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2,573 results on '"Berlin Institute of Health (BIH)"'

1. Characterization of Endogenous SERINC5 Protein as Anti-HIV-1 Factor

Author: Jens Bohne, Daniel Todt, Steppich K, Sergej Franz, Angelina Malassa, Thomas Zillinger, Eike Steinmann, Xu S, Nicoletta Casartelli, Passos, Christine Goffinet, Winfried Barchet, Wachs As, Oliver Schwartz, Schilling H, Kathrin Sutter, Ulf Dittmer, Centre for Experimental and Clinical Infection Research [Hanover] (TWINCORE), Instituto de Ciências Biomédicas de Abel Salazar (ICBAS), Universidade do Porto, Institute of Clinical Chemistry and Clinical Pharmacology [Bonn, Allemagne], University of Bonn, Virus et Immunité - Virus and immunity, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Hannover Medical School [Hannover] (MHH), Ruhr University Bochum (RUB), University of Duisburg-Essen, German Centre for Infection Research (DZIF), Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Berlin Institute of Health (BIH), Vânia Passos and Sergej Franz are supported by the Infection Biology International Ph.D. Program of the Hannover Biomedical Research School. Vânia Passos is supported by the GABBA Ph.D. Program and the Fundação para a Ciência e Tecnologia (FCT). Thomas Zillinger and Winfried Barchet acknowledge Bonfor and DZIF funding and German Research Foundation (Deutsche Forschungsgemeinschaft [DFG]) grants EXC1023: ImmunoSensation and CRCs 670 and 704. This work is supported by DFG funding to Christine Goffinet (Collaborative Research Centre SFB900, Microbial Persistence and its Control, project C8 and Priority Program 1923, Innate Sensing and Restriction of Retroviruses, GO2153/4 grant) and funding from the HZI and the Berlin Institute of Health (BIH) to Christine Goffinet., Universidade do Porto = University of Porto, Universität Bonn = University of Bonn, Virus et Immunité - Virus and immunity (CNRS-UMR3569), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Universität Duisburg-Essen = University of Duisburg-Essen [Essen], and TWINCORE, Zentrum für experimentelle und klinische Infektionsforschung GmbH,Feodor-Lynen Str. 7, 30625 Hannover, Germany.
Subjects: MESH: Gene Editing, MESH: CRISPR-Cas Systems, T-Lymphocytes, Mutant, Medizin, HIV Infections, Endogeny, Jurkat cells, Epitope, MESH: HIV-1, MESH: Genotype, Gene Knockout Techniques, SERINC5, MESH: nef Gene Products, Human Immunodeficiency Virus, MESH: Anti-HIV Agents, Internalization, media_common, MESH: Gene Knockout Techniques, Gene Editing, 0303 health sciences, human immunodeficiency virus, 030302 biochemistry & molecular biology, virus diseases, MESH: HIV Infections, MESH: Gene Expression Regulation, Virus-Cell Interactions, 3. Good health, Cell biology, interferons, MESH: HEK293 Cells, Host-Pathogen Interactions, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, MESH: Virion, MESH: Membrane Proteins, MESH: Interferon-alpha, Genotype, Anti-HIV Agents, media_common.quotation_subject, Immunology, Alpha interferon, Heterologous, Biology, Microbiology, Cell Line, 03 medical and health sciences, Virology, Nitriles, Humans, nef Gene Products, Human Immunodeficiency Virus, antiviral factor, CRISPR/Cas9, 030304 developmental biology, Nef, MESH: Humans, Cell Membrane, MESH: Host-Pathogen Interactions, Virion, Interferon-alpha, Membrane Proteins, Subcellular localization, MESH: Cell Line, HEK293 Cells, Pyrimidines, MESH: T-Lymphocytes, Gene Expression Regulation, Insect Science, HIV-1, Pyrazoles, CRISPR-Cas Systems, MESH: Pyrazoles, MESH: Cell Membrane
Abstract: SERINC5 is the long-searched-for antiviral factor that is counteracted by the HIV-1 accessory gene product Nef. Here, we engineered, via CRISPR/Cas9 technology, T-cell lines that express endogenous SERINC5 alleles tagged with a knocked-in HA epitope. This genetic modification enabled us to study basic properties of endogenous SERINC5 and to verify proposed mechanisms of HIV-1 Nef-mediated counteraction of SERINC5. Using this unique resource, we identified the susceptibility of endogenous SERINC5 protein to posttranslational modulation by type I IFNs and suggest uncoupling of Nef-mediated functional antagonism from SERINC5 exclusion from virions., When expressed in virus-producing cells, the cellular multipass transmembrane protein SERINC5 reduces the infectivity of HIV-1 particles and is counteracted by HIV-1 Nef. Due to the unavailability of an antibody of sufficient specificity and sensitivity, investigation of SERINC5 protein expression and subcellular localization has been limited to heterologously expressed SERINC5. We generated, via CRISPR/Cas9-assisted gene editing, Jurkat T-cell clones expressing endogenous SERINC5 bearing an extracellularly exposed hemagglutinin (HA) epitope [Jurkat SERINC5(iHA knock-in) T cells]. This modification enabled quantification of endogenous SERINC5 protein levels and demonstrated a predominant localization in lipid rafts. Interferon alpha (IFN-α) treatment enhanced cell surface levels of SERINC5 in a ruxolitinib-sensitive manner in the absence of modulation of mRNA and protein quantities. Parental and SERINC5(iHA knock-in) T cells shared the ability to produce infectious wild-type HIV-1 but not an HIV-1 Δnef mutant. SERINC5-imposed reduction of infectivity involved a modest reduction of virus fusogenicity. An association of endogenous SERINC5 protein with HIV-1 Δnef virions was consistently detectable as a 35-kDa species, as opposed to heterologous SERINC5, which presented as a 51-kDa species. Nef-mediated functional counteraction did not correlate with virion exclusion of SERINC5, arguing for the existence of additional counteractive mechanisms of Nef that act on virus-associated SERINC5. In HIV-1-infected cells, Nef triggered the internalization of SERINC5 in the absence of detectable changes of steady-state protein levels. These findings establish new properties of endogenous SERINC5 expression and subcellular localization, challenge existing concepts of HIV-1 Nef-mediated antagonism of SERINC5, and uncover an unprecedented role of IFN-α in modulating SERINC5 through accumulation at the cell surface. IMPORTANCE SERINC5 is the long-searched-for antiviral factor that is counteracted by the HIV-1 accessory gene product Nef. Here, we engineered, via CRISPR/Cas9 technology, T-cell lines that express endogenous SERINC5 alleles tagged with a knocked-in HA epitope. This genetic modification enabled us to study basic properties of endogenous SERINC5 and to verify proposed mechanisms of HIV-1 Nef-mediated counteraction of SERINC5. Using this unique resource, we identified the susceptibility of endogenous SERINC5 protein to posttranslational modulation by type I IFNs and suggest uncoupling of Nef-mediated functional antagonism from SERINC5 exclusion from virions.
Published: 2019

2. 2019 ARIA Care pathways for allergen immunotherapy

Author: Dana Wallace, Karin C. Lødrup Carlsen, M. T. Ventura, Igor Kaidashev, Stephen R. Durham, Motohiro Ebisawa, Oliver Pfaar, Hae-Sim Park, Daniel Laune, Wytske Fokkens, Antonella Muraro, Moises A. Calderon, Torsten Zuberbier, Mohamed H. Shamji, Mark S. Dykewicz, Roy Gerth van Wijk, Josep M. Antó, Samantha Walker, Petr Panzner, Giorgio Walter Canonica, Nelson Rosario, Juan Carlos Ivancevich, Holger J. Schünemann, Susanne Halken, Lorenzo Cecchi, Sinthia Bosnic-Anticevich, Violeta Kvedariene, Stefania La Grutta, João Fonseca, Marek L Kowalski, Tari Haahtela, Aziz Sheikh, Montserrat Fernandez-Rivas, Nhan Pham-Thi, Isabelle Bosse, Jean Bousquet, Lan Le, Despo Ierodiakonou, Tomohisa Iinuma, Lars Jacobsen, Christine Rolland, Gert Marien, Wienczyslawa Czarlewski, Glenis Scadding, Ioana Agache, Bolesław Samoliński, Olga Lourenço, Ludger Klimek, Yoshitaka Okamoto, Ulrich Wahn, Joaquim Mullol, Erkka Valovirta, Luigi Caraballo, Sanna Toppila-Salmi, Ioanna Tsiligianni, Derek K. Chu, Ruby Pawankar, Jean Luc Fauquert, Musa Khaitov, Jorg Kleine Tebbe, Jean-François Fontaine, Victoria Cardona, Désirée Larenas-Linemann, Thomas B. Casale, Omer Kalayci, Alvaro A. Cruz, Arunas Valiulis, Anna Bedbrook, Susanne Lau, Alkis Togias, H.-J. Malling, Claus Bachert, Dermot Ryan, Elísio Costa, Giovanni Passalacqua, Ignacio J. Ansotegui, Ana Todo Bom, Marek Jutel, Enrica Menditto, Piotr Kuna, Nikolaos G. Papadopoulos, Gregoire Mercier, Mario Sánchez-Borges, Karl-Christian Bergmann, Susan Waserman, Gunter J. Sturm, Maryline Valentin-Rostan, Arzu Yorgancioglu, Giovanni Battista Pajno, Jan Brozek, George Du Toit, Robyn E O'Hehir, Peter Hellings, Graham Roberts, uBibliorum, Contre les MAladies Chroniques pour un VIeillissement Actif en Languedoc-Roussillon (MACVIA-LR), Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Universitaire de Nîmes (CHU Nîmes)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-European Innovation Partnership on Active and Healthy Ageing Reference Site (EIP on AHA), Commission Européenne-Commission Européenne-Organisation Mondiale de la Santé / World Health Organization Office (OMS / WHO), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Center for Rhinology and Allergology, National Institute of Allergy and Infectious Diseases [Bethesda] (NIAID-NIH), National Institutes of Health [Bethesda] (NIH), Department of Clinical Epidemiology and Biostatistics and Medicine, McMaster University [Hamilton, Ontario], Department of Allergy and Immunology, Hospital Quiròn Bizkaia Erandio, UPC Research Laboratories, Allergy Department, University of Crete [Heraklion] (UOC), Department of Allergy and Clinical Immunology, Transylvania University of Brasov, Universitat Pompeu Fabra [Barcelona] (UPF), Ghent University Hospital, Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Department of Dermatology and Allergy [Berlin, Allemagne], Comprehensive Allergy Center [Berlin, Allemagne], Berlin Institute of Health (BIH)-Berlin Institute of Health (BIH), The University of Sydney, Woolcock Institute of Medical Research [Sydney], CHU Montpellier, Departments of Clinical Epidemiology and Biostatistics and Medicine [Ontario], Section of Allergy and Clinical Immunology [London, UK], Imperial College London-Royal Brompton Hospital-National Heart and Lung Institute, Humanitas Clinical and Research Center [Rozzano, Milan, Italy], Institute for Immunological Research (University of Cartagena), University of Cartagena, Allergy Section, Department of Internal Medicine, Vall d'Hebron University Hospital [Barcelona], Division of Allergy and Immunology, Department of Medicine, Creighton University, Department of Health Research Methods, Evidence and Impact, McMaster University, Hamilton, ON, Canada, Universidade do Porto, Instituto de Biologia Molecular e Celular (IBMC), Universidade Federal da Bahia (UFBA), UCB Pharma, Colombes, Section of Allergy and Clinical Immunology, Imperial College London-Royal Brompton Hospital-National Heart and Lung Institute [UK], King‘s College London, Saint Louis University School of Medicine [St Louis], Sagamihara National Hospital, CHU Estaing [Clermont-Ferrand], CHU Clermont-Ferrand, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos [Madrid, Spain] (IdISSC), European Forum for Research and Education in Allergy and Airway Diseases (EUFOREA), Center of Research in Health Technologies and Information Systems (CINTESIS), Department of Allergology, Erasmus University Medical Center [Rotterdam] (Erasmus MC), Helsinki University Hospital, Odense University Hospital, University Hospitals Leuven [Leuven], Chiba University Hospital, Servicio de Alergia e ImmunologiaBuenos Aires (Clinica Santa Isabel), Research Centre for Prevention and Health (RCPH), Department of Public Health [Copenhagen], Faculty of Health and Medical Sciences, University of Copenhagen = Københavns Universitet (KU)-University of Copenhagen = Københavns Universitet (KU)-Faculty of Health and Medical Sciences, University of Copenhagen = Københavns Universitet (KU)-University of Copenhagen = Københavns Universitet (KU)-Capital Region of Denmark, Department of Clinical Immunology, Wroclaw Medical University, Ukrainina Medical Stomatological Academy [Poltava, Ukraine], Laboratory of Molecular Immunology [Moscow, Russian Federation] (National Research Center), Institute of Immunology [Moscow, Russian Federation]-Federal Medicobiological Agency [Moscow, Russian Federation], Hacettepe University = Hacettepe Üniversitesi, Allergy & Asthma Center Westend, Outpatient Clinic Hanf, Department of Immunology, Rheumatology and Allergy, Division of Internal Medicine, Asthma and Allergy, Medical University of Łódź (MUL)-Barlicki University Hospital, Vilnius University [Vilnius], CNR-IBIM : National Research Council-Institute of Biomedicine and Molecular Immunology, Department of Pediatric Pneumology and Immunology, Ho Chi Minh City University of Technology (HCMUT), University of Oslo (UiO), Faculty of Health Sciences and CICS-UB (Health Sciences Research Centre), 'Federico II' University of Naples Medical School, Centro de Investigación Biomédica en Red Enfermedades Respiratorias (CIBERES), Food Allergy Referral Centre Veneto Region [Padua, Italy], Universita degli Studi di Padova, Monash University [Melbourne], Department of Otorhinolaryngology, Department of Pediatrics, Allergy Unit, University of Messina, Ajou University School of Medicine, Department of Allergology and Clinical Immunology, Medical Faculty in Pilsen-Charles University in Prague - the First Faculty of Medicine, Allergy and Respiratory Diseases, University of Genoa (UNIGE), Saint Mary's Hospital [London], St Mary's Hospital [London], Department of Pediatrics, Nippon Medical School, Pediatrics, Universidade Federal do Paraná (UFPR), Medical Centre, Woodbrook Medical Centre, Medical University of Warsaw - Poland, Department of Prevention of Environmental Hazards and Allergology, Medical University of Warsaw - Poland-Faculté de Pharmacie de Paris, Department of Allergy and Clinical Immunology [Caracas, Venezuela], Centro Medico-Docente La Trinidad, The Royal National Throat, Nose and Ear Hospital, Imperial College London, Centre for Population Health Sciences, University of Edinburgh, Medical University Graz, University of Coimbra [Portugal] (UC), Vilnius University Clinic of Children's Diseases, Suomen Terveystalo Allergy Clinic, Università degli studi di Bari Aldo Moro (UNIBA), Department for Pediatric Pneumology and Immunology, Asthma UK Centre in Allergic Mechanisms of Asthma, King's College London, (MRC), Guy's Hospital [London], Nova Southeastern University (NSU), Department of Pulmonology, Manisa Celal Bayar University, Department of Dermatology, Medical School-Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Association Asthme et Allergie, Internal Medicine, Bousquet, J., Pfaar, O., Togias, A., Schunemann, H. J., Ansotegui, I., Papadopoulos, N. G., Tsiligianni, I., Agache, I., Anto, J. M., Bachert, C., Bedbrook, A., Bergmann, K. -C., Bosnic-Anticevich, S., Bosse, I., Brozek, J., Calderon, M. A., Canonica, G. W., Caraballo, L., Cardona, V., Casale, T., Cecchi, L., Chu, D., Costa, E., Cruz, A. A., Czarlewski, W., Durham, S. R., Du Toit, G., Dykewicz, M., Ebisawa, M., Fauquert, J. L., Fernandez-Rivas, M., Fokkens, W. J., Fonseca, J., Fontaine, J. -F., Gerth van Wijk, R., Haahtela, T., Halken, S., Hellings, P. W., Ierodiakonou, D., Iinuma, T., Ivancevich, J. C., Jacobsen, L., Jutel, M., Kaidashev, I., Khaitov, M., Kalayci, O., Kleine Tebbe, J., Klimek, L., Kowalski, M. L., Kuna, P., Kvedariene, V., La Grutta, S., Larenas-Linemann, D., Lau, S., Laune, D., Le, L., Lodrup Carlsen, K., Lourenco, O., Malling, H. -J., Marien, G., Menditto, E., Mercier, G., Mullol, J., Muraro, A., O'Hehir, R., Okamoto, Y., Pajno, G. B., Park, H. -S., Panzner, P., Passalacqua, G., Pham-Thi, N., Roberts, G., Pawankar, R., Rolland, C., Rosario, N., Ryan, D., Samolinski, B., Sanchez-Borges, M., Scadding, G., Shamji, M. H., Sheikh, A., Sturm, G. J., Todo Bom, A., Toppila-Salmi, S., Valentin-Rostan, M., Valiulis, A., Valovirta, E., Ventura, M. -T., Wahn, U., Walker, S., CORBO UGULINO, Wallace, Waserman, S., Yorgancioglu, A., Zuberbier, T., Hospital Quirónsalud Bizkaia [Bilbao], Sagamihara National Hospital [Kanagawa, Japan], Universidade do Porto = University of Porto, University of Copenhagen = Københavns Universitet (UCPH)-University of Copenhagen = Københavns Universitet (UCPH)-Faculty of Health and Medical Sciences, University of Copenhagen = Københavns Universitet (UCPH)-University of Copenhagen = Københavns Universitet (UCPH)-Capital Region of Denmark, Wrocław Medical University, Università degli Studi di Padova = University of Padua (Unipd), Charles University [Prague] (CU)-Medical Faculty in Pilsen, Università degli studi di Genova = University of Genoa (UniGe), Centro Médico Docente La Trinidad, Università degli studi di Bari Aldo Moro = University of Bari Aldo Moro (UNIBA), and Hibade, Monique
Subjects: Cost effectiveness, [SDV]Life Sciences [q-bio], Cost-Benefit Analysis, Comorbidity, medicine.disease_cause, 0302 clinical medicine, Allergen, Cost of Illness, Immunology and Allergy, Medicine, 030212 general & internal medicine, [SDV.IMM.ALL]Life Sciences [q-bio]/Immunology/Allergology, Precision Medicine, mHealth, Children, media_common, Allergen immunotherapy, Rhinitis, Disease Management, 3. Good health, [SDV] Life Sciences [q-bio], rhiniti, Treatment Outcome, Practice Guidelines as Topic, Critical Pathways, [SDV.IMM]Life Sciences [q-bio]/Immunology, Disease Susceptibility, [SDV.IMM.ALL] Life Sciences [q-bio]/Immunology/Allergology, medicine.medical_specialty, [SDV.IMM] Life Sciences [q-bio]/Immunology, Attitude of Health Personnel, Immunology, Clinical Decision-Making, 03 medical and health sciences, Pharmacotherapy, rhinitis, stratification, children, media_common.cataloged_instance, Animals, Humans, European union, Intensive care medicine, allergen immunotherapy, asthma, children, mHealth, rhinitis, stratification, Asthma, business.industry, Allergens, asthma, medicine.disease, Rhinitis, Allergic, Review article, 030228 respiratory system, Desensitization, Immunologic, allergen immunotherapy, Stratification, business, Biomarkers
Abstract: Allergen immunotherapy (AIT) is a proven therapeutic option for the treatment of allergic rhinitis and/or asthma. Many guidelines or national practice guidelines have been produced but the evidence-based method varies, many are complex and none propose care pathways. This paper reviews care pathways for AIT using strict criteria and provides simple recommendations that can be used by all stakeholders including health professionals. The decision to prescribe AIT for the patient should be individualized and based on the relevance of the allergens, the persistence of symptoms despite appropriate medications according to guidelines as well as on the availability of good-quality and efficacious extracts. Allergen extracts cannot be regarded as generics. Immunotherapy is selected by specialists for stratified patients. There are no currently available validated biomarkers that can predict AIT success. In adolescents and adults, AIT should be reserved for patients with moderate/severe rhinitis or for those with moderate asthma who, despite appropriate pharmacotherapy and adherence, continue to exhibit exacerbations that appear to be related to allergen exposure, except in some specific cases. Immunotherapy may be even more advantageous in patients with multimorbidity. In children, AIT may prevent asthma onset in patients with rhinitis. mHealth tools are promising for the stratification and follow up of patients. This article is protected by copyright. All rights reserved.
Published: 2019

3. Dyskalemia in people at increased risk for heart failure

Author: Luca Monzo, João Pedro Ferreira, John G.F. Cleland, Pierpaolo Pellicori, Beatrice Mariottoni, Job A.J. Verdonschot, Mark R. Hazebroek, Tim J. Collier, Joe J. Cuthbert, Burkert Pieske, Frank Edelmann, Johannes Petutschnigg, Javed Khan, Fozia Z. Ahmed, Nicolas Girerd, Erwan Bozec, Javier Díez, Arantxa González, Andrew L. Clark, Franco Cosmi, Jan A. Staessen, Stephane Heymans, Patrick Rossignol, 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), 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), 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 ), Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome] (UNIROMA), Universidade do Porto = University of Porto, University of Glasgow, Department of Cardiology, Cortona Hospital, Maastricht University Medical Centre (MUMC), Maastricht University [Maastricht], London School of Hygiene and Tropical Medicine (LSHTM), Castle Hill Hospital, University of Hull [United Kingdom], Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Berlin Institute of Health (BIH), German Center for Cardiovascular Research (DZHK), Manchester University NHS Foundation Trust (MFT), Manchester Academic Health Science Centre (MAHSC), University of Manchester [Manchester], Studies Coordinating Centre, Research Unit Hypertension and Cardiovascular Epidemiology, KU Leuven Department of Cardiovascular Sciences, University of Leuven, Department of Cardiovascular Sciences [Leuven], Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), The Netherlands Heart Institute, European Project: 305507, BOZEC, Erwan, HOMAGE (Heart Omics in Ageing consortium) - 305507 - INCOMING, MUMC+: MA Med Staf Artsass Cardiologie (9), RS: Carim - H02 Cardiomyopathy, Cardiologie, and MUMC+: MA Med Staf Spec Cardiologie (9)
Subjects: Hyperkalaemia, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, heart failure prevention, hyperkalaemia, hypokalaemia, steroidal mineralocorticoid receptor antagonist, Heart failure prevention, Cardiology and Cardiovascular Medicine, Hypokalaemia, Steroidal mineralocorticoid receptor antagonist, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system
Abstract: AIMS: In people at risk of heart failure (HF) enrolled in the Heart 'OMics' in AGEing (HOMAGE) trial, spironolactone reduced circulating markers of collagen synthesis, natriuretic peptides, and blood pressure and improved cardiac structure and function. In the present report, we explored factors associated with dyskalaemia. METHODS AND RESULTS: The HOMAGE trial was an open-label study comparing spironolactone (up to 50 mg/day) versus standard care in people at risk for HF. After randomization, serum potassium was assessed at 1 and 9 months and was defined as low when ≤3.5 mmol/L (hypokalaemia) and high when ≥5.5 mmol/L (hyperkalaemia). Multivariable logistic regression models were constructed to identify clinical predictors of dyskalaemia. A total of 513 participants (median age 74 years, 75% men, median estimated glomerular filtration rate 71 mL/min/1.73 m2 ) had serum potassium available and were included in this analysis. At randomization, 88 had potassium 5.0 mmol/L. During follow-up, on at least one occasion, a serum potassium 5.0 mmol/L was observed in 38 (8%) and >5.5 mmol/L in 5 (1.0%) participants. The median (percentile25-75 ) increase in serum potassium with spironolactone during the study was 0.23 (0.16; 0.29) mmol/L. Because of the low incidence of dyskalaemia, for regression analysis, hypokalaemia and hyperkalaemia thresholds were set at 5.0 mmol/L, respectively. The occurrence of a serum potassium > 5.0 mmol/L during follow-up was positively associated with the presence of diabetes mellitus {odds ratio [OR]: 1.21 [95% confidence interval (CI) 2.14; 3.79]} and randomization to spironolactone (OR: 2.83 [95% CI 1.49; 5.37]). Conversely, the occurrence of a potassium concentration
Published: 2022

4. Spironolactone effect on cardiac structure and function of patients with heart failure and preserved ejection fraction: a pooled analysis of three randomized trials

