Isite LUE(2015), and ANR-15-RHUS-0004,FIGHT-HF,Combattre l'insuffisance cardiaque(2015)
Subjects: medicine.medical_specialty, [SDV]Life Sciences [q-bio], MEDLINE, 030204 cardiovascular system & hematology, [SDV.MHEP.UN]Life Sciences [q-bio]/Human health and pathology/Urology and Nephrology, Adrenergic beta-Antagonists, law.invention, Heart failure patients with severe chronic kidney disease, 03 medical and health sciences, Beta-blockers, 0302 clinical medicine, Text mining, Randomized controlled trial, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, law, Internal medicine, medicine, 030212 general & internal medicine, Beta (finance), ComputingMilieux_MISCELLANEOUS, Transplantation, business.industry, Extramural, medicine.disease, 3. Good health, Nephrology, Heart failure, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Kidney disease
Abstract: International audience
Published: 2019
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62. Peripheral blood mononuclear cells extracts VEGF protein levels and VEGF mRNA: Associations with inflammatory molecules in a healthy population

Author: Gorenjak, Vesna, Vance, Dwaine R., Petrelis, Alexandros M., Stathopoulou, Maria G., Dadé, Sébastien, Shamieh, Said El, Murray, Helena, Masson, Christine, Lamont, John, Fitzgerald, Peter, Visvikis-Siest, Sophie, Interactions Gène-Environnement en Physiopathologie Cardio-Vasculaire (IGE-PCV), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Randox Laboratories Limited [Crumlin, Irlande du Nord], Department of Medical Laboratory Technology [Beyrouth, Liban], Faculty of Health Sciences [Beyrouth, Liban], Beirut Arab University [Beyrouth, Liban] (BAU)-Beirut Arab University [Beyrouth, Liban] (BAU), Department of Internal Medicine and Geriatrics [Vandoeuvre-lès-Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Technopôle de Nancy-Brabois [Vandoeuvre-lès-Nancy], VG was partially funded by the 'Région Lorraine'., IMPACT GEENAGE, ANR-15-IDEX-0004,LUE (ISITE),Lorraine Université d'Excellence(2016), ANR-15-RHUS-0004,FIGHT-HF,Combattre l'insuffisance cardiaque(2015), European Project, Bodescot, Myriam, ISITE - Isite LUE - - LUE2015 - ANR-15-IDEX-0004 - IDEX - VALID, Combattre l'insuffisance cardiaque - - FIGHT-HF2015 - ANR-15-RHUS-0004 - RHUS - VALID, PO FEDER-FSE Lorraine et Massif de Vosges 2014-2020 - INCOMING, and ANR-15-IDEX-0004,LUE,Isite LUE(2015)
Subjects: Computer and Information Sciences, [SDV.IMM] Life Sciences [q-bio]/Immunology, Physiology, Protein Extraction, Science, Immune Cells, Immunology, Cancer Treatment, Pathology and Laboratory Medicine, Research and Analysis Methods, Infographics, Monocytes, White Blood Cells, Signs and Symptoms, Endocrinology, Diagnostic Medicine, Animal Cells, Immune Physiology, Growth Factors, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Medicine and Health Sciences, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Immune Response, Inflammation, Extraction Techniques, Innate Immune System, Blood Cells, Endocrine Physiology, Interleukins, Data Visualization, Biology and Life Sciences, Cell Biology, Molecular Development, Oncology, Immune System, Medicine, Cytokines, [SDV.IMM]Life Sciences [q-bio]/Immunology, Cellular Types, Graphs, Research Article, Developmental Biology
Abstract: BackgroundVascular endothelial growth factor (VEGF) is a signal protein, implicated in various physiological and pathophysiological processes together with other common inflammatory biomarkers. However, their associations have not yet been fully elucidated. In the present study, we investigated associations between VEGF and four specific VEGF mRNA isoforms with levels of 11 inflammation molecules, derived from peripheral blood mononuclear cells (PBMCs) extracts.MethodsHealthy participants from the STANISLAS Family Study (n = 285) were included. Levels of VEGF (four mRNA isoforms and protein levels) and inflammatory molecules (IL-1α, IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, INF-γ, TNF-α, MCP-1, EGF) were measured in PBMCs extracts. Multiple regression analyses were performed, adjusted for age and gender.ResultsThe analyses revealed significant associations between VEGF protein levels and levels of IL-4 (β = 0.028, P = 0.013), MCP-1 (β = 0.015, PConclusionsTo our knowledge, the present study represents the first investigation that successfully demonstrates links between VEGF protein levels and inflammatory molecules levels derived from PBMCs extracts and identifies associations between specific VEGF mRNA isoforms and inflammatory molecules.ImpactThese findings provide novel insights that may assist in the development of new tissue and mRNA isoform specific measurements of VEGF levels, which may positively contribute to predicting the risk of common complex diseases and response of currently used anti-VEGF agents, and developing of novel targeted therapies for VEGF-related pathophysiology.
Published: 2019
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63. Heritability of a resting heart rate in a 20-year follow-up family cohort with GWAS data: Insights from the STANISLAS cohort

Author: Patrick Rossignol, Edith Le Floch, Pierre de Villemereuil, João Pedro Ferreira, Jean-François Deleuze, Constance Xhaard, Claire Dandine-Roulland, Delphine Bacq-Daian, Faiez Zannad, Jean-Loup Machu, Nicolas Girerd, Défaillance Cardiovasculaire Aiguë et Chronique (DCAC), Université de Lorraine (UL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Centre d'investigation clinique plurithématique Pierre Drouin [Nancy] (CIC-P), Centre d'investigation clinique [Nancy] (CIC), Université de Lorraine (UL)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM), Cardiovascular and Renal Clinical Trialists [Vandoeuvre-les-Nancy] (INI-CRCT), Institut Lorrain du Coeur et des Vaisseaux Louis Mathieu [Nancy], French-Clinical Research Infrastructure Network - F-CRIN [Paris] (Cardiovascular & Renal Clinical Trialists - CRCT ), Centre National de Recherche en Génomique Humaine (CNRGH), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Centre d’Ecologie Fonctionnelle et Evolutive (CEFE), Université Paul-Valéry - Montpellier 3 (UPVM)-Centre international d'études supérieures en sciences agronomiques (Montpellier SupAgro)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD [France-Sud])-Institut national d’études supérieures agronomiques de Montpellier (Montpellier SupAgro), Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Programme Hospitalier de Recherche Clinique Interrégional, Contrat de Plan Etat Région Lorraine and FEDER IT2MP, IMPACT GEENAGE, ANR-15-IDEX-0004,LUE,Isite LUE(2015), ANR-15-RHUS-0004,FIGHT-HF,Combattre l'insuffisance cardiaque(2015), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Université Paul-Valéry - Montpellier 3 (UPVM)-Institut National de la Recherche Agronomique (INRA)-Centre international d'études supérieures en sciences agronomiques (Montpellier SupAgro)-École Pratique des Hautes Études (EPHE), Interactions Arbres-Microorganismes (IAM), Université de Lorraine (UL)-Institut National de la Recherche Agronomique (INRA), Laboratoire d'Ecologie Alpine (LECA), Centre National de la Recherche Scientifique (CNRS)-Université Savoie Mont Blanc (USMB [Université de Savoie] [Université de Chambéry])-Université Joseph Fourier - Grenoble 1 (UJF)-Université Grenoble Alpes (UGA), Institut de Génomique d'Evry (IG), Institut de Biologie François JACOB (JACOB), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Centre d'investigation clinique plurithématique Pierre Drouin (CIC-P), Centre National de Génotypage (CNG), CIC-Nancy, Institut Lorrain du Coeur et des Vaisseaux Louis Mathieu [Nancy]-Institut National de la Santé et de la Recherche Médicale (INSERM), Center for Molecular and Vascular Biology, Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), ANR-15-IDEX-04-LUE,LUE,Lorraine Université d'Excellence(2016), ANR-15-RHU-0004,FIGHT-HF ,Fighting Heart Failure, Université Paul-Valéry - Montpellier 3 (UPVM)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD [France-Sud])-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut Agro - Montpellier SupAgro, and Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)
Subjects: medicine.medical_specialty, Epidemiology, Gwas data, [SDV]Life Sciences [q-bio], Genome-wide association study, 030204 cardiovascular system & hematology, heritability, RESTING HEART RATE, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Heart Rate, Internal medicine, Heart rate, medicine, Humans, family study, 030304 developmental biology, 0303 health sciences, [SDV.GEN]Life Sciences [q-bio]/Genetics, genetic relatedness matrix, business.industry, Heritability, medicine.disease, cardiovascular diseases, Pedigree, Heart failure, Cohort, Cardiology and Cardiovascular Medicine, business, Cardiovascular outcomes, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Follow-Up Studies, Genome-Wide Association Study
Abstract: Background The association between resting heart rate (HR) and cardiovascular outcomes, especially heart failure, is now well established. However, whether HR is mainly an integrated marker of risk associated with other features, or rather a genetic origin risk marker, is still a matter for debate. Previous studies reported a heritability ranging from 14% to 65%. Design We assessed HR heritability in the STANISLAS family-study, based on the data of four visits performed over a 20-year period, and adjusted for most known confounding effects. Methods These analyses were conducted using a linear mixed model, adjusted on age, sex, tea or coffee consumption, beta-blocker use, physical activity, tobacco use, and alcohol consumption to estimate the variance captured by additive genetic effects, via average information restricted maximum likelihood analysis, with both self-reported pedigree and genetic relatedness matrix (GRM) calculated from genome-wide association study data. Results Based on the data of all visits, the HR heritability (h2) estimate was 23.2% with GRM and 24.5% with pedigree. However, we found a large heterogeneity of HR heritability estimations when restricting the analysis to each of the four visits (h2 from 19% to 39% using pedigree, and from 14% to 32% using GRM). Moreover, only a little part of variance was explained by the common household effect ( Conclusion Using a comprehensive analysis based on a family cohort, including the data of multiple visits and GRM, we found that HR variability is about 25% from genetic origin, 25% from repeated measures and 50% remains unexplained.
Published: 2019
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64. Mineralocorticoid receptor antagonists and kidney diseases: pathophysiological basis

