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152 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. 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

4. 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

5. 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

6. 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

7. 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

8. 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

9. 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

10. 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

11. 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

12. 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

13. 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

14. 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

15. 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

16. 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

17. 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

18. 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

19. 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

20. 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

21. 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

22. 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

23. 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

24. 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

25. 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

26. 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

27. 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

28. 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

29. 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

30. 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

31. 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

32. The effect of spironolactone on cardiovascular function and markers of fibrosis in people at increased risk of developing heart failure: the heart ‘OMics’ in AGEing (HOMAGE) randomized clinical trial

Author: Cleland, John, Ferreira, João Pedro, Mariottoni, Beatrice, Pellicori, Pierpaolo, Cuthbert, Joe, Verdonschot, Job, Petutschnigg, Johannes, Ahmed, Fozia, COSMI, FRANCO, Brunner La Rocca, Hans-Peter, Mamas, Mamas, Clark, Andrew, Edelmann, Frank, Pieske, Burkert, Khan, Javed, McDonald, Ken, Rouet, Philippe, Staessen, Jan, Mujaj, Blerim, González, Arantxa, Diez, Javier, Hazebroek, Mark, Heymans, Stephane, Latini, Roberto, Grojean, Stéphanie, Pizard, Anne, Girerd, Nicolas, Rossignol, Patrick, Collier, Tim, Zannad, Faiez, Atar, Dan, Kober, Lars, Dickstein, Kenneth, Lange, Theis, RS: Carim - H02 Cardiomyopathy, Cardiologie, MUMC+: MA Med Staf Spec Cardiologie (9), MUMC+: MA Med Staf Artsass Cardiologie (9), University of Glasgow, Robertson Centre for Biostatistics, University of Glasgow, Institute of Health and Wellbeing, University of Glasgow-Gartnavel General Hospital, Glasgow, Défaillance Cardiovasculaire Aiguë et Chronique (DCAC), Université de Lorraine (UL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Centre d'investigation clinique plurithématique Pierre Drouin [Nancy] (CIC-P), Centre d'investigation clinique [Nancy] (CIC), Université de Lorraine (UL)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM), 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], Cortona Hospital, Castle Hill Hospital, University of Hull [United Kingdom], Maastricht University Medical Centre (MUMC), Maastricht University [Maastricht], Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Berlin Institute of Health (BIH), German Center for Cardiovascular Research (DZHK), Manchester Academic Health Science Centre (MAHSC), University of Manchester [Manchester], Division of Cardiovascular Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, Keele University [Keele], University College Dublin [Dublin] (UCD), Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Universitäts Klinikum Freiburg, Universidad de Navarra [Pamplona] (UNAV), Institute of Health Carlos III, Instituto de Investigación Sanitaria de Navarra [Pamplona, Spain] (IdiSNA), IRCCS - Istituto di Ricerche Farmacologiche 'Mario Negri', Fondation Force, Research and Consulting Department, EDDH, Centre de Médecine Préventive, and London School of Hygiene and Tropical Medicine (LSHTM)
Subjects: Male, Aging, Cardiac & Cardiovascular Systems, Spironolactone, 030204 cardiovascular system & hematology, Q1, Gastroenterology, chemistry.chemical_compound, 0302 clinical medicine, Fibrosis, Clinical endpoint, AcademicSubjects/MED00200, 030212 general & internal medicine, Mineralocorticoid Receptor Antagonists, Collagen markers, R735, Heart failure prevention, RC666, 16. Peace & justice, 3. Good health, Female, Cardiology and Cardiovascular Medicine, Life Sciences & Biomedicine, Procollagen, Cardiac function curve, medicine.medical_specialty, 03 medical and health sciences, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, N-terminal telopeptide, Clinical Research, Internal medicine, medicine, Humans, Heart Failure and Cardiomyopathies, Aged, Heart Failure, Science & Technology, business.industry, medicine.disease, R1, Peptide Fragments, Procollagen peptidase, Blood pressure, chemistry, Heart failure, Cardiovascular System & Cardiology, ras Proteins, business, RA, Biomarkers
Abstract: Importance: Cardiovascular accumulation of collagen (fibrosis) may contribute to the progression from ventricular dysfunction to heart failure. Galectin-3, a potential marker of pro-fibrotic activity, might identify those at greater risk.\ud Objective: To investigate the effects of spironolactone, according to serum galectin-3 concentration, on serum markers of fibrosis and on cardiac structure and function, in people at increased risk of developing heart failure.\ud Design: Prospective, randomized, open-label, blinded endpoint (PROBE) trial.\ud Setting: Clinical research facilities in ten European hospitals.\ud Participants: People with, or at high-risk of, coronary disease with increased plasma concentrations of B-type natriuretic peptides (BNP or NT-proBNP).\ud Interventions: spironolactone (up to 50 mg/day) or control for up to nine months.\ud Main Outcomes and Measures: The primary outcome was the interaction between baseline serum galectin-3 and change in serum procollagen type-III N-terminal pro-peptide (PIIINP), a by-product of type-III collagen synthesis. Serum procollagen type-I C-terminal pro-peptide (PICP) and collagen type-1 C-terminal telopeptide (CITP), respectively reflecting synthesis and degradation of type-I collagen, were also measured.\ud Results: Of 527 participants, the median age was 73 years and 26% were women. Median follow-up was 267 days. Changes in PIIINP were similar for those assigned to spironolactone and control (mean difference -0.15; 95% confidence interval [CI] -0.44 to 0.15 μg/L; p=0.32) and did not differ when serum galectin-3 was above or below median. Those assigned to spironolactone had greater declines in PICP (mean difference -8.1; -95% CI -11.9 to -4.3 μg/L; p
Published: 2020

33. Atypical clinical presentation of COVID-19 infection in residents of a long-term care facility

Author: Mylène Albrand, Stéphanie Miot, Jean Bousquet, Nadia Giacosa, Yves Rolland, Hubert Blain, Athanase Benetos, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Gérontopôle, Epidémiologie et analyses en santé publique : risques, maladies chroniques et handicaps (LEASP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse], Défaillance Cardiovasculaire Aiguë et Chronique (DCAC), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Service de Gériatrie [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Berlin Institute of Health (BIH), Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Humboldt-Universität zu Berlin, Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Humboldt University Of Berlin, and Herrada, Anthony
Subjects: Male, Pediatrics, Delayed Diagnosis, rRT-PCR, Testing for SARS-CoV-2, Disease, Polymerase Chain Reaction, Hypoxemia, MESH: Long-Term Care, MESH: Aged, 80 and over, 0302 clinical medicine, MESH: COVID-19, Medicine, Infection control, MESH: Skilled Nursing Facilities, 030212 general & internal medicine, MESH: Aged, Aged, 80 and over, [SDV.MHEP.GEG] Life Sciences [q-bio]/Human health and pathology/Geriatry and gerontology, [SDV.MHEP.GEG]Life Sciences [q-bio]/Human health and pathology/Geriatry and gerontology, Brief Report, MESH: Accidental Falls, 3. Good health, MESH: Diarrhea, Diarrhea, COVID-19 Nucleic Acid Testing, Female, medicine.symptom, Presentation (obstetrics), Long-term-care facility, MESH: Pandemics, medicine.medical_specialty, Health Personnel, Asymptomatic, MESH: COVID-19 Nucleic Acid Testing, 03 medical and health sciences, Humans, MESH: SARS-CoV-2, Pandemics, Aged, Skilled Nursing Facilities, MESH: Humans, 030214 geriatrics, SARS-CoV-2, business.industry, COVID-19, MESH: Polymerase Chain Reaction, Long-Term Care, MESH: Male, MESH: Delayed Diagnosis, Long-term care, MESH: Health Personnel, Delirium, Accidental Falls, business, MESH: Female
Abstract: Key summary points Aim To assess the magnitude of the infection in residents from—and staff working in—a long-term-care facility (LTCF) 7 days after the identification of one resident with confirmed COVID-19 infection and the clinical presentation of the infected residents. Findings Two weeks after the first case, 50.9% of residents and 27.5% of the workers were tested positive for SARS-CoV-2. Diarrhea, fall, delirium, and hypothermia can be initial symptoms of COVID-19 in LTCF residents. Message The rapid dissemination of a COVID-19 infection in a LTCF may be due to a delay in the diagnosis of the first case, whose presentation could be atypical in residents., Purpose To assess the magnitude of the infection in residents from—and staff working in—a long-term-care facility (LTCF) 7 days after the identification of one resident with confirmed COVID-19 infection and to assess the clinical presentation of the infected residents. Methods All residents and staff members of a LTCF were tested for SARS-CoV-2 by real-time reverse-transcriptase polymerase chain reaction on nasopharyngeal swab. Residents were studied clinically 4 weeks after the first COVID diagnosis. Results Thirty-eight of the 79 residents (48.1%) tested positive for SARS-CoV-2. Respiratory symptoms were preceded by diarrhea (26.3%), a fall (18.4%), fluctuating temperature with hypothermia (34.2%) and delirium in one resident. Respiratory symptoms, including cough and oxygen desaturation, appeared after those initial symptoms or as the first sign in 36.8% and 52.2%, respectively. At any time of the disease, fever was observed in 65.8%. Twelve deaths occurred among the COVID-19 residents. Among the 41 residents negative for SARS-CoV-2, symptoms included cough (21.9%), diarrhea (7.3%), fever (21.9%), hypothermia (9.7%), and transient hypoxemia (9.8%). No deaths were observed in this group. 27.5% of the workers were also COVID-19 positive. Conclusion The rapid dissemination of the COVID-19 infection may be explained by the delay in the diagnosis of the first cases due to atypical presentation. Early recognition of symptoms compatible with COVID-19 may help to diagnose COVID-19 residents earlier and test for SARS-CoV-2 symptomatic and asymptomatic staff and residents earlier to implement appropriate infection control practices.
Published: 2020