Author: João Pedro Ferreira, John G. Cleland, Nicolas Girerd, Erwan Bozec, Patrick Rossignol, Pierpaolo Pellicori, Franco Cosmi, Beatrice Mariottoni, Scott D. Solomon, Bertram Pitt, Marc A. Pfeffer, Amil M. Shah, Johannes Petutschnigg, Burkert Pieske, Frank Edelmann, 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), 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), 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 ), Faculdade de Medicina da Universidade do Porto (FMUP), Universidade do Porto = University of Porto, University of Glasgow, Cortona Hospital, Brigham and Women's Hospital [Boston], University of Michigan [Ann Arbor], University of Michigan System, Charité Campus Virchow-Klinikum (CVK), German Center for Cardiovascular Research (DZHK), Berlin Institute of Health (BIH), and European Project: 305507
Subjects: [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Cardiology and Cardiovascular Medicine
Abstract: International audience; Aims: Spironolactone is currently used in a large proportion of patients with heart failure and preserved ejection fraction (HFpEF), yet its effect on cardiac structure and function in a large population has not been well established. The aim of this study was to evaluate the impact of spironolactone on key echocardiographic parameters in HFpEF.Methods and results: An individual-patient-data meta-analysis of three randomized trials (HOMAGE, Aldo-DHF, and TOPCAT) was performed comparing spironolactone (9-12 month exposure) to placebo (or control) for the changes in left atrial volume index (LAVi), left ventricular mass index (LVMi), interventricular septum (IVS) thickness, E/e' ratio, and left ventricular ejection fraction (LVEF) among patients with stage B (HOMAGE) or C (Aldo-DHF and TOPCAT) HFpEF. Analysis of covariance was used to test the effect of spironolactone on echocardiographic changes. A total of 984 patients were included in this analysis: 452 (45.9%) from HOMAGE, 398 (40.4%) from Aldo-DHF, and 134 (13.6%) from TOPCAT. The pooled-cohort patient's median age was 71 (66-77) years and 39% were women. Median LAVi was 29 (24-35) ml/m2 , LVMi 100 (84-118) g/m2 , IVS thickness 12 (10-13) mm, E/e' ratio 11 (9-13), and LVEF 64 (59-69)%. Spironolactone reduced LAVi by -1.1 (-2.0 to -0.1) ml/m2 (p = 0.03); LVMi by -3.6 (-6.4 to -0.8) g/m2 (p = 0.01); IVS thickness by -0.2 (-0.3 to -0.1) mm (p = 0.01); E/e' ratio by -1.3 (-2.4 to -0.2) (p = 0.02); and increased LVEF by 1.7 (0.8-2.6)% (p < 0.01). No treatment-by-study heterogeneity was found except for E/e' ratio with a larger effect in Aldo-DHF and TOPCAT (interaction p < 0.01).Conclusions: Spironolactone improved cardiac structure and function of patients with HFpEF.
Published: 2022

5. Uric acid and sodium-glucose cotransporter-2 inhibition with empagliflozin in heart failure with reduced ejection fraction: the EMPEROR-reduced trial

Author: Wolfram Doehner, Stefan D Anker, Javed Butler, Faiez Zannad, Gerasimos Filippatos, João Pedro Ferreira, Afshin Salsali, Carolyn Kaempfer, Martina Brueckmann, Stuart J Pocock, James L Januzzi, Milton Packer, Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], German Center for Cardiovascular Research (DZHK), Berlin Institute of Health (BIH), Berlin-Brandenburg Center for Regenerative Medicine [Berlin, Germany] (BCRT), University of Mississippi Medical Center (UMMC), Baylor College of Medecine, 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), 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), National and Kapodistrian University of Athens (NKUA), Université d'Athènes (UOA), University of Athens, Attikon Hospital, Cardiovascular R&D Centre-UnIC@RISE, Faculdade de Medicina da Universidade do Porto (FMUP), Universidade do Porto = University of Porto, Boehringer Ingelheim Pharmaceuticals, Inc, Ridgefield, Rutgers University [Camden], Rutgers University System (Rutgers), mainanalytics GmbH, Sulzbach, Boehringer Ingelheim International GmbH, Medizinische Fakultät Mannheim, London School of Hygiene and Tropical Medicine (LSHTM), Massachusetts General Hospital [Boston], Harvard Medical School [Boston] (HMS), Imperial College London, This study was funded by Boehringer Ingelheim and Eli Lilly. Graphical assistance was provided by 7.4 Ltd and was funded by Boehringer Ingelheim, and BOZEC, Erwan
Subjects: Heart Failure, Male, Sodium, Empagliflozin, Hyperuricemia, Heart failure with reduced ejection fraction, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Uric Acid, Hospitalization, Metabolism, Glucose, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Diabetes Mellitus, Type 2, Glucosides, Humans, Female, Benzhydryl Compounds, Cardiology and Cardiovascular Medicine, Sodium-Glucose Transporter 2 Inhibitors, Outcome
Abstract: Background The sodium-glucose cotransporter-2 inhibitor empagliflozin decreases the risk of cardiovascular death or hospitalization for heart failure (HF) in patients with HF with reduced ejection fraction. Empagliflozin reduces serum uric acid (SUA), but the relevance of this effect in patients with HF is unclear. This study aimed to investigate the effect of empagliflozin on SUA levels and the therapeutic efficacy of empagliflozin in relation to SUA. Methods The association between SUA and the composite primary outcome of cardiovascular death or hospitalization for worsening HF, its components, and all-cause mortality was investigated in 3676 patients of the EMPEROR-Reduced trial (98.6% of the study cohort). The treatment effect of empagliflozin was studied in relation to SUA as continuous variable, to clinical hyperuricaemia (SUA >5.7 mg/dL for women, >7.0 mg/dL for men) and in subgroups of patients of tertiles of SUA. Results Hyperuricaemia was prevalent in 53% of patients with no sex differences. Elevated SUA (highest tertile, mean SUA 9.38 ± 1.49 mg/dL) was associated with advanced severity of HF and with worst outcome [composite outcome, hazard ratio (HR) 1.64 (95% confidence interval, CI 1.28–2.10); cardiovascular mortality, HR 1.98 (95% CI 1.35–2.91); all-cause mortality, HR 1.8 (95% CI 1.29–2.49), all P Conclusion Hyperuricaemia is common in HF and is an independent predictor of advanced disease severity and increased mortality. Empagliflozin induced a rapid and sustained reduction of SUA levels and of clinical events related to hyperuricaemia. The benefit of empagliflozin on the primary outcome was observed independently of SUA.
Published: 2022

6. A machine learning derived echocardiographic algorithm identifies people at risk of heart failure with distinct cardiac structure, function, and response to spironolactone: findings from the HOMAGE trial

Author: Kobayashi, Masatake, Huttin, Olivier, Ferreira, João Pedro, Duarte, Kevin, González, Arantxa, Heymans, Stephane, Verdonschot, Job A.J., Rocca, Hans‐peter Brunner‐la, Pellicori, Pierpaolo, Clark, Andrew, Petutschnigg, Johannes, Edelmann, Frank, Cleland, John, Rossignol, Patrick, Zannad, Faiez, Girerd, Nicolas, 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), 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), 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 ), Faculdade de Medicina da Universidade do Porto (FMUP), Universidade do Porto = University of Porto, Navarra Institute for Health Research / Instituto de Investigación Sanitaria de Navarra (IdiSNA), Universidad Pública de Navarra [Espagne] = Public University of Navarra (UPNA)-Universidad de Navarra [Pamplona] (UNAV)-Clínica Universidad de Navarra [Pamplona], Institute of Health Carlos III, Center for Applied Medical Research [Plamplona] (CIMA), Universidad de Navarra [Pamplona] (UNAV), Cardiovascular Research Institute Maastricht (CARIM), Maastricht University [Maastricht], Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), University of Glasgow, University of Hull [United Kingdom], Castle Hill Hospital, Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], German Center for Cardiovascular Research (DZHK), Berlin Institute of Health (BIH), and European Project: 305507,EC:FP7:HEALTH,FP7-HEALTH-2012-INNOVATION-1,HOMAGE(2013)
Subjects: collagen, spironolactone, [SDV]Life Sciences [q-bio], biomarkers, Heart failure, Heart failure echocardiogram collagen spironolactone biomarkers, echocardiogram
Abstract: International audience; Background: An echocardiographic algorithm derived by machine learning (e'VM) characterizes preclinical individuals with different cardiac structure and function, biomarkers, and long-term risk of heart failure (HF). Our aim was the external validation of the e'VM algorithm and to explore whether it may identify subgroups who benefit from spironolactone.Methods: The HOMAGE (Heart OMics in Aging) trial enrolled participants at high risk of developing HF randomly assigned to spironolactone or placebo over 9 months. The e'VM algorithm was applied to 416 participants (mean age 74±7years, 25% women) with available echocardiographic variables (i.e., e' mean, left ventricular [LV] end-diastolic volume and mass indexed by body surface area [LVMi]). The effects of spironolactone on changes in echocardiographic and biomarker variables were assessed across e'VM phenotypes.Results: A majority (>80%) had either "diastolic changes (D)", or "diastolic changes with structural remodeling (D/S)" phenotype. D/S phenotype had the highest LVMi, left atrial volume, E/e', natriuretic peptide and troponin levels (all p0.10; Pinteraction
Published: 2023

7. Empagliflozin and serum potassium in heart failure: an analysis from EMPEROR-Pooled

Author: João Pedro Ferreira, Faiez Zannad, Javed Butler, Gerasimos Filipattos, Ivana Ritter, Elke Schüler, Bettina J Kraus, Stuart J Pocock, Stefan D Anker, Milton Packer, 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), 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), 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 ), Faculdade de Medicina da Universidade do Porto (FMUP), Universidade do Porto = University of Porto, University of Mississippi Medical Center (UMMC), National and Kapodistrian University of Athens School of Medicine, Boehringer Ingelheim International GmbH, mainanalytics GmbH, Department of Internal Medicine I, University Hospital Würzburg, Comprehensive Heart Failure Centre, University and University Hospital of Würzburg, London School of Hygiene and Tropical Medicine (LSHTM), Berlin-Brandenburg Center for Regenerative Therapies [Berlin, Germany], Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], German Center for Cardiovascular Research (DZHK), Berlin Institute of Health (BIH), Baylor College of Medecine, Imperial College London, and The EMPEROR-Reduced and Preserved trials were funded by Boehringer Ingelheim and Eli Lilly and Company (EMPEROR-Reduced ClinicalTrials.gov number, NCT03057977 and EMPEROR-Preserved ClinicalTrials.gov number, NCT03057951).
Subjects: Heart Failure, Aminobutyrates, Biphenyl Compounds, Empagliflozin, Hypokalemia, Stroke Volume, Ventricular Function, Left, Hyperkalaemia, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Glucosides, Potassium, Humans, Hyperkalemia, Benzhydryl Compounds, Cardiology and Cardiovascular Medicine
Abstract: Aims Hyperkalaemia frequently leads to interruption and discontinuation of neurohormonal antagonists, which may worsen heart failure prognosis. Some studies suggested that sodium-glucose cotransporter 2 inhibitors reduce hyperkalaemia, an effect that may have important clinical implications. This analysis evaluates the effect of empagliflozin on the occurrence of hyper- and hypokalaemia in HF. Methods and results EMPEROR-Pooled (i.e. EMPEROR-Reduced and EMPEROR-Preserved combined) included 9583 patients with available serum potassium levels at baseline (98.6% of the total EMPEROR-Pooled population, n = 9718). Hyperkalaemia was identified by investigators’ reports of adverse events, and by a laboratory serum potassium value above 5.5 mmol/L and 6.0 mmol/L. The main outcome was a composite of investigator-reported hyperkalaemia or initiation of potassium binders. Patients with high potassium at baseline were more frequently diagnosed with diabetes and ischaemic HF aetiology and had lower left ventricular ejection fraction and estimated glomerular filtration rate but were more frequently treated with sacubitril/valsartan or mineralocorticoid receptor antagonists. Empagliflozin (compared with placebo) reduced the composite of investigator-reported hyperkalaemia or initiation of potassium binders [6.5% vs. 7.7%, hazard ratio (HR) 0.82, 95% confidence interval (CI) 0.71–0.95, P = 0.01]. Empagliflozin reduced hyperkalaemia rates regardless of the definition used (serum potassium >5.5 mmol/l: 8.6% vs. 9.9%, HR 0.85, 95% CI 0.74–0.97, P = 0.017; serum potassium >6.0 mmol/l: 1.9% vs. 2.9%, HR 0.62, 95% CI 0.48–0.81, P Conclusions Empagliflozin reduced the incidence of hyperkalaemia without significant increase in hypokalaemia.
Published: 2022

8. Sex differences in imaging and clinical characteristics of patients from the WAKE--UP trial

Author: Anke Wouters, Lauranne Scheldeman, Hannelore Liessens, Patrick Dupont, Florent Boutitie, Bastian Cheng, Martin Ebinger, Matthias Endres, Jochen B. Fiebach, Christian Gerloff, Keith W. Muir, Norbert Nighoghossian, Salvador Pedraza, Claus Z. Simonsen, Vincent Thijs, Götz Thomalla, Robin Lemmens, University Hospitals Leuven [Leuven], Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Leuven Center for Cancer Biology (VIB-KU-CCB), Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven)-Vlaams Instituut voor Biotechnologie [Ghent, Belgique] (VIB), Amsterdam UMC - Amsterdam University Medical Center, Leuven Brain Institute [Leuven, Belgium] (LBI), Hospices Civils de Lyon (HCL), Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), Universitaetsklinikum Hamburg-Eppendorf = University Medical Center Hamburg-Eppendorf [Hamburg] (UKE), Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Medical Park Berlin Humboldtmühle [Berlin, Germany] (MPBH), German Center for Cardiovascular Research (DZHK), Berlin Institute of Health (BIH), German Research Center for Neurodegenerative Diseases - Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), University of Glasgow, Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Université de Lyon-Université de Lyon-Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Centre de Recherche en Acquisition et Traitement de l'Image pour la Santé (CREATIS), 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)-Hospices Civils de Lyon (HCL)-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut d'Investigació Biomèdica de Girona Dr. Josep Trueta - Girona Biomedical Research Institute (IDIBGI), Aarhus University Hospital, University of Melbourne, Austin Hospital [Melbourne], Austin Health, CarMeN, laboratoire, and Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Male, Sex Characteristics, Time Factors, Ischemic stroke, [SDV.BA] Life Sciences [q-bio]/Animal biology, [SDV.BA]Life Sciences [q-bio]/Animal biology, methods [Thrombolytic Therapy], wake-up, drug therapy [Stroke], therapeutic use [Tissue Plasminogen Activator], Neurology, Wake-up, methods [Diffusion Magnetic Resonance Imaging], diagnostic imaging [Stroke], ischemic stroke, Humans, drug therapy [Brain Ischemia], sex, Female, Sex, ddc:610, Neurology (clinical), Mri, MRI
Abstract: BACKGROUND AND PURPOSE: Sex-based differences in acute ischemic stroke are a well-known phenomenon. We aimed to explore these differences between women and men in the Efficacy and Safety of MRI-Based Thrombolysis in Wake-Up Stroke (WAKE-UP) trial. METHODS: We compared baseline demographic and imaging characteristics (visual fluid-attenuated inversion recovery [FLAIR] positivity, relative FLAIR signal intensity, collateral status) between women and men in all screened patients. In randomized patients (i.e., those with diffusion-weighted imaging (DWI)-FLAIR mismatch), we evaluated a modifying role of sex on the treatment effect of alteplase in multivariable logistic regression, with treatment adjusted for National Institute of Health Stroke Scale (NIHSS) score and age. Dependent variables were modified Rankin Scale (mRS) score of 0-1 at 90 days and distribution of mRS scores at 90 days. RESULTS: Of 1362 screened patients, 529 (38.8%) were women. Women were older than men, had higher baseline NIHSS scores and smoked less frequently. FLAIR positivity of the DWI lesion was equally present in women (174/529, 33.1%) and men (273/833, 33.3%; p = 1.00) and other imaging variables also did not differ between the sexes. In a total of 503 randomized patients, of whom 178 were women (35.4%), sex did not modify the treatment effect of alteplase on mRS score 0-1 or on the total distribution of mRS scores. CONCLUSION: As in many other stroke trials, more men than women were included in the WAKE-UP trial, but the presence of a visual DWI-FLAIR mismatch and the relative FLAIR signal intensity did not differ between the sexes. The treatment effect of alteplase was not modified by sex. ispartof: EUROPEAN JOURNAL OF NEUROLOGY vol:30 issue:3 pages:641-647 ispartof: location:England status: published
Published: 2023

9. Urinary Marker Profiles in Heart Failure with Reduced Versus Preserved Ejection Fraction

Author: Koen W. Streng, Hans L. Hillege, Jozine M. ter Maaten, Dirk J. van Veldhuisen, Kenneth Dickstein, Nilesh J. Samani, Leong L. Ng, Marco Metra, Gerasimos S. Filippatos, Piotr Ponikowski, Faiez Zannad, Stefan D. Anker, Peter van der Meer, Chim C. Lang, Adriaan A. Voors, Kevin Damman, University of Groningen [Groningen], University Medical Center Groningen [Groningen] (UMCG), Stavanger University Hospital, University of Bergen (UiB), University of Leicester, Glenfield Hospital, NIHR Leicester Biomedical Research Centre, Glenfield Hospital, Università degli Studi di Brescia = University of Brescia (UniBs), National and Kapodistrian University of Athens (NKUA), University of Athens, Attikon Hospital, University of Cyprus = Université de Chypre, Wrocław Medical University, Cardiology Department, Military Hospital, 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), 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), 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 ), German Center for Cardiovascular Research (DZHK), Berlin Institute of Health (BIH), Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Center for Biomaterial Development and Berlin-Brandenburg Center for Regenerative Therapies (BCRT), Institute for Polymer Research, GKSS Research Center GmbH, Teltow, Germany, University of Dundee, This work was supported by the Netherlands Cardiovascular Research Initiative: an initiative with support of the Dutch Heart Foundation [CVON2014-11 RECONNECT] and a grant from the European Commission [FP7-242209-BIOSTAT-CHF]. There is no relation with industry., and European Project: 242209,EC:FP7:HEALTH,FP7-HEALTH-2009-single-stage,BIOSTAT-CHF(2010)
Subjects: Heart failure, Proximal tubule, Renal function, Urinary markers, [SDV]Life Sciences [q-bio], Heart failure Renal function Urinary markers Proximal tubule, Genetics, Pharmaceutical Science, Molecular Medicine, Cardiology and Cardiovascular Medicine, Genetics (clinical)
Abstract: Background Recent data suggest different causes of renal dysfunction between heart failure with reduced (HFrEF) versus preserved ejection fraction (HFpEF). We therefore studied a wide range of urinary markers reflecting different nephron segments in heart failure patients. Methods In 2070, in chronic heart failure patients, we measured several established and upcoming urinary markers reflecting different nephron segments. Results Mean age was 70 ± 12 years, 74% was male and 81% (n = 1677) had HFrEF. Mean estimated glomerular filtration rate (eGFR) was lower in patients with HFpEF (56 ± 23 versus 63 ± 23 ml/min/1.73 m2, P = 0.001). Patients with HFpEF had significantly higher values of NGAL (58.1 [24.0–124.8] versus 28.1 [14.6–66.9] μg/gCr, P P = 0.001). These differences were more pronounced in patients with an eGFR > 60 ml/min/1.73m2. Conclusions HFpEF patients showed more evidence of tubular damage and/or dysfunction compared with HFrEF patients, in particular when glomerular function was preserved.
Published: 2023

10. Dystrophin myonuclear domain restoration governs treatment efficacy in dystrophic muscle

Author: Adrien Morin, Amalia Stantzou, Olga N. Petrova, John Hildyard, Thomas Tensorer, Meriem Matouk, Mina V. Petkova, Isabelle Richard, Tudor Manoliu, Aurélie Goyenvalle, Sestina Falcone, Markus Schuelke, Corinne Laplace-Builhé, Richard J. Piercy, Luis Garcia, Helge Amthor, Handicap neuromusculaire : Physiopathologie, Biothérapie et Pharmacologies appliquées (END-ICAP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Institut National de la Santé et de la Recherche Médicale (INSERM), Royal Veterinary College [London], University of London [London], Université de Versailles Saint-Quentin-en-Yvelines - UFR Sciences de la santé Simone Veil (UVSQ Santé), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Berlin Institute of Health (BIH), Généthon, Immunologie moléculaire et biothérapies innovantes (IMBI), École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université d'Évry-Val-d'Essonne (UEVE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Généthon, Analyse moléculaire, modélisation et imagerie de la maladie cancéreuse (AMMICa), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Institut Gustave Roussy (IGR), Centre Scientifique de Monaco (CSM), Centre de recherche en Myologie – U974 SU-INSERM, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Institut de Myologie, Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Hôpital Raymond Poincaré [Garches], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris-Saclay, Association Française contre les Myopathies, AFM, Agence Nationale de la Recherche, ANR, Deutsch-Französische Hochschule, DFH: CDFA-06-11, We thank Thomas Bestetti, Chloé Dambrune, Karima Relizani, and Cécile Gastaldi for technical assistance. We thank Dr. Feng Zhang for providing the plasmid pX601-AAV-CMV::NLS-SaCas9-NLS-3xHA-bGHpA, and U6::BsaIsgRNA. We also thank Frederic De Leeuw for assistance with multiphoton imaging and Matthieu Dos Santos for preliminary RNA scope experiments. This work was supported by the Association Monegasque contre les Myopathies (AMM, Monaco), the Université Franco-Allemande (CDFA-06-11, UFA), the Association Française contre les Myopathies (AFM, France), and the Agence National de la Recherche (ANR, France).
Subjects: Gene Editing, Multidisciplinary, [SDV]Life Sciences [q-bio], Muscles, dystrophin-EGFP, nuclear domain, Dystrophin, Muscular Dystrophy, Duchenne, Mice, Disease Models, Animal, Treatment Outcome, Mice, Inbred mdx, Animals, Female, mdx mouse, myotendinous junction, Muscle, Skeletal
Abstract: Dystrophin is essential for muscle health: its sarcolemmal absence causes the fatal, X-linked condition, Duchenne muscular dystrophy (DMD). However, its normal, spatial organization remains poorly understood, which hinders the interpretation of efficacy of its therapeutic restoration. Using female reporter mice heterozygous for fluorescently tagged dystrophin ( Dmd EGFP ), we here reveal that dystrophin distribution is unexpectedly compartmentalized, being restricted to myonuclear-defined sarcolemmal territories extending ~80 µm, which we called “basal sarcolemmal dystrophin units (BSDUs).” These territories were further specialized at myotendinous junctions, where both Dmd transcripts and dystrophin protein were enriched. Genome-level correction in X-linked muscular dystrophy mice via CRISPR/Cas9 gene editing restored a mosaic of separated dystrophin domains, whereas transcript-level Dmd correction, following treatment with tricyclo-DNA antisense oligonucleotides, restored dystrophin initially at junctions before extending along the entire fiber—with levels ~2% sufficient to moderate the dystrophic process. We conclude that widespread restoration of fiber dystrophin is likely critical for therapeutic success in DMD, perhaps most importantly, at muscle–tendon junctions.
Published: 2023

11. Albuminuria as a marker of systemic congestion in patients with heart failure

Author: Eva M Boorsma, Jozine M ter Maaten, Kevin Damman, Bart J van Essen, Faiez Zannad, Dirk J van Veldhuisen, Nilesh J Samani, Kenneth Dickstein, Marco Metra, Gerasimos Filippatos, Chim C Lang, Leong Ng, Stefan D Anker, John G Cleland, Pierpaolo Pellicori, Ron T Gansevoort, Hiddo J L Heerspink, Adriaan A Voors, Johanna E Emmens, BOZEC, Erwan, University Medical Center Groningen [Groningen] (UMCG), 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), 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), 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 Cardiovascular Sciences [Leicester], University of Leicester, NIHR Leicester Biomedical Research Centre, Glenfield Hospital, Stavanger University Hospital, Università degli Studi di Brescia = University of Brescia (UniBs), National and Kapodistrian University of Athens (NKUA), University of Athens, Attikon Hospital, University of Dundee, Ninewells Hospital and Medical School [Dundee], Berlin-Brandenburg Center for Regenerative Medicine [Berlin, Germany] (BCRT), Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], German Center for Cardiovascular Research (DZHK), Berlin Institute of Health (BIH), National Heart and Lung Institute [London] (NHLI), Imperial College London-Royal Brompton and Harefield NHS Foundation Trust, Cardiovascular Centre (CVC), Groningen Kidney Center (GKC), and Real World Studies in PharmacoEpidemiology, -Genetics, -Economics and -Therapy (PEGET)
Subjects: EXCRETION, SICKLE-CELL-DISEASE, MODELS, PROTEINURIA, PRESSURE, DIAGNOSIS, EJECTION FRACTION, PREVALENCE, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, PULMONARY-HYPERTENSION, Central venous pressure, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, HOSPITALIZATION, Cardiorenal interaction, Congestion, Albuminuria, Biomarkers, Cardiology and Cardiovascular Medicine
Abstract: Aims Albuminuria is common in patients with heart failure and associated with worse outcomes. The underlying pathophysiological mechanism of albuminuria in heart failure is still incompletely understood. The association of clinical characteristics and biomarker profile with albuminuria in patients with heart failure with both reduced and preserved ejection fractions were evaluated. Methods and results Two thousand three hundred and fifteen patients included in the index cohort of BIOSTAT-CHF were evaluated and findings were validated in the independent BIOSTAT-CHF validation cohort (1431 patients). Micro-albuminuria and macro-albuminuria were defined as urinary albumin–creatinine ratio (UACR) >30 mg/gCr and >300 mg/gCr in spot urines, respectively. The prevalence of micro- and macro-albuminuria was 35.4% and 10.0%, respectively. Patients with albuminuria had more severe heart failure, as indicated by inclusion during admission, higher New York Heart Association functional class, more clinical signs and symptoms of congestion, and higher concentrations of biomarkers related to congestion, such as biologically active adrenomedullin, cancer antigen 125, and N-terminal pro-B-type natriuretic peptide (NT-proBNP) (all P < 0.001). The presence of albuminuria was associated with increased risk of mortality and heart failure (re)hospitalization in both cohorts. The strongest independent association with log UACR was found for log NT-proBNP (standardized regression coefficient 0.438, 95% confidence interval 0.35–0.53, P < 0.001). Hierarchical clustering analysis demonstrated that UACR clusters with markers of congestion and less with indices of renal function. The validation cohort yielded similar findings. Conclusion In patients with new-onset or worsening heart failure, albuminuria is consistently associated with clinical, echocardiographic, and circulating biomarkers of congestion.
Published: 2023