Author: Jonatan Barrera-Chimal, Sophie Girerd, Frederic Jaisser, Universidad Nacional Autónoma de México (UNAM), Instituto Nacional de Cardiologia Ignacio Chavez, Service de Néphrologie [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Défaillance Cardiovasculaire Aiguë et Chronique (DCAC), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Cardiovascular and Renal Clinical Trialists [Vandoeuvre-les-Nancy] (INI-CRCT), Institut Lorrain du Coeur et des Vaisseaux Louis Mathieu [Nancy], French-Clinical Research Infrastructure Network - F-CRIN [Paris] (Cardiovascular & Renal Clinical Trialists - CRCT ), Centre d'investigation clinique plurithématique Pierre Drouin [Nancy] (CIC-P), Centre d'investigation clinique [Nancy] (CIC), Université de Lorraine (UL)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université de Paris (UP), National Autonomous University of Mexico – DGAPA - PAPIIT (IA200117 and IN202919 to JBC), IMPACT GEENAGE, ANR-16-CE14-0021,RENOMIR,Bénéfice de l'antagonisme du récepteur minéralocorticoïde en pathologie rénale: mécanismes et implications thérapeutiques(2016), ANR-15-IDEX-0004,LUE,Isite LUE(2015), ANR-15-RHUS-0004,FIGHT-HF,Combattre l'insuffisance cardiaque(2015), École pratique des hautes études (EPHE)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Centre de Recherche des Cordeliers (CRC), Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), ANR-16-CE14-0021,RENOMIR,Bénéfice de l’antagonisme du récepteur minéralocorticoïde en pathologie rénale: mécanismes et implications thérapeutiques(2016), ANR-15-IDEX-04-LUE,LUE,Lorraine Université d'Excellence(2016), and ANR: ANR-15-RHU-0004,Programme Investissement d'Avenir ANR-15-RHU-0004
Subjects: 0301 basic medicine, [SDV]Life Sciences [q-bio], Calcineurin Inhibitors, Drug Evaluation, Preclinical, 030232 urology & nephrology, Global Health, Kidney, Bioinformatics, [SDV.MHEP.UN]Life Sciences [q-bio]/Human health and pathology/Urology and Nephrology, Global Burden of Disease, Diabetic nephropathy, 03 medical and health sciences, 0302 clinical medicine, Mineralocorticoid receptor, Prevalence, medicine, Animals, Humans, Renal Insufficiency, Chronic, Kidney transplantation, Mineralocorticoid Receptor Antagonists, Clinical Trials as Topic, business.industry, urogenital system, Acute kidney injury, Glomerulonephritis, Acute Kidney Injury, medicine.disease, 3. Good health, Calcineurin, Disease Models, Animal, Oxidative Stress, Receptors, Mineralocorticoid, Treatment Outcome, 030104 developmental biology, medicine.anatomical_structure, Regional Blood Flow, Nephrology, Disease Progression, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Kidney disease
Abstract: International audience; Chronic kidney disease (CKD) represents a global health concern, and its prevalence is increasing. The ultimate therapeutic option for CKD is kidney transplantation. However, the use of drugs that target specific pathways to delay or halt CKD progression, such as angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and sodium-glucose co-transporter-2 (SGLT-2) inhibitors is limited in clinical practice. Mineralocorticoid receptor activation in nonclassical tissues, such as the endothelium, smooth muscle cells, inflammatory cells, podocytes, and fibroblasts may have deleterious effects on kidney structure and function. Several preclinical studies have shown that mineralocorticoid receptor antagonists (MRAs) ameliorate or cure kidney injury and dysfunction in different models of kidney disease. In this review, we present the preclinical evidence showing a benefit of MRAs in acute kidney injury, the transition from acute kidney injury to CKD, hypertensive and diabetic nephropathy, glomerulonephritis, and kidney toxicity induced by calcineurin inhibitors. We also discuss the molecular mechanisms responsible for renoprotection related to MRAs that lead to reduced oxidative stress, inflammation, fibrosis, and hemodynamic alterations. The available clinical data support a benefit of MRA in reducing proteinuria in diabetic kidney disease and improving cardiovascular outcomes in CKD patients. Moreover, a benefit of MRAs in kidney transplantation has also been observed. The past and present clinical trials describing the effect of MRAs on kidney injury are presented, and the risk of hyperkalemia and use of other options, such as potassium binding agents or nonsteroidal MRAs, are also addressed. Altogether, the available preclinical and clinical data support a benefit of using MRAs in CKD, an approach that should be further explored in future clinical trials.Copyright © 2019 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.
Published: 2019
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65. Nondipping Pattern and Cardiovascular and Renal Damage in a Population-Based Study (The STANISLAS Cohort Study)

Author: Patrick Rossignol, Faiez Zannad, Jean-Loup Machu, Jean-Jacques Mourad, Nicolas Girerd, João Pedro Ferreira, Erwan Bozec, M. Lopez-Sublet, Centre d'investigation clinique plurithématique Pierre Drouin (CIC-P), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), CIC-Nancy, Institut Lorrain du Coeur et des Vaisseaux Louis Mathieu [Nancy]-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Service de Cardiologie [CHRU Nancy], Hôpital Avicenne, IMPACT GEENAGE, ANR-15-IDEX-04-LUE,LUE,Lorraine Université d'Excellence(2016), ANR: ANR-15-RHU-0004,Programme Investissement d'Avenir ANR-15-RHU-0004, Service de médecine interne [Avicenne], Hôpital Avicenne [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Cardiovascular and Renal Clinical Trialists [Vandoeuvre-les-Nancy] (INI-CRCT), Institut Lorrain du Coeur et des Vaisseaux Louis Mathieu [Nancy], Centre d'investigation clinique plurithématique Pierre Drouin [Nancy] (CIC-P), Centre d'investigation clinique [Nancy] (CIC), Université de Lorraine (UL)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM), Défaillance Cardiovasculaire Aiguë et Chronique (DCAC), Université de Lorraine (UL)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM), Faculdade de Medicina da Universidade do Porto (FMUP), Universidade do Porto, ANR-15-IDEX-0004,LUE,Isite LUE(2015), and ANR-15-RHUS-0004,FIGHT-HF,Combattre l'insuffisance cardiaque(2015)
Subjects: Carotid Artery Diseases, Male, Time Factors, [SDV]Life Sciences [q-bio], 030204 cardiovascular system & hematology, Kidney, Left ventricular hypertrophy, [SDV.MHEP.UN]Life Sciences [q-bio]/Human health and pathology/Urology and Nephrology, Ventricular Function, Left, Ventricular Dysfunction, Left, 0302 clinical medicine, renal disease, Risk Factors, Longitudinal Studies, 030212 general & internal medicine, Pulse wave velocity, education.field_of_study, Ventricular Remodeling, blood pressure, Middle Aged, Circadian Rhythm, 3. Good health, arterial stiffness, Cohort, Cardiology, Female, Hypertrophy, Left Ventricular, Kidney Diseases, France, Cohort study, Adult, medicine.medical_specialty, Ambulatory blood pressure, hypertension, The STANISLAS Cohort, microalbuminuria, Population, Risk Assessment, 03 medical and health sciences, echocardiographic diastolic dysfunction, nondipping pattern, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Internal medicine, Internal Medicine, medicine, Albuminuria, Humans, education, intima-media thickness, business.industry, medicine.disease, ambulatory blood pressure monitoring, Blood pressure, Arterial stiffness, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: OBJECTIVE The attenuation of physiological nocturnal decline of blood pressure (BP)—called nondipper pattern—has previously been reported to be associated with target organ damage in hypertensive subjects. However, this association remains debated and poorly studied in normotensive patients. This study aimed to investigate the association between nondipper pattern and subclinical cardiovascular and renal damage in an initially healthy population-based cohort study. METHODS The STANISLAS Cohort is a single-center, familial longitudinal cohort composed of 1,006 families (4,295 subjects) recruited in 1993–1995 for a 5-year periodic health examination. A total of 1,334 subjects from the 4th visit (2011–2016) of the STANISLAS cohort were included. This 4th examination included estimated glomerular filtration rate, albumin/creatinine ratio, pulse wave velocity, central systolic BP, carotid intima–media thickness and distensibility, left ventricular mass index, left ventricular hypertrophy, diastolic dysfunction, and ambulatory blood pressure monitoring (ABPM). Nondipping status was defined as a mean reduction in systolic BP (SBP) or diastolic BP (DBP) lower than 10% during nighttime. RESULTS Data were obtained from 798 normotensive subjects (45 ± 14 years, 395 [49%] nondippers, SBP/DBP mmHg 24 hours: 116/71 ± 7/5) and 536 hypertensive patients (56 ± 11 years, 257 [48%] nondippers, SBP/DBP mmHg 24 hours: 127/78 ± 10/7). Mean 24-hour and daytime ABPM measurements were within the normal range, even in hypertensive participants (19% treated). The nondipping pattern was not associated with cardiovascular or renal alterations in this population. CONCLUSION In this middle-aged population with an overall 24-hour optimal BP control, the nondipper pattern was not associated with increased cardiovascular or renal damage.
Published: 2019
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66. Arterial Remodeling and Dysfunction in the ZSF1 Rat Model of Heart Failure With Preserved Ejection Fraction

Author: Faiez Zannad, André P. Lourenço, Inês Falcão-Pires, Jaime Ibarrola, Adelino F. Leite-Moreira, Amaya Fernández-Celis, Dulce Fontoura, Natalia López-Andrés, Patrick Rossignol, Sara Leite, Rui J Cerqueira, Walter Paulus, IDISNA, Pamplona, CIC-Nancy, Institut Lorrain du Coeur et des Vaisseaux Louis Mathieu [Nancy]-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Clinical Neurophysiology, Georg-August-Universität Göttingen, Faculdade de Medicina da Universidade do Porto [Porto] (FMUP), Center for Molecular and Vascular Biology, Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Universidade de Lisboa (ULISBOA), Contrat de Plan Etat Région LorraineFEDER IT2MP., S. Leite and D. Fontoura were supported by Portuguese Foundation for Science and Technology (SFRH/BD/110404/2015 and SFRH/BD/126088/2016, respectively)., Grants from Portuguese Foundation for Science and Technology (PTDC/DTP-PIC/4104/2014, NORTE-01- 0145-FEDER-000003-DocNET, and SAICT-PAC/0047/2015, 01/12/2016-NETDIAMOND., IMPACT GEENAGE, ANR-15-IDEX-04-LUE,LUE,Lorraine Université d'Excellence(2016), ANR: ANR-15-RHU-0004,Programme Investissement d'Avenir ANR-15-RHU-0004, European Project: 261409,EC:FP7:HEALTH,FP7-HEALTH-2010-single-stage,MEDIA(2011), European Project: ERA-CVD/0001/2016,MINOTAUR, Faculdade de Medicina da Universidade do Porto (FMUP), Universidade do Porto, Hospital de São João [Porto], Universidad Pública de Navarra [Espagne] = Public University of Navarra (UPNA), Défaillance Cardiovasculaire Aiguë et Chronique (DCAC), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Centre d'investigation clinique plurithématique Pierre Drouin [Nancy] (CIC-P), Centre d'investigation clinique [Nancy] (CIC), Université de Lorraine (UL)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM), VU University Medical Center [Amsterdam], ANR-15-IDEX-0004,LUE,Isite LUE(2015), ANR-15-RHUS-0004,FIGHT-HF,Combattre l'insuffisance cardiaque(2015), ACS - Heart failure & arrhythmias, Physiology, Universidade do Porto = University of Porto, and Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL)
Subjects: Male, medicine.medical_specialty, hypertension, Heart Ventricles, extracellular matrix, vascular remodeling, [SDV]Life Sciences [q-bio], Rat model, heart failure, 030204 cardiovascular system & hematology, Rats, Inbred WKY, Ventricular Function, Left, 03 medical and health sciences, 0302 clinical medicine, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Internal medicine, medicine, Animals, Obesity, Aorta, 030304 developmental biology, 0303 health sciences, business.industry, biology, Stroke Volume, medicine.disease, Heart failure, Cardiology, Cardiology and Cardiovascular Medicine, business, Heart failure with preserved ejection fraction, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: Background: The interplay between the stiffened heart and vessels has long been viewed as a core mechanism in heart failure with preserved ejection fraction, but the incremental vascular molecular remodeling mechanisms from systemic arterial hypertension to heart failure with preserved ejection fraction remain poorly investigated. Our aim was to characterize central arterial remodeling and dysfunction in ZSF1 obese rats and to compare it with hypertensive ZSF1 lean and healthy Wistar-Kyoto controls. Methods and Results: Twenty-week-old male ZSF1 obese (n=9), lean (n=9), and Wistar-Kyoto rats (n=9) underwent left ventricular pressure-volume loop evaluation and synchronous acquisition of ascending aortic flow and pressure. Aortic rings underwent functional evaluation, histology, and molecular biology studies. Although mean arterial pressure, characteristic aortic impedance, and reactivity to phenylephrine were similarly increased in hypertensive ZSF1 lean and obese, only ZSF1 obese showed impaired relaxation and upward-shifted end-diastolic pressure-volume relationships despite preserved systolic function indexes, denoting heart failure with preserved ejection fraction. ZSF1 obese phenotype further showed decreased aortic compliance, increased wave reflection, and impaired direct NO donor and endothelial-mediated vasodilation which were accompanied on structural and molecular grounds by aortic media thickening, higher collagen content and collagen/elastin ratio, increased fibronectin and α-5 integrin protein expression and upregulated TGF (transforming growth factor)-β and CTGF (connective tissue growth factor) levels. Conclusions: Functional, molecular, and structural disturbances of central vessels and their potentially underlying pathways were newly characterized in experimental heart failure with preserved ejection fraction rendering the ZSF1 obese rat model suitable for preclinical testing.
Published: 2019
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67. Proteomic Bioprofiles and Mechanistic Pathways of Progression to Heart Failure