34. Influence of ejection fraction on biomarker expression and response to spironolactone in people at risk of heart failure: findings from the HOMAGE trial

Author: João Pedro Ferreira, Job A.J. Verdonschot, Nicolas Girerd, Erwan Bozec, Pierpaolo Pellicori, Timothy Collier, Beatrice Mariottoni, Franco Cosmi, Mark Hazebroek, Joe Cuthbert, Johannes Petutschnigg, Stephane Heymans, Jan A. Staessen, Burkert Pieske, Frank Edelman, Andrew L. Clark, Javier Díez, Arantxa González, Patrick Rossignol, John G. Cleland, 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], Faculdade de Medicina da Universidade do Porto (FMUP), Universidade do Porto = University of Porto, Maastricht University Medical Centre (MUMC), Maastricht University [Maastricht], University of Glasgow, London School of Hygiene and Tropical Medicine (LSHTM), Cortona Hospital, University of Hull [United Kingdom], Charité Campus Virchow-Klinikum (CVK), German Center for Cardiovascular Research (DZHK), Berlin Institute of Health (BIH), Studies Coordinating Centre [Louvain, Belgique], Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Institute of Health Carlos III, Universidad de Navarra [Pamplona] (UNAV), European Project: 305507,EC:FP7:HEALTH,FP7-HEALTH-2012-INNOVATION-1,HOMAGE(2013), MUMC+: DA KG Lab Centraal Lab (9), RS: Carim - H02 Cardiomyopathy, MUMC+: MA Med Staf Artsass Cardiologie (9), Cardiologie, and MUMC+: MA Med Staf Spec Cardiologie (9)
Subjects: Heart Failure, Inflammation, Ejection fraction, INTERLEUKIN-8, IMPACT, PROGNOSTIC IMPORTANCE, Stroke Volume, Spironolactone, Fibrosis, Ventricular Function, Left, DISEASE, EVENTS, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, S100A12, Tissue Plasminogen Activator, Natriuretic Peptide, Brain, cardiovascular system, Humans, cardiovascular diseases, Cardiology and Cardiovascular Medicine, Biomarkers, Mineralocorticoid Receptor Antagonists, circulatory and respiratory physiology
Abstract: Aims: \ud Left ventricular ejection fraction (LVEF) can provide haemodynamic information and may influence the response to spironolactone and other heart failure (HF) therapies. We aimed to study patient characteristics and circulating protein associations with LVEF, and whether LVEF influenced the response to spironolactone.\ud \ud Methods and results: \ud HOMAGE enrolled patients aged >60 years at high risk of developing HF with a LVEF ≥45%. Overall, 527 patients were randomized to either spironolactone or standard of care for ≈9 months, and 276 circulating proteins were measured using Olink® technology. A total of 364 patients had available LVEF determined by the Simpson's biplane method. The respective LVEF tertiles were: tertile 1: 65% (n = 121). Patients with a LVEF >65% had smaller left ventricular chamber size and volumes, and lower natriuretic peptide levels. Compared to patients with a LVEF 65% had higher levels of circulating c-c motif chemokine ligand-23 and interleukin-8, and lower levels of tissue plasminogen activator, brain natriuretic peptide (BNP), S100 calcium binding protein A12, and collagen type I alpha 1 chain (COL1A1). Spironolactone significantly reduced the circulating levels of BNP and COL1A1 without significant treatment-by-LVEF heterogeneity: BNP change β = −0.36 log2 and COL1A1 change β = −0.16 log2 (p 0.1 for both). Spironolactone increased LVEF from baseline to month 9 by 1.1% (p = 0.007).\ud \ud Conclusion: \ud Patients with higher LVEF had higher circulating levels of chemokines and inflammatory markers and lower levels of stretch, injury, and fibrosis markers. Spironolactone reduced the circulating levels of natriuretic peptides and type 1 collagen, and increased LVEF.
Published: 2022

35. Early benefit with empagliflozin in heart failure with preserved ejection fraction: insights from the EMPEROR-Preserved trial

Author: Javed Butler, Tariq Jamal Siddiqi, Gerasimos Filippatos, João Pedro Ferreira, Stuart J. Pocock, Faiez Zannad, Stefan D. Anker, 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), Cardiovascular and Renal Clinical Trialists [Vandoeuvre-les-Nancy] (INI-CRCT), Institut Lorrain du Coeur et des Vaisseaux Louis Mathieu [Nancy], Centre d'investigation clinique plurithématique Pierre Drouin [Nancy] (CIC-P), Centre d'investigation clinique [Nancy] (CIC), 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 ), Faculdade de Medicina da Universidade do Porto (FMUP), Universidade do Porto = University of Porto, 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), Charité Campus Virchow-Klinikum (CVK), and BOZEC, Erwan
Subjects: Heart Failure, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Glucosides, Humans, Stroke Volume, Benzhydryl Compounds, Cardiology and Cardiovascular Medicine, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system
Abstract: Patients with chronic or worsening heart failure (HF) are at a high risk for morbidity, mortality and impaired health related quality of life (HRQoL). This risk is present in the short-term and increases significantly once hospitalized. Thus, it is crucial that HF therapies not only improve outcomes, but do so early post -initiation. The recent EMPEROR-Preserved (Empagliflozin Outcome Trial in Patients with Chronic Heart Failure with Preserved Ejection Fraction) trial studied empagliflozin in patients with HFpEF and showed a significant reduction in the risk of cardiovascular death or HF hospitalization. This benefit also extended to health and functional status. We highlight that this benefit was early with Cox regression analysis achieved nominal statistical significance for separation between the empagliflozin and the placebo arms by day-18 for time to cardiovascular death or HF hospitalization (hazard ratio at 18 days, 0.41 [95% CI, 0.17–0.99]) and sustained for the rest of the trial period. A similar pattern of early and sustained benefit was seen for all domains of HRQoL scores and New York Heart Association functional class with significant improvement when first assessed at 3-months and 4 weeks, respectively. Our results reinforce the importance of early initiation of treatment in patients with HFpEF.
Published: 2022

36. Genome-wide associations of aortic distensibility suggest causality for aortic aneurysms and brain white matter hyperintensities

Author: Catherine M. Francis, Matthias E. Futschik, Jian Huang, Wenjia Bai, Muralidharan Sargurupremraj, Alexander Teumer, Monique M. B. Breteler, Enrico Petretto, Amanda S. R. Ho, Philippe Amouyel, Stefan T. Engelter, Robin Bülow, Uwe Völker, Henry Völzke, Marcus Dörr, Mohammed-Aslam Imtiaz, N. Ahmad Aziz, Valerie Lohner, James S. Ware, Stephanie Debette, Paul Elliott, Abbas Dehghan, Paul M. Matthews, UK DRI Ltd, Imperial College London, Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), German Center for Cardiovascular Research (DZHK), Berlin Institute of Health (BIH), University of Medicine Greifswald, German Research Center for Neurodegenerative Diseases - Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), National University of Singapore (NUS), Facteurs de Risque et Déterminants Moléculaires des Maladies liées au Vieillissement - U 1167 (RID-AGE), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Agence Nationale de la Recherche, European Research Council, ANR-18-RHUS-0002,SHIVA,Stopping cognitive decline and dementia by fighting covert cerebral small vessel disease(2018), European Project: 640643,H2020,ERC-2014-STG,SEGWAY(2015), European Project: 667375,H2020,H2020-PHC-2015-two-stage,CoSTREAM(2015), European Project: 754517 ,PRESTIGE-AF (2017), Admin, Oskar, Stopping cognitive decline and dementia by fighting covert cerebral small vessel disease - - SHIVA2018 - ANR-18-RHUS-0002 - RHUS - VALID, Study on Environmental and GenomeWide predictors of early structural brain Alterations in Young students - SEGWAY - - H20202015-12-01 - 2020-11-30 - 640643 - VALID, Common mechanisms and pathways in Stroke and Alzheimer's disease. - CoSTREAM - - H20202015-12-01 - 2020-11-30 - 667375 - VALID, and PREvention of STroke in Intracerebral haemorrhaGE survivors with Atrial Fibrillation - PRESTIGE-AF - 2017-12-01 - 2023-05-31 - 754517 - VALID
Subjects: Male, General Physics and Astronomy, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, SMALL-VESSEL DISEASE, General Biochemistry, Genetics and Molecular Biology, diagnostic imaging [White Matter], diagnostic imaging [Aorta], [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, MISSENSE MUTATION, GENETIC-VARIANTS, Humans, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Phenomics, METAANALYSIS, Aorta, RISK, Multidisciplinary, Science & Technology, General Chemistry, White Matter, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Aortic Aneurysm, Multidisciplinary Sciences, LOEYS-DIETZ SYNDROME, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, PULSE-WAVE VELOCITY, CARDIOVASCULAR-DISEASE, MENDELIAN RANDOMIZATION, Science & Technology - Other Topics, diagnostic imaging [Aortic Aneurysm], [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Female, ddc:500, ARTERIAL STIFFNESS, genetics [Aortic Aneurysm], Genome-Wide Association Study
Abstract: Aortic dimensions and distensibility are key risk factors for aortic aneurysms and dissections, as well as for other cardiovascular and cerebrovascular diseases. We present genome-wide associations of ascending and descending aortic distensibility and area derived from cardiac magnetic resonance imaging (MRI) data of up to 32,590 Caucasian individuals in UK Biobank. We identify 102 loci (including 27 novel associations) tagging genes related to cardiovascular development, extracellular matrix production, smooth muscle cell contraction and heritable aortic diseases. Functional analyses highlight four signalling pathways associated with aortic distensibility (TGF-β, IGF, VEGF and PDGF). We identify distinct sex-specific associations with aortic traits. We develop co-expression networks associated with aortic traits and apply phenome-wide Mendelian randomization (MR-PheWAS), generating evidence for a causal role for aortic distensibility in development of aortic aneurysms. Multivariable MR suggests a causal relationship between aortic distensibility and cerebral white matter hyperintensities, mechanistically linking aortic traits and brain small vessel disease.
Published: 2022