12. Long COVID and the cardiovascular system—elucidating causes and cellular mechanisms in order to develop targeted diagnostic and therapeutic strategies : A joint Scientific Statement of the ESC Working Groups on Cellular Biology of the Heart and Myocardial and Pericardial Diseases

Author: Mariann Gyöngyösi, Pilar Alcaide, Folkert W Asselbergs, Bianca J J M Brundel, Giovanni G Camici, Paula da Costa Martins, Péter Ferdinandy, Marianna Fontana, Henrique Girao, Massimiliano Gnecchi, Can Gollmann-Tepeköylü, Petra Kleinbongard, Thomas Krieg, Rosalinda Madonna, Melanie Paillard, Antonis Pantazis, Cinzia Perrino, Maurizio Pesce, Gabriele G Schiattarella, Joost P G Sluijter, Sabine Steffens, Carsten Tschöpe, Sophie Van Linthout, Sean M Davidson, Martins, Paula da Costa [0000-0002-0695-1187], Fontana, Marianna [0000-0002-9233-9831], Girao, Henrique [0000-0002-5786-8447], Gnecchi, Massimiliano [0000-0001-7435-4328], Kleinbongard, Petra [0000-0003-3576-3772], Krieg, Thomas [0000-0002-5192-580X], Perrino, Cinzia [0000-0002-2274-0048], Pesce, Maurizio [0000-0002-3097-8961], Sluijter, Joost PG [0000-0003-2088-9102], Steffens, Sabine [0000-0002-6892-9751], Van Linthout, Sophie [0000-0002-7581-7870], Apollo - University of Cambridge Repository, Medizinische Universität Wien = Medical University of Vienna, Tufts University School of Medicine [Boston], University Medical Center [Utrecht], Utrecht University [Utrecht], University College of London [London] (UCL), Amsterdam UMC - Amsterdam University Medical Center, Vrije Universiteit Amsterdam [Amsterdam] (VU), Universität Zürich [Zürich] = University of Zurich (UZH), University hospital of Zurich [Zurich], Maastricht University [Maastricht], Semmelweis University [Budapest], Pharmahungary Group [Szeged, Hungary] (PG), University of Coimbra [Portugal] (UC), Coimbra Institute for Clinical and Biomedical Research [Coimbra, Portugal] (iCBR - Faculty of Medicine), Università degli Studi di Pavia = University of Pavia (UNIPV), Fondazione IRCCS Policlinico San Matteo [Pavia], Innsbruck Medical University = Medizinische Universität Innsbruck (IMU), Universitätsklinikum Essen [Universität Duisburg-Essen] (Uniklinik Essen), Addenbrooke's Hospital, Cambridge University NHS Trust, University of Pisa - Università di Pisa, Jefferson (Philadelphia University + Thomas Jefferson University), Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Imperial College London, Royal Brompton and Harefield NHS Foundation Trust, University of Naples Federico II = Università degli studi di Napoli Federico II, Centro Cardiologico Monzino [Milano], Dpt di Scienze Cliniche e di Comunità [Milano] (DISCCO), Università degli Studi di Milano = University of Milan (UNIMI)-Università degli Studi di Milano = University of Milan (UNIMI)-Istituti di Ricovero e Cura a Carattere Scientifico (IRCCS), Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], German Center for Cardiovascular Research (DZHK), Berlin Institute of Health (BIH), Max Delbrück Center for Molecular Medicine [Berlin] (MDC), Helmholtz-Gemeinschaft = Helmholtz Association, Utrecht Brain Center [UMC], Ludwig-Maximilians-Universität München (LMU), Charité Campus Virchow-Klinikum (CVK), The Hatter Cardiovascular Institute (THCI), CarMeN, laboratoire, Gyöngyösi, Mariann, Alcaide, Pilar, Asselbergs, Folkert W, Brundel, Bianca J J M, Camici, Giovanni G, da Costa Martins, Paula, Ferdinandy, Péter, Fontana, Marianna, Girao, Henrique, Gnecchi, Massimiliano, Gollmann-Tepeköylü, Can, Kleinbongard, Petra, Krieg, Thoma, Madonna, Rosalinda, Paillard, Melanie, Pantazis, Antoni, Perrino, Cinzia, Pesce, Maurizio, Schiattarella, Gabriele G, Sluijter, Joost P G, Steffens, Sabine, Tschöpe, Carsten, Van Linthout, Sophie, and Davidson, Sean M
Subjects: Long COVID, Heart Diseases, Physiology, SARS-CoV-2, [SDV]Life Sciences [q-bio], Myocardium, Medizin, COVID-19, Heart, virus, Post COVID, Cardiovascular, [SDV] Life Sciences [q-bio], Post-Acute COVID-19 Syndrome, COVID-19 Testing, Cardiovascular and Metabolic Diseases, Physiology (medical), Humans, Cardiology and Cardiovascular Medicine, Cardiac
Abstract: Long COVID has become a world-wide, non-communicable epidemic, caused by long-lasting multiorgan symptoms that endure for weeks or months after SARS-CoV-2 infection has already subsided. This scientific document aims to provide insight into the possible causes and therapeutic options available for the cardiovascular manifestations of long COVID. In addition to chronic fatigue, which is a common symptom of long COVID, patients may present with chest pain, ECG abnormalities, postural orthostatic tachycardia, or newly developed supraventricular or ventricular arrhythmias. Imaging of the heart and vessels has provided evidence of chronic, post-infectious perimyocarditis with consequent left or right ventricular failure, arterial wall inflammation, or microthrombosis in certain patient populations. Better understanding of the underlying cellular and molecular mechanisms of long COVID will aid in the development of effective treatment strategies for its cardiovascular manifestations. A number of mechanisms have been proposed, including those involving direct effects on the myocardium, microthrombotic damage to vessels or endothelium, or persistent inflammation. Unfortunately, existing circulating biomarkers, coagulation, and inflammatory markers, are not highly predictive for either the presence or outcome of long COVID when measured 3 months after SARS-CoV-2 infection. Further studies are needed to understand underlying mechanisms, identify specific biomarkers, and guide future preventive strategies or treatments to address long COVID and its cardiovascular sequelae.
Published: 2023

13. The molecular evolution of spermatogenesis across mammals

Author: Svante Pääbo, Henrik Kaessmann, Thoomke Brüning, Frank Grützner, Philipp Khaitovich, Francesco Lamanna, Mari Sepp, Meritxell Riera Belles, Julia Schmidt, Katharina Mößinger, Christian Conrad, Rüdiger Behr, Celine Schneider, Ronald E. Bontrop, Sofia B. Winge, Kristian Almstrup, Timo Trefzer, Florent Murat, Ivanela Kondova, Margarida Cardoso-Moreira, Evgeny Leushkin, Noe Mbengue, Mikkel H. Schierup, Tomas Marques-Bonet, Theoretical Biology and Bioinformatics, Sub Theoretical Biology, Center for Molecular Biology - Zentrum für Molekulare Biologie [Heidelberg, Germany] (ZMBH), Universität Heidelberg [Heidelberg], Aarhus University [Aarhus], University of Copenhagen = Københavns Universitet (KU), Berlin Institute of Health (BIH), Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], The Francis Crick Institute [London], Biomedical Primate Research Centre [Rijswijk] (BPRC), German Primate Center - Deutsches Primatenzentrum -- Leibniz Insitute for Primate Research -- [Göttingen, Allemagne] (GPC - DPZ), German Center for Cardiovascular Research (DZHK), Skolkovo Institute of Science and Technology [Moscow] (Skoltech), Max Planck Institute for Evolutionary Anthropology [Leipzig], Max-Planck-Gesellschaft, Institut de Biologia Evolutiva [Barcelona] (IBE / UPF - CSIC), Universitat Pompeu Fabra [Barcelona] (UPF), Institució Catalana de Recerca i Estudis Avançats (ICREA), Centre for Genomic Regulation [Barcelona] (CRG), Universitat Pompeu Fabra [Barcelona] (UPF)-Centro Nacional de Analisis Genomico [Barcelona] (CNAG), Barcelona Institute of Science and Technology (BIST), Universitat Autònoma de Barcelona (UAB), Robinson Research Institute, and University of Adelaide
Subjects: Male, [SDV]Life Sciences [q-bio], Gene Expression, Cell-adhesion, 0302 clinical medicine, Ecology,Evolution & Ethology, Origins, Sex-chromosomes, Features, X chromosome, X-chromosome, 0303 health sciences, Spermatogenic Cell, Human Biology & Physiology, Multidisciplinary, Chromatin/genetics, Sertoli cell, Gene expression profiling, Dynamics, Chromatin, medicine.anatomical_structure, Sexual selection, Genetics & Genomics, Macaque, Model organisms, Evolution, Mammals/genetics, Biology, Chromosomes, Evolutionary genetics, Evolution, Molecular, 03 medical and health sciences, Meiosis, Molecular evolution, medicine, Animals, mammals, General, 030304 developmental biology, Computational & Systems Biology, Spermatogenesis/genetics, Molecular, Chromosome, Evolutionary pressure, spermatogenesis, Genes, Meiosis/genetics, Evolutionary biology, Testis/metabolism, 030217 neurology & neurosurgery, Developmental Biology
Abstract: The testis produces gametes through spermatogenesis and evolves rapidly at both the morphological and molecular level in mammals1-6, probably owing to the evolutionary pressure on males to be reproductively successful7. However, the molecular evolution of individual spermatogenic cell types across mammals remains largely uncharacterized. Here we report evolutionary analyses of single-nucleus transcriptome data for testes from 11 species that cover the three main mammalian lineages (eutherians, marsupials and monotremes) and birds (the evolutionary outgroup), and include seven primates. We find that the rapid evolution of the testis was driven by accelerated fixation rates of gene expression changes, amino acid substitutions and new genes in late spermatogenic stages, probably facilitated by reduced pleiotropic constraints, haploid selection and transcriptionally permissive chromatin. We identify temporal expression changes of individual genes across species and conserved expression programs controlling ancestral spermatogenic processes. Genes predominantly expressed in spermatogonia (germ cells fuelling spermatogenesis) and Sertoli (somatic support) cells accumulated on X chromosomes during evolution, presumably owing to male-beneficial selective forces. Further work identified transcriptomal differences between X- and Y-bearing spermatids and uncovered that meiotic sex-chromosome inactivation (MSCI) also occurs in monotremes and hence is common to mammalian sex-chromosome systems. Thus, the mechanism of meiotic silencing of unsynapsed chromatin, which underlies MSCI, is an ancestral mammalian feature. Our study illuminates the molecular evolution of spermatogenesis and associated selective forces, and provides a resource for investigating the biology of the testis across mammals. We thank all members of the Kaessmann group, S. Tirier for discussions and N. Trost for the administration of the Kaessmann laboratory server. Computations were performed on the Kaessmann laboratory server and the bwForCluster from the Heidelberg University Computational Center (supported by the state of Baden-Württemberg through bwHPC and the German Research Foundation grant no. INST 35/1134-1 FUGG). This research was supported by grants from the ERC (grant no. 615253, OntoTransEvol) and German Research Council (DFG, grant nos. SFB 873 and KA 1710/4-1) to H.K., by the CellNetworks Postdoc Fellowship and EMBO Long-Term Fellowship to F.M. (grant no. ALTF 591-2017), and by the Australian Research Council (grant no. FT160100267) to F.G. and by the Novo Nordisk Foundation (grant no. NNF21OC0069913) to K.A. and (grant no. NNF18OC0031004) to M.H.S. The use of all other mammalian samples for the type of work described in this study was approved by ERC ethics screening panels (ERC starting grant no. 242597, SexGenTransEvolution and ERC consolidator grant no. 615253, OntoTransEvol).
Published: 2023
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14. Clinical and prognostic associations of autoantibodies recognizing adrenergic/muscarinic receptors in patients with heart failure

Author: Markousis-Mavrogenis, George, Minich, Waldemar B, Al-Mubarak, Ali A, Anker, Stefan D, Cleland, John G F, Dickstein, Kenneth, Lang, Chim C, Leong L, Ng, Samani, Nilesh J, Zannad, Faiez, Metra, Marco, Seemann, Petra, Hoeg, Antonia, Lopez, Patricio, van Veldhuisen, Dirk J, de Boer, Rudolf A, Voors, Adriaan A, van der Meer, Peter, Schomburg, Lutz, Bomer, Nils, University Medical Center Groningen [Groningen] (UMCG), University of Groningen [Groningen], Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], ImmunometriX GmbH i.L., Charité Campus Virchow-Klinikum (CVK), Berlin-Brandenburg Center for Regenerative Medicine [Berlin, Germany] (BCRT), German Center for Cardiovascular Research (DZHK), Berlin Institute of Health (BIH), University Medical Center Göttingen (UMG), University of Glascow, National Heart and Lung Institute [London] (NHLI), Imperial College London-Royal Brompton and Harefield NHS Foundation Trust, University of Bergen (UiB), Stavanger University Hospital, University of Dundee, Department of Cardiovascular Sciences [Leicester], University of Leicester, NIHR Leicester Cardiovascular Biomedical Research Unit, 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), 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), 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 ), University of Brescia, Azienda Socio Sanitaria Territoriale Spedali Civili di Brescia [Brescia], European Project: 242209,EC:FP7:HEALTH,FP7-HEALTH-2009-single-stage,BIOSTAT-CHF(2010), and European Project
Subjects: immune system, Physiology, Physiology (medical), [SDV]Life Sciences [q-bio], autoimmunity, M2, beta 1, beta 2, beta 3, Cardiology and Cardiovascular Medicine, beta 1 beta 2 beta 3 M2 immune system autoimmunity
Abstract: AimsThe importance of autoantibodies (AABs) against adrenergic/muscarinic receptors in heart failure (HF) is not well-understood. We investigated the prevalence and clinical/prognostic associations of four AABs recognizing the M2-muscarinic receptor or the β1-, β2-, or β3-adrenergic receptor in a large and well-characterized cohort of patients with HF.Methods and resultsSerum samples from 2256 patients with HF from the BIOSTAT-CHF cohort and 299 healthy controls were analysed using newly established chemiluminescence immunoassays. The primary outcome was a composite of all-cause mortality and HF rehospitalization at 2-year follow-up, and each outcome was also separately investigated. Collectively, 382 (16.9%) patients and 37 (12.4%) controls were seropositive for ≥1 AAB (P = 0.045). Seropositivity occurred more frequently only for anti-M2 AABs (P = 0.025). Amongst patients with HF, seropositivity was associated with the presence of comorbidities (renal disease, chronic obstructive pulmonary disease, stroke, and atrial fibrillation) and with medication use. Only anti-β1 AAB seropositivity was associated with the primary outcome [hazard ratio (95% confidence interval): 1.37 (1.04–1.81), P = 0.024] and HF rehospitalization [1.57 (1.13–2.19), P = 0.010] in univariable analyses but remained associated only with HF rehospitalization after multivariable adjustment for the BIOSTAT-CHF risk model [1.47 (1.05–2.07), P = 0.030]. Principal component analyses showed considerable overlap in B-lymphocyte activity between seropositive and seronegative patients, based on 31 circulating biomarkers related to B-lymphocyte function.ConclusionsAAB seropositivity was not strongly associated with adverse outcomes in HF and was mostly related to the presence of comorbidities and medication use. Only anti-β1 AABs were independently associated with HF rehospitalization. The exact clinical value of AABs remains to be elucidated.
Published: 2023

15. The evidence base of US Food and Drug Administration approvals of novel cancer therapies from 2000 to 2020

Author: Viktoria Gloy, Andreas M. Schmitt, Pascal Düblin, Julian Hirt, Cathrin Axfors, Hanna Kuk, Tiago V. Pereira, Clara Locher, Laura Caquelin, Martin Walter‐Claudi, Mark P. Lythgoe, Amanda Herbrand, Benjamin Kasenda, Lars G. Hemkens, University Hospital Basel [Basel], Stanford University, Uppsala University, University of Ottawa [Ottawa], University of Leicester, CHU Pontchaillou [Rennes], Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), École des Hautes Études en Santé Publique [EHESP] (EHESP), Centre d'Investigation Clinique [Rennes] (CIC), Université de Rennes (UR)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), Hammersmith Hospital NHS Imperial College Healthcare, Berlin Institute of Health (BIH), Krebsliga Schweiz. Grant Number: KFS-4842-08-2019, and Open access funding provided by Universitat Basel
Subjects: Cancer Research, Cancer och onkologi, Oncology, quality of life, drug approval, health care policy, [SDV]Life Sciences [q-bio], Cancer and Oncology, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, [SDV.CAN]Life Sciences [q-bio]/Cancer, evidence-based medicine
Abstract: International audience; Concerns have been raised that regulatory programs to accelerate approval of cancer drugs in cancer may increase uncertainty about benefits and harms for survival and quality of life (QoL). We analyzed all pivotal clinical trials and all non-pivotal randomized controlled trials (RCTs) for all cancer drugs approved for the first time by the FDA between 2000 and 2020. We report regulatory and trial characteristics. Effects on overall survival (OS), progression-free survival and tumor response were summarized in meta-analyses. Effects on QoL were qualitatively summarized. Between 2000 and 2020, the FDA approved 145 novel cancer drugs for 156 indications based on 190 clinical trials. Half of indications (49%) were approved without RCT evidence; 82% had a single clinical trial only. OS was primary endpoint in 14% of trials and QoL data were available from 25%. The median OS benefit was 2.55 months (IQR, 1.33-4.28) with a mean hazard ratio for OS of 0.75 (95%CI, 0.72-0.79, I(2) = 42). Improvement for QoL was reported for 7 (4%) of 156 indications. Over time, priority review was used increasingly and the mean number of trials per indication decreased from 1.45 to 1.12. More trials reported results on QoL (19% in 2000-2005; 41% in 2016-2020). For 21 years, novel cancer drugs have typically been approved based on one single, often uncontrolled, clinical trial, measuring surrogate endpoints. This leaves cancer patients without solid evidence that novel drugs improve their survival or QoL and there is no indication towards improvement.
Published: 2023
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16. Sudden cardiac death while waiting: do we need the wearable cardioverter-defibrillator?

Author: Israel, Carsten, Staudacher, Ingo, Leclercq, Christophe, Botto, Giovanni Luca, Scherr, Daniel, Fach, Andreas, Duru, Firat, Zylla, Maura M, Katus, Hugo A, Thomas, Dierk, Children’s Center Bethel (EvkB), Heidelberg University Hospital [Heidelberg], Laboratoire Traitement du Signal et de l'Image (LTSI), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Pontchaillou [Rennes], Medical University Graz, Universität Zürich [Zürich] = University of Zurich (UZH), German Center for Cardiovascular Research (DZHK), Berlin Institute of Health (BIH), Projekt DEAL, University of Zurich, Thomas, Dierk, and Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Electric Countershock, 610 Medicine & health, Ventricular tachycardia, General Medicine, 2705 Cardiology and Cardiovascular Medicine, Implantable cardioverter-defibrillator, Defibrillators, Implantable, Wearable Electronic Devices, Sudden cardiac death, Myocardial infarction, Death, Sudden, Cardiac, 10209 Clinic for Cardiology, Humans, [SDV.IB]Life Sciences [q-bio]/Bioengineering, cardiovascular diseases, Wearable cardioverter-defibrillator, Cardiomyopathies, Cardiology and Cardiovascular Medicine, Defibrillators, Randomized Controlled Trials as Topic
Abstract: Sudden cardiac death (SCD) is the most frequent cause of cardiovascular death in industrialized nations. Patients with cardiomyopathy are at increased risk for SCD and may benefit from an implantable cardioverter-defibrillator (ICD). The risk of SCD is highest in the first months after myocardial infarction or first diagnosis of severe non-ischemic cardiomyopathy. On the other hand, left ventricular function may improve in a subset of patients to such an extent that an ICD might no longer be needed. To offer protection from a transient risk of SCD, the wearable cardioverter-defibrillator (WCD) is available. Results of the first randomized clinical trial investigating the role of the WCD after myocardial infarction were recently published. This review is intended to provide insight into data from the VEST trial, and to put these into perspective with studies and clinical experience. As a non-invasive, temporary therapy, the WCD may offer advantages over early ICD implantation. However, recent data demonstrate that patient compliance and education play a crucial role in this new concept of preventing SCD.
Published: 2022

17. Targeted therapies in genetic dilated and hypertrophic cardiomyopathies: from molecular mechanisms to therapeutic targets. A position paper from the Heart Failure Association (HFA) and the Working Group on Myocardial Function of the European Society of Cardiology (ESC)

Author: Rudolf A. de Boer, Stephane Heymans, Johannes Backs, Lucie Carrier, Andrew J.S. Coats, Stefanie Dimmeler, Thomas Eschenhagen, Gerasimos Filippatos, Lior Gepstein, Jean‐Sebastien Hulot, Ralph Knöll, Christian Kupatt, Wolfgang A. Linke, Christine E. Seidman, C. Gabriele Tocchetti, Jolanda van der Velden, Roddy Walsh, Petar M. Seferovic, Thomas Thum, Publica, Cardiologie, MUMC+: MA Med Staf Spec Cardiologie (9), RS: Carim - H02 Cardiomyopathy, HULOT, Jean-Sébastien, University of Groningen [Groningen], Maastricht University Medical Centre (MUMC), Maastricht University [Maastricht], Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Heidelberg University, German Center for Cardiovascular Research (DZHK), Berlin Institute of Health (BIH), Universitaetsklinikum Hamburg-Eppendorf = University Medical Center Hamburg-Eppendorf [Hamburg] (UKE), University of Warwick [Coventry], Goethe University [Germany], National and Kapodistrian University of Athens (NKUA), Technion - Israel Institute of Technology [Haifa], CIC - HEGP (CIC 1418), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Paris-Centre de Recherche Cardiovasculaire (PARCC (UMR_S 970/ U970)), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Karolinska Institutet [Stockholm], AstraZeneca, Technische Universität München = Technical University of Munich (TUM), University Hospital Münster - Universitaetsklinikum Muenster [Germany] (UKM), Harvard Medical School [Boston] (HMS), Brigham & Women’s Hospital [Boston] (BWH), Howard Hughes Medical Institute [Boston] (HHMI), Howard Hughes Medical Institute (HHMI)-Harvard Medical School [Boston] (HMS), University of Naples Federico II = Università degli studi di Napoli Federico II, Vrije Universiteit Amsterdam [Amsterdam] (VU), University of Amsterdam [Amsterdam] (UvA), Serbian Academy of Sciences and Arts (SASA), University of Belgrade [Belgrade], Hannover Medical School [Hannover] (MHH), Fraunhofer Institute for Toxicology and Experimental Medicine (Fraunhofer ITEM), Fraunhofer (Fraunhofer-Gesellschaft), Cardiology, Cardiovascular Centre (CVC), Physiology, and ACS - Heart failure & arrhythmias
Subjects: Cardiomyopathy, Dilated, GENOMIC DNA, Cardiac & Cardiovascular Systems, Cardiomyopathy, Molecular biology, RESTORES DYSTROPHIN EXPRESSION, [SDV]Life Sciences [q-bio], Cardiology, Dilated cardiomyopathy, Heart failure, DOUBLE-BLIND, Gene therapy, Humans, GENOME-WIDE ASSOCIATION, MUTATION, Pharmacology, Science & Technology, CARDIAC MYOSIN, Myocardium, MOUSE MODEL, Cardiomyopathy, Hypertrophic, Hypertrophic cardiomyopathy, [SDV] Life Sciences [q-bio], ATP TURNOVER, Cardiovascular System & Cardiology, Disease mechanism, Cardiomyopathies, Cardiology and Cardiovascular Medicine, PHOSPHOLAMBAN, SARCOMERE FUNCTION, Life Sciences & Biomedicine, PLURIPOTENT STEM-CELLS
Abstract: Genetic cardiomyopathies are disorders of the cardiac muscle, most often explained by pathogenic mutations in genes encoding sarcomere, cytoskeleton, or ion channel proteins. Clinical phenotypes such as heart failure and arrhythmia are classically treated with generic drugs, but aetiology-specific and targeted treatments are lacking. As a result, cardiomyopathies still present a major burden to society, and affect many young and older patients. The Translational Committee of the Heart Failure Association (HFA) and the Working Group of Myocardial Function of the European Society of Cardiology (ESC) organized a workshop to discuss recent advances in molecular and physiological studies of various forms of cardiomyopathies. The study of cardiomyopathies has intensified after several new study setups became available, such as induced pluripotent stem cells, three-dimensional printing of cells, use of scaffolds and engineered heart tissue, with convincing human validation studies. Furthermore, our knowledge on the consequences of mutated proteins has deepened, with relevance for cellular homeostasis, protein quality control and toxicity, often specific to particular cardiomyopathies, with precise effects explaining the aberrations. This has opened up new avenues to treat cardiomyopathies, using contemporary techniques from the molecular toolbox, such as gene editing and repair using CRISPR-Cas9 techniques, antisense therapies, novel designer drugs, and RNA therapies. In this article, we discuss the connection between biology and diverse clinical presentation, as well as promising new medications and therapeutic avenues, which may be instrumental to come to precision medicine of genetic cardiomyopathies. ispartof: EUROPEAN JOURNAL OF HEART FAILURE vol:24 issue:3 pages:406-420 ispartof: location:England status: published
Published: 2022