Author: João Pedro, Ferreira, Job, Verdonschot, Timothy, Collier, Ping, Wang, Anne, Pizard, Christian, Bär, Jens, Björkman, Alessandro, Boccanelli, Javed, Butler, Andrew, Clark, John G, Cleland, Christian, Delles, Javier, Diez, Nicolas, Girerd, Arantxa, González, Mark, Hazebroek, Anne-Cécile, Huby, Wouter, Jukema, Roberto, Latini, Joost, Leenders, Daniel, Levy, Alexandre, Mebazaa, Harald, Mischak, Florence, Pinet, Patrick, Rossignol, Naveed, Sattar, Peter, Sever, Jan A, Staessen, Thomas, Thum, Nicolas, Vodovar, Zhen-Yu, Zhang, Stephane, Heymans, Faiez, Zannad, Défaillance Cardiovasculaire Aiguë et Chronique (DCAC), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Centre d'investigation clinique plurithématique Pierre Drouin [Nancy] (CIC-P), Centre d'investigation clinique [Nancy] (CIC), Université de Lorraine (UL)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM), Cardiovascular and Renal Clinical Trialists [Vandoeuvre-les-Nancy] (INI-CRCT), Institut Lorrain du Coeur et des Vaisseaux Louis Mathieu [Nancy], French-Clinical Research Infrastructure Network - F-CRIN [Paris] (Cardiovascular & Renal Clinical Trialists - CRCT ), Universidade do Porto, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University [Maastricht], Maastricht University Medical Centre (MUMC), London School of Hygiene and Tropical Medicine (LSHTM), Institut de biologie de l'ENS Paris (IBENS), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Département de Biologie - ENS Paris, École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institute for Molecular and Translational Therapeutic Strategies - IMTTS [Hannover, Germany], TATAA Biocenter AB, Casa di Cura Quisisana, University of Mississippi Medical Center (UMMC), Hannover Medical School [Hannover] (MHH), Hull York Medical School, Institute of Health and Wellbeing, University of Glasgow-Gartnavel General Hospital, Glasgow, University of Glasgow, Institute of Cardiovascular and Medical Sciences [Glasgow], Center for Applied Medical Research [Plamplona] (CIMA), Universidad de Navarra [Pamplona] (UNAV), Institute of Health Carlos III, Instituto de Investigación Sanitaria de Navarra (IdiSNA), University Clinic of Navarra, Leiden University Medical Center (LUMC), IRCCS - Istituto di Ricerche Farmacologiche 'Mario Negri' [Milan, Italy], ACS Biomarker, Framingham Heart Study, Boston University [Boston] (BU)-National Heart, Lung, and Blood Institute [Bethesda] (NHLBI), Université Paris Diderot - Paris 7 (UPD7), Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Mosaiques Diagnostics GmbH [Hannover, Germany], Mosaiques Diagnostics and Therapeutics AG [Hannover, Germany], Facteurs de Risque et Déterminants Moléculaires des Maladies liées au Vieillissement - U 1167 (RID-AGE), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Université de Lille-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Imperial College London, Department of Cardiovascular Sciences [Leuven], Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Institute of Molecular and Translational Therapeutic Strategies (IMTTS), IMPACT GEENAGE, ANR-15-IDEX-0004,LUE,Isite LUE(2015), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Universidade do Porto = University of Porto, Département de Biologie - ENS Paris, École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Universiteit Leiden, Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), and Institut de biologie de l'ENS Paris (UMR 8197/1024) (IBENS)
Subjects: Heart Failure, Male, Proteomics, Proteome, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Case-Control Studies, Disease Progression, Humans, Female, Biomarkers, Article, Aged
Abstract: International audience; Background Identifying the mechanistic pathways potentially associated with incident heart failure (HF) may provide a basis for novel preventive strategies. Methods and Results To identify proteomic biomarkers and the potential underlying mechanistic pathways that may be associated with incident HF defined as the first hospitalization for HF, a nested-matched case-control design was used with cases (incident HF) and controls (without HF) selected from 3 cohorts (>20 000 individuals). Controls were matched on cohort, follow-up time, age, and sex. Two independent sample sets (a discovery set with 286 cases and 591 controls and a replication set with 276 cases and 280 controls) were used to discover and replicate the findings. Two hundred fifty-two circulating proteins in the plasma were studied. Adjusting for the matching variables age, sex, and follow-up time (and correcting for multiplicity of tests), 89 proteins were found to be associated with incident HF in the discovery phase, of which 38 were also associated with incident HF in the replication phase. These 38 proteins pointed to 4 main network clusters underlying incident HF: (1) inflammation and apoptosis, indicated by the expression of the TNF (tumor necrosis factor)-family members; (2) extracellular matrix remodeling, angiogenesis and growth, indicated by the expression of proteins associated with collagen metabolism, endothelial function, and vascular homeostasis; (3) blood pressure regulation, indicated by the expression of natriuretic peptides and proteins related to the renin-angiotensin-aldosterone system; and (4) metabolism, associated with cholesterol and atherosclerosis. Conclusions Clusters of biomarkers associated with mechanistic pathways leading to HF were identified linking inflammation, apoptosis, vascular function, matrix remodeling, blood pressure control, and metabolism. These findings provide important insight on the pathophysiological mechanisms leading to HF. Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT02556450.
Published: 2019
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68. Income level and inequality as complement to geographical differences in cardiovascular trials

Author: Patrick Rossignol, William B. White, Zohra Lamiral, Bertram Pitt, João Pedro Ferreira, John J.V. McMurray, Pooja Dewan, Faiez Zannad, Centre d'investigation clinique plurithématique Pierre Drouin [Nancy] (CIC-P), Centre d'investigation clinique [Nancy] (CIC), Université de Lorraine (UL)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM), Center for Molecular and Vascular Biology, Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), University of Michigan [Ann Arbor], University of Michigan System, BHF Glasgow Cardiovascular Research Centre, University of Glasgow, Université de Lorraine (UL)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM), Contrat de Plan Etat-Lorraine and FEDER Lorraine, Pfizer (EPHESUS, EMPHASIS-HF), Takeda (EXAMINE), IMPACT GEENAGE, ANR-15-IDEX-0004,LUE,Isite LUE(2015), ANR-15-RHUS-0004,FIGHT-HF,Combattre l'insuffisance cardiaque(2015), Centre d'investigation clinique plurithématique Pierre Drouin (CIC-P), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), CIC-Nancy, Institut Lorrain du Coeur et des Vaisseaux Louis Mathieu [Nancy]-Institut National de la Santé et de la Recherche Médicale (INSERM), ANR-15-IDEX-04-LUE,LUE,Lorraine Université d'Excellence(2016), and ANR-15-RHU-0004,FIGHT-HF ,Fighting Heart Failure
Subjects: Male, Inequality, media_common.quotation_subject, [SDV]Life Sciences [q-bio], Ethnic group, low-middle income (LMICs), 030204 cardiovascular system & hematology, cardiovascular (CV) trials, 03 medical and health sciences, 0302 clinical medicine, Economic inequality, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Cause of Death, Health care, Outcome Assessment, Health Care, Medicine, Humans, Multicenter Studies as Topic, 030212 general & internal medicine, country or regional differences, Acute Coronary Syndrome, 10. No inequality, Developing Countries, media_common, Cause of death, Aged, Randomized Controlled Trials as Topic, Heart Failure, business.industry, Mortality rate, Developed Countries, 1. No poverty, Age Factors, countries with greater inequality, Per capita income, medicine.disease, Prognosis, Comorbidity, MESH: Acute Coronary Syndrome/ethnology, Acute Coronary Syndrome/mortality, Acute Coronary Syndrome/therapy, Developed Countries/economics, Developing Countries/economics, Female, Guideline Adherence/statistics & numerical data, Heart Failure/ethnology, Heart Failure/mortality, Heart Failure/therapy, Income, Outcome Assessment, Health Care, Socioeconomic Factors, 3. Good health, Guideline Adherence, Cardiology and Cardiovascular Medicine, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Demography
Abstract: International audience; BACKGROUND:Analyses of country or regional differences in cardiovascular (CV) trials are based on geographical subgroup analyses. However, apart from map location and related racial, ethnic, and genetic variations, identified differences may also depend on social structure and provision and access to health care, for which country income and income inequality are indicators. The aim of the study was to examine the association between country per capita income and income inequality and prognosis in patients with heart failure or an acute coronary syndrome in 3 international trials (EMPHASIS-HF, EPHESUS, and EXAMINE).METHODS:Countries were classified into high income or low-middle income (LMICs) and into low, middle, or high inequality using the Gini index. The main outcome measures were all-cause and CV death.RESULTS:Patients from LMICs and countries with higher inequality were younger, were less often white, had fewer comorbid conditions, and were less often treated with guideline-recommended therapies, including devices. These patients had higher adjusted mortality rates (+15% to +70%) compared with patients from high-income countries and countries with less inequality. Patients from countries with the combination of greater inequality and low-middle income had particularly high mortality rates (+80% to +190%) compared with those that did not have both characteristics. Living in a country that is poor and has inequality had more impact on death rates than any comorbidity. These findings were reproduced in 3 trials.CONCLUSIONS:Patients from LMICs and countries with greater inequality had the highest mortality rates. The prognostic impact of income and inequality is substantial and should be considered when looking into subgroup differences in CV trials.Copyright © 2019 Elsevier Inc. All rights reserved.
Published: 2019
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69. Global Burden Related to Nitrous Oxide Exposure in Medical and Recreational Settings: A Systematic Review and Individual Patient Data Meta-Analysis

Author: Oussalah, Abderrahim, Julien, Mélissa, Lévy, Julien, Hajjar, Olivia, Franczak, Claire, Stephan, Charlotte, Laugel, Elodie, Wandzel, Marion, Filhine-Tresarrieu, Pierre, Green, Ralph, Guéant, Jean-Louis, Nutrition-Génétique et Exposition aux Risques Environnementaux (NGERE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Centre de référence des maladies héréditaires du métabolisme (MaMEA Nancy-Brabois), University of California [Davis] (UC Davis), University of California, IMPACT GEENAGE, ANR-15-IDEX-04-LUE,LUE,Lorraine Université d'Excellence(2016), and ANR-15-IDEX-0004,LUE,Isite LUE(2015)
Subjects: methylmalonic acid, Clinical Sciences, lcsh:R, Neurosciences, lcsh:Medicine, global health, N2O-related toxicity, Review, homocysteine, medical and recreational settings, one-carbon metabolism, global burden related to nitrous oxide exposure, Vitamin B12 deficiency, Individual Patient Data Meta-Analysis, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Nitrous Oxide Exposure, vitamin B12 deficiency, individual patient data meta-analysis, Nutrition, nitrous oxide-related toxicity
Abstract: The risk of adverse effects of nitrous oxide (N2O) exposure is insufficiently recognized despite its widespread use. These effects are mainly reported through case reports. We conducted an individual patient data meta-analysis to assess the prevalence of clinical, laboratory, and magnetic resonance findings in association with N2O exposure in medical and recreational settings. We calculated the pooled estimates for the studied outcomes and assessed the potential bias related to population stratification using principal component analysis. Eighty-five publications met the inclusion criteria and reported on 100 patients with a median age of 27 years and 57% of recreational users. The most frequent outcomes were subacute combined degeneration (28%), myelopathy (26%), and generalized demyelinating polyneuropathy (23%). A T2 signal hyperintensity in the spinal cord was reported in 68% (57.2–78.8%) of patients. The most frequent clinical manifestations included paresthesia (80%; 72.0–88.0%), unsteady gait (58%; 48.2–67.8%), and weakness (43%; 33.1–52.9%). At least one hematological abnormality was retrieved in 71.7% (59.9–83.4%) of patients. Most patients had vitamin B12 deficiency: vitamin B12 15 µmol/L (90.3%; 79.3–100%), and methylmalonic acid >0.4 µmol/L (93.8%; 80.4–100%). Consistently, 85% of patients exhibited a possibly or probably deficient vitamin B12 status according to the cB12 scoring system. N2O can produce severe outcomes, with neurological or hematological disorders in almost all published cases. More than half of them are reported in the setting of recreational use. The N2O-related burden is dominated by vitamin B12 deficiency. This highlights the need to evaluate whether correcting B12 deficiency would prevent N2O-related toxicity, particularly in countries with a high prevalence of B12 deficiency.
Published: 2019
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70. Vitamin B-12 and liver activity and expression of methionine synthase are decreased in fetuses with neural tube defects