37. Mental health-related risk factors and interventions in patients with heart failure: a position paper endorsed by the European Association of Preventive Cardiology (EAPC)

Author: Karl-Heinz Ladwig, Thomas C Baghai, Frank Doyle, Mark Hamer, Christoph Herrmann-Lingen, Evelyn Kunschitz, Cédric Lemogne, Margarita Beresnevaite, Angelo Compare, Roland von Känel, Hendrik B Sager, Willem Johan Kop, University of Zurich, Ladwig, Karl-Heinz, Technische Universität München = Technical University of Munich (TUM), German Center for Cardiovascular Research (DZHK), Berlin Institute of Health (BIH), University of Regensburg, Royal College of Surgeons in Ireland (RCSI), University College of London [London] (UCL), Georg-August-University = Georg-August-Universität Göttingen, Hanusch Krankenhaus [Vienna, Austria] (HK), Institut de psychiatrie et neurosciences de Paris (IPNP - U1266 Inserm), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Hôpital Hôtel-Dieu [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Lithuanian University of health Sciences [Kaunas], University of Bergamo, Centro Diagnostico Italiano (CDI), Universität Zürich [Zürich] = University of Zurich (UZH), Tilburg University [Tilburg], Netspar, and Martinez Rico, Clara
Subjects: Heart failure, psychological factors, depression, anxiety, palliative care, review, risk factors, psychosocial, Epidemiology, [SDV.MHEP.PSM] Life Sciences [q-bio]/Human health and pathology/Psychiatrics and mental health, Cardiology, ATHEROSCLEROSIS RISK, 610 Medicine & health, Review, Anxiety, 2705 Cardiology and Cardiovascular Medicine, IMPLANTABLE CARDIOVERTER-DEFIBRILLATORS, Risk Factors, Settore M-PSI/08 - Psicologia Clinica, ANTIDEPRESSANT USE, Humans, Prospective Studies, COGNITIVE-BEHAVIORAL THERAPY, ALL-CAUSE MORTALITY, Heart Failure, Depression, Palliative Care, Psychological Factors, DISEASE MANAGEMENT, Mental Health, 10057 Klinik für Konsiliarpsychiatrie und Psychosomatik, MYOCARDIAL-INFARCTION, [SDV.MHEP.PSM]Life Sciences [q-bio]/Human health and pathology/Psychiatrics and mental health, DEPRESSIVE SYMPTOMS, Chronic Disease, VENTRICULAR ASSIST DEVICES, Cardiology and Cardiovascular Medicine, Psychosocial, 2713 Epidemiology
Abstract: The prevalence and public health burden of chronic heart failure (CHF) in Europe is steadily increasing mainly caused by the ageing population and prolonged survival of patients with CHF. Frequent hospitalizations, high morbidity and mortality rates, and enormous healthcare costs contribute to the health-related burden. However, multidisciplinary frameworks that emphasize effective long-term management and the psychological needs of the patients are sparse. The present position paper endorsed by the European Association of Preventive Cardiology (EAPC) provides a comprehensive overview on the scientific evidence of psychosocial aspects of heart failure (HF). In order to synthesize newly available information and reinforce best medical practice, information was gathered via literature reviews and consultations of experts. It covers the evidence for aetiological and prospective psychosocial risk factors and major underlying psycho-biological mechanisms. The paper elucidates the need to include psychosocial aspects in self-care concepts and critically reviews the current shortcomings of psychotherapeutic and psycho-pharmacological interventions. It also highlights the need for involvement of psychological support in device therapy for patients with HF and finally calls for better palliative care in the final stage of HF progression.
Published: 2022
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38. Association of COVID-19 mortality with serum selenium, zinc and copper : six observational studies across Europe

Author: Kamil Demircan, Thilo Samson Chillon, Tommy Bracken, Ilaria Bulgarelli, Irene Campi, Gijs Du Laing, Samira Fafi-Kremer, Laura Fugazzola, Alejandro Abner Garcia, Raban Heller, David J. Hughes, Louis Ide, Georg Jochen Klingenberg, Pawel Komarnicki, Zbigniew Krasinski, Alain Lescure, Patrick Mallon, Arash Moghaddam, Luca Persani, Mirko Petrovic, Marek Ruchala, Morgane Solis, Linos Vandekerckhove, Lutz Schomburg, univOAK, Archive ouverte, Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Berlin Institute of Health (BIH), University College Dublin [Dublin] (UCD), Immuno-Rhumatologie Moléculaire, Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Architecture et Réactivité de l'ARN (ARN), Institut de biologie moléculaire et cellulaire (IBMC), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), and Universiteit Gent = Ghent University (UGENT)
Subjects: [SDV.MHEP.ME] Life Sciences [q-bio]/Human health and pathology/Emerging diseases, [SDV.MHEP.ME]Life Sciences [q-bio]/Human health and pathology/Emerging diseases, SARS-CoV-2, Immunology, COVID-19, trace elements, Sciences du Vivant [q-bio]/Biochimie, Biologie Moléculaire, mortality, [SDV.IMM.II]Life Sciences [q-bio]/Immunology/Innate immunity, Zinc, Selenium, nutrition, [SDV.IMM.IA]Life Sciences [q-bio]/Immunology/Adaptive immunology, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, [SDV.IMM.IA] Life Sciences [q-bio]/Immunology/Adaptive immunology, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Medicine and Health Sciences, Humans, Immunology and Allergy, biomarker, trace elements, SARS-CoV-2, mortality, biomarker, nutrition, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, [SDV.IMM.II] Life Sciences [q-bio]/Immunology/Innate immunity, Copper
Abstract: IntroductionCertain trace elements are essential for life and affect immune system function, and their intake varies by region and population. Alterations in serum Se, Zn and Cu have been associated with COVID-19 mortality risk. We tested the hypothesis that a disease-specific decline occurs and correlates with mortality risk in different countries in Europe.MethodsSerum samples from 551 COVID-19 patients (including 87 non-survivors) who had participated in observational studies in Europe (Belgium, France, Germany, Ireland, Italy, and Poland) were analyzed for trace elements by total reflection X-ray fluorescence. A subset (n=2069) of the European EPIC study served as reference. Analyses were performed blinded to clinical data in one analytical laboratory.ResultsMedian levels of Se and Zn were lower than in EPIC, except for Zn in Italy. Non-survivors consistently had lower Se and Zn concentrations than survivors and displayed an elevated Cu/Zn ratio. Restricted cubic spline regression models revealed an inverse nonlinear association between Se or Zn and death, and a positive association between Cu/Zn ratio and death. With respect to patient age and sex, Se showed the highest predictive value for death (AUC=0.816), compared with Zn (0.782) or Cu (0.769).DiscussionThe data support the potential relevance of a decrease in serum Se and Zn for survival in COVID-19 across Europe. The observational study design cannot account for residual confounding and reverse causation, but supports the need for intervention trials in COVID-19 patients with severe Se and Zn deficiency to test the potential benefit of correcting their deficits for survival and convalescence.
Published: 2022

39. Diffusion-Weighted Imaging and Fluid-Attenuated Inversion Recovery Quantification to Predict Diffusion-Weighted Imaging-Fluid-Attenuated Inversion Recovery Mismatch Status in Ischemic Stroke With Unknown Onset

Author: Lauranne Scheldeman, Anke Wouters, Patrick Dupont, Søren Christensen, 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), GrayNumber Analytics [Lomma, Sweden] (GNA), Hospices Civils de Lyon (HCL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon, 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 Neurology
Subjects: Advanced and Specialized Nursing, diagnostic imaging [Ischemic Stroke], sensitivity and specificity, [SDV]Life Sciences [q-bio], United States, brain ischemia, [SDV] Life Sciences [q-bio], Stroke, retrospective studies, Diffusion Magnetic Resonance Imaging, methods [Magnetic Resonance Imaging], methods [Diffusion Magnetic Resonance Imaging], Humans, magnetic resonance imaging, cardiovascular diseases, Neurology (clinical), ddc:610, Cardiology and Cardiovascular Medicine, logistic models, Ischemic Stroke
Abstract: Background: Visual rating of diffusion-weighted imaging (DWI)–fluid-attenuated inversion recovery (FLAIR) mismatch can be challenging. We evaluated quantification of DWI and FLAIR to predict DWI-FLAIR mismatch status in ischemic stroke. Methods: In screened patients from the WAKE-UP trial (Efficacy and Safety of Magnetic Resonance Imaging-Based Thrombolysis in Wake-Up Stroke), we retrospectively studied relative DWI (rDWI SI) and FLAIR signal intensity (rFLAIR SI). We defined the optimal mean rFLAIR SI and interquartile range of the rDWI SI in the DWI lesion to predict DWI-FLAIR mismatch status. We investigated agreement between each quantitative parameter and the DWI-FLAIR mismatch and the association between both quantitative parameters. We evaluated the predictive value of the quantitative parameters for excellent functional outcome by logistic regression, adjusted for DWI lesion volume, treatment, age, and National Institutes of Health Stroke Scale score. Results: In the rFLAIR and rDWI SI analysis, 213/369 and 241/421 subjects respectively had a DWI-FLAIR mismatch. A mean rFLAIR SI cutoff of 1.09 and interquartile range rDWI SI cutoff of 0.47 were optimal to predict the DWI-FLAIR mismatch with a sensitivity and specificity of 77% (95% CI, 71%–83%) and 67% (95% CI, 59%–74%), and 76% (95% CI, 70%–81%) and 72% (95% CI, 65%–79%), respectively. For both quantitative parameters, agreement with the DWI-FLAIR mismatch was fair (73%, κ=0.44 [95% CI, 0.35–0.54] for rFLAIR and 74%, κ=0.48 [95% CI, 0.39–0.56] for rDWI). Both quantitative parameters correlated moderately (Pearson R=0.54 [95% CI, 0.46–0.61]; P P =0.01). Conclusions: Agreement between the quantitative and qualitative approach may be insufficient to advocate DWI or FLAIR quantification as alternative for visual rating.
Published: 2022