18. Optical excitation processes: general discussion

Author: Martin Appleby, Kyle Barlow, Martina Basini, Lara Benfatto, Yorrick Boeije, Andrew Burnett, Lin X. Chen, Eric Collet, Hermann A. Dürr, Graham Fleming, Aswathy V. Girija, Mohammed Th. Hassan, Hamoon Hedayat, Shinichiro Iwai, J. Olof Johansson, Steven L. Johnson, Kota Katsumi, Pyosang Kim, James K. McCusker, Ryan Phelps, Jan Michael Rost, Erica Sutcliffe, Julian Wagner, Julia Weinstein, Serhane Zerdane, Univ Roma La Sapienza, Dept Phys, CNR ISC, I-00185 Rome, Italy, Chemical Sciences and Engineering Division [Argonne], Argonne National Laboratory [Lemont] (ANL), Institut de Physique de Rennes (IPR), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS), Centre for Functional Biodiversity, School of Life Sciences, University of KwaZulu-Natal, Pietermaritzburg, South Africa, Institute of Cardiovascular Regeneration [Frankfurt, Germany] (Centre for Molecular Medicine), Goethe-University Frankfurt am Main, German Center for Cardiovascular Research (DZHK), and Berlin Institute of Health (BIH)
Subjects: [PHYS.COND]Physics [physics]/Condensed Matter [cond-mat], Physical and Theoretical Chemistry
Abstract: International audience
Published: 2022

19. Effect of empagliflozin in patients with heart failure across the spectrum of left ventricular ejection fraction

Author: Javed Butler, Milton Packer, Gerasimos Filippatos, Joao Pedro Ferreira, Cordula Zeller, Janet Schnee, Martina Brueckmann, Stuart J Pocock, Faiez Zannad, Stefan D Anker, BOZEC, Erwan, University of Mississippi Medical Center (UMMC), Baylor Heart and Vascular Institute, Baylor Jack and Jane Hamilton, National and Kapodistrian University of Athens (NKUA), Université d'Athènes (UOA), Attikon University Hospital, 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), 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), 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 ), Boehringer Ingelheim Pharma GmbH & Co. KG, Boehringer Ingelheim Pharmaceuticals, Inc, Ridgefield, Boehringer Ingelheim International GmbH, University of Heidelberg, Medical Faculty, London School of Hygiene and Tropical Medicine (LSHTM), Berlin-Brandenburg Center for Regenerative Medicine [Berlin, Germany] (BCRT), Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], German Center for Cardiovascular Research (DZHK), Berlin Institute of Health (BIH), Funding for the EMPEROR trials was provided by Boehringer Ingelheim and Eli Lilly and Company., and Université de Lorraine (UL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)
Subjects: Ejection fraction, animal structures, Empagliflozin, Stroke Volume, Heart failure, 030204 cardiovascular system & hematology, Ventricular Function, Left, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, 3. Good health, Hospitalization, 03 medical and health sciences, 0302 clinical medicine, Glucosides, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Humans, Sex, 030212 general & internal medicine, Benzhydryl Compounds, Cardiology and Cardiovascular Medicine
Abstract: Aims No therapy has shown to reduce the risk of hospitalization for heart failure across the entire range of ejection fractions seen in clinical practice. We assessed the influence of ejection fraction on the effect of the sodium–glucose cotransporter 2 inhibitor empagliflozin on heart failure outcomes. Methods and results A pooled analysis was performed on both the EMPEROR-Reduced and EMPEROR-Preserved trials (9718 patients; 4860 empagliflozin and 4858 placebo), and patients were grouped based on ejection fraction: Conclusion The magnitude of the effect of empagliflozin on heart failure outcomes was clinically meaningful and similar in patients with ejection fractions Key Question How does ejection fraction influence the effects of empagliflozin in patients with heart failure and either a reduced or a preserved ejection fraction? Key Finding The magnitude of the effect of empagliflozin on heart failure outcomes and health status was similar in patients with ejection fractions Take Home Message The consistency of the response in patients with ejection fractions of
Published: 2021

20. Regional and ethnic influences on the response to empagliflozin in patients with heart failure and a reduced ejection fraction

Author: Subodh Verma, Milton Packer, Stefan D. Anker, Carolyn S.P. Lam, Daniel Cotton, Stuart J. Pocock, Martina Brueckmann, David Sim, Janet Schnee, Javed Butler, Egon Pfarr, Gerasimos Filippatos, João Pedro Ferreira, Hiroyuki Tsutsui, Faiez Zannad, Naveed Sattar, Cardiovascular Centre (CVC), National Heart Centre Singapore (NHCS), University Medical Center Groningen [Groningen] (UMCG), 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), 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), 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 ), Boehringer Ingelheim International GmbH, Department of Cardiovascular Medicine, Kyushu University, Higashi-ku, Kyushu University [Fukuoka], Berlin-Brandenburg Center for Regenerative Therapies [Berlin, Germany], Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], German Center for Cardiovascular Research (DZHK), Berlin Institute of Health (BIH), Mississippi State University [Mississippi], Attikon University Hospital, National and Kapodistrian University of Athens (NKUA), London School of Hygiene and Tropical Medicine (LSHTM), Institute of Cardiovascular and Medical Sciences [Glasgow], University of Glasgow, St. Michael's Hospital, University of Toronto, University of Heidelberg, Medical Faculty, Boehringer Ingelheim Pharmaceuticals, Inc, Baylor University Medical Center, Baylor College of Medecine, Imperial College London, and The EMPEROR-Reduced trial was funded by Boehringer Ingelheim and Eli Lilly (EMPEROR-Reduced ClinicalTrials.gov number, NCT03057977)
Subjects: Relative risk reduction, Ethnic group, Empagliflozin, Fast Track Clinical Research, Heart failure, 030204 cardiovascular system & hematology, Placebo, Racial differences, 03 medical and health sciences, 0302 clinical medicine, Primary outcome, Glucosides, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Ethnicity, Medicine, Humans, In patient, AcademicSubjects/MED00200, 030212 general & internal medicine, Benzhydryl Compounds, 10. No inequality, Heart Failure and Cardiomyopathies, Ejection fraction, business.industry, Geographic differences, Stroke Volume, medicine.disease, 3. Good health, Cardiology and Cardiovascular Medicine, business, Demography
Abstract: Aims The aim of this article is to explore the influence of region and race/ethnicity on the effects of empagliflozin in the Empagliflozin Outcome Trial in Patients with Chronic Heart Failure and a Reduced Ejection Fraction (EMPEROR-Reduced) trial. Methods and results Of 3730 patients, 1353 (36.3%) were enrolled in Europe, 1286 (34.5%) in Latin America, 425 (11.4%) in North America, and 493 (13.2%) in Asia; 2629 (70.5%) were White, 257 (6.9%) Black, and 672 (18.0%) Asian. Placebo event rates (per 100 patient-years) for cardiovascular death or heart failure (HF) hospitalization varied by region (Asia 27.7, North America 26.4, Latin America 21.4, and Europe 17.5) and race/ethnicity (Black 34.4, Asian 24.3, and White 18.7); driven by differences in HF hospitalization. The ratio of total HF hospitalization to cardiovascular death varied from 5.4 in Asia and 4.8 in North America to 2.1 in Europe; and from 4.8 in Black and 4.2 in Asian to 2.2 in White patients. Groups with the highest ratio had the greatest reduction in the primary outcome with empagliflozin. Inclusion of outpatient worsening HF episodes added more events in Europe vs. other regions; enhanced the placebo event rates in Europe vs. other regions; and increased the relative risk reduction with empagliflozin in Europe from 6% to 26%. Conclusions There were notable differences in the placebo event rates for major HF events across diverse regions and race/ethnic groups. The benefit of empagliflozin was most pronounced in groups with the highest ratio of HF hospitalization to cardiovascular death. Regional differences were attenuated when the definition of HF events was expanded to include outpatient worsening HF events., Graphical Abstract Effect of empagliflozin by region and race in EMPEROR-Reduced. Inclusion of outpatient events in the extended composite endpoint attenuated the between-region differences in the effect of empagliflozin seen in the primary outcome of EMPEROR-Reduced.
Published: 2021

21. Hemoglobin and Clinical Outcomes in the Vericiguat Global Study in Patients With Heart Failure and Reduced Ejection Fraction (VICTORIA)

Author: Javed Butler, Adrian F. Hernandez, Paul W. Armstrong, Justin A. Ezekowitz, Piotr Ponikowski, Cynthia M. Westerhout, Vojtěch Melenovský, Burkert Pieske, Ciaran McMullan, Yinggan Zheng, Adriaan A. Voors, Jorge Escobedo, Christopher DeFilippi, Lothar Roessig, Carolyn S.P. Lam, Christopher M. O'Connor, Alain Cohen-Solal, leboeuf, Christophe, University of Alberta, Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Marqueurs cardiovasculaires en situation de stress (MASCOT (UMR_S_942 / U942)), 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) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité)-Université Sorbonne Paris Nord, Institute of Clinical and Experimental Medicine [Prague, Czech Republic] (ICEM), Mexican Social Security Institute [Mexico City] (M2SI), University of Mississippi Medical Center (UMMC), Duke University Medical Center, Duke-National University of Singapore Graduate Medical School, Inova Heart and Vascular Institute [Falls Church, VA, USA] (IHVI), Berlin Institute of Health (BIH), Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Wrocław Medical University, University of Groningen [Groningen], Merck & Co., Inc. [Kenilworth, NJ, États-Unis], Bayer AG [Wuppertal, Germany], and Cardiovascular Centre (CVC)
Subjects: Male, medicine.medical_specialty, Anemia, vericiguat, heart failure, World Health Organization, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Physiology (medical), Internal medicine, medicine, Humans, In patient, hemoglobins, Aged, Ejection fraction, business.industry, Stroke Volume, medicine.disease, anemia, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Treatment Outcome, Heart failure, Cardiology, Vericiguat, Female, Hemoglobin, Cardiology and Cardiovascular Medicine, business
Abstract: Background: In the VICTORIA trial (Vericiguat Global Study in Patients with Heart Failure with Reduced Ejection Fraction), anemia occurred more often in patients treated with vericiguat (7.6%) than with placebo (5.7%). We explored the association between vericiguat, randomization hemoglobin, development of anemia, and whether the benefit of vericiguat related to baseline hemoglobin. Methods: Anemia was defined as hemoglobin Results: At baseline, 1719 (35.7%) patients had World Health Organization anemia; median hemoglobin was 13.4 g/L (25th, 75th percentile: 12.1, 14.7 g/dL). At 16 weeks from randomization, 1643 patients had World Health Organization anemia (284 new for vericiguat and 219 for placebo), which occurred more often with vericiguat than placebo ( P Conclusions: Anemia was common at randomization and lower hemoglobin was associated with a greater frequency of clinical events. Although vericiguat modestly lowered hemoglobin by 16 weeks, this effect did not further progress nor was it related to the treatment benefit of vericiguat. Registration: URL: https://www.clinicaltrials.gov : Unique identifier: NCT02861534.
Published: 2021

22. Sociodemographic and behavioural factors of adherence to the no-screen guideline for toddlers among parents from the French nationwide Elfe birth cohort

Author: Lorraine Poncet, Mélèa Saïd, Malamine Gassama, Marie-Noëlle Dufourg, Falk Müller-Riemenschneider, Sandrine Lioret, Patricia Dargent-Molina, Marie-Aline Charles, Jonathan Y. Bernard, Centre de Recherche Épidémiologie et Statistique Sorbonne Paris Cité (CRESS (U1153 / UMR_A_1125 / UMR_S_1153)), Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Etude longitudinale française depuis l'enfance (UMS : Ined-Inserm-EFS) (ELFE), Institut national d'études démographiques (INED)-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), Saw Swee Hock School of Public Health [Singapore, Singapore], National University of Singapore (NUS), Berlin Institute of Health (BIH), Singapore Institute for Clinical Sciences [Singapour] (SICS), Agency for science, technology and research [Singapore] (A*STAR), and Bernard, Jonathan
Subjects: Adult, Parents, Nutrition and Dietetics, Parenting, Infant, Newborn, Child Behavior, Medicine (miscellaneous), Physical Therapy, Sports Therapy and Rehabilitation, Screen time, Sedentary behavior, Pregnancy, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, Child, Preschool, Humans, Female, Television, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Smartphone, Child, Tablet, Exercise, Birth cohort
Abstract: Background Excessive screen time in infancy and childhood has been associated with consequences on children’s development and health. International guidelines call for no screen time before age 2 years, whereas in France, the most prominent guidelines recommend no screen before age 3 years. However, data are lacking on parental adherence to the no-screen guideline for toddlers and factors of adherence in France. Using data from the French nationwide Elfe birth cohort, we estimated adherence to the no-screen guideline at age 2 years and examined related factors, including sociodemographic characteristics, parental leisure activities and screen time. Methods In 2011, 18,329 newborns and their parents were enrolled in 349 randomly selected maternity units across mainland France. At age 2 years, screen exposure of 13,117 toddlers was reported by parents in phone interviews. Data on sociodemographic characteristics, parental leisure activities and screen time were collected from both parents. Three patterns of parental leisure activities were derived by principal component analysis: literate (e.g.,reading), screen-based, and physical/artistic activities. Multivariable logistic regression models were used to examine the associations of sociodemographic characteristics, parental leisure activities and parental screen time with adherence to the no-screen guideline for toddlers. Results Overall, 1809/13,117 (13.5%) families adhered to the no-screen guideline for toddlers. Adherence was reduced with maternal age Conclusions Adherence to the no-screen guideline for toddlers in France was low. Parental leisure activities and parental screen time are major factors of adherence to the no-screen guideline and could be considered in targeted public health interventions.
Published: 2022

23. Empagliflozin Improves Cardiovascular and Renal Outcomes in Heart Failure Irrespective of Systolic Blood Pressure

Author: Gerasimos Filippatos, João Pedro Ferreira, Anne Pernille Ofstad, Waheed Jamal, Christoph Wanner, Javed Butler, Elke Schüler, Martina Brueckmann, Investigators, Stuart J. Pocock, Milton Packer, Faiez Zannad, EMPEROR-Reduced Trial Committees, Piotr Ponikowski, Stefan D. Anker, Michael Böhm, Felix Mahfoud, Saarland University [Saarbrücken], Berlin Institute of Health Center for Regenerative Therapies, German Center for Cardiovascular Research (DZHK), Berlin Institute of Health (BIH), Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], University of Mississippi Medical Center (UMMC), National and Kapodistrian University of Athens (NKUA), 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), 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), 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 ), London School of Hygiene and Tropical Medicine (LSHTM), Boehringer Ingelheim International GmbH, University of Heidelberg, Medical Faculty, Boehringer Ingelheim Norway KS, mainanalytics GmbH, Wroclaw Medical University, University Hospital of Würzburg, Baylor University Medical Center, Baylor College of Medecine, Imperial College London, BOZEC, Erwan, and Wrocław Medical University
Subjects: Male, systolic blood pressure, medicine.medical_specialty, animal structures, empagliflozin, heart failure, Blood Pressure, 030204 cardiovascular system & hematology, Cardiovascular death, 03 medical and health sciences, 0302 clinical medicine, Glucosides, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Internal medicine, Empagliflozin, medicine, Humans, In patient, 030212 general & internal medicine, Benzhydryl Compounds, Sodium-Glucose Transporter 2 Inhibitors, Aged, Ejection fraction, business.industry, kidney outcomes, Middle Aged, medicine.disease, cardiovascular outcomes, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, 3. Good health, Treatment Outcome, Blood pressure, Heart failure, Cardiology, Female, Cardiology and Cardiovascular Medicine, business, Cardiovascular outcomes, Glomerular Filtration Rate, Heart Failure, Systolic
Abstract: International audience; Background: Empagliflozin reduces the risk of cardiovascular death or heart failure (HF) hospitalization in patients with reduced ejection fraction. Its interplay with systolic blood pressure (SBP) is not known.Objectives: The goal of this study was to evaluate the interplay of SBP and the effects of empagliflozin in EMPEROR-Reduced (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Reduced Ejection Fraction).Methods: Study patients (N = 3,730) were randomly assigned to groups according to SBP at baseline (130 mm Hg, n = 1,047). This study explored the influence of SBP on the effects of empagliflozin on cardiovascular death or HF hospitalization (primary outcome), as well as on total HF hospitalizations, rate of decline in estimated glomerular filtration rate, renal outcomes, and empagliflozin's effects and significance on SBP.Results: Over a median of 16 months considering only patients receiving placebo, baseline SBP and the risk of cardiovascular death or hospitalization for HF (P trend = 0.0015) were inversely related. Corrected for placebo, a slight early increase was observed in SBP at 130 mm Hg. These between-group differences were of borderline significance (P for interaction trend = 0.05-0.10) after 4 and 12 weeks but were not significant later. SBP at baseline did not influence the effect of empagliflozin to reduce the risk of HF events or renal endpoints. When treated with empagliflozin, patients with SBP
Published: 2021

24. On the clinical relevance of using complete high-resolution HLA typing for an accurate interpretation of posttransplant immune-mediated graft outcomes

Author: Meneghini, Maria, Perona, Anna, Crespo, Elena, Bemelman, Frederike, Reinke, Petra, Viklicky, Ondrej, Giral, Magali, Palou, Eduard, Torija, Alba, Donadeu, Laura, Melilli, Edoardo, Zuñiga, Jose, Sefrin, Anett, Lachmann, Nils, Hu, Liu, Hruba, Petra, Guillot-Gueguen, C. cile, Brouard, Sophie, Grinyo, Josep, Bestard, Oriol, Institut Català de la Salut, [Meneghini M, Bestard O] Unitat de Trasplantament Hepàtic, Servei de Nefrologia, Vall d’Hebron Hospital Universitari, Barcelona, Spain. Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain. Universitat Autònoma de Barcelona, Bellaterra, Spain. [Perona A] Department of Medicine, Barcelona University, Barcelona, Spain. [Crespo E, Torija A, Donadeu L] Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain. Universitat Autònoma de Barcelona, Bellaterra, Spain. [Bemelman F] Renal Transplant Unit, Department of Internal Medicine, Amsterdam University Medical Centers, Academic Medical Center - University of Amsterdam, Amsterdam, Netherlands. [Reinke P] Berlin Center for Advanced Therapies (BeCAT), Berlin Institute of Health Center for Regenerative Therapies (BCRT) and Department of Nephrology and Intensive Care, Charité Universitätsmedizin Berlin, Berlin Institute of Health, Berlin, Germany. [Viklicky O] Transplant Laboratory, Institute for Clinical and Experimental Medicine (IKEM), Prague, Czechia. Department of Nephrology, Institute for Clinical and Experimental Medicine (IKEM), Prague, Czechia. [Zuñiga J] Unitat de Trasplantament Hepàtic, Servei de Nefrologia, Vall d’Hebron Hospital Universitari, Barcelona, Spain, Vall d'Hebron Barcelona Hospital Campus, Vall d'Hebron University Hospital [Barcelona], Universitat Autònoma de Barcelona (UAB), University of Barcelona, University of Amsterdam [Amsterdam] (UvA), Berlin Institute of Health (BIH), Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Transplant laboratory [Prague, Czech Republic], Institute for Clinical and Experimental Medicine (IKEM), Team 4 : Deciphering organ immune regulation in inflammation and transplantation (DORI-t) (U1064 Inserm - CR2TI), Centre de Recherche en Transplantation et Immunologie - Center for Research in Transplantation and Translational Immunology (U1064 Inserm - CR2TI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Nantes Université - UFR de Médecine et des Techniques Médicales (Nantes Univ - UFR MEDECINE), Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Nantes Université - UFR de Médecine et des Techniques Médicales (Nantes Univ - UFR MEDECINE), Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ), Centre hospitalier universitaire de Nantes (CHU Nantes), Institut de Transplantation et de Recherche en Transplantation [CHU Nantes] (ITERT), Institut de transplantation urologie-néphrologie (ITUN), Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), Clinic Barcelona Hospital Universitari, KERANDEL-DION, Céline, Nephrology, AII - Inflammatory diseases, and APH - Aging & Later Life
Subjects: Empelt contra l'hoste, Malaltia de l', Biological Factors::Antigens::Antigens, Surface::Histocompatibility Antigens::HLA Antigens [CHEMICALS AND DRUGS], Graft Rejection, [SDV]Life Sciences [q-bio], precision medicine, Immunology, Trasplantament renal, kidney transplantation, HLA-C Antigens, Immune System Phenomena::Transplantation Immunology::Host vs Graft Reaction::Graft Rejection [PHENOMENA AND PROCESSES], donor-specific antibodies, Kidney transplantation, Antígens HLA, HLA Antigens, Humans, Immunology and Allergy, Histocompatibilitat - Proves, kidney transplantation HLA typing donor-specific antibodies allograft rejection precision medicine, allograft rejection, Histocompatibility Testing, Graft Survival, factores biológicos::antígenos::antígenos de superficie::antígenos de histocompatibilidad::antígenos HLA [COMPUESTOS QUÍMICOS Y DROGAS], diagnóstico::técnicas y procedimientos diagnósticos::técnicas de laboratorio clínico::pruebas inmunológicas::pruebas de histocompatibilidad [TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS], [SDV] Life Sciences [q-bio], Rebuig (Biologia), HLA typing, Diagnosis::Diagnostic Techniques and Procedures::Clinical Laboratory Techniques::Immunologic Tests::Histocompatibility Testing [ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES, AND EQUIPMENT], Graft rejection, fenómenos del sistema inmunitario::inmunología del trasplante::reacción huésped contra injerto::rechazo del injerto [FENÓMENOS Y PROCESOS]
Abstract: HLA typing; Donor-specific antibodies; Kidney transplantation Tipificación de HLA; Anticuerpos específicos del donante; Trasplante de riñón Tipificació de HLA; Anticossos específics del donant; Trasplantament de ronyó Complete and high-resolution (HR) HLA typing improves the accurate assessment of donor–recipient compatibility and pre-transplant donor-specific antibodies (DSA). However, the value of this information to identify de novo immune-mediated graft events and its impact on outcomes has not been assessed. In 241 donor/recipient kidney transplant pairs, DNA samples were re-evaluated for six-locus (A/B/C/DRB1/DQB1+A1/DPB1) HR HLA typing. De novo anti-HLA antibodies were assessed using solid-phase assays, and dnDSA were classified either (1) as per current clinical practice according to three-locus (A/B/DRB1) low-resolution (LR) typing, estimating donor HLA-C/DQ typing with frequency tables, or (2) according to complete six-locus HR typing. The impact on graft outcomes was compared between groups. According to LR HLA typing, 36 (15%) patients developed dnDSA (LR_dnDSA+). Twenty-nine out of 36 (80%) were confirmed to have dnDSA by HR typing (LR_dnDSA+/HR_dnDSA+), whereas 7 (20%) did not (LR_dnDSA+/HR_dnDSA−). Out of 49 LR_dnDSA specificities, 34 (69%) were confirmed by HR typing whereas 15 (31%) LR specificities were not confirmed. LR_dnDSA+/HR_dnDSA+ patients were at higher risk of ABMR as compared to dnDSA− and LR_dnDSA+/HR_dnDSA− (logRank < 0.001), and higher risk of death-censored graft loss (logRank = 0.001). Both LR_dnDSA+ (HR: 3.51, 95% CI = 1.25–9.85) and LR_dnDSA+/HR_dnDSA+ (HR: 4.09, 95% CI = 1.45–11.54), but not LR_dnDSA+/HR_dnDSA− independently predicted graft loss. The implementation of HR HLA typing improves the characterization of biologically relevant de novo anti-HLA DSA and discriminates patients with poorer graft outcomes. This work was supported by the Biomarker-Driven Immunosuppression Minimization (BIO-DRIM) Consortium (EU FP7-health, grant agreement number 305147; FP7/2012-2017) and by the Instituto de Salud Carlos III (ISCIII) (grant numbers ICI14/00242, PI16/01321, and PI19/01710), co-funded by European Regional Development Fund (ERDF), a way to build Europe. Also, this work was partly supported by the SLT002/16/00183 grant, from the Department of Health of the Generalitat de Catalunya by the call “Acció instrumental de programes de recerca orientats en l’àmbit de la recerca i la innovació en salut”.
Published: 2022