Author: Rosa-Maria Guéant-Rodriguez, Jean-Marc Alberto, Jean-Louis Guéant, François Feillet, Bernard Foliguet, Ma'atem B Fofou-Caillierez, Thierry Forges, Céline Chéry, Philippe Gerard, Thomas Josse, Nutrition-Génétique et Exposition aux Risques Environnementaux (NGERE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Centre de référence des maladies héréditaires du métabolisme (MaMEA Nancy-Brabois), Maternité Régionale Adolphe Pinard [Nancy], IMPACT GEENAGE, and ANR-15-IDEX-0004,LUE (ISITE),Lorraine Université d'Excellence(2016)
Subjects: 0301 basic medicine, Vitamin, Male, medicine.medical_specialty, congenital, hereditary, and neonatal diseases and abnormalities, Homocysteine, Medicine (miscellaneous), Gestational Age, 5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Folic Acid, Pregnancy, Internal medicine, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], medicine, Humans, ductase, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Methionine synthase, Vitamin B12, Neural Tube Defects, Methylenetetrahydrofolate Reductase (NADPH2), methionine synthase, 2. Zero hunger, methylenetetrahydrofolate rel tube defects, Nutrition and Dietetics, Methionine, Intrinsic factor, S-adenosylmethionine, gastric intrinsic factor, biology, (Methionine synthase) reductase, neuravitamin B-12, 3. Good health, Ferredoxin-NADP Reductase, spina bifida, Fetal Diseases, Vitamin B 12, 030104 developmental biology, Endocrinology, chemistry, Liver, Methylenetetrahydrofolate reductase, Case-Control Studies, biology.protein, Female, 030217 neurology & neurosurgery
Abstract: International audience; ABSTRACTBackground: The risk of neural tube defects (NTDs) is influenced by nutritional factors and genetic determinants of one-carbon metabolism. A key pathway of this metabolism is the vitamin B12– and folate-dependent remethylation of homocysteine, which depends on methionine synthase (MS, encoded by MTR), methionine synthase reductase, and methylenetetrahydrofolate reductase. Methionine, the product of this pathway, is the direct precursor of Sadenosylmethionine (SAM), the universal methyl donor needed for epigenetic mechanisms. Objectives: This study aimed to evaluate whether the availability of vitamin B-12 and folate and the expression or activity of the target enzymes of the remethylation pathway are involved in NTD risk. Methods: We studied folate and vitamin B-12 concentrations and activity, expression, and gene variants of the 3 enzymes in liver from 14 NTD and 16 non-NTD fetuses. We replicated the main findings in cord blood from pregnancies of 41 NTD fetuses compared with 21 fetuses with polymalformations (metabolic and genetic findings) and 375 control pregnancies (genetic findings).Results: The tissue concentration of vitamin B-12 (P = 0.003), but not folate, and the activity (P = 0.001), transcriptional level (P = 0.016), and protein expression (P = 0.003) of MS were decreased and the truncated inactive isoforms of MS were increased in NTD livers. SAM was significantly correlated with MS activity and vitamin B-12. A gene variant in exon 1 of GIF (Gastric Intrinsic Factor gene) was associated with a dramatic decrease of liver vitamin B-12 in 2 cases. We confirmed the decreased vitamin B-12 in cord blood from NTD pregnancies. A gene variant of GIF exon 3 was associated with NTD risk.Conclusions: The decreased vitamin B-12 in liver and cord blood and decreased expression and activity of MS in liver point out theimpaired remethylation pathway as hallmarks associated with NTD risk. We suggest evaluating vitamin B-12 in the nutritional recommendations for prevention of NTD risk beside folate fortification or supplementation. Am J Clin Nutr 2019;00:674–683.
Published: 2019
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71. Telomere Dynamics and Aging Related Diseases

Author: Athanese Benetos, Simon Toupance, Défaillance Cardiovasculaire Aiguë et Chronique (DCAC), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), IMPACT GEENAGE, and ANR-15-IDEX-0004,LUE (ISITE),Lorraine Université d'Excellence(2016)
Subjects: 0303 health sciences, 03 medical and health sciences, 0302 clinical medicine, Evolutionary biology, [SDV]Life Sciences [q-bio], Dynamics (mechanics), Biology, 030217 neurology & neurosurgery, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, Telomere
Abstract: International audience
Published: 2019
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72. Dipeptidyl Peptidase-4 Inhibitors and the Risk of Heart Failure

Author: Zannad, Faiez, Rossignol, Patrick, Centre d'investigation clinique [Nancy] (CIC), Université de Lorraine (UL)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Lorrain du Coeur et des Vaisseaux Louis Mathieu [Nancy], IMPACT GEENAGE, ANR-15-IDEX-0004,LUE,Isite LUE(2015), ANR-15-RHUS-0004,FIGHT-HF,Combattre l'insuffisance cardiaque(2015), CIC-Nancy, Institut Lorrain du Coeur et des Vaisseaux Louis Mathieu [Nancy]-Institut National de la Santé et de la Recherche Médicale (INSERM), Center for Molecular and Vascular Biology, Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), ANR-15-IDEX-04-LUE,LUE,Lorraine Université d'Excellence(2016), and ANR: ANR-15-RHU-0004,Programme Investissement d'Avenir ANR-15-RHU-0004
Subjects: [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, DPP-4 inhibitors, [SDV]Life Sciences [q-bio], diabetes mellitus, Editorials, trials, heart failure, ComputingMilieux_MISCELLANEOUS, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: International audience
Published: 2019
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73. Determinants of anti-fibrotic response to mineralocorticoid receptor antagonist therapy: insights from the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS) and Early Eplerenone Treatment in Patients with Acute ST-elevation Myocardial Infarction without Heart Failure (REMINDER) trials

Author: Verdonschot, Job, Collier, Timothy, Wang, Ping, Pizard, Anne, Bär, Christian, Björkman, Jens, Boccanelli, Alessandro, Butler, Javed, Clark, Andrew, Cleland, John, Delles, Christian, Díez, Javier, González, Arantxa, Hazebroek, Mark, Huby, Anne-Cécile, Jukema, Wouter, Latini, Roberto, Leenders, Joost, Lévy, Daniel, Mebazaa, Alexandre, Mischak, Harald, Pinet, Florence, Sattar, Naveed, Sever, Peter, Staessen, Jan, Thum, Thomas, Vodovar, Nicolas, Zhang, Zhen-Yu, Heymans, Stephane, Stienen, Susan, Rossignol, Patrick, Barros, Antonio, Girerd, Nicolas, Pitt, Bertram, Zannad, Faiez, Ferreira, Joao Pedro, Institut Lorrain du Coeur et des Vaisseaux Louis Mathieu [Nancy], Centre d'investigation clinique [Nancy] (CIC), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Défaillance Cardiovasculaire Aiguë et Chronique (DCAC), Cardiovascular and Renal Clinical Trialists [Vandoeuvre-les-Nancy] (INI-CRCT), Universidade do Porto, University of Michigan Medical School [Ann Arbor], University of Michigan [Ann Arbor], University of Michigan System-University of Michigan System, Contrat de plan Etat-lorraine and FEDER Lorraine, IMPACT GEENAGE, ANR-15-IDEX-0004,LUE (ISITE),Lorraine Université d'Excellence(2016), ANR-15-RHUS-0004,FIGHT-HF,Combattre l'insuffisance cardiaque(2015), DE CARVALHO, Philippe, ISITE - Isite LUE - - LUE2015 - ANR-15-IDEX-0004 - IDEX - VALID, Combattre l'insuffisance cardiaque - - FIGHT-HF2015 - ANR-15-RHUS-0004 - RHUS - VALID, Universidade do Porto = University of Porto, ANR-15-IDEX-0004,LUE,Isite LUE(2015), Cardiovascular Research Institute Maastricht (CARIM), Maastricht University [Maastricht], London School of Hygiene and Tropical Medicine (LSHTM), Universität Potsdam, TATAA Biocenter AB, Queensland University of Technology [Brisbane] (QUT), Institute of Health and Wellbeing, University of Glasgow-Gartnavel General Hospital, Glasgow, BHF Glasgow Cardiovascular Research Centre (BHF GCRC), University of Glasgow, Universidad de Navarra [Pamplona] (UNAV), Center for Applied Medical Research [Plamplona] (CIMA), Remodelage et Reparation du Tissu Renal, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Leiden University Medical Center (LUMC), IRCCS - Istituto di Ricerche Farmacologiche 'Mario Negri' [Milan, Italy], Paris-Jourdan Sciences Economiques (PSE), École normale supérieure - Paris (ENS Paris)-Institut National de la Recherche Agronomique (INRA)-École des hautes études en sciences sociales (EHESS)-École des Ponts ParisTech (ENPC)-Centre National de la Recherche Scientifique (CNRS), Biomarqueurs CArdioNeuroVASCulaires (BioCANVAS), Université Paris 13 (UP13)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institute of Cardiovascular and Medical Sciences [Glasgow], Centre d'investigation clinique plurithématique Pierre Drouin (CIC-P), Department of Pathological Biochemistry, Royal Infirmary, Imperial College London, Department of Epidemiology, Institute of Molecular and Translational Therapeutic Strategies (IMTTS), Hannover Medical School [Hannover] (MHH), Service de Biochimie et de Biologie Moléculaire [AP-HP Hôpital Lariboisière] (Inserm U942), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Lariboisière-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Cardiovascular Sciences [Leuven], Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), University of Porto, ANR-15-IDEX-04-LUE,LUE,Lorraine Université d'Excellence(2016), ANR: ANR-15-RHU-0004,Programme Investissement d'Avenir ANR-15-RHU-0004, CIC-Nancy, and Institut Lorrain du Coeur et des Vaisseaux Louis Mathieu [Nancy]-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Male, Time Factors, [SDV]Life Sciences [q-bio], 030204 cardiovascular system & hematology, 0302 clinical medicine, Mineralocorticoid receptor, Risk Factors, 030212 general & internal medicine, Myocardial infarction, Mineralocorticoid Receptor Antagonists, Randomized Controlled Trials as Topic, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Ventricular Remodeling, General Medicine, Middle Aged, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, 3. Good health, Eplerenone, [SDV] Life Sciences [q-bio], Treatment Outcome, Cardiology, Female, Collagen, Cardiology and Cardiovascular Medicine, Procollagen, medicine.drug, medicine.medical_specialty, Randomization, Clinical Decision-Making, Placebo, 03 medical and health sciences, Reperfusion therapy, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Predictive Value of Tests, Internal medicine, Diabetes mellitus, medicine, Humans, Aged, Heart Failure, business.industry, Myocardium, Patient Selection, Reproducibility of Results, medicine.disease, Fibrosis, Peptide Fragments, Heart failure, ST Elevation Myocardial Infarction, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Biomarkers
Abstract: International audience; INTRODUCTION:After myocardial infarction complicated by heart failure or diabetes, eplerenone (compared to placebo) significantly decreases amino-terminal propeptide of type III procollagen (PIIINP). Determining the subset of patients who are more prone to have a decrease in PIIINP and those who may respond better to the anti-fibrotic effects of mineralocorticoid receptor antagonists (MRA) therapy may be relevant for a personalized treatment approach. The aim of this study is to identify predictors of a PIIINP decrease and assess potential subgroups of "responders" to eplerenone.METHODS:Clinical factors and biomarkers were evaluated as predictors of a PIIINP decrease from randomization to month 9 in 323 patients from the biomarker substudy of Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS). Additionally, the association between PIIINP decrease and the composite of cardiovascular (CV) death or CV hospitalization were also explored. External validation was performed in the REMINDER trial.RESULTS:Female sex, eplerenone, reperfusion therapy, potassium
Published: 2019
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74. GNAI2 variants predict nonsteroidal anti-inflammatory drug hypersensitivity in a genome-wide study