40. Cardiac remodelling - Part 1: From cells and tissues to circulating biomarkers. A review from the Study Group on Biomarkers of the Heart Failure Association of the European Society of Cardiology

Author: Arantxa González, A. Mark Richards, Rudolf A. de Boer, Thomas Thum, Henrike Arfsten, Martin Hülsmann, Inês Falcao‐Pires, Javier Díez, Roger S.Y. Foo, Mark Y. Chan, Alberto Aimo, Chukwuemeka G. Anene‐Nzelu, Magdy Abdelhamid, Stamatis Adamopoulos, Stefan D. Anker, Yuri Belenkov, Tuvia Ben Gal, Alain Cohen‐Solal, Michael Böhm, Ovidiu Chioncel, Victoria Delgado, Michele Emdin, Ewa A. Jankowska, Finn Gustafsson, Loreena Hill, Tiny Jaarsma, James L. Januzzi, Pardeep S. Jhund, Yuri Lopatin, Lars H. Lund, Marco Metra, Davor Milicic, Brenda Moura, Christian Mueller, Wilfried Mullens, Julio Núñez, Massimo F. Piepoli, Amina Rakisheva, Arsen D. Ristić, Patrick Rossignol, Gianluigi Savarese, Carlo G. Tocchetti, Sophie Van Linthout, Maurizio Volterrani, Petar Seferovic, Giuseppe Rosano, Andrew J.S. Coats, Antoni Bayés‐Genís, Center for Applied Medical Research [Plamplona] (CIMA), Universidad de Navarra [Pamplona] (UNAV), 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], Instituto de Salud Carlos III [Madrid] (ISC), Yong Loo Lin School of Medicine [Singapore], National University of Singapore (NUS), University of Otago [Dunedin, Nouvelle-Zélande], University Medical Center Groningen [Groningen] (UMCG), Hannover Medical School [Hannover] (MHH), Fraunhofer Institute for Toxicology and Experimental Medicine (Fraunhofer ITEM), Fraunhofer (Fraunhofer-Gesellschaft), Medizinische Universität Wien = Medical University of Vienna, German Center for Cardiovascular Research (DZHK), Berlin Institute of Health (BIH), Faculdade de Medicina da Universidade do Porto (FMUP), Universidade do Porto = University of Porto, Departments of Cardiology and Cardiac Surgery, and Nephrology, Clínica Universidad de Navarra, Clínica Universidad de Navarra [Pamplona], Scuola Universitaria Superiore Sant'Anna [Pisa] (SSSUP), Fondazione Toscana Gabriele Monasterio, Montreal Heart Institute - Institut de Cardiologie de Montréal, Cairo University - Faculty of Medicine, Onassis Cardiac Surgery Center [Athens] (OCSC), Charité Campus Virchow-Klinikum (CVK), Berlin-Brandenburg Center for Regenerative Medicine [Berlin, Germany] (BCRT), Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Université d'État Lomonossov de Moscou = Lomonosov Moscow State University (MSU), Cardiology Department, Rabin Medical Center, Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Saarland University Hospital (UKS), Emergency Institute for Cardiovascular Diseases 'Prof. Dr. C.C. Iliescu' [Bucharest, Romania], Leiden University Medical Center (LUMC), Wrocław Medical University, Hôpital national = Rigshospitalet [Copenhagen, Denmark] (HNC), Queen's University [Belfast] (QUB), Linköping University (LIU), Massachusetts General Hospital [Boston], Baim Institute for Clinical Research Boston MA, British Heart Foundation Glasgow Cardiovascular Research Centre (BHF GCRC), University of Glasgow-NHS Greater Glasgow and Clyde, Volgograd State Medical University [Russian Federation] (VSMU), Karolinska University Hospital [Stockholm], Karolinska Institutet [Stockholm], Azienda Socio Sanitaria Territoriale Spedali Civili di Brescia [Brescia], Università degli Studi di Brescia = University of Brescia (UniBs), University of Zagreb, Cardiology Department, Porto Armed Forces Hospital, University Hospital Basel [Basel], Ziekenhuis Oost-Limburg (ZOL), Universitat de València (UV), Hospital Clínico Universitario de Valencia, Cardiology Division, Castelsangiovanni Hospital, Scientific Research Institute of Cardiology and Internal Medicine [Almaty, Kazakhstan], University Clinical Centre of Serbia, 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 Naples Federico II = Università degli studi di Napoli Federico II, IRCCS Ospedale San Raffaele [Milan, Italy], Serbian Academy of Sciences and Arts (SASA), University of Belgrade [Belgrade], St George’s University Hospitals, University of Warwick [Coventry], Germans Trias i Pujol University Hospital [Badalona, Barcelona, Spain] (GTPUH), Universitat Autònoma de Barcelona (UAB), This work was supported by grants from the Spanish Ministry of Science, Innovation and Universities Institute of Health Carlos III (ISCIII) (PI18/01469 and PI21/00946 to A.G., CB16/11/00403 to A.B.-G and CB16/11/00483 to J.D. projects co-funded by the European Regional Development Funds), the European Commission (H2020 CRUCIAL project 2019–848109-2 to A.G.), the European Research Council (ERC CoG 818715 to R.A.d.B., ERC-PoC Megfib to T.T.), the National Medical Research Council of Singapore (NMRC, NMRC/STaR/0022/2014 to A.M.R. and MOH-000280 to M.Y.C.), the Health Research Council of New Zealand (02/152, 08/070, 11/1070), National Heart Foundation of New Zealand, New Zealand Lotteries Grant Board, Foundation for Research, Science and Technology and the Christchurch Heart Institute Trust to A.M.R., the Netherlands Heart Foundation (2017-21, 2017-11, 2018-30, 2020B005) to R.A.d.B., the leDucq Foundation (Cure-PLaN) to R.A.d.B., the Deutsche Forschungsgemeinschaft (KFO311 and TRR267 to T.T., TTR 219 to M.B., and TRR 1470 to S.V.L.), the Karolinska Institutet, the Swedish Research Council (523–2014-2336), the Swedish Heart Lung Foundation (20150557, 20190310), and the Stockholm County Council (20170112, 20190525) to L.H.L., European Project, BOZEC, Erwan, H2020 CRUCIAL project 2019–848109-2 - INCOMING, and Universiteit Leiden
Subjects: Heart Failure, Tissue, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Biomarkers, Cells, Remodeling, Endothelial Cells, Humans, Ventricular Remodeling, Cardiology, Cardiology and Cardiovascular Medicine, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system
Abstract: International audience; Cardiac remodelling refers to changes in left ventricular structure and function over time, with a progressive deterioration that may lead to heart failure (HF) development (adverse remodelling) or vice versa a recovery (reverse remodelling) in response to HF treatment. Adverse remodelling predicts a worse outcome, whilst reverse remodelling predicts a better prognosis. The geometry, systolic and diastolic function and electric activity of the left ventricle are affected, as well as the left atrium and on the long term even right heart chambers. At a cellular and molecular level, remodelling involves all components of cardiac tissue: cardiomyocytes, fibroblasts, endothelial cells and leucocytes. The molecular, cellular and histological signatures of remodelling may differ according to the cause and severity of cardiac damage, and clearly to the global trend toward worsening or recovery. These processes cannot be routinely evaluated through endomyocardial biopsies, but may be reflected by circulating levels of several biomarkers. Different classes of biomarkers (e.g. proteins, non-coding RNAs, metabolites and/or epigenetic modifications) and several biomarkers of each class might inform on some aspects on HF development, progression and long-term outcomes, but most have failed to enter clinical practice. This may be due to the biological complexity of remodelling, so that no single biomarker could provide great insight on remodelling when assessed alone. Another possible reason is a still incomplete understanding of the role of biomarkers in the pathophysiology of cardiac remodelling. Such role will be investigated in the first part of this review paper on biomarkers of cardiac remodelling.
Published: 2022

41. Early effect of thrombolysis on structural brain network organisation after anterior-circulation stroke in the randomized WAKE-UP trial