25. Association of Empagliflozin Treatment With Albuminuria Levels in Patients With Heart Failure

Author: Ferreira, João Pedro, Zannad, Faiez, Butler, Javed, Filippatos, Gerasimos, Pocock, Stuart, Brueckmann, Martina, Steubl, Dominik, Schueler, Elke, Anker, Stefan, Packer, Milton, 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), 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), 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 ), Faculdade de Medicina da Universidade do Porto (FMUP), Universidade do Porto = University of Porto, University of Mississippi Medical Center (UMMC), Baylor Scott and White Research Institute, National and Kapodistrian University of Athens (NKUA), University of Athens, Attikon Hospital, London School of Hygiene and Tropical Medicine (LSHTM), Boehringer Ingelheim International GmbH, Medizinische Fakultät Mannheim, Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM), mainanalytics GmbH, Berlin-Brandenburg Center for Regenerative Therapies [Berlin, Germany], Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], German Center for Cardiovascular Research (DZHK), Berlin Institute of Health (BIH), Imperial College London, The EMPEROR-Reduced and Preserved trials were funded by Boehringer Ingelheim and Eli Lilly, and BOZEC, Erwan
Subjects: [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system
Abstract: International audience; Importance Albuminuria, routinely assessed as spot urine albumin-to-creatinine ratio (UACR), indicates structural damage of the glomerular filtration barrier and is associated with poor kidney and cardiovascular outcomes. Sodium-glucose cotransporter-2 (SGLT2) inhibitors have been found to reduce UACR in patients with type 2 diabetes, but its use in patients with heart failure (HF) is less well studied. Objective To analyze the association of empagliflozin with study outcomes across baseline levels of albuminuria and change in albuminuria in patients with HF across a wide range of ejection fraction levels. Design, Setting, and Participants This post hoc analysis included all patients with HF from the EMPEROR-Pooled analysis using combined individual patient data from the international multicenter randomized double-blind parallel-group, placebo-controlled EMPEROR-Reduced and EMPEROR-Preserved trials. Participants in the original trials were excluded from this analysis if they were missing baseline UACR data. EMPEROR-Preserved was conducted from March 27, 2017, to April 26, 2021, and EMPEROR-Reduced was conducted from April 6, 2017, to May 28, 2020. Data were analyzed from January to June 2022. Interventions Randomization to empagliflozin or placebo. Main Outcomes and Measures New-onset macroalbuminuria and regression to normoalbuminuria and microalbuminuria. Results A total of 9673 patients were included (mean [SD] age, 69.9 [10.4] years; 3551 [36.7%] female and 6122 [63.3%] male). Of these, 5552 patients had normoalbuminuria (UACR 300 mg/g). Compared with normoalbuminuria, macroalbuminuria was associated with younger age, races other than White, obesity, male sex, site region other than Europe, higher levels of N-terminal pro–hormone brain natriuretic peptide and high-sensitivity troponin T, higher blood pressure, higher New York Heart Association class, greater HF duration, more frequent previous HF hospitalizations, diabetes, hypertension, lower eGFR, and less frequent use of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers and mineralocorticoid receptor antagonists. An increase in events was observed in individuals with higher UACR levels. The association of empagliflozin with cardiovascular mortality or HF hospitalization was consistent across UACR categories (hazard ratio [HR], 0.80; 95% CI, 0.69-0.92 for normoalbuminuria; HR, 0.74; 95% CI, 0.63-0.86 for microalbuminuria; HR, 0.78; 95% CI, 0.63-0.98 for macroalbuminuria; interaction P trend = .71). Treatment with empagliflozin was associated with lower incidence of new macroalbuminuria (HR, 0.81; 95% CI, 0.70-0.94; P = .005) and an increase in rate of remission to sustained normoalbuminuria or microalbuminuria (HR, 1.31; 95% CI, 1.07-1.59; P = .009) but not with a reduction in UACR in the overall population; however, UACR was reduced in patients with diabetes, who had higher UACR levels than patients without diabetes (geometric mean for diabetes at baseline, 0.91; 95% CI, 0.85-0.98 and for no diabetes at baseline, 1.08; 95% CI, 1.01-1.16; interaction P = .008). Conclusions and Relevance In this post hoc analysis of a randomized clinical trial, compared with placebo, empagliflozin was associated with reduced HF hospitalizations or cardiovascular death irrespective of albuminuria levels at baseline, reduced progression to macroalbuminuria, and reversion of macroalbuminuria. Trial Registration ClinicalTrials.gov Identifiers: NCT03057977 and NCT03057951
Published: 2022

26. Dilated Cardiomyopathy – Results, Conclusions and Perspectives

Author: Garnier, S, Harakalova, M, Weiss, S, Mokry, M, Isnard, R, Duboscq-Bidot, L, Komajda, M, Cambien, F, Deleuze, J-F, Dörr, M, Asselbergs F, W, Villard, E, Trégouët, D-A, Charron, P, Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière] (IHU ICAN), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Utrecht University [Utrecht], Universität Greifswald - University of Greifswald, Centre National de Recherche en Génomique Humaine (CNRGH), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Laboratory of Excellence GENMED [Paris] (Medical Genomics), University of Medicine Greifswald, German Center for Cardiovascular Research (DZHK), Berlin Institute of Health (BIH), 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), and GenMed consortuium
Subjects: [SDV]Life Sciences [q-bio]
Abstract: International audience
Published: 2022

27. Association between long-term exposure to air pollution and rhinitis and asthma comorbidities in the Constances cohort

Author: Marine Savouré, Emeline Lequy, Jean Bousquet, Kees de Hoogh, Marcel Goldberg, Danielle Vienneau, Marie Zins, Rachel Nadif, Bénédicte Jacquemin, Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, French Environment and Energy Management Agency (FEEMA), Cohortes épidémiologiques en population (CONSTANCES), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Université Paris Cité (UPCité), Berlin Institute of Health (BIH), Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], CHU Montpellier, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), MASK-air, Swiss Tropical and Public Health Institute [Basel], University of Basel (Unibas), Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), and International Society for Environmental Epidemiology
Subjects: Air pollution, General Earth and Planetary Sciences, [SDV.MHEP.PSR]Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, Asthma, General Environmental Science, Rhinitis
Abstract: International audience; BACKGROUND AND AIM - Asthma and rhinitis are two related respiratory conditions. However, studies that investigated their associations with air pollution have considered them separately. We aimed to study the association between exposure to air pollution and phenotypes of current rhinitis (CR) and current asthma (CA) in Constances, a large French population-based adult cohort. METHODS - CR was defined by the report of sneezing, runny or blocked nose in the last 12 months. CA was defined by the report of lifetime asthma plus having in the last 12 months: taken asthma medication or had an asthma attack, wheezed, woken up with breathing discomfort, been short of breath at rest or exercise, or woken up with shortness of breath. Four categories were considered: non-CR/non-CA, CR/non-CA, non-CR/CA, and CR/CA. Annual exposure to nitrogen dioxide (NO2), particulate matter ≤2.5 µm (PM2.5) and black carbon (BC) was estimated at the participants' residential address by land-use regression models. Cross-sectional analyses at inclusion were performed between air pollutants and the four phenotypes using a multinomial logistic model adjusted for age, sex, smoking, education level and French deprivation index. RESULTS - Among the 173,805 participants included in this analysis (mean age: 47, 54% women), 108,637 (63%) were classified as non-CR/non-CA, 48,712 (28%) CR/non-CA, 6,282 (4%) non-CR/CA, and 10,174 (6%) CR/CA. Using non-CR/non-CA as reference, an increase of an interquartile range of BC (0.86 10-5m-1) was significantly associated with CR/non-CA (OR (CI95%): 1.17 (1.15-1.20)), non-CR/CA (1.10 (1.05-1.15)), and CR/CA (1.12 (1.08-1.16)). Similar associations were observed for PM2.5, NO2, and BC residuals. Regardless of pollutant, associations were significantly higher for the CR/non-CA than for the other groups. CONCLUSIONS - Our results suggest that CR/non-CA phenotype may be more sensitive to the effects of air pollution and that among traffic related air pollutants, BC may be of special interest.
Published: 2022

28. Effects of Empagliflozin in Women and Men With Heart Failure and Preserved Ejection Fraction

Author: Javed Butler, Gerasimos Filippatos, Tariq Jamal Siddiqi, João Pedro Ferreira, Martina Brueckmann, Edimar Bocchi, Michael Böhm, Vijay K. Chopra, Nadia Giannetti, Tomoko Iwata, James L. Januzzi, Sanjay Kaul, Ileana L. Piña, Piotr Ponikowski, Ursula Rauch-Kröhnert, Sanjiv J. Shah, Michele Senni, Mikhail Sumin, Subodh Verma, Jian Zhang, Stuart J. Pocock, Faiez Zannad, Milton Packer, Stefan D. Anker, Baylor Scott and White Research Institute, University of Mississippi Medical Center (UMMC), National and Kapodistrian University of Athens (NKUA), Attikon University Hospital, 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), 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), 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 ), Faculdade de Medicina da Universidade do Porto (FMUP), Universidade do Porto = University of Porto, Boehringer Ingelheim International GmbH, Medizinische Fakultät Mannheim, Universidade de São Paulo = University of São Paulo (USP), Universität des Saarlandes [Saarbrücken], Saarland University Hospital (UKS), Max Superspeciality Hospital, Saket, McGill University Health Center [Montreal] (MUHC), Boehringer Ingelheim Pharma GmbH & Co. KG, Massachusetts General Hospital [Boston, MA, USA], Harvard Medical School [Boston] (HMS), Baim Institute for Clinical Research Boston MA, Cedars-Sinai Medical Center, Central Michigan University (CMU), Wrocław Medical University, Department of Cardiology, Charité University Medicine Berlin, Campus Benjamin-Franklin, German Center for Cardiovascular Research (DZHK), Berlin Institute of Health (BIH), Northwestern University Feinberg School of Medicine, Hospital Papa Giovanni XXIII (Hosp P Giovanni XXIII), St. Michael's Hospital, Fuwai Hospital Chinese Academic of Medical Science, London School of Hygiene and Tropical Medicine (LSHTM), Baylor Heart and Vascular Institute, Baylor University Medical Center, Imperial College London, Charité Campus Virchow-Klinikum (CVK), Berlin-Brandenburg Center for Regenerative Medicine [Berlin, Germany] (BCRT), Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], The EMPEROR-Preserved trial was supported by the Boehringer Ingelheim andEli Lilly and Company Diabetes Alliance, and BOZEC, Erwan
Subjects: Heart Failure, Male, Stroke Volume, Ventricular Function, Left, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Uric Acid, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Glucosides, Physiology (medical), Humans, Female, Benzhydryl Compounds, Cardiology and Cardiovascular Medicine, Cardiomyopathies
Abstract: Background: Women and men with heart failure (HF) and preserved ejection fraction may differ in their clinical characteristics and their response to therapy. The aim of this study was to evaluate the influence of sex on the effects of empagliflozin in patients with HF and preserved ejection fraction enrolled in the EMPEROR-Preserved trial (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Preserved Ejection Fraction). Methods: The effects of empagliflozin on the primary outcome of cardiovascular death or hospitalization for HF and on secondary outcomes (including total HF hospitalization, cardiovascular and all-cause mortality, and Kansas City Cardiomyopathy Questionnaire scores) were compared in women and men in the overall cohort and in subgroups defined by left ventricular ejection fraction (41%–49%, 50%–59%, and ≥60%). The effects of empagliflozin on physiological measures, including changes in systolic blood pressure, uric acid, hemoglobin, body weight, and natriuretic peptide levels, were also assessed. Results: Of the 5988 patients randomized, 2676 (44.7%) were women. In the placebo arm, women tended to have lower risk for adverse outcomes, including a lower risk of all-cause mortality (hazard ratio, 0.69 [95% CI, 0.56, 0.84]). Compared with placebo, empagliflozin reduced the risk of cardiovascular death or hospitalization for HF to a similar degree in both sexes (hazard ratio, 0.81 [95% CI, 0.69, 0.96] for men; and hazard ratio, 0.75 [95% CI, 0.61, 0.92] for women; P interaction =0.54). Sex did not modify the relationship between empagliflozin and outcomes across ejection fraction groups. Similar results were seen for secondary outcomes and physiological measures. Compared with placebo, empagliflozin improved the Kansas City Cardiomyopathy Questionnaire Clinical Summary Score to a similar extent in both sexes (1.38 for men versus 1.63 for women at 52 weeks; P interaction =0.77); the results were similar for Kansas City Cardiomyopathy Questionnaire overall summary score and total summary score. Conclusions: Empagliflozin produced similar benefits on outcomes and health status in women and men with HF and preserved ejection fraction. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03057951.
Published: 2022

29. Insulin‐like growth factor binding protein 7 (IGFBP7), a link between heart failure and senescence

Author: Valentina Bracun, Bart van Essen, Adriaan A. Voors, Dirk J. van Veldhuisen, Kenneth Dickstein, Faiez Zannad, Marco Metra, Stefan Anker, Nilesh J. Samani, Piotr Ponikowski, Gerasimos Filippatos, John G.F. Cleland, Chim C. Lang, Leong L. Ng, Canxia Shi, Sanne de Wit, Joseph Pierre Aboumsallem, Wouter C. Meijers, IJsbrand T. Klip, Peter van der Meer, Rudolf A. de Boer, University Medical Center Groningen [Groningen] (UMCG), Stavanger University Hospital, 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), 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), 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 ), Università degli Studi di Brescia = University of Brescia (UniBs), Berlin-Brandenburg Center for Regenerative Therapies [Berlin, Germany], Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], German Center for Cardiovascular Research (DZHK), Berlin Institute of Health (BIH), Charité Campus Virchow-Klinikum (CVK), University of Leicester, NIHR Leicester Biomedical Research Centre, Glenfield Hospital, Wrocław Medical University, National and Kapodistrian University of Athens (NKUA), Attikon University Hospital, Imperial College London, University of Glasgow, University of Dundee, Ninewells Hospital and Medical School [Dundee], This work was supported by a grant from the European Research Council (ERC CoG 818715, SECRETE-HF). Furthermore, support was received from grants from the Netherlands Heart Foundation (CVON SHE-PREDICTS-HF, grant 2017-21, CVON RED-CVD, grant 2017-11, CVON PREDICT2, grant 2018-30, and CVON DOUBLE DOSE, grant 2020B005), and by a grant from the leDucq Foundation [Cure PhosphoLambaN induced Cardiomyopathy (Cure-PLaN)]., European Project, BOZEC, Erwan, ERC CoG 818715, SECRETE‐HF - INCOMING, and Cardiovascular Centre (CVC)
Subjects: senescence, MODELS, BIOSTAT-CHF, HFpEF, HFrEF, IGFBP7, heart failure, Stroke Volume, Prognosis, DYSFUNCTION, EJECTION FRACTION, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Insulin-Like Growth Factor Binding Proteins, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Humans, OXIDATIVE STRESS, Cardiology and Cardiovascular Medicine, Biomarkers, Aged
Abstract: International audience; Aims Insulin like growth factor binding protein 7 (IGFBP7) is a marker of senescence secretome and a novel biomarker in patients with heart failure (HF). We evaluated the prognostic value of IGFBP7 in patients with heart failure and examined associations to uncover potential new pathophysiological pathways related to increased plasma IGFBP7 concentrations. Methods and results We have measured plasma IGFBP7 concentrations in 2250 subjects with new-onset or worsening heart failure (BIOSTAT-CHF cohort). Higher IGFBP7 plasma concentrations were found in older subjects, those with worse kidney function, history of atrial fibrillation, and diabetes mellitus type 2, and in subjects with higher number of HF hospitalizations. Higher IGFBP7 levels also correlate with the levels of several circulating biomarkers, including higher NT-proBNP, hsTnT, and urea levels. Cox regression analyses showed that higher plasma IGFBP7 concentrations were strongly associated with increased risk of all three main endpoints (hospitalization, all-cause mortality, and combined hospitalization and mortality) (HR 1.75, 95% CI 1.25-2.46; HR 1.71, 95% CI 1.39-2.11; and HR 1.44, 95% CI 1.23-1.70, respectively). IGFBP7 remained a significant predictor of these endpoints in patients with both reduced and preserved ejection fraction. Likelihood ratio test showed significant improvement of all three risk prediction models, after adding IGFBP7 (P < 0.001). A biomarker network analysis showed that IGFBP7 levels activate different pathways involved in the regulation of the immune system. Results were externally validated in BIOSTAT-CHF validation cohort. Conclusions IGFPB7 presents as an independent and robust prognostic biomarker in patients with HF, with both reduced and preserved ejection fraction. We validate the previously published data showing IGFBP7 has correlations with a number of echocardiographic markers. Lastly, IGFBP7 pathways are involved in different stages of immune system regulation, linking heart failure to senescence pathways.
Published: 2022

30. Coronary artery disease and revascularization associated with immune checkpoint blocker myocarditis: Report from an international registry

Author: Joseph Nowatzke, Paul Guedeney, Nicholas Palaskas, Lorenz Lehmann, Stephane Ederhy, Han Zhu, Jennifer Cautela, Sanjeev Francis, Pierre-Yves Courand, Anita Deswal, Steven M. Ewer, Mandar Aras, Dimitri Arangalage, Kambiz Ghafourian, Charlotte Fenioux, Daniel Finke, Giovanni Peretto, Vlad Zaha, Osnat Itzhaki Ben Zadok, Kazuko Tajiri, Nausheen Akhter, Joshua Levenson, Lauren Baldassarre, John Power, Shi Huang, Jean-Philippe Collet, Javid Moslehi, Joe-Elie Salem, Nazanin Aghel, Joachim Alexandre, Kazutaka Aonuma, Aarti H. Asnani, Juliane Behling, Mehmet Bilen, Wendy Bottinor, Eve Cariou, Johnny Chahine, Weiting Chan, Aman Chauhan, Max Cohen, Shanthini Crusz, Suran Fernando, Roberta Florido, Mauro Frigeri, Satoshi Fukushima, Elizabeth Gaughan, Benjamin P. Geisler, Lauren Gilstrap, Christian Grohe, Avirup Guha, Manhal Habib, Eva Haegler-Laube, Andrew Haydon, Salim Hayek, Andrew Hughes, Rysk Imai, Yumi Katsume, Hideki Kimura, Lily Koo Lin, Carrie Lenneman, Daryl Leong, Vicky Makker, Nicolas Martinez-Calle, Melissa Moey, Masahiro Mohri, Ryota Morimoto, Yoshinobu Moritoki, Anna Narezkina, Martin Nicol, Ajay Nooka, Olusola Orimoloye, Milan Patel, Michal Perl, Nicolas Piriou, Jayant K. Raikhelkar, Yasmin Raza, Anjali Rao, Sunil Reddy, Nobuhiko Seki, Karl Stangl, Andrew Stewart, Bryan Stringer, Balaji K. Tamarappoo, Yuichi Tamura, Frank Thuny, Sean Tierney, Romain Tresorier, Waqas Ullah, Jean-Jacques Von Hunolstein, Ellen Warner, Allison Weppler, Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière] (IHU ICAN), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut de cardiologie [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Universität Heidelberg [Heidelberg] = Heidelberg University, German Center for Cardiovascular Research (DZHK), Berlin Institute of Health (BIH), CHU Saint-Antoine [AP-HP], Groupe de REcherche en Cardio Oncologie (GRC 27 - GRECO), Sorbonne Université (SU), Centre recherche en CardioVasculaire et Nutrition = Center for CardioVascular and Nutrition research (C2VN), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon, Imagerie Ultrasonore, Centre de Recherche en Acquisition et Traitement de l'Image pour la Santé (CREATIS), 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)-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), The University of Texas Medical School at Houston, University of Wisconsin-Madison, University of California [San Francisco] (UC San Francisco), University of California (UC), AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), University of Heidelberg, Medical Faculty, Division of Endocrinology, Metabolism, and Diabetes, University of Utah, Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases [IHU ICAN], Universität Heidelberg [Heidelberg], Service de Cardiologie [CHU Saint-Antoine], Groupe de REcherche en Cardio Oncologie [CHU Saint-Antoine] (GRC 27 GRECO), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Service de Pharmacologie médicale [CHU Pitié-Salpêtrière]
Subjects: Cancer Research, Coronary Artery Disease, Prognosis, Coronary revascularization, Myocarditis, Oncology, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Risk Factors, Immune-related adverse events, [INFO.INFO-IM]Computer Science [cs]/Medical Imaging, Humans, Registries, Immune checkpoint blockers, Acute coronary syndrome, [PHYS.MECA.BIOM]Physics [physics]/Mechanics [physics]/Biomechanics [physics.med-ph], Immune Checkpoint Inhibitors, Retrospective Studies
Abstract: International audience; Purpose: Immune checkpoint blocker (ICB) associated myocarditis (ICB-myocar-ditis) may present similarly and/or overlap with other cardiac pathology including acute cor-onary syndrome presenting a challenge for prompt clinical diagnosis.Methods: An international registry was used to retrospectively identify cases of ICB-myocarditis. Presence of coronary artery disease (CAD) was defined as coronary artery steno-sis >70% in patients undergoing coronary angiogram.Results: Among 261 patients with clinically suspected ICB-myocarditis who underwent a coro-nary angiography, CAD was present in 59/261 patients (22.6%). Coronary revascularization was performed during the index hospitalisation in 19/59 (32.2%) patients. Patients undergoing coro-nary revascularization less frequently received steroids administration within 24 h of admission compared to the other groups (p = 0.029). Myocarditis-related 90-day mortality was 9/17 (52.7%) in the revascularised cohort, compared to 5/31 (16.1%) in those not revascularized and 25/156 (16.0%) in those without CAD (p = 0.001). Immune-related adverse event-related 90-day mortality was 9/17 (52.7%) in the revascularized cohort, compared to 6/31 (19.4%) in those not revascularized and 31/156 (19.9%) in no CAD groups (p = 0.007). All-cause 90-day mortality was 11/17 (64.7%) in the revascularized cohort, compared to 13/31 (41.9%) in no revas-cularization and 60/158 (38.0%) in no CAD groups (p = 0.10). After adjustment of age and sex, coronary revascularization remained associated with ICB-myocarditis-related death at 90 days (hazard ratio [HR] = 4.03, 95% confidence interval [CI] 1.84-8.84, p < 0.001) and was margin-ally associated with all-cause death (HR = 1.88, 95% CI, 0.98-3.61, p = 0.057).Conclusion: CAD may exist concomitantly with ICB-myocarditis and may portend a poorer outcome when revascularization is performed. This is potentially mediated through delayed diag-nosis and treatment or more severe presentation of ICB-myocarditis.
Published: 2022

31. Escherichia coliSPFH membrane microdomain proteins HflKC contribute to aminoglycoside and oxidative stress tolerance

Author: Aimee K. Wessel, Yutaka Yoshii, Alexander Reder, Rym Boudjemaa, Magdalena Szczesna, Jean-Michel Betton, Joaquin Bernal-Bayard, Christophe Beloin, Daniel Lopez, Uwe Völker, Jean-Marc Ghigo, Génétique des Biofilms - Genetics of Biofilms, Université Paris Cité (UPCité)-Microbiologie Intégrative et Moléculaire (UMR6047), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Interfaculty Institute for Genetics and Functional Genomics, Universität Greifswald - University of Greifswald, Abbelight [Cachan, France], Imperial College London, Adaptation au stress et Métabolisme chez les entérobactéries - Stress adaptation and metabolism in enterobacteria (SAMe), Universidad de Sevilla / University of Sevilla, Universidad Autónoma de Madrid (UAM), Ernst-Moritz-Arndt-Universität Greifswald, German Center for Cardiovascular Research (DZHK), Berlin Institute of Health (BIH), This work was supported by EU Horizon 2020 Rafts4Biotech grant 720776 (to JMG, DL, AKW, YY, AR, UV and MS), the French government’s Investissement d’Avenir Program, Laboratoire d’Excellence 'Integrative Biology of Emerging Infectious Diseases' (grant n°ANR-10-LABX-62-IBEID) and the Fondation pour la Recherche Médicale (grant no. DEQ20180339185). This work benefited from the facilities and expertise of Add Photonic BioImaging platform (UTechS PBI, Institut Pasteur). A.K.W. was supported by a Pasteur-Roux-Cantarini postdoctoral and a grant from the Philippe Foundation., ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), and European Project: 206568,European Union’s Horizon 2020 research and innovation programme,grant agreement No 720776,R4B(2017)
Subjects: Lipid raft, Flotillin, [SDV]Life Sciences [q-bio], Stress tolerance, Escherichia coli, SPFH proteins, Membrane microdomains, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology
Abstract: Many eukaryotic membrane-dependent functions are often spatially and temporally regulated by membrane microdomains (FMMs) also known as lipid rafts. These domains are enriched in polyisoprenoid lipids and scaffolding proteins belonging to the Stomatin, Prohibitin, Flotillin, and HflK/C (SPFH) protein superfamily that was also identified in Gram-positive bacteria. By contrast, little is still known about FMMs in Gram-negative bacteria. InEscherichia coliK12, 4 SPFH proteins, YqiK, QmcA, HflK, and HflC, were shown to localize in discrete polar or lateral inner-membrane locations, raising the possibility thatE. coliSPFH proteins could contribute to the assembly of inner-membrane FMMs and the regulation of cellular processes.Here we studied the determinant of the localization of QmcA and HflC and showed that FMM-associated cardiolipin lipid biosynthesis is required for their native localization pattern. Using Biolog phenotypic arrays, we showed that a mutant lacking all SPFH genes displayed increased sensitivity to aminoglycosides and oxidative stress that is due to the absence of HflKC. Our study therefore provides further insights into the contribution of SPFH proteins to stress tolerance inE. coli.IMPORTANCEEukaryotic cells often segregate physiological processes in cholesterol-rich functional membrane micro-domains. These domains are also called lipid rafts and contain proteins of the Stomatin, Prohibitin, Flotillin, and HflK/C (SPFH) superfamily, which are also present in prokaryotes but were mostly studied in Gram-positive bacteria. Here, we showed that the cell localization of the SPFH proteins QmcA and HflKC in the Gram-negative bacteriaE. coliis altered in absence of cardiolipin lipid synthesis. This suggests that cardiolipins contribute toE. colimembrane microdomain assembly. Using a broad phenotypic analysis, we also showed that HflKC contribute toE. colitolerance to aminoglycosides and oxidative stress. Our study, therefore, provides new insights into the cellular processes associated with SPFH proteins inE. coli.
Published: 2022

32. Biomarker‐driven prognostic models in chronic heart failure with preserved ejection fraction: the EMPEROR –Preserved trial