Author: Jose A. Cornejo-Garcia, Rosa-Maria Guéant-Rodriguez, Jean-Louis Guéant, Lara Bossini Castillo, Inmaculada Doña, Miguel Blanca, Abderrahim Oussalah, Céline Chéry, Gabriela Canto, Pierre Rouyer, F.D. Carmona, Natalia Blanca-López, Cristobalina Mayorga, Javier Martín, María José Torres, Nutrition-Génétique et Exposition aux Risques Environnementaux (NGERE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Allergy Service [Hospital Universitario Infanta Leonor], Hospital Universitario Infanta Leonor [Madrid], Instituto de Investigación Biomédica de Málaga [Malaga, Espagne] (IBIMA), Universidad de Málaga [Málaga], Hospital Regional Universitario de Málaga [Spain], Instituto de Parasitología y Biomedicina 'López-Neyra', The Andalusian Center for Nanomedicine and Biotechnology (BIONAND), IMPACT GEENAGE, ANR-15-IDEX-04-LUE,LUE,Lorraine Université d'Excellence(2016), Universidad de Málaga [Málaga] = University of Málaga [Málaga], and ANR-15-IDEX-0004,LUE (ISITE),Lorraine Université d'Excellence(2016)
Subjects: Drug, musculoskeletal diseases, G protein, medicine.drug_class, media_common.quotation_subject, [SDV]Life Sciences [q-bio], Immunology, Pharmacology, Genome, digestive system, Anti-inflammatory, Drug Hypersensitivity, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, GNAI2, medicine, Immunology and Allergy, Humans, skin and connective tissue diseases, 030304 developmental biology, media_common, 0303 health sciences, Nonsteroidal, business.industry, Anti-Inflammatory Agents, Non-Steroidal, Drug hypersensitivity reactions (DHRs), Nonsteroidal anti-inflammatory drugs (NSAID), digestive system diseases, 3. Good health, 030228 respiratory system, chemistry, GTP-Binding Protein alpha Subunit, Gi2, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Genome-Wide Association Study
Abstract: International audience; Nonsteroidal anti-inflammatory drugs (NSAIDs) are the drugs most frequently involved in drug hypersensitivity reactions through mechanisms that may involve genetic predisposition. We performed a fine-mapping GWAS in patients with NSAID-induced hypersen-sitivity reactions with cross-intolerance belonging to the group of NSAID-induced urticaria, angioedema, and anaphylaxis (NIUAA) (2) and matched controls from South Spain, and we replicated the re-sults in patients and paired controls from central Spain. GNAI2 was a significant predictor of NSAID-induced hypersensitivity reactions. This association may reflect its influence on the activation of leukot-riene receptors and the recruitment of immune cells involved in the pathological mechanisms of NSAID hypersensitivity.
Published: 2019
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75. Exome sequencing of cases with neural tube defects identifies candidate genes involved in one-carbon/vitamin B12 metabolisms and Sonic Hedgehog pathway

Author: Olivier Klein, Jean-Louis Guéant, Rosa-Maria Guéant-Rodriguez, Bruno Leheup, François Feillet, Thomas Josse, Jimmy Voirin, Céline Chéry, Abderrahim Oussalah, Pascal Perrin, Emeline Renard, Denise Tramoy, Nutrition-Génétique et Exposition aux Risques Environnementaux (NGERE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Département de pédiatrie [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Service de Chirurgie Pédiatrique [CHRU Nancy], IMPACT GEENAGE, and ANR-15-IDEX-0004,LUE (ISITE),Lorraine Université d'Excellence(2016)
Subjects: Adult, Male, Candidate gene, congenital, hereditary, and neonatal diseases and abnormalities, animal structures, Adolescent, [SDV]Life Sciences [q-bio], [SDV.BC]Life Sciences [q-bio]/Cellular Biology, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Biology, Genome, 03 medical and health sciences, Young Adult, GLI3, Exome Sequencing, Genetics, medicine, Humans, Exome, Hedgehog Proteins, Neural Tube Defects, Sonic hedgehog, Child, Gene, Genetics (clinical), Exome sequencing, Genetic Association Studies, 030304 developmental biology, 0303 health sciences, [SDV.GEN]Life Sciences [q-bio]/Genetics, Vitamin B12, 030305 genetics & heredity, Neural tube, Hedgehog signaling pathway, Carbon, 3. Good health, Vitamin B 12, medicine.anatomical_structure, Child, Preschool, biology.protein, Female, Hedgehog Protein, Biomarkers, Signal Transduction
Abstract: International audience; Neural tube defects (NTD) result from complex mechanisms between genes, nutrition and environment. The identifcation of genetic predictors by genome exome sequencing and their infuence on genome methylation need further consideration. Gene variants related to 1-CM metabolism (1-CM) could infuence the methylation of genes involved in neural tube embryogenesis through impaired synthesis of S-adenosyl methionine. We performed exome sequencing of 6116 genes referenced in OMIM and NTD risk and genome-wide methylation in 23 NTD cases. We replicated the most signifcant associations in 81 other cases. The analysis of exome sequencing identifed one gene of 1-CM, LRP2, and one gene of Sonic Hedgehog (SHH), GLI3, in the 23 NTD cases. The analysis restricted to genes of 1-CM and neural tube embryogenesis identifed fve gene predictors of 1-CM (LRP2, rs137983840; MMAA, rs148142853; TCN2, rs35838082; FPGS, rs41306702; BHMT, rs763726268) and two of SHH (GLI3, rs35364414; MKS1, rs151023718). We replicated the association of TCN2, BHMT and GLI3 with NTD risk in the 81 cases. We found a signifcant hemimethylation of CFAP46 that may infuence SHH activation in one case, who carried risk alleles in BHMT, LRP2, MMAA and GLI3. In conclusion, we identifed new candidate genes and rare variants that highlight an interacting infuence of genes involved in SHH and 1-CM in the puzzle of genetic components of NTD risk.
Published: 2018
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76. EPURE Transplant (Eplerenone in Patients Undergoing Renal Transplant) study: study protocol for a randomized controlled trial

Author: Philippe Rieu, Yannick Le Meur, Frederic Jaisser, Luc Frimat, Christophe Mariat, Sophie Girerd, Ludovic Merckle, Nicolas Girerd, Xavier Lepage, Didier Ducloux, Christiane Mousson, Nassim Dali-Youcef, Bruno Moulin, Patrick Rossignol, Service de Néphrologie [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Défaillance Cardiovasculaire Aiguë et Chronique (DCAC), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Cardiovascular and Renal Clinical Trialists [Vandoeuvre-les-Nancy] (INI-CRCT), Institut Lorrain du Coeur et des Vaisseaux Louis Mathieu [Nancy], Université de Lorraine (UL), Service de Néphrologie [CHRU Besançon], Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), CHRU Brest - Service de Nephrologie (CHU - BREST - Nephrologie), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Université de Brest (UBO), CHU Saint-Etienne, Université Jean Monnet - Saint-Étienne (UJM), Service de néphrologie et hémodialyse [CHU de Strasbourg], CHU Strasbourg, Université de Strasbourg (UNISTRA), Service de néphrologie (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Université Bourgogne Franche-Comté [COMUE] (UBFC), Centre Hospitalier Universitaire de Reims (CHU Reims), Université de Reims Champagne-Ardenne (URCA), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre d'investigation clinique [Nancy] (CIC), Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité), This work was supported by INI-CRCT. The EPURE Transplant study was supported by a grant from the French Ministry of Health (Programme Hospitalier de Recherche Clinique Inter Régional 2014). The authors are supported by a public grant overseen by the French National Research Agency (ANR) as part of the second 'Investissements d’Avenir' program (reference: ANR-15-RHU-0004), and GEENAGE Impact Lorraine Université d’Excellence- reference ANR-15-IDEX-04-LUE)., IMPACT GEENAGE, ANR-15-IDEX-0004,LUE,Isite LUE(2015), ANR-15-RHUS-0004,FIGHT-HF,Combattre l'insuffisance cardiaque(2015), DALI-YOUCEF, Nassim, ISITE - Isite LUE - - LUE2015 - ANR-15-IDEX-0004 - IDEX - VALID, Combattre l'insuffisance cardiaque - - FIGHT-HF2015 - ANR-15-RHUS-0004 - RHUS - VALID, Service de néphrologie-hémodialyse-transplantation [CHRU Nancy], Service d'urologie, andrologie et transplantation rénale, Hôpital Saint-Jacques-Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), CHRU - Service de néphrologie, dialyse et transplantation rénale, Service de néphrologie et tranplantation, CHU Saint-Etienne-Hôpital nord, Service de Néphrologie et Transplantation, Centre d'investigation clinique plurithématique Pierre Drouin [Nancy] (CIC-P), Université de Lorraine (UL)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Sorbonne Université - Faculté de Médecine (SU FM), Sorbonne Université (SU), Université Paris Descartes - Paris 5 (UPD5), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Hôpital Saint-Jacques, and Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL)
Subjects: medicine.medical_specialty, Hyperkalemia, medicine.medical_treatment, [SDV]Life Sciences [q-bio], Population, 030232 urology & nephrology, Urology, Medicine (miscellaneous), Renal function, 030204 cardiovascular system & hematology, Expanded Criteria Donor, law.invention, Kidney transplantation, 03 medical and health sciences, Study Protocol, 0302 clinical medicine, Randomized controlled trial, Double-Blind Method, law, medicine, Humans, Multicenter Studies as Topic, Pharmacology (medical), education, Dialysis, ComputingMilieux_MISCELLANEOUS, Mineralocorticoid Receptor Antagonists, Randomized Controlled Trials as Topic, education.field_of_study, lcsh:R5-920, business.industry, Mineralocorticoid receptor antagonist, Expanded criteria donor, medicine.disease, Tissue Donors, 3. Good health, Eplerenone, [SDV] Life Sciences [q-bio], Data Interpretation, Statistical, Reperfusion Injury, Hemodialysis, medicine.symptom, business, lcsh:Medicine (General), Ischemia/reperfusion lesions, Glomerular Filtration Rate
Abstract: Background Despite advances in immunosuppressive therapy, kidney graft survival has failed to improve during the last decades. Ischemia/reperfusion injury (IRI) is one of the main pathophysiological mechanisms underlying delayed graft function, which is associated with poor long-term graft survival. Due to organ shortage, the proportion of grafts from expanded criteria donors (ECDs) is ever growing. These grafts may particularly benefit from IRI prevention. In preclinical models, mineralocorticoid receptor antagonists (MRAs) have been shown to efficiently prevent IRI. This study aims to assess the effect of MRA administration in the early phase of kidney transplantation (KT) among recipients of ECD grafts on mid-term graft function. Methods/design This is a multicenter, double-blind, placebo-controlled, randomized clinical trial. Patients on hemodialysis and undergoing a single or a dual KT from an ECD will be eligible for inclusion. We plan to randomize 132 patients. Included patients will be randomized (1:1) to receive either eplerenone 25 mg every 12 h during 4 days (the first dose being administered just prior to KT) or placebo. The primary outcome is graft function at 3 months, assessed by glomerular filtration rate (GFR, in mL/min/1.73m2) measured using iohexol clearance. Secondary outcomes include (1) proportion of patients with either dialysis dependency or a GFR
Published: 2018
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77. Fibrosis mechanistic phenotyping and antifibrotic response determination with biomarkers in heart failure: one single biomarker may not fit all settings