Author: Eckhard Schlemm, Märit Jensen, Amy Kuceyeski, Keith Jamison, Thies Ingwersen, Carola Mayer, Alina Königsberg, Florent Boutitie, Martin Ebinger, Matthias Endres, Jochen B. Fiebach, Jens Fiehler, Ivana Galinovic, Robin Lemmens, Keith W. Muir, Norbert Nighoghossian, Salvador Pedraza, Josep Puig, Claus Z. Simonsen, Vincent Thijs, Anke Wouters, Christian Gerloff, Götz Thomalla, Bastian Cheng, Universitaetsklinikum Hamburg-Eppendorf = University Medical Center Hamburg-Eppendorf [Hamburg] (UKE), Weill Cornell Medicine [Cornell University], Cornell University [New York], University Hospital Hamburg-Eppendorf, 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), 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 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), 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)-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), Girona Biomedical Research Institute [Girona, Spain] (IDIBGI), Aarhus University Hospital, University of Melbourne, Austin Hospital [Melbourne], Austin Health, Amsterdam UMC - Amsterdam University Medical Center, Weill Cornell Medicine [New York], 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 CarMeN, laboratoire
Subjects: [SDV.BA] Life Sciences [q-bio]/Animal biology, RECANALIZATION, Neuroimaging, CONNECTOME, Brain Ischemia, Fibrinolytic Agents, CONNECTIVITY, therapeutic use [Fibrinolytic Agents], diagnostic imaging [Stroke], ischemic stroke, systemic thrombolysis, Humans, Thrombolytic Therapy, Radiology, Nuclear Medicine and imaging, structural connectivity, ACUTE ISCHEMIC-STROKE, ddc:610, diagnostic imaging [Brain], adverse effects [Tissue Plasminogen Activator], Science & Technology, Radiological and Ultrasound Technology, network neuroscience, [SDV.BA]Life Sciences [q-bio]/Animal biology, Radiology, Nuclear Medicine & Medical Imaging, Neurosciences, Brain, ASSOCIATION, methods [Thrombolytic Therapy], RECOVERY, adverse effects [Fibrinolytic Agents], COGNITIVE IMPAIRMENT, REGIONS, adverse effects [Thrombolytic Therapy], DYSFUNCTION, drug therapy [Stroke], Stroke, therapeutic use [Tissue Plasminogen Activator], Treatment Outcome, Neurology, TISSUE, diagnostic imaging [Brain Ischemia], Tissue Plasminogen Activator, drug therapy [Brain Ischemia], Neurosciences & Neurology, Neurology (clinical), Anatomy, Life Sciences & Biomedicine
Abstract: The symptoms of acute ischemic stroke can be attributed to disruption of the brain network architecture. Systemic thrombolysis is an effective treatment that preserves structural connectivity in the first days after the event. Its effect on the evolution of global network organisation is, however, not well understood. We present a secondary analysis of 269 patients from the randomized WAKE-UP trial, comparing 127 imaging-selected patients treated with alteplase with 142 controls who received placebo. We used indirect network mapping to quantify the impact of ischemic lesions on structural brain network organisation in terms of both global parameters of segregation and integration, and local disruption of individual connections. Network damage was estimated before randomization and again 22 to 36 h after administration of either alteplase or placebo. Evolution of structural network organisation was characterised by a loss in integration and gain in segregation, and this trajectory was attenuated by the administration of alteplase. Preserved brain network organization was associated with excellent functional outcome. Furthermore, the protective effect of alteplase was spatio-topologically nonuniform, concentrating on a subnetwork of high centrality supported in the salvageable white matter surrounding the ischemic cores. This interplay between the location of the lesion, the pathophysiology of the ischemic penumbra, and the spatial embedding of the brain network explains the observed potential of thrombolysis to attenuate topological network damage early after stroke. Our findings might, in the future, lead to new brain network-informed imaging biomarkers and improved prognostication in ischemic stroke. ispartof: HUMAN BRAIN MAPPING vol:43 issue:16 pages:5053-5065 ispartof: location:United States status: published
Published: 2022

42. Characteristics and outcomes of patients screened for transcatheter mitral valve implantation: 1-year results from the CHOICE-MI registry

Author: Ben Ali, Walid, Ludwig, Sebastian, Duncan, Alison, Weimann, Jessica, Nickenig, Georg, Tanaka, Tetsu, Coisne, Augustin, Vincentelli, Andre, Makkar, Raj, Webb, John G., Akodad, Mariama, Muller, David W.M., Praz, Fabien, Wild, Mirjam G., Hausleiter, Jörg, Goel, Sachin S., von Ballmoos, Moritz Wyler, Denti, Paolo, Chehab, Omar, Redwood, Simon, Dahle, Gry, Baldus, Stephan, Adam, Matti, Ruge, Hendrik, Lange, Rüdiger, Kaneko, Tsuyoshi, Leroux, Lionel, Dumonteil, Nicolas, Tchetche, Didier, Treede, Hendrik, Flagiello, Michele, Obadia, Jean Francois, Walther, Thomas, Taramasso, Maurizio, Søndergaard, Lars, Bleiziffer, Sabine, Rudolph, Tanja K., Fam, Neil, Kempfert, Joerg, Granada, Juan F., Tang, Gilbert H.L., von Bardeleben, Ralph Stephan, Conradi, Lenard, Modine, Thomas, Kalbacher, Daniel, Blankenberg, Stefan, Koell, Benedikt, Schofer, Niklas, Westermann, Dirk, Weber, Marcel, CarMeN, laboratoire, Montreal Heart Institute - Institut de Cardiologie de Montréal, Universitaetsklinikum Hamburg-Eppendorf = University Medical Center Hamburg-Eppendorf [Hamburg] (UKE), German Center for Cardiovascular Research (DZHK), Berlin Institute of Health (BIH), Cardiovascular Research Foundation [New York, NY, USA] (CRF), Royal Brompton Hospital, Heart Center Bonn [Bonn, Germany] (HCB), University Hospital Bonn, CHU Lille, Cedars-Sinai Medical Center, St. Paul’s Hospital - University of British Columbia [Vancouver, BC, Canada] (SPH-UBC), St. Vincent's Hospital, Sydney, Bern University Hospital [Berne] (Inselspital), Ludwig Maximilian University [Munich] (LMU), Houston Methodist Hospital [Houston, TX, USA], IRCCS Ospedale San Raffaele [Milan, Italy], Guy's and St Thomas' Hospital [London], Oslo University Hospital [Oslo], University Hospital of Cologne [Cologne], German Heart Center = Deutsches Herzzentrum München [Munich, Germany] (GHC), Brigham and Women’s Hospital [Boston, MA], Harvard Medical School [Boston] (HMS), CHU Bordeaux [Bordeaux], Clinique Pasteur [Toulouse], University Medical Center [Mainz], Hôpital Louis Pradel [CHU - HCL], Hospices Civils de Lyon (HCL), Frankfurt University Hospital, Heart Center Hirslanden = HerzZentrum Hirslanden [Zürich, Switzerland] (HCL), Hôpital national = Rigshospitalet [Copenhagen, Denmark] (HNC), Heart and Diabetes Center NRW [Bad Oeynhausen, Germany] (HDC), St. Michael's Hospital, Mount Sinai Hospital [New York City, NY, USA] (MSH), University Heart Center [Hamburg], CHOICE-MI Investigators: Daniel Kalbacher, Stefan Blankenberg, Benedikt Koell, Niklas Schofer, Dirk Westermann, Marcel Weber, Johanna Vogelhuber, François Pontana, Eric Van Belle, Sung-Han Yoon, Anthony Chuang, Robert H Boone, Paul Jansz, Ning Song, Sara Hungerford, Stephan Windecker, David Reineke, Michael Reardon, Neal S Kleiman, Alessandra Sala, Eustachio Agricola, Francesco Maisano, Ronak Rajani, Bernard Prendergast, Kjell A Rein, Maria I Koerber, Laurin Ochs, Keti Vitanova, Magdalena Erlebach, Pinak Shah, Morgan Harloff, Guillaume Bonnet, Mathieu Pernot, Melchior Jonveaux, Felix Kreidel, Tobias Ruf, Matteo Pozzi, Razvan Dragulescu, Tomas Holubec, Heike Strohschnitter, Claudia Walther, Alberto Pozzoli, Ivan Wong, Kai Friedrichs, Mark Peterson, Axel Unbehaun, Markus Kofler., Ben Ali, Walid, Ludwig, Sebastian, Duncan, Alison, Weimann, Jessica, Nickenig, Georg, Tanaka, Tetsu, Coisne, Augustin, Vincentelli, Andre, Makkar, Raj, Webb, John G, Akodad, Mariama, Muller, David W M, Praz, Fabien, Wild, Mirjam G, Hausleiter, Jörg, Goel, Sachin S, von Ballmoos, Moritz Wyler, Denti, Paolo, Chehab, Omar, Redwood, Simon, Dahle, Gry, Baldus, Stephan, Adam, Matti, Ruge, Hendrik, Lange, Rüdiger, Kaneko, Tsuyoshi, Leroux, Lionel, Dumonteil, Nicola, Tchetche, Didier, Treede, Hendrik, Flagiello, Michele, Obadia, Jean-Francoi, Walther, Thoma, Taramasso, Maurizio, Søndergaard, Lar, Bleiziffer, Sabine, Rudolph, Tanja K, Fam, Neil, Kempfert, Joerg, Granada, Juan F, Tang, Gilbert H L, von Bardeleben, Ralph Stephan, Conradi, Lenard, Modine, Thoma, and Agricola, Eustachio
Subjects: Heart Failure, Heart Valve Prosthesis Implantation, Cardiac Catheterization, Medical therapy, [SDV]Life Sciences [q-bio], 610 Medizin, Mitral valve surgery, Mitral Valve Insufficiency, 610 Medicine & health, [SDV] Life Sciences [q-bio], Treatment Outcome, 610 Medical sciences, Humans, Mitral Valve, Registries, Cardiology and Cardiovascular Medicine, Transcatheter mitral valve implantation, Transcatheter edge-to-edge repair, Mitral regurgitation
Abstract: AIMS Transcatheter mitral valve implantation (TMVI) represents a novel treatment option for patients with mitral regurgitation (MR) unsuitable for established therapies. The CHOICE-MI registry aimed to investigate outcomes of patients undergoing screening for TMVI. METHODS AND RESULTS From 05/2014 to 03/2021, patients with MR considered suboptimal candidates for transcatheter edge-to-edge repair (TEER) and at high risk for mitral valve surgery underwent TMVI screening at 26 centres. Characteristics and outcomes were investigated for patients undergoing TMVI and for TMVI-ineligible patients referred to bailout-TEER, high-risk surgery or medical therapy (MT). The primary composite endpoint was all-cause mortality or heart failure hospitalisation after 1 year. Among 746 patients included (78.5 years [IQR 72.0-83.0], EuroSCORE II 4.7% [IQR 2.7-9.7]), 229 patients (30.7%) underwent TMVI with ten different dedicated devices. At 1 year, residual MR ≤1+ was present in 95.2% and the primary endpoint occurred in 39.2% of patients treated with TMVI. In TMVI-ineligible patients (N = 517, 69.3%), rates of residual MR ≤1+ were 37.2%, 100.0% and 2.4% after bailout-TEER, high-risk surgery and MT, respectively. The primary endpoint at 1 year occurred in 28.8% of patients referred to bailout-TEER, in 42.9% of patients undergoing high-risk surgery and in 47.9% of patients remaining on MT. CONCLUSION This registry included the largest number of patients treated with TMVI to date. TMVI with ten dedicated devices resulted in predictable MR elimination and sustained functional improvement at 1 year. In TMVI-ineligible patients, bailout-TEER and high-risk surgery represented reasonable alternatives, while MT was associated with poor clinical and functional outcomes. This article is protected by copyright. All rights reserved.
Published: 2022