Author: Stuart J. Pocock, João Pedro Ferreira, Milton Packer, Faiez Zannad, Gerasimos Filippatos, Toru Kondo, John J.V. McMurray, Scott D. Solomon, James L. Januzzi, Tomoko Iwata, Afshin Salsali, Javed Butler, Stefan D. Anker, London School of Hygiene and Tropical Medicine (LSHTM), 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), 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), 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 ), Baylor University Medical Center, Baylor College of Medecine, Imperial College London, National and Kapodistrian University of Athens (NKUA), Attikon University Hospital, Nagoya University, British Heart Foundation Glasgow Cardiovascular Research Centre (BHF GCRC), University of Glasgow-NHS Greater Glasgow and Clyde, Brigham and Women’s Hospital [Boston, MA], Harvard Medical School [Boston] (HMS), Massachusetts General Hospital [Boston], Boehringer Ingelheim Pharma GmbH & Co. KG, Baylor Scott and White Research Institute, University of Mississippi Medical Center (UMMC), Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Charité Campus Virchow-Klinikum (CVK), Berlin-Brandenburg Center for Regenerative Medicine [Berlin, Germany] (BCRT), German Center for Cardiovascular Research (DZHK), Berlin Institute of Health (BIH), The EMPEROR-Reduced trial was supported by Boehringer Ingelheim and Eli Lilly and Company. Dr. Januzzi is supported in part by the Hutter Family Professorship at Harvard Medical School., and BOZEC, Erwan
Subjects: [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Cardiology and Cardiovascular Medicine, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system
Abstract: International audience; Aims: Biomarker-driven prognostic models incorporating N-terminal pro-B-type natriuretic peptide (NT-proBNP) and high-sensitivity cardiac troponin T (hs-cTnT) in heart failure (HF) with preserved ejection fraction (HFpEF) are lacking. We aimed to generate a biomarker-driven prognostic tool for patients with chronic HFpEF enrolled in EMPEROR-Preserved.Methods and results: Multivariable Cox regression models were created for (i) the primary composite outcome of HF hospitalization or cardiovascular death, (ii) all-cause death, (iii) cardiovascular death, and (iv) HF hospitalization. PARAGON-HF was used as a validation cohort. NT-proBNP and hs-cTnT were the dominant predictors of the primary outcome, and in addition, a shorter time since last hospitalization, New York Heart Association (NYHA) class III or IV, history of chronic obstructive pulmonary disease (COPD), insulin-treated diabetes, low haemoglobin, and a longer time since HF diagnosis were key predictors (eight variables, all p < 0.001). The consequent primary outcome risk score discriminated well (c-statistic = 0.75) with patients in the top 10th of risk having an event rate >22× higher than those in the bottom 10th. A model for HF hospitalization alone had even better discrimination (c = 0.79). Empagliflozin reduced the risk of cardiovascular death or hospitalization for HF in patients across all risk levels. NT-proBNP and hs-cTnT were also the dominant predictors of all-cause and cardiovascular mortality followed by history of COPD, low albumin, older age, left ventricular ejection fraction ≥50%, NYHA class III or IV and insulin-treated diabetes (eight variables, all p < 0.001). The mortality risk model had similar discrimination for all-cause and cardiovascular mortality (c-statistic = 0.72 for both). External validation provided c-statistics of 0.71, 0.71, 0.72, and 0.72 for the primary outcome, HF hospitalization alone, all-cause death, and cardiovascular death, respectively.Conclusions: The combination of NT-proBNP and hs-cTnT along with a few readily available clinical variables provides effective risk discrimination both for morbidity and mortality in patients with HFpEF. A predictive tool-kit facilitates the ready implementation of these risk models in routine clinical practice.
Published: 2022

33. Empagliflozin Improves Outcomes in Patients With Heart Failure and Preserved Ejection Fraction Irrespective of Age

Author: Michael Böhm, Javed Butler, Gerasimos Filippatos, João Pedro Ferreira, Stuart J. Pocock, Amr Abdin, Felix Mahfoud, Martina Brueckmann, Nicholas D. Gollop, Tomoko Iwata, Piotr Ponikowski, Christoph Wanner, Faiez Zannad, Milton Packer, Stefan D. Anker, Saarland University [Saarbrücken], Saarland University Hospital (UKS), University of Mississippi Medical Center (UMMC), National and Kapodistrian University of Athens (NKUA), Université d'Athènes (UOA), University of Athens, Attikon Hospital, 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), Institut Lorrain du Coeur et des Vaisseaux Louis Mathieu [Nancy], French-Clinical Research Infrastructure Network - F-CRIN [Paris] (Cardiovascular & Renal Clinical Trialists - CRCT ), London School of Hygiene and Tropical Medicine (LSHTM), Boehringer Ingelheim International GmbH, Medizinische Fakultät Mannheim, Boehringer Ingelheim Pharma GmbH & Co. KG, University of Wrocław [Poland] (UWr), University Hospital of Würzburg, Baylor University Medical Center, Baylor College of Medecine, Imperial College London, Berlin-Brandenburg Center for Regenerative Therapies [Berlin, Germany], Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], German Center for Cardiovascular Research (DZHK), Berlin Institute of Health (BIH), All authors were involved in the EMPEROR-Preserved trial, which was funded by Boehringer Ingelheim and Eli Lilly, and BOZEC, Erwan
Subjects: Aged, 80 and over, Heart Failure, Treatment Outcome, Glucosides, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Chronic Disease, Humans, Stroke Volume, Benzhydryl Compounds, Middle Aged, Cardiology and Cardiovascular Medicine, Aged, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system
Abstract: Background: Empagliflozin reduces cardiovascular death (CVD) or heart failure (HF) hospitalization (HFH) in patients with HF and preserved ejection fraction. Treatment effects and safety in relation to age have not been studied. Objectives: The purpose of this study was to evaluate the interplay of age and empagliflozin effects in EMPEROR-Preserved (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Preserved Ejection Fraction). Methods: We grouped patients (n = 5,988) according to their baseline age (80 years (P interaction = 0.51). Empagliflozin improved Kansas City Cardiomyopathy Questionnaire–Clinical Summary Score at week 52 and attenuated the decline of estimated glomerular filtration rate without age interaction (P = 0.48 and P = 0.32, respectively). There were no clinically relevant differences in adverse events between empagliflozin and placebo across the age groups. Conclusions: Empagliflozin reduced primary outcomes and first and recurrent HFH and improved symptoms across a broad age spectrum. High age was not associated with reduced efficacy or meaningful intolerability. (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Preserved Ejection Fraction [EMPEROR-Preserved]; NCT0305951)
Published: 2022

34. COVID-19-related cardiac complications from clinical evidences to basic mechanisms: opinion paper of the ESC Working Group on Cellular Biology of the Heart

Author: Can Gollmann-Tepeköylü, Sabine Steffens, Ivan Tancevski, Sean M. Davidson, Maurizio Pesce, Joost P.G. Sluijter, Piergiuseppe Agostoni, Raffaele De Caterina, Sandrine Lecour, Bianca J.J.M. Brundel, Jean-Sébastien Hulot, Cinzia Perrino, Péter Ferdinandy, Hans-Erik Bøtker, Henrique Girão, Mariann Gyöngyösi, Rainer Schulz, Rosalinda Madonna, Carsten Tschöpe, Sophie Van Linthout, Centro Cardiologico Monzino [Milano], Dpt di Scienze Cliniche e di Comunità [Milano] (DISCCO), Università degli Studi di Milano = University of Milan (UNIMI)-Università degli Studi di Milano = University of Milan (UNIMI)-Istituti di Ricovero e Cura a Carattere Scientifico (IRCCS), Università degli Studi di Milano = University of Milan (UNIMI), Aarhus University Hospital, Amsterdam UMC - Amsterdam University Medical Center, University College of London [London] (UCL), University of Pisa - Università di Pisa, Semmelweis University [Budapest], University of Coimbra [Portugal] (UC), Medizinische Universität Wien = Medical University of Vienna, CIC - HEGP (CIC 1418), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Paris-Centre de Recherche Cardiovasculaire (PARCC (UMR_S 970/ U970)), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), CArdiovasculaire Rénal Transplantation nEurovasculaire [Paris] (DMU CARTE), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), University of Cape Town, University of Naples Federico II = Università degli studi di Napoli Federico II, Justus-Liebig-Universität Gießen = Justus Liebig University (JLU), Utrecht University [Utrecht], Ludwig-Maximilians-Universität München (LMU), Innsbruck Medical University = Medizinische Universität Innsbruck (IMU), Charité Campus Virchow-Klinikum (CVK), Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], German Center for Cardiovascular Research (DZHK), Berlin Institute of Health (BIH), The University of Texas Medical School at Houston, and HULOT, Jean-Sébastien
Subjects: 0301 basic medicine, Heart Diseases, Physiology, [SDV]Life Sciences [q-bio], medicine.medical_treatment, Inflammation, Disease, 030204 cardiovascular system & hematology, Bioinformatics, Vascular occlusion, 03 medical and health sciences, 0302 clinical medicine, Viral entry, Physiology (medical), medicine, Coagulopathy, Animals, Humans, Myocytes, Cardiac, Blood Coagulation, Cause of death, Myocytes, Ventricular Remodeling, SARS-CoV-2, business.industry, COVID-19, Heart, medicine.disease, Omics, Disease modelling, Infection, Myocardial injury, Biomarkers, Fibrosis, Host-Pathogen Interactions, Inflammation Mediators, [SDV] Life Sciences [q-bio], 030104 developmental biology, Cytokine, medicine.symptom, Cardiology and Cardiovascular Medicine, business, Cardiac
Abstract: The pandemic of coronavirus disease (COVID)-19 is a global threat, causing high mortality, especially in the elderly. The main symptoms and the primary cause of death are related to interstitial pneumonia. Viral entry also into myocardial cells mainly via the angiotensin converting enzyme type 2 (ACE2) receptor and excessive production of pro-inflammatory cytokines, however, also make the heart susceptible to injury. In addition to the immediate damage caused by the acute inflammatory response, the heart may also suffer from long-term consequences of COVID-19, potentially causing a post-pandemic increase in cardiac complications. Although the main cause of cardiac damage in COVID-19 remains coagulopathy with micro- (and to a lesser extent macro-) vascular occlusion, open questions remain about other possible modalities of cardiac dysfunction, such as direct infection of myocardial cells, effects of cytokines storm, and mechanisms related to enhanced coagulopathy. In this opinion paper, we focus on these lesser appreciated possibilities and propose experimental approaches that could provide a more comprehensive understanding of the cellular and molecular bases of cardiac injury in COVID-19 patients. We first discuss approaches to characterize cardiac damage caused by possible direct viral infection of cardiac cells, followed by formulating hypotheses on how to reproduce and investigate the hyperinflammatory and pro-thrombotic conditions observed in the heart of COVID-19 patients using experimental in vitro systems. Finally, we elaborate on strategies to discover novel pathology biomarkers using omics platforms.
Published: 2021

35. Clopidogrel vs. prasugrel vs. ticagrelor in patients with acute myocardial infarction complicated by cardiogenic shock: a pooled IABP-SHOCK II and CULPRIT-SHOCK trial sub-analysis

Author: Gilles Montalescot, Steffen Desch, Peter Clemmensen, Martin Orban, Paul M Haller, Steffen Schneider, Dariusz Dudek, Jan Kleeberger, Steffen Massberg, Uwe Zeymer, Holger Thiele, Alexander Neumer, Jörg Hausleiter, Anne Freund, Marko Noc, Kurt Huber, Georg Fuernau, Hans-Josef Feistritzer, Taoufik Ouarrak, Tobias Geisler, Ludwig-Maximilians-Universität München (LMU), German Center for Cardiovascular Research (DZHK), Berlin Institute of Health (BIH), Klinikum Ludwigshafen [Germany], Leipzig University, Universität zu Lübeck [Lübeck], Universitätsklinikum Tübingen - University Hospital of Tübingen, Eberhard Karls Universität Tübingen = Eberhard Karls University of Tuebingen, Sigmund Freud University (SFU), Uniwersytet Jagielloński w Krakowie = Jagiellonian University (UJ), University Medical Centre Ljubljana [Ljubljana, Slovenia] (UMCL), CHU Pitié-Salpêtrière [AP-HP], and Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)
Subjects: Male, Ticagrelor, medicine.medical_specialty, Prasugrel, [SDV]Life Sciences [q-bio], Myocardial Infarction, Shock, Cardiogenic, Hemorrhage, 030204 cardiovascular system & hematology, 03 medical and health sciences, Percutaneous Coronary Intervention, 0302 clinical medicine, Internal medicine, medicine, Clinical endpoint, Humans, cardiovascular diseases, Prospective Studies, 030212 general & internal medicine, Myocardial infarction, Cardiogenic shock, Aged, Aged, 80 and over, Original Paper, Intra-Aortic Balloon Pumping, business.industry, Bleeding, General Medicine, Middle Aged, medicine.disease, Clopidogrel, 3. Good health, Shock (circulatory), Conventional PCI, Cardiology, Female, medicine.symptom, Cardiology and Cardiovascular Medicine, business, ADP-receptor antagonists, Prasugrel Hydrochloride, Platelet Aggregation Inhibitors, Follow-Up Studies, medicine.drug
Abstract: Aims The aim of this pooled sub-analysis of the Intraaortic Balloon Pump in Cardiogenic Shock II (IABP-SHOCK II) and Culprit Lesion Only PCI versus Multivessel PCI in Cardiogenic Shock (CULPRIT-SHOCK) trial was to compare the clinical outcome of patients with acute myocardial infarction complicated by cardiogenic shock treated either with clopidogrel or the newer, more potent ADP-receptor antagonists prasugrel or ticagrelor. Methods and results For the current analysis the primary endpoint was 1-year mortality and the secondary safety endpoint was moderate or severe bleedings until hospital discharge with respect to three different ADP-receptor antagonists. 856 patients were eligible for analysis. Of these, 507 patients (59.2%) received clopidogrel, 178 patients (20.8%) prasugrel and 171 patients (20.0%) ticagrelor as acute antiplatelet therapy. The adjusted rate of mortality after 1-year did not differ significantly between prasugrel and clopidogrel (hazard ratio [HR]: 0.81, 95% confidence interval [CI] 0.60–1.09, padj = 0.17) or between ticagrelor and clopidogrel treated patients (HR: 0.86, 95% CI 0.65–1.15, padj = 0.31). In-hospital bleeding events were significantly less frequent in patients treated with ticagrelor vs. clopidogrel (HR: 0.37, 95% CI 0.20 -0.69, padj = 0.002) and not significantly different in patients treated with prasugrel vs. clopidogrel (HR: 0.73, 95% CI 0.43 -1.24, padj = 0.24). Conclusion This pooled sub-analysis is the largest analysis on safety and efficacy of three oral ADP-receptor antagonists and shows that acute therapy with either clopidogrel, prasugrel or ticagrelor is no independent predictor of 1-year mortality. Treatment with ticagrelor seems independently associated with less in-hospital moderate and severe bleeding events compared to clopidogrel. This finding might be due to selection bias and should be interpreted with caution. Graphic abstract
Published: 2021

36. Quality of life in men and women with heart failure: association with outcome, and comparison between the Kansas City Cardiomyopathy Questionnaire and the EuroQol 5 dimensions questionnaire

Author: Nilesh J. Samani, João Pedro Ferreira, Kenneth Dickstein, Faiez Zannad, Sven Meyer, Marco Metra, John R. Teerlink, Carlo Lombardi, Chim C. Lang, Alice Ravera, Adriaan A. Voors, Iziah E Sama, Bernadet T. Santema, Valentina Carubelli, Stefan D. Anker, Dirk J. van Veldhuisen, University Medical Center Groningen [Groningen] (UMCG), Azienda Socio Sanitaria Territoriale Spedali Civili di Brescia [Brescia], Università degli Studi di Brescia = University of Brescia (UniBs), Carl Von Ossietzky Universität Oldenburg = Carl von Ossietzky University of Oldenburg (OFFIS), 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), 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), 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 ), University of Dundee, Ninewells Hospital and Medical School [Dundee], University of Bergen (UiB), Stavanger University Hospital, Berlin-Brandenburg Center for Regenerative Medicine [Berlin, Germany] (BCRT), Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], German Center for Cardiovascular Research (DZHK), Berlin Institute of Health (BIH), University of Leicester, NIHR Leicester Biomedical Research Centre, Glenfield Hospital, University of California [San Francisco] (UC San Francisco), University of California (UC), Veterans Affairs Medical Center, San Francisco, California, European Project: 242209,EC:FP7:HEALTH,FP7-HEALTH-2009-single-stage,BIOSTAT-CHF(2010), Cardiovascular Centre (CVC), BOZEC, Erwan, A systems BIOlogy Study to TAilored Treatment in Chronic Heart Failure - BIOSTAT-CHF - - EC:FP7:HEALTH2010-04-01 - 2015-03-31 - 242209 - VALID, Institute of Cardiology, ASST Spedali Civili, Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, University of Brescia, Heart Center Oldenburg, Department of Cardiology, European Medical School Oldenburg-Groningen, Carl von Ossietzky University Oldenburg, and Department of Cardiovascular Sciences, University of Leicester, NIHR (National Institute for Health Research) Leicester Biomedical Research Centre, Glenfield Hospital
Subjects: Male, medicine.medical_specialty, 030204 cardiovascular system & hematology, Heart failure, Outcome, Quality of life, Sex, Women, Female, Humans, Kansas, Quality of Life, Stroke Volume, Surveys and Questionnaires, Cardiomyopathies, Heart Failure, 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, Ejection fraction, business.industry, medicine.disease, Tailored treatment, humanities, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Clinical trial, Kansas City Cardiomyopathy Questionnaire, Cardiology and Cardiovascular Medicine, business
Abstract: Aims: We sought to analyse quality of life (QoL) measures derived from two questionnaires widely used in clinical trials, the Kansas City Cardiomyopathy Questionnaire (KCCQ) and the EuroQoL 5 dimensions (EQ-5D), and to compare their prognostic value in men and women with heart failure and reduced ejection fraction (HFrEF).Methods and results: From the BIOlogy Study to TAilored Treatment in Chronic Heart Failure (BIOSTAT-CHF) we compared KCCQ and EQ-5D at baseline and after 9 months in 1276 men and 373 women with new-onset or worsening symptoms of HFrEF, who were sub-optimally treated and in whom there was an anticipated up-titration of guideline-derived medical therapies. Women had significantly worse baseline QoL (median) as compared with men, both when assessed with KCCQ overall score (KCCQ-OS, 44 vs. 53, P < 0.001) and EQ-5D utility score (0.62 vs. 0.73, P < 0.001). QoL improved equally in women and men at follow-up. All summary measures of QoL were independently associated with all-cause mortality, with KCCQ-OS showing the most remarkable association with mortality up to 1 year compared to the EQ-5D scores (C-statistic 0.650 for KCCQ-OS vs. 0.633 and 0.599 for EQ-5D utility score and EQ-5D visual analogue scale, respectively). QoL was associated with all outcomes analysed, both in men and women (all P for interaction with sex >0.2).Conclusion: Amongst patients with HFrEF, women reported significantly worse QoL than men. QoL was independently associated with subsequent outcome, similarly in men and women. The KCCQ in general, and the KCCQ-OS in particular, showed the strongest independent association with outcome.
Published: 2021

37. Empagliflozin for Heart Failure With Preserved Left Ventricular Ejection Fraction With and Without Diabetes

Author: Gerasimos, Filippatos, Javed, Butler, Dimitrios, Farmakis, Faiez, Zannad, Anne Pernille, Ofstad, João Pedro, Ferreira, Jennifer B, Green, Julio, Rosenstock, Sven, Schnaidt, Martina, Brueckmann, Stuart J, Pocock, Milton, Packer, Stefan D, Anker, National and Kapodistrian University of Athens (NKUA), 'Attikon' University Hospital, Baylor Scott and White Research Institute, University of Mississippi Medical Center (UMMC), University of Cyprus [Nicosia] (UCY), 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), Institut Lorrain du Coeur et des Vaisseaux Louis Mathieu [Nancy], French-Clinical Research Infrastructure Network - F-CRIN [Paris] (Cardiovascular & Renal Clinical Trialists - CRCT ), Medical Department, Boehringer Ingelheim Norway KS, Asker, Oslo Diabetes Research Center, Centre d'investigation clinique plurithématique Pierre Drouin [Nancy] (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)-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 = University of Porto, Duke University [Durham], Dallas Diabetes Research Center at Medical City, Boehringer Ingelheim Pharma GmbH & Co. KG, Medizinische Fakultät Mannheim, Boehringer Ingelheim International GmbH, London School of Hygiene and Tropical Medicine (LSHTM), Baylor College of Medecine, Imperial College London, Berlin-Brandenburg Center for Regenerative Medicine [Berlin, Germany] (BCRT), Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], German Center for Cardiovascular Research (DZHK), Berlin Institute of Health (BIH), Wrocław Medical University, EMPEROR-Preserved (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Preserved Ejection Fraction) was funded by the Boehringer Ingelheim and Eli Lilly and Company Diabetes Alliance. Graphical assistance was supported financially by Boehringer Ingelheim., and BOZEC, Erwan
Subjects: Heart Failure, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Diabetes Mellitus, Type 2, Glucosides, Physiology (medical), Humans, Stroke Volume, Benzhydryl Compounds, Cardiology and Cardiovascular Medicine, Sodium-Glucose Transporter 2 Inhibitors, Ventricular Function, Left, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system
Abstract: Background: Empagliflozin improves outcomes in patients with heart failure with a preserved ejection fraction, but whether the effects are consistent in patients with and without diabetes remains to be elucidated. Methods: Patients with class II through IV heart failure and a left ventricular ejection fraction >40% were randomized to receive empagliflozin 10 mg or placebo in addition to usual therapy. We undertook a prespecified analysis comparing the effects of empagliflozin versus placebo in patients with and without diabetes. Results: Of the 5988 patients enrolled, 2938 (49%) had diabetes. The risk of the primary outcome (first hospitalization for heart failure or cardiovascular death), total hospitalizations for heart failure, and estimated glomerular filtration rate decline was higher in patients with diabetes. Empagliflozin reduced the rate of the primary outcome irrespective of diabetes status (hazard ratio, 0.79 [95% CI, 0.67, 0.94] for patients with diabetes versus hazard ratio, 0.78 [95% CI, 0.64, 0.95] in patients without diabetes; P interaction =0.92). The effect of empagliflozin to reduce total hospitalizations for heart failure was also consistent in patients with and without diabetes. The effect of empagliflozin to attenuate estimated glomerular filtration rate decline during double-blind treatment was also present in patients with and without diabetes, although more pronounced in patients with diabetes (1.77 in diabetes versus 0.98 mL/min/1.73m 2 in patients without diabetes; P interaction =0.01). Across these 3 end points, the effect of empagliflozin did not differ in patients with prediabetes or normoglycemia (33% and 18% of the patient population, respectively). When investigated as a continuous variable, baseline hemoglobin A1c did not modify the effects on the primary outcome ( P interaction =0.26). There was no increased risk of hypoglycemic events in either subgroup as compared with placebo. Conclusions: In patients with heart failure and a preserved ejection fraction enrolled in the EMPEROR-Preserved (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Preserved Ejection Fraction), empagliflozin significantly reduced the risk of heart failure outcomes irrespective of diabetes status at baseline. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03057951.
Published: 2022

38. Development and Validation of Multivariable Prediction Models of Serological Response to SARS-CoV-2 Vaccination in Kidney Transplant Recipients

Author: Bilgin Osmanodja, Johannes Stegbauer, Marta Kantauskaite, Lars Christian Rump, Andreas Heinzel, Roman Reindl-Schwaighofer, Rainer Oberbauer, Ilies Benotmane, Sophie Caillard, Christophe Masset, Clarisse Kerleau, Gilles Blancho, Klemens Budde, Fritz Grunow, Michael Mikhailov, Eva Schrezenmeier, Simon Ronicke, Freie Universität Berlin, Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Heinrich Heine Universität Düsseldorf = Heinrich Heine University [Düsseldorf], University Hospital Düsseldorf, Medizinische Universität Wien = Medical University of Vienna, CHU Strasbourg, Immuno-Rhumatologie Moléculaire, Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Team 4 : Deciphering organ immune regulation in inflammation and transplantation (DORI-t) (U1064 Inserm - CR2TI), Centre de Recherche en Transplantation et Immunologie - Center for Research in Transplantation and Translational Immunology (U1064 Inserm - CR2TI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Nantes Université - UFR de Médecine et des Techniques Médicales (Nantes Univ - UFR MEDECINE), Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Nantes Université - UFR de Médecine et des Techniques Médicales (Nantes Univ - UFR MEDECINE), Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ), Centre hospitalier universitaire de Nantes (CHU Nantes), Institut de transplantation urologie-néphrologie (ITUN), Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), Team 3 : Integrative transplantation, HLA, Immunology and genomics of kidney injury (U1064 Inserm - CR2TI), Berlin Institute of Health (BIH), and KERANDEL-DION, Céline
Subjects: clinical decision support, [SDV] Life Sciences [q-bio], immunosuppression therapy, COVID-19 Vaccines, SARS-CoV-2, [SDV]Life Sciences [q-bio], Immunology, Vaccination, Immunology and Allergy, Humans, COVID-19, Kidney Transplantation
Abstract: BackgroundRepeated vaccination against SARS-CoV-2 increases serological response in kidney transplant recipients (KTR) with high interindividual variability. No decision support tool exists to predict SARS-CoV-2 vaccination response in KTR.MethodsWe developed, internally and externally validated five different multivariable prediction models of serological response after the third and fourth vaccine dose against SARS-CoV-2 in KTR. Using 27 candidate predictor variables, we applied statistical and machine learning approaches including logistic regression (LR), LASSO-regularized LR, random forest, and gradient boosted regression trees. For development and internal validation, data from 585 vaccinations were used. External validation was performed in four independent, international validation datasets comprising 191, 184, 254, and 323 vaccinations, respectively.FindingsLASSO-regularized LR performed on the whole development dataset yielded a 23- and 11- variable model, respectively. External validation showed AUC-ROC of 0.855, 0.749, 0.828, and 0.787 for the sparser 11-variable model, yielding an overall performance 0.819.InterpretationAn 11-variable LASSO-regularized LR model predicts vaccination response in KTR with good overall accuracy. Implemented as an online tool, it can guide decisions when choosing between different immunization strategies to improve protection against COVID-19 in KTR.
Published: 2022