Author: Girerd, Sophie, Frimat, Luc, Ducloux, Didier, Le Meur, Yannick, Mariat, Christophe, Moulin, Bruno, Mousson, Christiane, Rieu, Philippe, Dali-Youcef, Nassim, Merckle, Ludovic, Lepage, Xavier, Girerd, Nicolas, Jaisser, Frederic, Rossignol, Patrick, Ferreira, Joao Pedro, Zannad, Faiez, Centre d'investigation clinique [Nancy] (CIC), Université de Lorraine (UL)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM), Défaillance Cardiovasculaire Aiguë et Chronique (DCAC), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Cardiovascular and Renal Clinical Trialists [Vandoeuvre-les-Nancy] (INI-CRCT), Institut Lorrain du Coeur et des Vaisseaux Louis Mathieu [Nancy], IMPACT GEENAGE, ANR-15-IDEX-0004,LUE (ISITE),Lorraine Université d'Excellence(2016), ANR-15-RHUS-0004,FIGHT-HF,Combattre l'insuffisance cardiaque(2015), Service de Néphrologie [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Service de Néphrologie et Urologie, Centre Hospitalier Régional Universitaire [Besançon] (CHRU Besançon)-Hôpital Saint-Jacques, CHRU Brest - Service de Nephrologie (CHU - BREST - Nephrologie), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), CHU Saint-Etienne, Service de Néphrologie et Transplantation, CHU Strasbourg, Service de néphrologie (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Centre Hospitalier Universitaire de Reims (CHU Reims), Laboratoire de Biochimie Générale et Spécialisée, Hôpitaux Universitaires de Strasbourg, Université de Lorraine (UL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Centre d'investigation clinique plurithématique Pierre Drouin (CIC-P), Centre de Recherche des Cordeliers (CRC), Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), CIC-Nancy, Institut Lorrain du Coeur et des Vaisseaux Louis Mathieu [Nancy]-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Cardiologie [CHRU Nancy], ANR-15-IDEX-04-LUE,LUE,Lorraine Université d'Excellence(2016), ANR: ANR-15-RHU-0004,Programme Investissement d'Avenir ANR-15-RHU-0004, DE CARVALHO, Philippe, ISITE - Isite LUE - - LUE2015 - ANR-15-IDEX-0004 - IDEX - VALID, Combattre l'insuffisance cardiaque - - FIGHT-HF2015 - ANR-15-RHUS-0004 - RHUS - VALID, and ANR-15-IDEX-0004,LUE,Isite LUE(2015)
Subjects: [SDV] Life Sciences [q-bio], [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, spironolactone, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, [SDV]Life Sciences [q-bio], heart failure, myocardial fibrosis, ComputingMilieux_MISCELLANEOUS, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system
Abstract: International audience; Biomarker-based phenotyping of myocardial fibrosis identifies patients with heart failure with preserved ejection fraction resistant to the beneficial effects of spironolactone: results from the Aldo-DHF trial. [Eur J Heart Fail. 2018]
Published: 2018
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78. Cardiorenal Syndrome Revisited

Author: Faiez Zannad, Patrick Rossignol, Service de Cardiologie [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), CIC-Nancy, Institut Lorrain du Coeur et des Vaisseaux Louis Mathieu [Nancy]-Institut National de la Santé et de la Recherche Médicale (INSERM), IMPACT GEENAGE, ANR-15-IDEX-04-LUE,LUE,Lorraine Université d'Excellence(2016), ANR: ANR-15-RHU-0004,Programme Investissement d'Avenir ANR-15-RHU-0004, Défaillance Cardiovasculaire Aiguë et Chronique (DCAC), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Centre d'investigation clinique plurithématique Pierre Drouin [Nancy] (CIC-P), Centre d'investigation clinique [Nancy] (CIC), Université de Lorraine (UL)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM), Cardiovascular and Renal Clinical Trialists [Vandoeuvre-les-Nancy] (INI-CRCT), Institut Lorrain du Coeur et des Vaisseaux Louis Mathieu [Nancy], French-Clinical Research Infrastructure Network - F-CRIN [Paris] (Cardiovascular & Renal Clinical Trialists - CRCT ), Association Lorraine pour le Traitement de l'Insuffisance Rénale (ALTIR), ANR-15-IDEX-0004,LUE,Isite LUE(2015), and ANR-15-RHUS-0004,FIGHT-HF,Combattre l'insuffisance cardiaque(2015)
Subjects: cardio-renal syndrome, [SDV]Life Sciences [q-bio], heart failure, Angiotensin-Converting Enzyme Inhibitors, Cardiorenal syndrome, Disease, 030204 cardiovascular system & hematology, Bioinformatics, Kidney, renal insufficiency, Renin-Angiotensin System, 03 medical and health sciences, Angiotensin Receptor Antagonists, 0302 clinical medicine, Mineralocorticoid receptor, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Fibrosis, Cardio-Renal Syndrome, Risk Factors, Physiology (medical), medicine, Humans, 030212 general & internal medicine, Endothelial dysfunction, Mineralocorticoid Receptor Antagonists, Ventricular Remodeling, business.industry, Myocardium, fibrosis, Heart, medicine.disease, Prognosis, 3. Good health, Oxidative Stress, Receptors, Mineralocorticoid, Heart failure, Inflammation Mediators, Cardiology and Cardiovascular Medicine, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Kidney disease, Signal Transduction
Abstract: International audience; Cardiorenal syndromes have been categorized into 5 clinical subtypes based on which organ is perceived to be the primary precipitant of the vicious and interrelated cycle of declining function in both organs. This clinical classification has broadened interest in cardiorenal interactions, but it is merely descriptive, does not rely on or inform predominant pathophysiology, and has produced little change in either practice or the research agenda. In contrast, recent scientific work identifies common pathophysiological pathways for several categories of cardiorenal syndromes, suggesting a unifying pathogenesis. Fibrosis is a common consequence of inflammation- and oxidative stress-related endothelial dysfunction in aging, hypertension, diabetes mellitus, obesity, ischemia, and organ injury. It is a common feature in heart failure and chronic kidney disease. Therefore, we suggest that fibrosis may be not only a marker but also the primary driver of pathophysiology in several cardiorenal syndromes. Interstitial fibrosis in the heart, large arteries, and kidneys may play a key role in the pathophysiology of the cardiorenal syndrome continuum. Focusing on fibrosis as a disease mediator might enable the identification of fibrosis-related biotargets that could potentially be modulated with renin-angiotensin-aldosterone system inhibitors, mineralocorticoid receptor antagonists, or other novel antifibrotic agents in development. This conceptual approach may be an effective new strategy for the prevention and treatment of fibrosis within the cardiorenal syndrome continuum.
Published: 2018
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79. N-homocysteinylation of tau and MAP1 is increased in autopsy specimens of Alzheimer's disease and vascular dementia

Author: Rémy Umoret, Jeffrey M. Sequeira, Edward V. Quadros, Jean-Louis Guéant, Jean-Michel Camadro, Valérie Rigau, Sylvain Lehmann, Carine Bossenmeyer-Pourié, Bernard Sablonnière, A. David Smith, Déborah Helle, Jean-Luc Daval, Racha Kerek, Rosa-Maria Guéant-Rodriguez, Vincent Deramecourt, Audrey Gabelle, Grégory Pourié, Nutrition-Génétique et Exposition aux Risques Environnementaux (NGERE), Université de Lorraine (UL)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de génétique humaine (IGH), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre de Biologie-Pathologie, UF de Neurobiologie-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Institut Jacques Monod (IJM (UMR_7592)), Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Service de Biopathologie [CHRU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), SUNY Downstate Medical Center, State University of New York (SUNY), IMPACT GEENAGE, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), University of Oxford [Oxford], Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Institut pour la Recherche sur le Cancer de Lille (U837 INSERM - IRCL), and Institut pour la recherche sur le cancer de Lille [Lille] (IRCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre de Recherche Jean-Pierre AUBERT - Neurosciences et Cancer -JPArc [Lille]
Subjects: 0301 basic medicine, medicine.medical_specialty, Hyperhomocysteinemia, Aging, Homocysteine, Normal diet, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Hippocampus, tau Proteins, folate, Pathology and Forensic Medicine, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Alzheimer Disease, Internal medicine, medicine, Animals, Humans, Cognitive Dysfunction, Vitamin B12, tau, Cognitive decline, Vascular dementia, Mice, Knockout, Alzheimer-type dementia, business.industry, Dementia, Vascular, microtubule-associated proteins, Brain, homocysteine, vitamin B12, medicine.disease, 3. Good health, Rats, 030104 developmental biology, Endocrinology, chemistry, Ageing, 030220 oncology & carcinogenesis, Female, Autopsy, business
Abstract: International audience; The pathomechanisms that associate a deficit in folate and/or vitamin B12 and the subsequent hyperhomocysteinemia with pathological brain ageing are unclear. We investigated the homocysteinylation of microtubule-associated proteins (MAPs) in brains of patients with Alzheimer's disease or vascular dementia, and in rats depleted in folate and vitamin B12, Cd320 KO mice with selective B12 brain deficiency and H19-7 neuroprogenitors lacking folate. Compared with controls, N-homocysteinylated tau and MAP1 were increased and accumulated in protein aggregates and tangles in the cortex, hippocampus and cerebellum of patients and animals. N-homocysteinylation dissociated tau and MAPs from β-tubulin, and MS analysis showed that it targets lysine residues critical for their binding to β-tubulin. N-homocysteinylation increased in rats exposed to vitamin B12 and folate deficit during gestation and lactation and remained significantly higher when they became 450 days-old, despite returning to normal diet at weaning, compared with controls. It was correlated with plasma homocysteine (Hcy) and brain expression of methionine tRNAsynthetase (MARS), the enzyme required for the synthesis of Hcy-thiolactone, the substrate of N-homocysteinylation. Experimental inactivation of MARS prevented the N-homocysteinylation of tau and MAP1, and the dissociation of tau and MAP1 from β-tubulin and PSD95 in cultured neuroprogenitors. In conclusion, increased N-homocysteinylation of tau and MAP1 is a mechanism of brain ageing that depends on Hcy concentration and expression of MARS enzyme. Its irreversibility and cumulative occurrence throughout life may explain why B12 and folate supplementation of the elderly has limited effects, if any, to prevent pathological brain ageing and cognitive decline. Copyright © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Published: 2018
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80. Data-Driven Approach to Identify Subgroups of Heart Failure With Reduced Ejection Fraction Patients With Different Prognoses and Aldosterone Antagonist Response Patterns