43. Patient-Reported Quality of Life After Intravenous Alteplase for Stroke in the WAKE-UP Trial

Author: Märit Jensen, Susanne Sehner, Bastian Cheng, Eckhard Schlemm, Fanny Quandt, Ewgenia Barow, Karl Wegscheider, Florent Boutitie, Martin Ebinger, Matthias Endres, Jochen B. Fiebach, Vincent Thijs, Robin Lemmens, Keith W. Muir, Norbert Nighoghossian, Salvador Pedraza, Claus Z. Simonsen, Götz Thomalla, Christian Gerloff, CarMeN, laboratoire, Universitaetsklinikum Hamburg-Eppendorf = University Medical Center Hamburg-Eppendorf [Hamburg] (UKE), University Hospital Hamburg-Eppendorf, Hospices Civils de Lyon (HCL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon, Service de Biostatistiques [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), 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 Melbourne, Austin Hospital [Melbourne], Austin Health, 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), 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, 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: drug therapy [Ischemic Stroke], [SDV.AEN] Life Sciences [q-bio]/Food and Nutrition, Treatment Outcome, Tissue Plasminogen Activator, chemically induced [Stroke], Quality of Life, Humans, ddc:610, Patient Reported Outcome Measures, Neurology (clinical), [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition, drug therapy [Stroke]
Abstract: Background and ObjectivesIntravenous alteplase improves functional outcome after acute ischemic stroke. However, little is known about the effects on self-reported health-related quality of life (HRQoL).MethodsWAKE-UP was a multicenter, randomized, placebo-controlled trial of MRI-guided intravenous alteplase in stroke with unknown onset time. HRQoL was assessed using the EuroQol five-dimensional questionnaire (EQ-5D) at 90 days, comprising the EQ-5D index and the EQ visual analogue scale (VAS). Functional outcome was assessed by the modified Rankin Scale (mRS). We calculated the effect of treatment on EQ-5D index and EQ VAS using multiple linear regression models. Mediation analysis was performed on stroke survivors to explore the extent to which the effect of alteplase on HRQoL was mediated by functional outcome.ResultsAmong 490 stroke survivors, the EQ-5D index was available for 452 (92.2%), of whom 226 (50%) were assigned to treatment with alteplase and 226 (50%) to placebo. At 90 days, mean EQ-5D index was higher, reflecting a better health state, in patients randomized to treatment with alteplase than with placebo (0.75 vs 0.67) with an adjusted mean difference of 0.07 (95% CI 0.02–0.12,p= 0.005). In addition, mean EQ VAS was higher with alteplase than with placebo (72.6 vs 64.9), with an adjusted mean difference of 7.6 (95% CI 3.9–11.8,p< 0.001). Eighty-five percent of the total treatment effect of alteplase on the EQ-5D index was mediated using the mRS score while there was no significant direct effect. By contrast, the treatment effect on the EQ VAS was mainly through the direct pathway (60%), whereas 40% was mediated by the mRS.DiscussionAssessment of patient-reported outcome measures reveals a potential benefit of intravenous alteplase for HRQoL beyond improvement of functional outcome.Trial Registration InformationClinicalTrials.govnumber,NCT01525290; EudraCT number, 2011-005906-32.
Published: 2022

44. Cerebral Microbleeds and Treatment Effect of Intravenous Thrombolysis in Acute Stroke:An Analysis of the WAKE-UP Randomized Clinical Trial

Author: Norbert Nighoghossian, Jan Vynckier, Josep Puig, Vincent Thijs, Claus Z Simonsen, Tim Bastian Braemswig, Götz Thomalla, Märit Jensen, Florent Boutitie, Ivana Galinovic, Christian H. Nolte, Christian Gerloff, Bastian Cheng, Martin Ebinger, Keith W. Muir, Jens Fiehler, Salvador Pedraza, Robin Lemmens, Matthias Endres, Jochen B. Fiebach, Ludwig Schlemm, Wake-Up investigators, Tae-Hee Cho, CarMeN, laboratoire, Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Klinik für Neurologie, Westfälische Wilhelms-Universität Münster = University of Münster (WWU), Humboldt University Of Berlin, Berlin Institute of Health (BIH), Center for Stroke Research Berlin, Freie Universität Berlin, 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), Bern University Hospital [Berne] (Inselspital), Universitaetsklinikum Hamburg-Eppendorf = University Medical Center Hamburg-Eppendorf [Hamburg] (UKE), 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), Josep Trueta University Hospital, Institut d'Investigació Biomèdica de Girona Dr. Josep Trueta - Girona Biomedical Research Institute (IDIBGI), University of Glasgow, German Center for Cardiovascular Research (DZHK), 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), and VIB Center for Brain & Disease Research [Leuven, Belgium]
Subjects: Male, medicine.medical_specialty, [SDV]Life Sciences [q-bio], medicine.medical_treatment, Placebo, law.invention, Fibrinolytic Agents, Randomized controlled trial, law, Modified Rankin Scale, Internal medicine, diagnostic imaging [Stroke], medicine, Humans, ddc:610, Prospective Studies, Stroke, adverse effects [Tissue Plasminogen Activator], Ischemic Stroke, Intracerebral hemorrhage, drug therapy [Cerebral Hemorrhage], business.industry, methods [Thrombolytic Therapy], Thrombolysis, Odds ratio, diagnostic imaging [Cerebral Hemorrhage], adverse effects [Thrombolytic Therapy], medicine.disease, etiology [Cerebral Hemorrhage], drug therapy [Stroke], [SDV] Life Sciences [q-bio], Treatment Outcome, Clinical research, Tissue Plasminogen Activator, Neurology (clinical), business
Abstract: Background and ObjectivesCerebral microbleeds (CMBs) are common in patients with acute ischemic stroke and are associated with increased risk of intracerebral hemorrhage (ICH) after intravenous thrombolysis. Whether CMBs modify the treatment effect of thrombolysis is unknown.MethodsWe performed a prespecified analysis of the prospective randomized controlled multicenter Efficacy and Safety of MRI-Based Thrombolysis in Wake-Up Stroke (WAKE-UP) trial including patients with acute ischemic stroke with unknown time of symptom onset and diffusion-weighted imaging–fluid-attenuated inversion recovery mismatch on MRI receiving alteplase or placebo. Patients were screened and enrolled between September 2012 and June 2017 (with final follow-up in September 2017). Patients were randomized to treatment with IV thrombolysis with alteplase at 0.9 mg/kg body weight or placebo. CMB status (presence, number, and distribution) was assessed after study completion by 3 raters blinded to clinical information following a standardized protocol. Outcome measures were excellent functional outcome at 90 days, defined by modified Rankin Scale (mRS) score ≤1, and symptomatic ICH according to National Institutes of Neurological Disease and Stroke trial criteria 22 to 36 hours after treatment.ResultsOf 503 patients enrolled in the WAKE-UP trial, 459 (91.3%; 288 [63%] men) were available for analysis. Ninety-eight (21.4%) had at least 1 CMB on baseline imaging; 45 (9.8%) had exactly 1 CMB; 37 (8.1%) had 2 to 4 CMBs; and 16 (3.5%) had ≥5 CMBs. Presence of CMBs was associated with a nonsignificant increased risk of symptomatic ICH (11.2% vs 4.2%; adjusted odds ratio [OR] 2.32, 95% confidence interval [CI] 0.99–5.43, p = 0.052) but had no effect on functional outcome at 90 days (mRS score ≤1: 45.8% vs 50.7%; adjusted OR 0.99, 95% CI 0.59–1.64, p = 0.955). Patients receiving alteplase had better functional outcome (mRS score ≤1: 54.6% vs 44.6%, adjusted OR 1.61, 95% CI 1.07–2.43, p = 0.022) without evidence of heterogeneity in relation to CMB presence (p of the interactive term = 0.546). Results were similar for subpopulations with strictly lobar (presumed cerebral amyloid angiopathy related) or not strictly lobar CMB distribution.DiscussionIn the randomized-controlled WAKE-UP trial, we saw no evidence of reduced treatment effect of alteplase in patients with acute ischemic stroke with ≥1 CMBs. Additional studies are needed to determine the treatment effect of alteplase and its benefit-harm ratio in patients with a larger number of CMBs.Trial Registration InformationClinicalTrials.gov identifier NCT01525290; ClinicalTrialsRegister.EU identifier 2011-005906-32.Classification of EvidenceThis study provides Class II evidence that for patients with acute ischemic stroke with unknown time of onset and diffusion-weighted imaging–fluid-attenuated inversion recovery mismatch who received IV alteplase, CMBs are not significantly associated with functional outcome at 90 days.
Published: 2022