39. Tacrolimus CYP3A Single-Nucleotide Polymorphisms and Preformed T- and B-Cell Alloimmune Memory Improve Current Pretransplant Rejection-Risk Stratification in Kidney Transplantation

Author: Elena Crespo, Anna Vidal-Alabró, Thomas Jouve, Pere Fontova, Maik Stein, Sonila Mocka, Maria Meneghini, Anett Sefrin, Petra Hruba, Montserrat Gomà, Alba Torija, Laura Donadeu, Alex Favà, Josep M. Cruzado, Edoardo Melilli, Francesc Moreso, Ondrej Viklicky, Frederike Bemelman, Petra Reinke, Josep Grinyó, Nuria Lloberas, Oriol Bestard, Institut Català de la Salut, [Crespo E, Torija A, Donadeu L] Laboratori de Nefrologia i Trasplantament Renal, Vall d'Hebron Institut de Recerca (VHIR), Barcelona, Spain. [Vidal-Alabró A, Fontova P, Mocka S] Experimental Nephrology and Transplantation Laboratory, Instituto de Investigación Biomédica de Bellvitge (IDIBELL), Barcelona, Spain. [Jouve T] Laboratori de Nefrologia i Trasplantament Renal, Vall d'Hebron Institut de Recerca (VHIR), Barcelona, Spain. Faculty of Health, Université Grenoble Alpes, Grenoble, France. Institute for Advanced Biosciences, INSERM 1209, CNRS 5309, Grenoble, France. [Stein M] Berlin Center for Advanced Therapies (BeCAT), Berlin, Germany. Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany. Berlin Institute of Health (BIH), Berlin, Germany. [Meneghini M, Bestard O] Laboratori de Nefrologia i Trasplantament Renal, Vall d'Hebron Institut de Recerca (VHIR), Barcelona, Spain. Unitat de Trasplantament Renal, Servei de Nefrologia, Vall d’Hebron Hospital, Barcelona, Spain. [Moreso F] Unitat de Trasplantament Renal, Servei de Nefrologia, Vall d’Hebron Hospital, Barcelona, Spain, Vall d'Hebron Barcelona Hospital Campus, Nephrology, AII - Inflammatory diseases, and APH - Aging & Later Life
Subjects: T-Lymphocytes, Immunology, Trasplantament renal, kidney transplantation, Cèl·lules B - Immunologia, Polymorphism, Single Nucleotide, Risk Assessment, acute rejection, Tacrolimus, Kidney transplantation, Cells::Antibody-Producing Cells::B-Lymphocytes [ANATOMY], fenómenos genéticos::variación genética::polimorfismo genético::polimorfismo de nucleótido único [FENÓMENOS Y PROCESOS], Memory B Cells, Therapeutics::Renal Replacement Therapy::Kidney Transplantation [ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES, AND EQUIPMENT], Immunology and Allergy, Cytochrome P-450 CYP3A, Humans, calcineurin inhibitors immunosuppression, genetics, Immunologia, immunobiology, células::células productoras de anticuerpos::linfocitos B [ANATOMÍA], Genetic Phenomena::Genetic Variation::Polymorphism, Genetic::Polymorphism, Single Nucleotide [PHENOMENA AND PROCESSES], Polimorfisme genètic, Ronyons - Trasplantació, Immunosupressive agents, terapéutica::tratamiento de reemplazo renal::trasplante de riñón [TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS], Immunosupressors
Abstract: Rechazo agudo; Genética; Inmunobiología Rebuig agut; Genètica; Immunobiologia Acute rejection; Genetics; Immunobiology Achieving fast immunosuppression blood exposure after kidney transplantation is key to abrogating both preformed and de novo anti-donor humoral and cellular alloresponses. However, while tacrolimus (TAC) is the cornerstone immunosuppressant inhibiting adaptive alloimmunity, its blood exposure is directly impacted by different single-nucleotide polymorphisms (SNPs) in CYP3A TAC-metabolizing enzymes. Here, we investigated how functional TAC-CYP3A genetic variants (CYP3A4*22/CYP3A5*3) influence the main baseline clinical and immunological risk factors of biopsy-proven acute rejection (BPAR) by means of preformed donor-specific antibodies (DSAs) and donor-specific alloreactive T cells (DSTs) in a large European cohort of 447 kidney transplants receiving TAC-based immunosuppression. A total of 70 (15.7%) patients developed BPAR. Preformed DSAs and DSTs were observed in 12 (2.7%) and 227 (50.8%) patients, respectively. According to the different CYP3A4*22 and CYP3A5*3 functional allele variants, we found 4 differential new clusters impacting fasting TAC exposure after transplantation; 7 (1.6%) were classified as high metabolizers 1 (HM1), 71 (15.9%) as HM2, 324 (72.5%) as intermediate (IM), and 45 (10.1%) as poor metabolizers (PM1). HM1/2 showed significantly lower TAC trough levels and higher dose requirements than IM and PM (p < 0.001) and more frequently showed TAC underexposure (
Published: 2022

40. Practical Guidance for Diagnosing and Treating Iron Deficiency in Patients with Heart Failure: Why, Who and How?

Author: Andrew Sindone, Wolfram Doehner, Nicolas Manito, Theresa McDonagh, Alain Cohen-Solal, Thibaud Damy, Julio Núñez, Otmar Pfister, Peter van der Meer, Josep Comin-Colet, Concord Repatriation General Hospital [Sydney, Australia] (CRGH), Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], German Center for Cardiovascular Research (DZHK), Berlin Institute of Health (BIH), University of Barcelona, Institut d'Investigació Biomèdica de Bellvitge [Barcelone] (IDIBELL), King‘s College London, Marqueurs cardiovasculaires en situation de stress (MASCOT (UMR_S_942 / U942)), 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) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité)-Université Sorbonne Paris Nord, CHU Henri Mondor, Centro de Investigación Biomédica en Red en Enfermedades Cardiovasculares (CIBERCV), Universitat de València (UV), University of Basel (Unibas), University Hospital Basel [Basel], University Medical Center Groningen [Groningen] (UMCG), and leboeuf, Christophe
Subjects: RISK, Dèficit de ferro, IMPACT, Heart diseases, PHASE, iron deficiency, General Medicine, THERAPY, ferric carboxymaltose, EXERCISE CAPACITY, PREVALENCE, chronic heart failure, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Malalties del cor, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, QUALITY-OF-LIFE, Iron deficiency diseases, HEALTH, guidelines, ANEMIA
Abstract: International audience; Iron deficiency (ID) is a comorbid condition frequently seen in patients with heart failure (HF). Iron has an important role in the transport of oxygen, and is also essential for skeletal and cardiac muscle, which depend on iron for oxygen storage and cellular energy production. Thus, ID per se, even without anaemia, can be harmful. In patients with HF, ID is associated with a poorer quality of life (QoL) and exercise capacity, and a higher risk of hospitalisations and mortality, even in the absence of anaemia. Despite its negative clinical consequences, ID remains under-recognised. However, it is easily diagnosed and managed, and the recently revised 2021 European Society of Cardiology (ESC) guidelines on HF provide specific recommendations for its diagnosis and treatment. Prospective randomised controlled trials in patients with symptomatic HF with reduced ejection fraction (HFrEF) show that correction of ID using intravenous iron (principally ferric carboxymaltose [FCM]) provides improvements in symptoms of HF, exercise capacity and QoL, and a recent trial demonstrated that FCM therapy following hospitalisation due to acute decompensated HF reduced the risk of subsequent HF hospitalisations. This review provides a summary of the epidemiology and pathophysiology of ID in HFrEF, and practical guidance on screening, diagnosing, and treating ID.
Published: 2022

41. New remote cerebral microbleeds in acute ischemic stroke: an analysis of the randomized, placebo-controlled WAKE-UP trial

Author: Braemswig, Tim, Vynckier, Jan, Puig, Josep, Thijs, Vincent, Fiebach, Jochen B, Muir, Keith W, Nighoghossian, Norbert, Ebinger, Martin, Pedraza, Salvador, Thomalla, Götz, Gerloff, Christian, Endres, Matthias, Jensen, Märit, Lemmens, Robin, Schlemm, Ludwig, Nolte, Christian, Investigators, WAKE-UP, Boutitie, Florent, Galinovic, Ivana, Simonsen, Claus Z, Cheng, Bastian, Cho, Tae-Hee, Scheitz, Jan F., Fiehler, Jens, CarMeN, laboratoire, Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Humboldt University Of Berlin, Berlin Institute of Health (BIH), Freie Universität Berlin, OLV Ziekenhuis Aalst Asse Ninove [Aalst, Belgium.], Universitaetsklinikum Hamburg-Eppendorf = University Medical Center Hamburg-Eppendorf [Hamburg] (UKE), Hospices Civils de Lyon (HCL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon, Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), Aarhus University Hospital, Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Université de Lyon-Université de Lyon-Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), German Center for Cardiovascular Research (DZHK), Institut d'Investigació Biomèdica de Girona Dr. Josep Trueta - Girona Biomedical Research Institute (IDIBGI), University of Melbourne, Austin Hospital [Melbourne], Austin Health, University of Glasgow, Medical Park Berlin Humboldtmühle [Berlin, Germany] (MPBH), German Research Center for Neurodegenerative Diseases - Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), University Hospitals Leuven [Leuven], Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Leuven Center for Cancer Biology (VIB-KU-CCB), and Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven)-Vlaams Instituut voor Biotechnologie [Ghent, Belgique] (VIB)
Subjects: Science & Technology, Stroke/complications/diagnostic imaging, Clinical Neurology, complications [Brain Ischemia], diagnostic imaging [Cerebral Hemorrhage], Brain Ischemia/complications/diagnostic imaging, Magnetic Resonance Imaging, Brain Ischemia, Cerebral Hemorrhage/complications/diagnostic imaging, Stroke, [SDV.AEN] Life Sciences [q-bio]/Food and Nutrition, Neurology, Ischemic Stroke, diagnostic imaging [Brain Ischemia], complications [Cerebral Hemorrhage], diagnostic imaging [Stroke], Humans, complications [Stroke], Neurosciences & Neurology, ddc:610, Neurology (clinical), Life Sciences & Biomedicine, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition, Cerebral Hemorrhage
Abstract: ispartof: JOURNAL OF NEUROLOGY vol:269 issue:10 pages:5660-5667 ispartof: location:Germany status: published
Published: 2022

42. Early changes in estimated glomerular filtration rate post-initiation of empagliflozin in EMPEROR-Reduced

Author: Faiez, Zannad, João Pedro, Ferreira, John, Gregson, Bettina Johanna, Kraus, Michaela, Mattheus, Sibylle Jenny, Hauske, Javed, Butler, Gerasimos, Filippatos, Christoph, Wanner, Stefan D, Anker, Stuart J, Pocock, Milton, Packer, BOZEC, Erwan, 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), 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), 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 ), Faculdade de Medicina da Universidade do Porto (FMUP), Universidade do Porto = University of Porto, London School of Hygiene and Tropical Medicine (LSHTM), University of Würzburg = Universität Würzburg, Boehringer Ingelheim International GmbH, Boehringer Ingelheim Pharma GmbH & Co. KG, Universität Heidelberg [Heidelberg], Mississippi State University [Mississippi], National and Kapodistrian University of Athens (NKUA), University Hospital Wuerzburg / Universitätsklinikum Würzburg, German Center for Cardiovascular Research (DZHK), Berlin Institute of Health (BIH), Charité Campus Virchow-Klinikum (CVK), Baylor Heart and Vascular Institute, Baylor University Medical Center, Imperial College London, and The EMPEROR-Reduced trial was funded by Boehringer Ingelheim and Eli Lilly
Subjects: Heart Failure, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Diabetes Mellitus, Type 2, Empagliflozin, Humans, Outcomes, Estimated glomerular filtration rate, Cardiology and Cardiovascular Medicine, Heart failure with reduced ejection fraction, Sodium-Glucose Transporter 2 Inhibitors, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Glomerular Filtration Rate
Abstract: International audience; Aims: Sodium-glucose cotransporter 2 inhibitors (SGLT2i) may induce an early post-initiation decrease of estimated glomerular filtration rate (eGFR), which does not impact the SGLT2i benefits. The occurrence, characteristics, determinants, and clinical significance of an initial eGFR change among patients with heart failure with reduced ejection fraction require further study. In this study we aimed to describe eGFR change from randomization to week 4 (as percent of change relative to randomization) and assess its impact in EMPEROR-Reduced.Methods and results: Landmark analyses (week 4) were performed. eGFR change was available in 3547 patients out of 3730 (95%). The tertiles of post-initiation % eGFR change for empagliflozin were: tertile 1 (T1) ≤-11.4%; T2 ≥-11.4% to ≤-1.0% and T3 ≥0.0%. The placebo group tertiles were: T1 ≤-6.5%; T2 ≥-6.4% to ≤+3.6%; and T3 ≥+3.6%. On average, empagliflozin induced a leftward distributional shift of initial eGFR changes of -2.5 ml/min/1.73 m2 versus placebo. In the empagliflozin group, after covariate adjustment, the risk of cardiovascular and renal outcomes did not differ between patients in whom early post-treatment initiation eGFR decreased (T1) and patients in whom it increased (T3). However, in the placebo group, patients in whom early post-treatment initiation eGFR decreased (T1) had a higher risk of sustained worsening kidney function and all-cause mortality compared to patients in whom eGFR increased (T3) (hazard ratio [HR] 2.38, 95% confidence interval [CI] 1.25-4.55 and HR 1.37, 95% CI 1.01-1.85, respectively).Conclusion: A mild eGFR decrease may be expected after the initiation of empagliflozin, and it is not associated with untoward heart failure, mortality, or kidney safety events. Clinicians should not be concerned with early eGFR changes post-initiation of empagliflozin.
Published: 2022

43. Whole blood transcriptomic profiling identifies molecular pathways related to cardiovascular mortality in heart failure

Author: Mintu Nath, Simon P.R. Romaine, Andrea Koekemoer, Stephen Hamby, Thomas R. Webb, Christopher P. Nelson, Marcos Castellanos‐Uribe, Manolo Papakonstantinou, Stefan D. Anker, Chim C. Lang, Marco Metra, Faiez Zannad, Gerasimos Filippatos, Dirk J. van Veldhuisen, John G. Cleland, Leong L. Ng, Sean T. May, Federica Marelli‐Berg, Adriaan A. Voors, James A. Timmons, Nilesh J. Samani, University of Leicester, NIHR Leicester Biomedical Research Centre, Glenfield Hospital, University of Aberdeen, University of Nottingham, UK (UON), Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], German Center for Cardiovascular Research (DZHK), Berlin Institute of Health (BIH), University of Dundee, Università degli Studi di Brescia = University of Brescia (UniBs), 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), 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), 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 and Kapodistrian University of Athens (NKUA), Université d'Athènes (UOA), University Medical Center Groningen [Groningen] (UMCG), National Heart and Lung Institute [London] (NHLI), Imperial College London-Royal Brompton and Harefield NHS Foundation Trust, University of Glasgow, Imperial College London, Queen Mary University of London (QMUL), Bart's and The London School of Medicine and Dentistry, University of Stirling, European Project: 242209,EC:FP7:HEALTH,FP7-HEALTH-2009-single-stage,BIOSTAT-CHF(2010), BOZEC, Erwan, A systems BIOlogy Study to TAilored Treatment in Chronic Heart Failure - BIOSTAT-CHF - - EC:FP7:HEALTH2010-04-01 - 2015-03-31 - 242209 - VALID, and Cardiovascular Centre (CVC)
Subjects: Heart Failure, PROGNOSIS, T-cells, Interleukins, IRON, Chronic heart failure, Drug-repurposing, Fibroblast growth factor 23, Iron, RNA, Biomarkers, Chronic Disease, Humans, Prognosis, Transcriptome, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, MODEL, TUMOR, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, MESH: Chronic Heart Failure, T-Cells, drug-repurposing, Cardiology and Cardiovascular Medicine
Abstract: Aims Chronic heart failure (CHF) is a systemic syndrome with a poor prognosis and a need for novel therapies. We investigated whether whole blood transcriptomic profiling can provide new mechanistic insights into cardiovascular (CV) mortality in CHF. Methods and results Transcriptome profiles were generated at baseline from 944 CHF patients from the BIOSTAT-CHF study, of whom 626 survived and 318 died from a CV cause during a follow-up of 21 months. Multivariable analysis, including adjustment for cell count, identified 1153 genes (6.5%) that were differentially expressed between those that survived or died and strongly related to a validated clinical risk score for adverse prognosis. The differentially expressed genes mainly belonged to five non-redundant pathways: adaptive immune response, proteasome-mediated ubiquitin-dependent protein catabolic process, T-cell co-stimulation, positive regulation of T-cell proliferation, and erythrocyte development. These five pathways were selectively related (RV coefficients >0.20) with seven circulating protein biomarkers of CV mortality (fibroblast growth factor 23, soluble ST2, adrenomedullin, hepcidin, pentraxin-3, WAP 4-disulfide core domain 2, and interleukin-6) revealing an intricate relationship between immune and iron homeostasis. The pattern of survival-associated gene expression matched with 29 perturbagen-induced transcriptome signatures in the iLINCS drug-repurposing database, identifying drugs, approved for other clinical indications, that were able to reverse in vitro the molecular changes associated with adverse prognosis in CHF. Conclusion Systematic modelling of the whole blood protein-coding transcriptome defined molecular pathways that provide a link between clinical risk factors and adverse CV prognosis in CHF, identifying both established and new potential therapeutic targets.
Published: 2022

44. Outcomes with empagliflozin in heart failure with preserved ejection fraction using DELIVER-like endpoint definitions

Author: Stefan D. Anker, Tariq Jamal Siddiqi, Gerasimos Filippatos, Faiez Zannad, João Pedro Ferreira, Stuart J. Pocock, Martina Brueckmann, Cordula Zeller, Milton Packer, Javed Butler, Charité Campus Virchow-Klinikum (CVK), Berlin-Brandenburg Center for Regenerative Medicine [Berlin, Germany] (BCRT), Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], German Center for Cardiovascular Research (DZHK), Berlin Institute of Health (BIH), Wrocław Medical University, University of Mississippi Medical Center (UMMC), National and Kapodistrian University of Athens (NKUA), University of Athens, Attikon Hospital, 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), 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), French-Clinical Research Infrastructure Network - F-CRIN [Paris] (Cardiovascular & Renal Clinical Trialists - CRCT ), Cardiovascular and Renal Clinical Trialists [Vandoeuvre-les-Nancy] (INI-CRCT), Institut Lorrain du Coeur et des Vaisseaux Louis Mathieu [Nancy], Faculdade de Medicina da Universidade do Porto (FMUP), Universidade do Porto = University of Porto, London School of Hygiene and Tropical Medicine (LSHTM), Boehringer Ingelheim International GmbH, Medizinische Fakultät Mannheim, Boehringer Ingelheim Pharma GmbH & Co. KG, Imperial College London, Baylor Scott and White Research Institute, The EMPEROR-Preserved trial was funded by the Boehringer Ingelheim & Eli Lilly and Company Diabetes Alliance., and BOZEC, Erwan
Subjects: Heart Failure with preserved ejection fraction, Heart Failure, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Glucosides, DELIVER, Empagliflozin, Humans, Stroke Volume, Outcomes, Benzhydryl Compounds, Cardiology and Cardiovascular Medicine, EMPEROR-Preserved, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system
Abstract: International audience; Aims: To report data from EMPEROR-Preserved according to prespecified endpoints of DELIVER.Methods and results: In order to assess the impact of DELIVER-like definition on EMPEROR-Preserved outcomes, the following differences were reconciled: (1) the primary outcome in DELIVER added urgent heart failure (HF) visits to cardiovascular death or HF hospitalizations; (2) the EMPEROR-Preserved trial did not require documentation of physical findings or laboratory tests for confirming a HF hospitalization and it included events of 12-24 h if intensification of treatment was not only oral diuretics; (3) DELIVER excluded undetermined causes of deaths from the primary endpoint; (4) the composite renal endpoint in DELIVER included a sustained ≥50% decline in estimated glomerular filtration rate and incorporated renal death; and (5) DELIVER will assess outcomes in the overall population and in patients with ejection fraction (EF)
Published: 2022

45. Rhinitis phenotypes and multimorbidities in the general population Constances cohort

Author: Marine Savouré, Jean Bousquet, Bénédicte Leynaert, Adeline Renuy, Valérie Siroux, Marcel Goldberg, Marie Zins, Bénédicte Jacquemin, Rachel Nadif, Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Agence de l'Environnement et de la Maîtrise de l'Energie (ADEME), CHU Montpellier, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Berlin Institute of Health (BIH), Cohortes épidémiologiques en population (CONSTANCES), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Université Paris Cité (UPCité), Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble) (IAB), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), L'Oreal USA, Caisse nationale d'assurance maladie, Merck Sharp and Dohme, Agence de l'Environnement et de la Maîtrise de l'Energie, AstraZeneca, Agence Nationale de la Recherche ANR-11-INBS-0002 Université Paris-Saclay, and ANR-11-INBS-0002,CONSTANCES,La cohorte CONSTANCES - Infrastructure épidémiologique ouverte pour la recherche et la surveillance(2011)
Subjects: Pulmonary and Respiratory Medicine, [SDV]Life Sciences [q-bio], [SDV.MHEP.PSR]Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract
Abstract: BackgroundScarce epidemiological studies have characterised allergic rhinitis (AR) and non-allergic rhinitis (NAR) in adults. In a population-based cohort, our aims were to 1) describe rhinitis, AR and NAR, and 2) explore how asthma and conjunctivitis may lead to the identification of novel rhinitis phenotypes.MethodsIn this cross-sectional analysis, current rhinitis was defined as present in the last 12 months using a questionnaire from the French CONSTANCES cohort. Participants with current rhinitis reporting nasal allergies were considered as AR, otherwise as NAR. We described AR and NAR phenotypes, and their phenotypes including co-occurrence with ever-asthma and ever-conjunctivitis.ResultsAmong the 20 772 participants included in this analysis (mean±sdage 52.6±12.6 years; 55.2% female), crude prevalences of AR and NAR were 28.0% and 10.9%. AR participants more frequently reported persistent rhinitis (31.6%versus25.1%) and moderate-to-severe rhinitis (40.1%versus24.2%) than NAR participants. Among AR or NAR participants, those with ever-asthma reported more moderate-to-severe rhinitis. Participants with AR, ever-asthma and ever-conjunctivitis had an earlier age of rhinitis onset, more severe rhinitis and higher eosinophil counts than participants in other groups. Results were replicated in another cohort.ConclusionsIn this large population-based cohort, 40% reported current rhinitis, with a lower prevalence of moderate-to-severe rhinitis than in clinical practice. For the first time in a general adult population, we showed that AR and NAR alone or in combination with asthma or in combination with asthma and conjunctivitis are different phenotypes. These results provide new insights on how best to manage rhinitis and its multimorbidities.
Published: 2022