Author: John Vincent, Bertram Pitt, Patrick Rossignol, Kevin Duarte, Faiez Zannad, Dirk J. van Veldhuisen, Jasper Tromp, João Pedro Ferreira, Tariq Ahmad, John J.V. McMurray, Centre d'investigation clinique plurithématique Pierre Drouin [Nancy] (CIC-P), Centre d'investigation clinique [Nancy] (CIC), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Défaillance Cardiovasculaire Aiguë et Chronique (DCAC), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Faculdade de Medicina da Universidade do Porto (FMUP), Universidade do Porto, British Heart Foundation Glasgow Cardiovascular Research Centre (BHF GCRC), University of Glasgow-NHS Greater Glasgow and Clyde, University of Michigan Medical School [Ann Arbor], University of Michigan [Ann Arbor], University of Michigan System-University of Michigan System, University Medical Center Groningen [Groningen] (UMCG), Pfizer, Yale University School of Medicine, IMPACT GEENAGE, ANR-15-IDEX-0004,LUE,Isite LUE(2015), ANR-15-RHUS-0004,FIGHT-HF,Combattre l'insuffisance cardiaque(2015), Centre d'investigation clinique plurithématique Pierre Drouin (CIC-P), Biology, genetics and statistics (BIGS), Inria Nancy - Grand Est, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Institut Élie Cartan de Lorraine (IECL), Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS)-Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), BHF Glasgow Cardiovascular Research Centre, University of Glasgow, University of Michigan Medical School, Division of Cardiology, Duke University Medical Center, CIC-Nancy, Institut Lorrain du Coeur et des Vaisseaux Louis Mathieu [Nancy]-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Cardiologie [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), ANR-15-IDEX-04-LUE,LUE,Lorraine Université d'Excellence(2016), ANR: ANR-15-RHU-0004,Programme Investissement d'Avenir ANR-15-RHU-0004, and Cardiovascular Centre (CVC)
Subjects: Male, Hyperkalemia, Myocardial Infarction, heart failure, Spironolactone, 030204 cardiovascular system & hematology, Ventricular Dysfunction, Left, chemistry.chemical_compound, 0302 clinical medicine, Risk Factors, FERRIC CARBOXYMALTOSE, 030212 general & internal medicine, Myocardial infarction, Mineralocorticoid Receptor Antagonists, Aged, 80 and over, 2. Zero hunger, Aldosterone, Ejection fraction, Middle Aged, Prognosis, 3. Good health, Eplerenone, Treatment Outcome, INTRAVENOUS IRON, diabetes mellitus, Cardiology, MESH: aldosterone, eplerenone, hyperkalemia, Female, medicine.symptom, Cardiology and Cardiovascular Medicine, medicine.drug, medicine.medical_specialty, Article, 03 medical and health sciences, MILD PATIENTS HOSPITALIZATION, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Internal medicine, Diabetes mellitus, medicine, Humans, Antihypertensive Agents, Aged, aldosterone, business.industry, KIDNEY-DISEASE, medicine.disease, WORSENING RENAL-FUNCTION, EMPHASIS-HF, HIGH-RISK, chemistry, MYOCARDIAL-INFARCTION, Heart failure, EPLERENONE, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Kidney disease
Abstract: Background: Patients with heart failure with reduced ejection fraction have a poor prognosis. The identification of subgroups with different outcomes and treatment response patterns may help to tailor strategies to each individual patient. We present an exploratory study of patients enrolled in the EMPHASIS-HF trial (Eplerenone in Patients With Systolic Heart Failure and Mild Symptoms) using latent class analysis with validation using the EPHESUS trial (Eplerenone, a Selective Aldosterone Blocker, in Patients With Left Ventricular Dysfunction After Myocardial Infarction) to identify subgroups of patients with different prognosis and response to eplerenone therapy. Methods and Results: Latent class analysis identifies mutually exclusive groups of individuals maximizing within-group similarities and between-group differences. In the EMPHASIS-HF trial, 2279 heart failure with reduced ejection fraction patients were randomized to eplerenone or placebo and were characterized according to 18 clinical features. Subgroup definitions were applied to 6472 patients enrolled in the EPHESUS trial to validate observations. Event-free survival and effect of eplerenone on the composite of cardiovascular death and heart failure hospitalization were determined for each subgroup. Four subgroups were identified with significant differences in event-free survival ( P =0.002). The subgroup C had the worst event-free survival in both studies and was characterized by older age, lower body mass index, worse renal function, higher baseline potassium levels, high prevalence of anemia, diabetes mellitus, previous revascularization and higher rates of eplerenone discontinuation, and hyperkalemia during follow-up. Two subgroups (B and C) showed a poorer response to eplerenone in both studies and these groups shared common features such as lower body mass index and high prevalence of anemia. Clinical profiles, prognosis, and treatment response patterns of the 4 subgroups applied in EPHESUS trial presented similarities to those observed in EMPHASIS. Conclusions: Using a data-driven approach, we identified heart failure with reduced ejection fraction subgroups with significantly different prognoses and potentially different responses to eplerenone. However, these data should be regarded as hypothesis-generating and prospective validation is warranted, to assess the potential clinical implications of these subgroups. Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT00232180.
Published: 2018
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81. Association between abdominal adiposity and 20-year subsequent aortic stiffness in an initially healthy population-based cohort

Author: Julie-Anne Nazare, Athanase Benetos, Nicolas Girerd, Erwan Bozec, Patrick Rossignol, Kevin Duarte, João Pedro Ferreira, Faiez Zannad, Martine Laville, Jean-Marc Boivin, Kénora Chau, Centre d'investigation clinique plurithématique Pierre Drouin (CIC-P), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Département de médecine générale [Univ. Lorraine], Université de Lorraine (UL), Cardiovascular and Renal Clinical Trialists [Vandoeuvre-les-Nancy] (INI-CRCT), Institut Lorrain du Coeur et des Vaisseaux Louis Mathieu [Nancy], University of Porto, Centre de Recherche en Nutrition Humaine Rhône-Alpes (CRNH-RH), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Recherche Agronomique (INRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Jean Monnet [Saint-Étienne] (UJM)-CHU Saint-Etienne-Hospices Civils de Lyon (HCL)-CHU Grenoble-Université Joseph Fourier - Grenoble 1 (UJF), Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hospices Civils de Lyon (HCL), IMPACT GEENAGE, ANR: 15-RHUS-0004,FIGHT-HF,Combattre l'insuffisance cardiaque(2015), ANR-15-IDEX-04-LUE,LUE,Lorraine Université d'Excellence(2016), European Project: 602904,EC:FP7:HEALTH,FP7-HEALTH-2013-INNOVATION-1,FIBRO-TARGETS(2013), European Project: 261409,EC:FP7:HEALTH,FP7-HEALTH-2010-single-stage,MEDIA(2011), Centre d'investigation clinique plurithématique Pierre Drouin [Nancy] (CIC-P), Centre d'investigation clinique [Nancy] (CIC), Université de Lorraine (UL)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM), Universidade do Porto, Centre de Recherche en Nutrition Humaine Rhône-Alpes (CRNH-RA), Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Recherche Agronomique (INRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Jean Monnet [Saint-Étienne] (UJM)-CHU Saint-Etienne-Hospices Civils de Lyon (HCL)-CHU Grenoble, Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM), ANR-15-RHUS-0004,FIGHT-HF,Combattre l'insuffisance cardiaque(2015), ANR-15-IDEX-0004,LUE,Isite LUE(2015), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Universidade do Porto = University of Porto, Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E)-Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), and Université de Lyon-Université de Lyon-CHU Grenoble-Hospices Civils de Lyon (HCL)-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])
Subjects: Male, obesity, Physiology, [SDV]Life Sciences [q-bio], 030204 cardiovascular system & hematology, Body Mass Index, Cohort Studies, 0302 clinical medicine, blood-pressure, Risk Factors, initially healthy adults, gender, 030212 general & internal medicine, Longitudinal Studies, Pulse wave velocity, ComputingMilieux_MISCELLANEOUS, visceral adiposity, cardiovascular risk-factors, Body Shape Index, Middle Aged, Circumference, Femoral Artery, arterial stiffness, Carotid Arteries, pulse-wave velocity, Cardiovascular Diseases, Obesity, Abdominal, Pulsatile Flow, Cohort, Cardiology, Aortic stiffness, Female, France, Waist Circumference, Cardiology and Cardiovascular Medicine, Adult, medicine.medical_specialty, hypertension, aortic stiffness, Waist, pulse wave velocity, men, Pulse Wave Analysis, 03 medical and health sciences, Vascular Stiffness, Internal medicine, Internal Medicine, medicine, Humans, business.industry, nutritional and metabolic diseases, longitudinal cohort study, medicine.disease, mortality, Confidence interval, Cardiovascular System & Cardiology, Arterial stiffness, Linear Models, business
Abstract: BACKGROUND Aortic stiffness is a feature of arterial aging and is associated with dismal cardiovascular prognosis. We examined whether central and general adiposity is an independent predictor of accelerated aortic stiffening 20 years later in initially healthy midlife individuals. METHODS Participants from the STANISLAS cohort study (826 initially healthy participants aged 30-60 from the Lorraine region in France) underwent clinical and biological measurements at baseline (1994-1995) and after ≈20 years (2011-2016). Adiposity measurements included waist circumference/BMI ratio, BMI, waist circumference, and 'body shape index' [waist circumference/(BMI height)]. Real carotid-femoral pulse wave velocity (cfPWV) was measured at end of follow-up. Our primary analysis was to test the association between waist circumference/BMI ratio and cfPWV. RESULTS In a multiple linear regression model adjusted for sex, age and mean arterial pressure, waist circumference -to-BMI ratio was positively associated (for 1SD increase) with higher cfPWV [regression coefficient β = 0.32, 95% confidence interval (CI) 0.19-0.45, P
Published: 2018
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82. Diagnostic and prognostic value of plasma volume status at emergency department admission in dyspneic patients: results from the PARADISE cohort

Author: Aurélien Buessler, Thibaut Hutter, Adrien Bassand, Gaetan Giacomin, Tahar Chouihed, Patrick Rossignol, Deborah Jaeger, Kevin Duarte, Nicolas Jay, Lionel Nace, Françoise Barbé, Sylvain Salignac, Faiez Zannad, Masatake Kobayashi, Nicolas Girerd, Sonia Sadoune, Défaillance Cardiovasculaire Aiguë et Chronique (DCAC), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), CIC-Nancy, Institut Lorrain du Coeur et des Vaisseaux Louis Mathieu [Nancy]-Institut National de la Santé et de la Recherche Médicale (INSERM), Cardiovascular and Renal Clinical Trialists [Vandoeuvre-les-Nancy] (INI-CRCT), Institut Lorrain du Coeur et des Vaisseaux Louis Mathieu [Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), The University of Tokyo, Service de Réanimation Médicale [CHRU Nancy], Service d'Hématologie [CHRU Nancy], Data Science, Knowledge, Reasoning and Engineering (K Team), Department of Natural Language Processing & Knowledge Discovery (LORIA - NLPKD), Laboratoire Lorrain de Recherche en Informatique et ses Applications (LORIA), Institut National de Recherche en Informatique et en Automatique (Inria)-Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche en Informatique et en Automatique (Inria)-Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS)-Laboratoire Lorrain de Recherche en Informatique et ses Applications (LORIA), Institut National de Recherche en Informatique et en Automatique (Inria)-Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche en Informatique et en Automatique (Inria)-Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), Service de Cardiologie [CHRU Nancy], Contrat de Plan État Région Lorraine and FEDER IT2MP, IMPACT GEENAGE, ANR-15-IDEX-04-LUE,LUE,Lorraine Université d'Excellence(2016), ANR-15-RHU-0004,FIGHT-HF ,Fighting Heart Failure, Centre d'investigation clinique [Nancy] (CIC), The University of Tokyo (UTokyo), K team (Data Science, Knowledge, Reasoning and Engineering), ANR-15-IDEX-0004,LUE,Isite LUE(2015), ANR-15-RHUS-0004,FIGHT-HF,Combattre l'insuffisance cardiaque(2015), Centre National de la Recherche Scientifique (CNRS)-Université de Lorraine (UL)-Institut National de Recherche en Informatique et en Automatique (Inria)-Centre National de la Recherche Scientifique (CNRS)-Université de Lorraine (UL)-Institut National de Recherche en Informatique et en Automatique (Inria)-Laboratoire Lorrain de Recherche en Informatique et ses Applications (LORIA), and Centre National de la Recherche Scientifique (CNRS)-Université de Lorraine (UL)-Institut National de Recherche en Informatique et en Automatique (Inria)-Centre National de la Recherche Scientifique (CNRS)-Université de Lorraine (UL)-Institut National de Recherche en Informatique et en Automatique (Inria)
Subjects: Male, Time Factors, 030204 cardiovascular system & hematology, Hematocrit, Logistic regression, [INFO.INFO-AI]Computer Science [cs]/Artificial Intelligence [cs.AI], Hospitals, University, 0302 clinical medicine, 030212 general & internal medicine, Hospital Mortality, Aged, 80 and over, medicine.diagnostic_test, General Medicine, Middle Aged, Prognosis, 3. Good health, Hospitalization, Survival Rate, Cohort, Acute Disease, Cardiology, Congestion, Female, France, Cardiology and Cardiovascular Medicine, Acute dyspnea, Emergency Service, Hospital, medicine.medical_specialty, Plasma volume, 03 medical and health sciences, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Internal medicine, medicine, Humans, In patient, Mortality, Plasma Volume, Aged, Retrospective Studies, Heart Failure, business.industry, Estimated plasma volume status, Acute heart failure, Emergency department, medicine.disease, Dyspnea, Heart failure, Emergency, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Biomarkers, Follow-Up Studies
Abstract: International audience; Background:Systemic congestion, evaluated by estimated plasma volume status (ePVS), is associated with in-hospital mortality in acute heart failure (AHF). However, the diagnostic and prognostic value of ePVS in patients with acute dyspnea has been insufficiently studied.-- Objectives:To assess the association between the first ePVS calculated from blood samples on admission in the emergency department (ED) and discharge diagnosis of AHF and in-hospital mortality in patients admitted for acute dyspnea.-- Methods:The study included 1369 patients admitted for dyspnea in the ED in 2015. ePVS was calculated from hematocrit and hemoglobin values at admission. Comparisons of baseline characteristics according to ePVS tertiles were carried out and then associations between ePVS and the two outcomes “AHF diagnosis” and “intra-hospital mortality” were assessed using a logistic regression model.-- Results:36.6% had a BNP > 400 pg/mL and median ePVS was 4.58 dL/g [3.96–5.55]. Overall in-hospital mortality was 11.1% (n = 149). In multivariable analysis, the third ePVS tertile (> 5.12 dL/g) had a significantly increased risk of having AHF (OR = 1.64 [1.16–2.33], p = 0.005). In-hospital mortality rose across ePVS tertiles (8.4–13.8% p
Published: 2018
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83. Zinc-Alpha-2-Glycoprotein in Inflammatory Bowel Disease