45. Mineralocorticoid Receptor Antagonists and Empagliflozin in Patients With Heart Failure and Preserved Ejection Fraction

Author: João Pedro Ferreira, Javed Butler, Faiez Zannad, Gerasimos Filippatos, Elke Schueler, Dominik Steubl, Cordula Zeller, James L. Januzzi, Stuart Pocock, Milton Packer, Stefan D. Anker, 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, Mississippi State University [Mississippi], National and Kapodistrian University of Athens (NKUA), Université d'Athènes (UOA), mainanalytics GmbH, Boehringer Ingelheim Pharma GmbH & Co. KG, Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM), Massachusetts General Hospital [Boston], Baim Institute for Clinical Research Boston MA, Harvard Medical School [Boston] (HMS), London School of Hygiene and Tropical Medicine (LSHTM), Baylor College of Medecine, Imperial College London, Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], German Center for Cardiovascular Research (DZHK), Berlin Institute of Health (BIH), and The EMPEROR-Reduced trial (NCT03057977) was funded by Boehringer Ingelheim and Eli Lilly.
Subjects: Heart Failure, heart failure with preserved ejection fraction, treatment effect, empagliflozin, Stroke Volume, hyperkalemia, eye diseases, nervous system diseases, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Glucosides, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Chronic Disease, cardiovascular system, Humans, cardiovascular diseases, Benzhydryl Compounds, mineralocorticoid receptor antagonists, Cardiology and Cardiovascular Medicine, circulatory and respiratory physiology
Abstract: BACKGROUND: Mineralocorticoid receptor antagonists (MRAs) may be beneficial in reducing heart failure (HF) hospitalizations in patients with HF with preserved ejection fraction. The effect of sodium-glucose cotransporter 2 inhibitors in patients with HF with preserved ejection fraction according to MRA background therapy has not been reported. OBJECTIVES: The aim of this study was to examine the effect of empagliflozin in MRA users and nonusers in the EMPEROR-Preserved (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Preserved Ejection Fraction) trial. METHODS: Survival analyses were conducted comparing the effects of empagliflozin vs placebo in MRA users and nonusers at baseline with treatment-by-MRA use interaction terms. RESULTS: A total of 5,988 patients were included, of whom 2,244 (37.5%) were using MRAs at baseline. MRA users had higher event rates than MRA nonusers (placebo group primary outcome 9.4 vs 8.2 events per 100 person-years). The benefit of empagliflozin to reduce the primary outcome was not significantly different between MRA nonusers and MRA users (HR: 0.73 [95% CI: 0.62-0.87] and HR: 0.87 [95% CI: 0.71-1.06]; interaction P = 0.22). The effect of empagliflozin to reduce first and recurrent HF hospitalizations was more pronounced in MRA nonusers than in MRA users (HR: 0.60 [95% CI: 0.47-0.77] and HR: 0.90 [95% CI: 0.68-1.19]; interaction P = 0.038). MRA users experienced almost twice as many hyperkalemia events as MRA nonusers, and empagliflozin reduced the risk for hyperkalemia or initiation of potassium binders regardless of MRA use (MRA nonusers: HR: 0.90 [95% CI: 0.69-1.19]; MRA users: HR: 0.74 [95% CI: 0.56-0.96]; interaction P = 0.29). CONCLUSIONS: The benefit of empagliflozin to reduce the primary outcome was not significantly different between MRA nonusers and MRA users. The effect of empagliflozin to reduce first and recurrent HF hospitalizations was more pronounced in MRA nonusers. Empagliflozin reduced hyperkalemia, with no significant treatment-by-MRA subgroup interaction. (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Preserved Ejection Fraction [EMPEROR-Preserved]; NCT03057951).
Published: 2022

46. Clinical implications of left atrial changes after optimization of medical therapy in patients with heart failure

Author: Riccardo M. Inciardi, Matteo Pagnesi, Carlo M. Lombardi, Stefan D. Anker, John G. Cleland, Kenneth Dickstein, Gerasimos S. Filippatos, Chim C. Lang, Leong L. Ng, Pierpaolo Pellicori, Piotr Ponikowski, Nilesh J. Samani, Faiez Zannad, Dirk J. van Veldhuisen, Scott D. Solomon, Adriaan A. Voors, Marco Metra, 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, EudraCT 2010–020808–29 - INCOMING, Università degli Studi di Brescia = University of Brescia (UniBs), Azienda Socio Sanitaria Territoriale Spedali Civili di Brescia [Brescia], 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), National Heart and Lung Institute [London] (NHLI), Imperial College London-Royal Brompton and Harefield NHS Foundation Trust, Robertson Centre for Biostatistics, University of Glasgow, University of Bergen (UiB), Stavanger University Hospital, National and Kapodistrian University of Athens (NKUA), Université d'Athènes (UOA), University of Athens, Attikon Hospital, University of Dundee, Ninewells Hospital and Medical School [Dundee], University of Leicester, NIHR Leicester Biomedical Research Centre, Glenfield Hospital, University of Glasgow, Glasgow Royal Infirmary, University of Wrocław [Poland] (UWr), 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 ), University Medical Center Groningen [Groningen] (UMCG), Brigham and Women’s Hospital [Boston, MA], Harvard Medical School [Boston] (HMS), The BIOSTAT-CHF project was funded by a grant from the European Commission (FP7-242209-BIOSTAT-CHF, EudraCT 2010–020808–29), European Project: 242209,EC:FP7:HEALTH,FP7-HEALTH-2009-single-stage,BIOSTAT-CHF(2010), and European Project
Subjects: Male, Guideline-directed medical therapy, Angiotensin-Converting Enzyme Inhibitors, Heart failure, Middle Aged, Left atrium, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Angiotensin Receptor Antagonists, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Atrial Fibrillation, Humans, Female, Cardiology and Cardiovascular Medicine, Aged
Abstract: Introduction: \ud Limited data exist regarding the prognostic relevance of changes in left atrial (LA) dimensions in patients with heart failure (HF). We assessed changes in LA dimension and their relation with outcomes after optimization of guideline-directed medical therapy (GDMT) in patients with worsening HF.\ud \ud Methods and Results: \ud LA diameter was assessed at baseline and 9 months after GDMT optimization in 632 patients (mean age 65.8±12.1 years, 22.3% female) enrolled in BIOSTAT-CHF. LA adverse remodelling (LAAR) was defined as an increase in LA diameter on transthoracic echocardiography between baseline and 9 months. After the 9-month visit, patients were followed for a median of 13 further months. LAAR was observed in 247 patients (39%). Larger baseline LA diameter (odds ratio (OR) 0.90; 95% confidence interval (95% CI) 0.87 – 0.93; p
Published: 2022

47. Identification of risk loci for primary aldosteronism in genome-wide association studies

Author: Edith Le Floch, Teresa Cosentino, Casper K. Larsen, Felix Beuschlein, Martin Reincke, Laurence Amar, Gian-Paolo Rossi, Kelly De Sousa, Stéphanie Baron, Sophie Chantalat, Benjamin Saintpierre, Livia Lenzini, Arthur Frouin, Isabelle Giscos-Douriez, Matthis Ferey, Alaa B. Abdellatif, Tchao Meatchi, Jean-Philippe Empana, Xavier Jouven, Christian Gieger, Melanie Waldenberger, Annette Peters, Daniele Cusi, Erika Salvi, Pierre Meneton, Mathilde Touvier, Mélanie Deschasaux, Nathalie Druesne-Pecollo, Sheerazed Boulkroun, Fabio L. Fernandes-Rosa, Jean-François Deleuze, Xavier Jeunemaitre, Maria-Christina Zennaro, Fernandes Rosa, Fabio, Centre National de Recherche en Génomique Humaine (CNRGH), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Institut de Biologie François JACOB (JACOB), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), 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), Ludwig-Maximilians University [Munich] (LMU), Universität Zürich [Zürich] = University of Zurich (UZH), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Università degli Studi di Padova = University of Padua (Unipd), Université Paris Cité (UPCité), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Helmholtz Zentrum München = German Research Center for Environmental Health, German Center for Diabetes Research - Deutsches Zentrum für Diabetesforschung [Neuherberg] (DZD), German Center for Cardiovascular Research (DZHK), Berlin Institute of Health (BIH), Consiglio Nazionale delle Ricerche [Milano] (CNR), Fondazione IRCCS Istituto Neurologico 'Carlo Besta', Laboratoire d'Informatique Médicale et Ingénierie des Connaissances en e-Santé (LIMICS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Sorbonne Paris Nord, Equipe 3: EREN- Equipe de Recherche en Epidémiologie Nutritionnelle (CRESS - U1153), Université Sorbonne Paris Nord-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)-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), and ANR-18-CE93-0003,GenAdEx,Contributeurs génétiques et moléculaires à l'excès d'hormones corticosurrénaliennes(2018)
Subjects: Male, [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, [SDV.GEN]Life Sciences [q-bio]/Genetics, Multidisciplinary, General Physics and Astronomy, Adrenalectomy, General Chemistry, Aldosterone, Animals, DNA-Binding Proteins, Genome-Wide Association Study, Humans, Mice, Transcription Factors, Adrenal Cortex Neoplasms, Adrenocortical Adenoma, Hyperaldosteronism, [SDV.GEN] Life Sciences [q-bio]/Genetics, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, General Biochemistry, Genetics and Molecular Biology, [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: Primary aldosteronism affects up to 10% of hypertensive patients and is responsible for treatment resistance and increased cardiovascular risk. Here we perform a genome-wide association study in a discovery cohort of 562 cases and 950 controls and identify three main loci on chromosomes 1, 13 and X; associations on chromosome 1 and 13 are replicated in a second cohort and confirmed by a meta-analysis involving 1162 cases and 3296 controls. The association on chromosome 13 is specific to men and stronger in bilateral adrenal hyperplasia than aldosterone producing adenoma. Candidate genes located within the two loci, CASZ1 and RXFP2, are expressed in human and mouse adrenals in different cell clusters. Their overexpression in adrenocortical cells suppresses mineralocorticoid output under basal and stimulated conditions, without affecting cortisol biosynthesis. Our study identifies the first risk loci for primary aldosteronism and highlights new mechanisms for the development of aldosterone excess.
Published: 2022