46. WAO-ARIA consensus on chronic cough – Part III

Author: Philip W. Rouadi, Samar A. Idriss, Jean Bousquet, Tanya M. Laidlaw, Cecilio R. Azar, Mona S. Al-Ahmad, Anahi Yañez, Maryam Ali Y. Al-Nesf, Talal M. Nsouli, Sami L. Bahna, Eliane Abou-Jaoude, Fares H. Zaitoun, Usamah M. Hadi, Peter W. Hellings, Glenis K. Scadding, Peter K. Smith, Mario Morais-Almeida, René Maximiliano Gómez, Sandra N. Gonzalez Diaz, Ludger Klimek, Georges S. Juvelekian, Moussa A. Riachy, Giorgio Walter Canonica, David Peden, Gary W.K. Wong, James Sublett, Jonathan A. Bernstein, Lianglu Wang, Luciana K. Tanno, Manana Chikhladze, Michael Levin, Yoon-Seok Chang, Bryan L. Martin, Luis Caraballo, Adnan Custovic, Jose Antonio Ortego-Martell, Olivia J.Ly Lesslar, Erika Jensen-Jarolim, Motohiro Ebisawa, Alessandro Fiocchi, Ignacio J. Ansotegui, Beirut Eye & ENT Specialist Hospital (BESH), Eye & Ear Hospital [Beirut], Hôpital Edouard Herriot [CHU - HCL], Hospices Civils de Lyon (HCL), Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Berlin Institute of Health (BIH), Contre les MAladies Chroniques pour un VIeillissement Actif en Languedoc-Roussillon (MACVIA-LR), Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Universitaire de Nîmes (CHU Nîmes)-Centre National de la Recherche Scientifique (CNRS)-European Innovation Partnership on Active and Healthy Ageing Reference Site (EIP on AHA), Commission Européenne-Commission Européenne-Organisation Mondiale de la Santé / World Health Organization Office (OMS / WHO)-Université de Montpellier (UM), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Brigham and Women’s Hospital [Boston, MA], Harvard Medical School [Boston] (HMS), American University of Beirut Faculty of Medicine and Medical Center (AUB), Middle East Institute of Health, Clemenceau Medical Center (CMC), Kuwait University, Investigaciones en Alergia y Enfermedades Respiratorias (InAER), Hamad Medical Corporation [Doha, Qatar], International Cough Institute (ICI), Louisiana State University (LSU), LAU Medical Center-Rizk Hospital, University Hospitals Leuven [Leuven], Department of Microbiology, Immunology and Transplantation [Leuven], Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Ghent University Hospital, Academic Medical Center - Academisch Medisch Centrum [Amsterdam] (AMC), University of Amsterdam [Amsterdam] (UvA), The Royal National Throat, Nose and Ear Hospital, Griffith University [Brisbane], Hospital CUF Descobertas, Facultad de Ciencias de la Salud [Salta], Universidad Nacional de Salta (UNSA), Universidad Autonoma de Nuevo Leon [Mexique] (UANL), Center for Rhinology and Allergology Wiesbaden, University Hospital Mannheim, Saint George Hospital University Medical Center [UOB LIBAN], University of Balamand [Liban] (UOB), Hôtel-Dieu de France (HDF), Université Saint-Joseph de Beyrouth (USJ), Humanitas Clinical and Research Center [Rozzano, Milan, Italy], UNC School of Medicine, The Chinese University of Hong Kong [Hong Kong], University of Louisville School of Medicine, University of Cincinnati College of Medicine, Peking Union Medical College Hospital [Beijing] (PUMCH), Institut Desbrest de santé publique (IDESP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), World Health Organisation (WHO), Organisation Mondiale de la Santé / World Health Organization Office (OMS / WHO), Akaki Tsereteli State University, University of Cape Town, Seoul National University Bundang Hospital (SNUBH), The Ohio State University Wexner Medical Center., University of Cartagena, National Heart and Lung Institute [London] (NHLI), Imperial College London-Royal Brompton and Harefield NHS Foundation Trust, Universidad Autónoma del Estado de Hidalgo (UAEH), LifeSpan medicine, Medizinische Universität Wien = Medical University of Vienna, Messerli Research Institute, University of Veterinary Medicine Vienna, Medical University Vienna, University of Vienna [Vienna]-University of Vienna [Vienna]-Medical University Vienna, University of Vienna [Vienna]-University of Vienna [Vienna], Sagamihara National Hospital [Kanagawa, Japan], Bambino Gesù Children’s Hospital [Rome, Italy], Hospital Quirónsalud Bizkaia [Bilbao], and Salvy-Córdoba, Nathalie
Subjects: EXHALED NITRIC-OXIDE, Pulmonary and Respiratory Medicine, Cough specialty care, Chronic cough management, Allergy, AIRWAY INFLAMMATION, Upper airway cough syndrome, Immunology, MUCOSAL EOSINOPHILIC INFLAMMATION, GASTROESOPHAGEAL-REFLUX DISEASE, INHALED CORTICOSTEROIDS, Lower airway disease, Speech therapy, QUALITY-OF-LIFE, CHEST GUIDELINE, Immunology and Allergy, [SDV.IMM.ALL]Life Sciences [q-bio]/Immunology/Allergology, Neuromodulators, VARIANT ASTHMA, Cough primary care, Science & Technology, CLINICAL-PRACTICE GUIDELINE, Reflux cough, REFRACTORY CHRONIC COUGH, Life Sciences & Biomedicine, [SDV.IMM.ALL] Life Sciences [q-bio]/Immunology/Allergology
Abstract: BACKGROUND: Chronic cough management necessitates a clear integrated care pathway approach. Primary care physicians initially encounter the majority of chronic cough patients, yet their role in proper management can prove challenging due to limited access to advanced diagnostic testing. A multidisciplinary approach involving otolaryngologists and chest physicians, allergists, and gastroenterologists, among others, is central to the optimal diagnosis and treatment of conditions which underly or worsen cough. These include infectious and inflammatory, upper and lower airway pathologies, or gastro-esophageal reflux. Despite the wide armamentarium of ancillary testing conducted in cough multidisciplinary care, such management can improve cough but seldom resolves it completely. This can be due partly to the limited data on the role of tests (eg, spirometry, exhaled nitric oxide), as well as classical pharmacotherapy conducted in multidisciplinary specialties for chronic cough. Other important factors include presence of multiple concomitant cough trigger mechanisms and the central neuronal complexity of chronic cough. Subsequent management conducted by cough specialists aims at control of cough refractory to prior interventions and includes cough-specific behavioral counseling and pharmacotherapy with neuromodulators, among others. Preliminary data on the role of neuromodulators in a proof-of-concept manner are encouraging but lack strong evidence on efficacy and safety. OBJECTIVES: The World Allergy Organization (WAO)/Allergic Rhinitis and its Impact on Asthma (ARIA) Joint Committee on Chronic Cough reviewed the recent literature on management of chronic cough in primary, multidisciplinary, and cough-specialty care. Knowledge gaps in diagnostic testing, classical and neuromodulator pharmacotherapy, in addition to behavioral therapy of chronic cough were also analyzed. OUTCOMES: This third part of the WAO/ARIA consensus on chronic cough suggests a management algorithm of chronic cough in an integrated care pathway approach. Insights into the inherent limitations of multidisciplinary cough diagnostic testing, efficacy and safety of currently available antitussive pharmacotherapy, or the recently recognized behavioral therapy, can significantly improve the standards of care in patients with chronic cough. ispartof: WORLD ALLERGY ORGANIZATION JOURNAL vol:15 issue:5 ispartof: location:United States status: published
Published: 2022

47. Effects of sacubitril/valsartan versus valsartan on renal function in patients with and without diabetes and heart failure with preserved ejection fraction: insights from PARAGON‐HF

Author: Alexander Peikert, Muthiah Vaduganathan, Finnian Mc Causland, Brian L. Claggett, Safia Chatur, Milton Packer, Marc A. Pfeffer, Faiez Zannad, Martin P. Lefkowitz, Burkert Pieske, Hans‐Dirk Düngen, John J.V. McMurray, Scott D. Solomon, BOZEC, Erwan, Brigham & Women’s Hospital [Boston] (BWH), Harvard Medical School [Boston] (HMS), Baylor Heart and Vascular Hospital, Baylor University Medical Center, 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), 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), 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 ), Novartis Pharmaceuticals Corporation [East Hanover, NJ], Charité Campus Virchow-Klinikum (CVK), Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], German Center for Cardiovascular Research (DZHK), Berlin Institute of Health (BIH), British Heart Foundation Glasgow Cardiovascular Research Centre (BHF GCRC), University of Glasgow-NHS Greater Glasgow and Clyde, and PARAGON-HF was funded by Novartis Pharmaceuticals
Subjects: Heart Failure, Aminobutyrates, Biphenyl Compounds, Diabetes, Tetrazoles, Stroke Volume, Kidney, Ventricular Function, Left, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Angiotensin Receptor Antagonists, Drug Combinations, Heart failure with preserved ejection fraction, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Diabetes Mellitus, Humans, Valsartan, Sacubitril/valsartan, Cardiology and Cardiovascular Medicine, Renal function
Abstract: Aims: \ud Diabetes is associated with a faster rate of renal function decline in patients with heart failure (HF). Sacubitril/valsartan attenuates the deterioration of renal function to a greater extent in patients with diabetes and HF with reduced ejection fraction compared with renin–angiotensin system inhibitors alone. We assessed whether the same may be true in HF with preserved ejection fraction (HFpEF).\ud \ud Methods and results: \ud In the PARAGON-HF trial in patients with HF and left ventricular ejection fraction of ≥45% (n = 4796), we characterized the effects of sacubitril/valsartan on changes in estimated glomerular filtration rate (eGFR) over a period of 192 weeks, and on the pre-specified renal composite outcome (eGFR reduction of ≥50%, end-stage renal disease, or death attributable to renal causes) in patients with (n = 2388) and without diabetes (n = 2408). The decline in eGFR was greater in patients with diabetes than in those without (−2.6 vs. −1.7 ml/min/1.73 m2 per year, p
Published: 2022

48. The Effect of Spironolactone in Patients With Obesity at Risk for Heart Failure: Proteomic Insights from the HOMAGE Trial

Author: Job A.J. Verdonschot, JoÃo Pedro Ferreira, Anne Pizard, Pierpaolo Pellicori, Hans-Peter Brunner La Rocca, Andrew L. Clark, Franco Cosmi, Joe Cuthbert, Nicolas Girerd, Olivia J. Waring, Michiel H.T.M. Henkens, Beatrice Mariottoni, Johannes Petutschnigg, Patrick Rossignol, Mark R. Hazebroek, John G.F. Cleland, Faiez Zannad, Stephane R.B. Heymans, Maastricht University Medical Centre (MUMC), Maastricht University [Maastricht], 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 ), University of Glasgow, University of Hull [United Kingdom], Cortona Hospital, Charité Campus Virchow-Klinikum (CVK), Berlin Institute of Health (BIH), German Center for Cardiovascular Research (DZHK), The research leading to these results has received funding from the European Union Commission's Seventh Framework programme under grant agreement N° 305507 (HOMAGE). S.H.: This manuscript has been possible thanks to the support of the the Netherlands Cardiovascular Research Initiative, an initiative with support of the Dutch Heart Foundation, CVON2016-Early HFPEF, 2015-10, CVON She-PREDICTS, grant 2017-21., European Project: 305507, BOZEC, Erwan, HOMAGE (Heart Omics in Ageing consortium) - 305507 - INCOMING, RS: Carim - H02 Cardiomyopathy, Cardiologie, MUMC+: MA Med Staf Spec Cardiologie (9), Pathologie, RS: Carim - B07 The vulnerable plaque: makers and markers, MUMC+: MA Med Staf Artsass Cardiologie (9), Université de Lorraine (UL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), 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), and Department of Cardiology, Cortona Hospital
Subjects: Male, Proteomics, obesity, Cardiac & Cardiovascular Systems, heart failure, 030204 cardiovascular system & hematology, 03 medical and health sciences, 0302 clinical medicine, LEPTIN, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, PEOPLE, Glucose Intolerance, Humans, Obesity, 030304 developmental biology, Mineralocorticoid Receptor Antagonists, 0303 health sciences, INSULIN-RESISTANCE, Science & Technology, 3. Good health, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Treatment Outcome, spironolactone, ADRENOMEDULLIN, FAT, Cardiovascular System & Cardiology, biomarker, Female, ADIPOKINE, Cardiology and Cardiovascular Medicine, Life Sciences & Biomedicine, Biomarkers
Abstract: BACKGROUND: Adipose tissue influences the expression and degradation of circulating biomarkers. We aimed to identify the biomarker profile and biological meaning of biomarkers associated with obesity to assess the effect of spironolactone on the circulating biomarkers and to explore whether obesity might modify the effect of spironolactone. METHODS AND RESULTS: Protein biomarkers (n = 276) from the Olink Proseek-Multiplex cardiovascular and inflammation panels were measured in plasma collected at baseline, 1 month and 9 months from the HOMAGE randomized controlled trial participants. Of the 510 participants, 299 had obesity defined as an increased waist circumference (≥102 cm in men and ≥88 cm in women). Biomarkers at baseline reflected adipogenesis, increased vascularization, decreased fibrinolysis, and glucose intolerance in patients with obesity at baseline. Treatment with spironolactone had only minor effects on this proteomic profile. Obesity modified the effect of spironolactone on systolic blood pressure (Pinteraction = 0.001), showing a stronger decrease of blood pressure in obese patients (-14.8 mm Hg 95% confidence interval -18.45 to -11.12) compared with nonobese patients (-3.6 mm Hg 95% confidence interval -7.82 to 0.66). CONCLUSIONS: Among patients at risk for heart failure, those with obesity have a characteristic proteomic profile reflecting adipogenesis and glucose intolerance. Spironolactone had only minor effects on this obesity-related proteomic profile, but obesity significantly modified the effect of spironolactone on systolic blood pressure. ispartof: JOURNAL OF CARDIAC FAILURE vol:28 issue:5 pages:778-786 ispartof: location:United States status: published
Published: 2022

49. Genome-wide association study of circulating interleukin 6 levels identifies novel loci

Author: Martina Müller-Nurasyid, Jerome I. Rotter, David M. Evans, John P. Kemp, Emelia J. Benjamin, Graciela E. Delgado, Vilmundur Gudnason, Ann Hammarstedt, Panos Deloukas, Aroon D. Hingorani, Riccardo E. Marioni, David Stacey, Jenny van Dongen, Eric Boerwinkle, Joachim Heinrich, Yongmei Liu, S. Goya Wannamethee, Delilah Zabaneh, Braxton D. Mitchell, Marie Standl, Jackie F. Price, Maria G. Stathopoulou, Yoav Ben-Shlomo, Joris Deelen, Eero Kajantie, Mohammadreza Abdollahi, Christie M. Ballantyne, Johan G. Eriksson, Ilkka Seppälä, Elnaz Naderi, Barbara J. Jefferis, Richard W Morris, Nicholas J. Timpson, George Dedoussis, Sirpa Jalkanen, Mika Kivimäki, Perminder S. Sachdev, Diana van Heemst, Melanie Waldenberger, Gaurav Singhal, Elisabeth Thiering, Olli T. Raitakari, Anders Hamsten, Zoltán Kutalik, L. Bain, Eco J. C. de Geus, Tarunveer S. Ahluwalia, Yuri Milaneschi, Hubert Scharnagl, Juan P. Casas, Georg Homuth, Claes Ohlsson, Abbas Dehghan, Nicola J. Armstrong, Behrooz Z. Alizadeh, Terho Lehtimäki, Steve E. Humphries, Naveed Sattar, Bram P. Prins, Peter Rossing, Sophie Visvikis-Siest, Joana A. Revez, Ilja M. Nolte, Stella Trompet, Harold Snieder, Marian Beekman, Diana Marek, Beate St Pourcain, Thorkild I. A. Sørensen, Silvia Naitza, Karen A. Mather, Uwe Völker, Eline Slagboom, Tina Shah, Magdalene C. Jawahar, Jens Baumert, Alexander Teumer, Dorret I. Boomsma, Marcus E. Kleber, Peter Vollenweider, Wolfgang Koenig, Brenda W.J.H. Penninx, Kenneth Rice, Ian J. Deary, Pedro Marques-Vidal, Donna K. Arnett, Eleonora Porcu, Jouke-Jan Hottenga, Maria Sabater-Lleal, Bruce M. Psaty, Matthias Nauck, Dan Mellström, Joel Eriksson, Bernhard T. Baune, Debbie A Lawlor, Catherine Toben, Peter H. Whincup, Toshiko Tanaka, Stavroula Kanoni, Katri Räikkönen, Gonneke Willemsen, Bengt Sennblad, Julian N. Trollor, Yalda Jamshidi, Sarah E. Harris, Jari Lahti, Joshua C. Bis, Peter Durda, Yen Pei C. Chang, Jorgen Engmann, Tom R. Gaunt, Stella Aslibekyan, Anbupalam Thalamuthu, Mary F. Feitosa, Angela Silveira, Tine Jess, Stela McLachlan, J. Wouter Jukema, Chen Lu, Simon P. Mooijaart, Tim D. Spector, Harald Grallert, Winfried März, Alexandros M. Petrelis, Manuel A. R. Ferreira, Meena Kumari, Stochastics, Biological Psychology, APH - Personalized Medicine, APH - Health Behaviors & Chronic Diseases, APH - Mental Health, APH - Methodology, CHARGE Inflammation Working Group, Epidemiology, Tampere University, Department of Clinical Chemistry, Clinical Medicine, Steno Diabetes Center, University of Copenhagen = Københavns Universitet (KU), University of Groningen [Groningen], Murdoch University, University of Alabama at Birmingham [ Birmingham] (UAB), QIMR Berghofer Medical Research Institute, University College of London [London] (UCL), Helmholtz-Zentrum München (HZM), Leiden University Medical Center (LUMC), University of Bristol [Bristol], University of Washington [Seattle], University of Maryland School of Medicine, University of Maryland System, Vrije Universiteit Amsterdam [Amsterdam] (VU), VU University Medical Center [Amsterdam], University of Heidelberg, Medical Faculty, Swiss Institute of Bioinformatics [Lausanne] (SIB), Université de Lausanne (UNIL), Sahlgrenska Academy at University of Gothenburg [Göteborg], National Institute for Health and Welfare [Helsinki], University of Helsinki, William Harvey Research Institute, Barts and the London Medical School, University of Queensland [Brisbane], School of Public Health [Boston], Boston University [Boston] (BU), MRC Institute of Genetics and Molecular Medicine [Edinburgh] (IGMM), University of Edinburgh-Medical Research Council, University of Edinburgh, Amsterdam UMC, Interactions Gène-Environnement en Physiopathologie Cardio-Vasculaire (IGE-PCV), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Istituto di Ricerca Genetica e Biomedica (IRGB), Consiglio Nazionale delle Ricerche [Roma] (CNR), Karolinska Institutet [Stockholm], University of Tampere [Finland], Adelaide Medical School [Australia], University of Adelaide, Universität Greifswald - University of Greifswald, University of New South Wales [Sydney] (UNSW), Prince of Wales Hospital, Ludwig-Maximilians-Universität München (LMU), Baylor College of Medicine (BCM), Baylor University, Boston University School of Medicine (BUSM), VA Boston Healthcare System, Harokopio University of Athens, Max planck Institute for Biology of Ageing [Cologne], Larner College of Medicine [University of Vermont, Burlington], University of Vermont [Burlington], Washington University School of Medicine in St. Louis, Washington University in Saint Louis (WUSTL), Interfaculty Institute for Genetics and Functional Genomics, Ernst-Moritz-Arndt-Universität Greifswald, University of Turku, St George's, University of London, Statens Serum Institut [Copenhagen], Medical Faculty [Mannheim], Wake Forest School of Medicine [Winston-Salem], Wake Forest Baptist Medical Center, Centre Hospitalier Universitaire Vaudois [Lausanne] (CHUV), Johannes Gutenberg - Universität Mainz (JGU), Vrije Universiteit Medical Centre (VUMC), British Heart Foundation Glasgow Cardiovascular Research Centre (BHF GCRC), University of Glasgow-NHS Greater Glasgow and Clyde, Medical University Graz, Uppsala Universitet [Uppsala], Max Planck Institute for Psycholinguistics, Max-Planck-Gesellschaft, Donders Institute for Brain, Cognition and Behaviour, Radboud university [Nijmegen], University of Kentucky, Melbourne Medical School [Melbourne], Faculty of Medicine, Dentistry and Health Sciences [Melbourne], University of Melbourne-University of Melbourne, University Hospital Münster - Universitaetsklinikum Muenster [Germany] (UKM), University of Maryland [Baltimore], Queen Mary University of London (QMUL), University of Iceland [Reykjavik], Ludwig Maximilian University [Munich] (LMU), Melbourne School of Population and Global Health [Melbourne], University of Melbourne, Deutsches Herzzentrum München (DHM), German Center for Cardiovascular Research (DZHK), Berlin Institute of Health (BIH), University of Ulm (UUlm), University of Essex, Greifswald University Hospital, Novo Nordisk Foundation Center for Basic Metabolic Research (CBMR), Faculty of Health and Medical Sciences, University of Copenhagen = Københavns Universitet (KU)-University of Copenhagen = Københavns Universitet (KU), King‘s College London, University of Cambridge [UK] (CAM), Harbor UCLA Medical Center [Torrance, Ca.], Erasmus University Medical Center [Rotterdam] (Erasmus MC), University of Texas Health Science Center, The University of Texas Health Science Center at Houston (UTHealth), Human Genome Sequencing Center [Houston] (HGSC), Baylor University-Baylor University, Psychiatry, Amsterdam Neuroscience - Complex Trait Genetics, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, APH - Digital Health, HUS Children and Adolescents, Lastentautien yksikkö, Children's Hospital, Clinicum, Department of Bacteriology and Immunology, Department of Public Health, Department of Psychology and Logopedics, Research Programs Unit, Johan Eriksson / Principal Investigator, Department of General Practice and Primary Health Care, Doctoral Programme in Human Behaviour, Life Course Epidemiology (LCE), Real World Studies in PharmacoEpidemiology, -Genetics, -Economics and -Therapy (PEGET), and Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI)
Subjects: AcademicSubjects/SCI01140, [SDV]Life Sciences [q-bio], Genome-wide association study, 030204 cardiovascular system & hematology, DISEASE, Pathogenesis, Cohort Studies, 0302 clinical medicine, cytokine, SYSTEMIC-LUPUS-ERYTHEMATOSUS, Association Studies Article, ComputingMilieux_MISCELLANEOUS, Genetics (clinical), Genetics, 0303 health sciences, ARCHITECTURE, CHRONIC INFLAMMATION, 1184 Genetics, developmental biology, physiology, General Medicine, RECEPTOR IL-6R GENE, C-REACTIVE PROTEIN, hla-drb1 gene, 3. Good health, Medical genetics, Medical Genetics, chromosomes, medicine.medical_specialty, SUSCEPTIBILITY LOCI, European Continental Ancestry Group, Locus (genetics), Single-nucleotide polymorphism, Biology, Polymorphism, Single Nucleotide, anti-inflammatory agents, White People, 03 medical and health sciences, medicine, Humans, Genetic Predisposition to Disease, Interleukin 6, Molecular Biology, Medicinsk genetik, 030304 developmental biology, PRODUCE IL-6, Interleukin-6, Chromosome, Receptors, Interleukin-6, RHEUMATOID-ARTHRITIS, Interleukin 1 Receptor Antagonist Protein, Gene Expression Regulation, Genetic Loci, CELLS, biology.protein, 1182 Biochemistry, cell and molecular biology, Human genome, 3111 Biomedicine, Genome-Wide Association Study, HLA-DRB1 Chains, Interleukin-1
Abstract: Interleukin 6 (IL-6) is a multifunctional cytokine with both pro- and anti-inflammatory properties with a heritability estimate of up to 61%. The circulating levels of IL-6 in blood have been associated with an increased risk of complex disease pathogenesis. We conducted a two-staged, discovery and replication meta genome-wide association study (GWAS) of circulating serum IL-6 levels comprising up to 67 428 (ndiscovery = 52 654 and nreplication = 14 774) individuals of European ancestry. The inverse variance fixed effects based discovery meta-analysis, followed by replication led to the identification of two independent loci, IL1F10/IL1RN rs6734238 on chromosome (Chr) 2q14, (Pcombined = 1.8 × 10−11), HLA-DRB1/DRB5 rs660895 on Chr6p21 (Pcombined = 1.5 × 10−10) in the combined meta-analyses of all samples. We also replicated the IL6R rs4537545 locus on Chr1q21 (Pcombined = 1.2 × 10−122). Our study identifies novel loci for circulating IL-6 levels uncovering new immunological and inflammatory pathways that may influence IL-6 pathobiology.
Published: 2021

50. αvβ8 integrin-expression by BATF3-dependent dendritic cells facilitates early IgA responses to Rotavirus

Author: Bernard Malissen, Joy Nakawesi, Julia Hütter, Sébastien This, Harry B. Greenberg, L. J. Gooday, A. Garcias López, V. Barateau, Katharina Lahl, K. Getachew Muleta, K. Fog Thomsen, Olivier Thaunat, M. Boucard-Jourdin, T. Defrance, Didier Poncet, Isabel Ulmert, H. Paidassi, Centre d'Immunologie de Marseille - Luminy (CIML), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), Centre International de Recherche en Infectiologie - UMR (CIRI), Institut National de la Santé et de la Recherche Médicale (INSERM)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Lund University [Lund], Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Technical University of Denmark - Division of Biopharma - Institut for Health Tech - Kongens, Berlin Institute of Health (BIH), Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Stanford University School of Medicine [CA, USA], VA Palo Alto Health Care System, Lymphocytes B effecteurs et à mémoire – Effector and memory B cells, Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), ANR-13-PDOC-0019,InteReg,Régulation de l'expression de l'intégrine alpha-v-beta-8 et son rôle dans le maintien de l'homéostasie immunitaire de l'intestin(2013), Biologie Moléculaire des Rotavirus (ROTA), Département Virologie (Dpt Viro), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Saclay, Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Saclay-Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Saclay-Institut de Biologie Intégrative de la Cellule (I2BC), Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Saclay-Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Saclay, Université Claude Bernard Lyon 1 (UCBL), Université de Lyon, Paul Scherrer Institute (PSI), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), and Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Rotavirus, 0301 basic medicine, Integrins, HOMEOSTASIS, [SDV]Life Sciences [q-bio], Immunology, Integrin, Context (language use), Antibodies, Viral, medicine.disease_cause, [SDV.IMM.II]Life Sciences [q-bio]/Immunology/Innate immunity, Rotavirus Infections, Virus, ACTIVATION, 03 medical and health sciences, 0302 clinical medicine, Antibody Specificity, INFECTION, TGF beta signaling pathway, medicine, Immunology and Allergy, Mesenteric lymph nodes, TGF-BETA-1, REGULATORY T-CELLS, ComputingMilieux_MISCELLANEOUS, TGF beta 1, biology, GROWTH-FACTOR-BETA, INDUCTION, TGF-BETA, Dendritic Cells, Immunoglobulin A, 3. Good health, Basic-Leucine Zipper Transcription Factors, 030104 developmental biology, medicine.anatomical_structure, [SDV.IMM.IA]Life Sciences [q-bio]/Immunology/Adaptive immunology, EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS, B-CELLS, Host-Pathogen Interactions, Immunoglobulin A, Secretory, biology.protein, Cytokines, [SDV.IMM]Life Sciences [q-bio]/Immunology, Homeostasis, 030215 immunology
Abstract: International audience; Secretory intestinal IgA can protect from re-infection with rotavirus (RV), but very little is known about the mechanisms that induce IgA production during intestinal virus infections. Classical dendritic cells (cDCs) in the intestine can facilitate both T cell-dependent and -independent secretory IgA. Here, we show that BATF3-dependent cDC1, but not cDC2, are critical for the optimal induction of RV-specific IgA responses in the mesenteric lymph nodes. This depends on the selective expression of the TGF beta-activating integrin alpha v beta 8 by cDC1. In contrast, alpha v beta 8 on cDC1 is dispensible for steady state immune homeostasis. Given that cDC2 are crucial in driving IgA during steady state but are dispensable for RV-specific IgA responses, we propose that the capacity of DC subsets to induce intestinal IgA responses reflects the context, as opposed to an intrinsic property of individual DC subsets.
Published: 2021

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