Author: Seiamak Bahram, Cécile Macquin, Laurent Peyrin-Biroulet, David Moulin, Véronique Rolli, Tunay Kökten, Ndeye-Coumba Ndiaye, Jean-Yves Jouzeau, Julie Hablot, Philippe Georgel, Patrick Netter, Immuno-Rhumatologie Moléculaire, Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Nutrition-Génétique et Exposition aux Risques Environnementaux (NGERE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Ingénierie Moléculaire et Physiopathologie Articulaire (IMoPA), Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), IMPACT GEENAGE, ANR-15-IDEX-0004,LUE,Isite LUE(2015), Université de Lorraine (UL)-Institut National de la Santé et de la Recherche Médicale (INSERM), Immunorhumathologie moléculaire, and Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: 0301 basic medicine, medicine.medical_specialty, Mice Knockout, [SDV]Life Sciences [q-bio], Zn-Alpha-2-Glycoprotein, Inflammatory bowel disease, Gastroenterology, Seminal Plasma Proteins/genetics, 03 medical and health sciences, Mice, Internal medicine, medicine, Immunology and Allergy, Animals, Humans, Colitis, ComputingMilieux_MISCELLANEOUS, Mice, Knockout, business.industry, Animal, Zinc-Alpha-2-Glycoprotein, Case-control study, Seminal Plasma Proteins, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, medicine.disease, Seminal Plasma Proteins/blood, Disease Models, Animal, 030104 developmental biology, Ulcerative/blood, Case-Control Studies, Disease Models, Colitis, Ulcerative, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: International audience
Published: 2018
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84. Lipid management in patients with chronic kidney disease

Author: Charles J. Ferro, Gunnar H. Heine, Gérard M. London, Jolanta Malyszko, Jose M. Valdivielso, Raymond Vanholder, Francesca Mallamaci, Robert Ekart, Patrick B. Mark, Carmine Zoccali, Ziad A. Massy, Marianne C. Verhaar, Mehmet Kanbay, Alberto Ortiz, Pantelis Sarafidis, Patrick Rossignol, University Hospitals Birmingham [Birmingham, Royaume-Uni], Institute of Cardiovascular and Medical Sciences [Glasgow], University of Glasgow, Koç University, Aristotle University of Thessaloniki, Universitätsklinikum des Saarlandes, Centre d'investigation clinique [Nancy] (CIC), Université de Lorraine (UL)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Ambroise Paré [AP-HP], Azienda Ospedaliera Ospedali Civili Riuniti, Nephrology Section [Ghent], Ghent University Hospital, Centre Hospitalier Manhès [Fleury-Mérogis], IIS‑Fundación Jiménez Diaz‑Autonoma University [Madrid, Spain], CNR-IFC Clinical Epidemiology and Pathophysiology of Renal Diseases and Hpertension Unit, Reggio Calabria, Reggio Calabria c/o Ospedali Riuniti, IMPACT GEENAGE, ANR-15-IDEX-0004,LUE,Isite LUE(2015), ANR-15-RHUS-0004,FIGHT-HF,Combattre l'insuffisance cardiaque(2015), Koc University, School of Medicine, Istanbul, CIC-Nancy, Institut Lorrain du Coeur et des Vaisseaux Louis Mathieu [Nancy]-Institut National de la Santé et de la Recherche Médicale (INSERM), Mécanismes physiologiques et conséquences des calcifications cardiovasculaires: rôle des remodelages cardiovasculaires et osseux, Université de Picardie Jules Verne (UPJV)-Institut National de la Santé et de la Recherche Médicale (INSERM), ANR-15-IDEX-04-LUE,LUE,Lorraine Université d'Excellence(2016), and ANR: ANR-15-RHU-0004,Programme Investissement d'Avenir ANR-15-RHU-0004
Subjects: medicine.medical_treatment, [SDV]Life Sciences [q-bio], Blood lipids, Disease, 030204 cardiovascular system & hematology, urologic and male genital diseases, [SDV.MHEP.UN]Life Sciences [q-bio]/Human health and pathology/Urology and Nephrology, chemistry.chemical_compound, 0302 clinical medicine, Lipid Management, Drug Discovery, 030212 general & internal medicine, education.field_of_study, biology, PCSK9 Inhibitors, Fibric Acids, 3. Good health, Nephrology, Cardiovascular Diseases, Low-density lipoprotein, Practice Guidelines as Topic, LDL cholesterol, lipids (amino acids, peptides, and proteins), Glomerular Filtration Rate, medicine.medical_specialty, Ronyons -- Malalties, Population, Renal function, 03 medical and health sciences, Internal medicine, Fatty Acids, Omega-3, medicine, Humans, Renal Insufficiency, Chronic, education, Dialysis, Dyslipidemias, Biological Products, business.industry, C-reactive protein, medicine.disease, Lipid Metabolism, Chronic Kidney Disease (CKD), End-stage renal disease (ESRD), Cholesterol Ester Transfer Proteins, chemistry, Lípids, biology.protein, Hydroxymethylglutaryl-CoA Reductase Inhibitors, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Kidney disease
Abstract: An increased risk of cardiovascular disease, independent of conventional risk factors, is present even at minor levels of renal impairment and is highest in patients with end-stage renal disease (ESRD) requiring dialysis. Renal dysfunction changes the level, composition and quality of blood lipids in favour of a more atherogenic profile. Patients with advanced chronic kidney disease (CKD) or ESRD have a characteristic lipid pattern of hypertriglyceridaemia and low HDL cholesterol levels but normal LDL cholesterol levels. In the general population, a clear relationship exists between LDL cholesterol and major atherosclerotic events. However, in patients with ESRD, LDL cholesterol shows a negative association with these outcomes at below average LDL cholesterol levels and a flat or weakly positive association with mortality at higher LDL cholesterol levels. Overall, the available data suggest that lowering of LDL cholesterol is beneficial for prevention of major atherosclerotic events in patients with CKD and in kidney transplant recipients but is not beneficial in patients requiring dialysis. The 2013 Kidney Disease: Improving Global Outcomes (KDIGO) Clinical Practice Guideline for Lipid Management in CKD provides simple recommendations for the management of dyslipidaemia in patients with CKD and ESRD. However, emerging data and novel lipid-lowering therapies warrant some reappraisal of these recommendations. AO was supported by Spanish Government ISCIII FEDER funds (PI16/02057, ISCIII-RETIC REDinREN RD16/0009) and Community of Madrid (B2017/BMD-3686 CIFRA2-CM).
Published: 2018
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85. Molecular dissection of lncRNA activities: ANRIL as Model System

Author: Alfeghaly, Charbel, Vautrot, Valentin, Marchand, Virginie, Motorin, Yuri, Behm-Ansmant, Isabelle, Maenner, Sylvain, BEHM-ANSMANT, Isabelle, ISITE - Isite LUE - - LUE2015 - ANR-15-IDEX-0004 - IDEX - VALID, Ingénierie Moléculaire et Physiopathologie Articulaire (IMoPA), Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), Ingénierie, Biologie et Santé en Lorraine (IBSLor), Université de Lorraine (UL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), ANR-15-IDEX-0004,LUE,Isite LUE(2015), and IMPACT GEENAGE
Subjects: [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, ComputingMilieux_MISCELLANEOUS
Abstract: International audience
Published: 2018

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51. Paradoxical gastrointestinal effects of interleukin-17 blockers

52. Longer Duration of Hypertension and MRI Microvascular Brain Alterations Are Associated with Lower Hippocampal Volumes in Older Individuals with Hypertension

53. Étude intégrative des facteurs environnementaux, de la génétique et de l’épigénétique du patient atteint d’obésité avant et après la chirurgie bariatrique

54. Population and evolutionary genetics of the PAH locus to uncover overdominance and adaptive mechanisms in phenylketonuria: Results from a multiethnic study

55. Cardiovascular and Non-Cardiovascular death distinction: the utility of Troponin beyond NT-proBNP. Findings from the BIOSTAT-CHF study

56. Management of hyperkalemia in the acutely ill patient

57. MRAs in Elderly HF Patients: Individual Patient-Data Meta-Analysis of RALES, EMPHASIS-HF, and TOPCAT

58. A PRDX1 mutant allele causes a MMACHC secondary epimutation in cblC patients

59. Telomeres: New players in immune-mediated inflammatory diseases?

60. Renin-angiotensin-aldosterone system and kidney interactions in heart failure

61. Beta-blockers in heart failure patients with severe chronic kidney disease—time for a randomized controlled trial?

62. Peripheral blood mononuclear cells extracts VEGF protein levels and VEGF mRNA: Associations with inflammatory molecules in a healthy population

63. Heritability of a resting heart rate in a 20-year follow-up family cohort with GWAS data: Insights from the STANISLAS cohort

64. Mineralocorticoid receptor antagonists and kidney diseases: pathophysiological basis

65. Nondipping Pattern and Cardiovascular and Renal Damage in a Population-Based Study (The STANISLAS Cohort Study)

66. Arterial Remodeling and Dysfunction in the ZSF1 Rat Model of Heart Failure With Preserved Ejection Fraction

67. Proteomic Bioprofiles and Mechanistic Pathways of Progression to Heart Failure

68. Income level and inequality as complement to geographical differences in cardiovascular trials

69. Global Burden Related to Nitrous Oxide Exposure in Medical and Recreational Settings: A Systematic Review and Individual Patient Data Meta-Analysis

70. Vitamin B-12 and liver activity and expression of methionine synthase are decreased in fetuses with neural tube defects

71. Telomere Dynamics and Aging Related Diseases

72. Dipeptidyl Peptidase-4 Inhibitors and the Risk of Heart Failure

74. GNAI2 variants predict nonsteroidal anti-inflammatory drug hypersensitivity in a genome-wide study

75. Exome sequencing of cases with neural tube defects identifies candidate genes involved in one-carbon/vitamin B12 metabolisms and Sonic Hedgehog pathway

76. EPURE Transplant (Eplerenone in Patients Undergoing Renal Transplant) study: study protocol for a randomized controlled trial

77. Fibrosis mechanistic phenotyping and antifibrotic response determination with biomarkers in heart failure: one single biomarker may not fit all settings

78. Cardiorenal Syndrome Revisited

79. N-homocysteinylation of tau and MAP1 is increased in autopsy specimens of Alzheimer's disease and vascular dementia

80. Data-Driven Approach to Identify Subgroups of Heart Failure With Reduced Ejection Fraction Patients With Different Prognoses and Aldosterone Antagonist Response Patterns

81. Association between abdominal adiposity and 20-year subsequent aortic stiffness in an initially healthy population-based cohort

82. Diagnostic and prognostic value of plasma volume status at emergency department admission in dyspneic patients: results from the PARADISE cohort

83. Zinc-Alpha-2-Glycoprotein in Inflammatory Bowel Disease

84. Lipid management in patients with chronic kidney disease

85. Molecular dissection of lncRNA activities: ANRIL as Model System

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