48. SGLT2 inhibitors in patients with heart failure with reduced ejection fraction: a meta-analysis of the EMPEROR-Reduced and DAPA-HF trials

Author: Milton Packer, Waheed Jamal, Stefan D. Anker, Stuart J. Pocock, João Pedro Ferreira, Javed Butler, Anne Pernille Ofstad, Gerasimos Filippatos, Martina Brueckmann, Egon Pfarr, Faiez Zannad, 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), London School of Hygiene and Tropical Medicine (LSHTM), Berlin Institute of Health (BIH), Department of Medicine, University of Washington [Seattle], and Imperial College London
Subjects: Male, medicine.medical_specialty, [SDV]Life Sciences [q-bio], Type 2 diabetes, 030204 cardiovascular system & hematology, Body Mass Index, Angiotensin Receptor Antagonists, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Glucosides, Cause of Death, Internal medicine, Diabetes mellitus, Empagliflozin, medicine, Clinical endpoint, Humans, 030212 general & internal medicine, Benzhydryl Compounds, Dapagliflozin, Sodium-Glucose Transporter 2 Inhibitors, Aged, Heart Failure, Clinical Trials as Topic, Ejection fraction, business.industry, Hazard ratio, Stroke Volume, General Medicine, Middle Aged, medicine.disease, 3. Good health, Death, Hospitalization, Patient Outcome Assessment, Diabetes Mellitus, Type 2, chemistry, Case-Control Studies, Heart failure, Cardiology, Drug Therapy, Combination, Female, Neprilysin, business, Glomerular Filtration Rate
Abstract: Both DAPA-HF (assessing dapagliflozin) and EMPEROR-Reduced (assessing empagliflozin) trials showed that sodium-glucose co-transporter-2 (SGLT2) inhibition reduced the combined risk of cardiovascular death or hospitalisation for heart failure in patients with heart failure with reduced ejection fraction (HFrEF) with or without diabetes. However, neither trial was powered to assess effects on cardiovascular death or all-cause death or to characterise effects in clinically important subgroups. Using study-level published data from DAPA-HF and patient-level data from EMPEROR-Reduced, we aimed to estimate the effect of SGLT2 inhibition on fatal and non-fatal heart failure events and renal outcomes in all randomly assigned patients with HFrEF and in relevant subgroups from DAPA-HF and EMPEROR-Reduced trials.We did a prespecified meta-analysis of the two single large-scale trials assessing the effects of SGLT2 inhibitors on cardiovascular outcomes in patients with HFrEF with or without diabetes: DAPA-HF (assessing dapagliflozin) and EMPEROR-Reduced (assessing empagliflozin). The primary endpoint was time to all-cause death. Additionally, we assessed the effects of treatment in prespecified subgroups on the combined risk of cardiovascular death or hospitalisation for heart failure. These subgroups were based on type 2 diabetes status, age, sex, angiotensin receptor neprilysin inhibitor (ARNI) treatment, New York Heart Association (NYHA) functional class, race, history of hospitalisation for heart failure, estimated glomerular filtration rate (eGFR), body-mass index, and region (post-hoc). We used hazard ratios (HRs) derived from Cox proportional hazard models for time-to-first event endpoints and Cochran's Q test for treatment interactions; the analysis of recurrent events was based on rate ratios derived from the Lin-Wei-Yang-Ying model.Among 8474 patients combined from both trials, the estimated treatment effect was a 13% reduction in all-cause death (pooled HR 0·87, 95% CI 0·77-0·98; p=0·018) and 14% reduction in cardiovascular death (0·86, 0·76-0·98; p=0·027). SGLT2 inhibition was accompanied by a 26% relative reduction in the combined risk of cardiovascular death or first hospitalisation for heart failure (0·74, 0·68-0·82; p0·0001), and by a 25% decrease in the composite of recurrent hospitalisations for heart failure or cardiovascular death (0·75, 0·68-0·84; p0·0001). The risk of the composite renal endpoint was also reduced (0·62, 0·43-0·90; p=0·013). All tests for heterogeneity of effect size between trials were not significant. The pooled treatment effects showed consistent benefits for subgroups based on age, sex, diabetes, treatment with an ARNI and baseline eGFR, but suggested treatment-by-subgroup interactions for subgroups based on NYHA functional class and race.The effects of empagliflozin and dapagliflozin on hospitalisations for heart failure were consistent in the two independent trials and suggest that these agents also improve renal outcomes and reduce all-cause and cardiovascular death in patients with HFrEF.Boehringer Ingelheim.
Published: 2020

49. Toward personalization of asthma treatment according to trigger factors

Author: Luis Caraballo, Susanne Greber-Platzer, W. Pohl, Bulent Enis Sekerel, Valérie Siroux, Elena S. Fedenko, Natalia Ilina, Paolo Maria Matricardi, Harald Renz, Petra Pazderova, Zhanat Ispayeva, Elopy Sibanda, Kian Fan Chung, Nikolaos G. Papadopoulos, Hugo Van Bever, Marianne van Hage, Alexander Emelyanov, S. G. Makarova, Roxana S. Bumbacea, Carmen Panaitescu, Erika von Mutius, Faith H. A. Osier, Sebastian L. Johnston, Jin Lyu Sun, Gary W.K. Wong, R S Fassakhov, Ludmila P. Sizyakina, Kristina Borochova, Jiu-Yao Wang, Evgeny Beltyukov, Zhongshan Gao, Kari C. Nadeau, Antonina Karsonova, Marco Idzko, Snezhana Bychkovskaya, A.N. Pampura, Katarzyna Niespodziana, Peter Errhalt, Tatiana Baranovskaya, Dmitry Kudlay, M. Gotua, Natalia Astafyeva, Thomas Schlederer, Marek L. Kowalski, Rezeda Fayzullina, Musa Khaitov, Tetiana Umanets, Ksenja Riabova, Leyla Namazova-Baranova, Pedro Giavina-Bianchi, Ruby Pawankar, Mohamed-Ridha Barbouche, Zsolt Szépfalusi, Sergii Zaikov, Hae-Sim Park, Guillermo Horacio Docena, Irina Evsegneeva, Mihaela Zidarn, Michael Levin, Adnan Custovic, Jean Bousquet, Elena Kovzel, Paul M. O'Byrne, Daria Fomina, Oleksandr Nazarenko, Elena Borzova, Thomas Eiwegger, Olga Naumova, Gunilla Hedlin, Omer Kalayci, Rudolf Valenta, Vanitha Sampath, Angelika Berger, Margarita Vasileva, Alexander Karaulov, Graduate School, Medical Microbiology and Infection Prevention, AII - Inflammatory diseases, Salvy-Córdoba, Nathalie, Medizinische Universität Wien = Medical University of Vienna, Saratov State Medical University, Partenaires INRAE, Belarusian Medical Academy of Post-Graduate Education [Minsk] (BelMAPGE), Laboratoire d'immunologie clinique [Institut Pasteur de Tunis], Institut Pasteur de Tunis, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), South Ural State Medical University, Russian Medical Academy for Continuous Medical Education [Moscow], Pirogov Russian National Research Medical University, Sechenov First Moscow State Medical University, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), 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), Humboldt University Of Berlin, Berlin Institute of Health (BIH), University of Medicine and Pharmacy 'Carol Davila' Bucharest (UMPCD), Krasnoyarsk State Medical University (KrasSMU), Universidad de Cartagena [Cartagena de Indias], National Heart and Lung Institute [London] (NHLI), Imperial College London-Royal Brompton and Harefield NHS Foundation Trust, Universidad Nacional de la Plata [Argentine] (UNLP), The Hospital for sick children [Toronto] (SickKids), North-Western State Medical University [St Petersburg, Russia], Krems University Hospital, Kazan Federal University (KFU), Bashkir State University (BASHEDU), NRC Institute of immunology FMBA, Moscow Russian federation, Zhejiang Gongshang University [Hangzhou] (ZJSU), Universidade de São Paulo = University of São Paulo (USP), Tbilisi State University, Astrid Lindgren Children's Hospital, Karolinska University Hospital [Stockholm], Karolinska Institutet [Stockholm], Al-Farabi Kazakh National University [Almaty] (KazNU), Faculty of Medicine [Hacettepe University], Hacettepe University = Hacettepe Üniversitesi, Nazarbayev University [Kazakhstan], Medical University of Łódź (MUL), University of Cape Town, Dmitry Rogachev National Research Center of Pediatric Hematology, Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Sean N. Parker Center for Allergy and Asthma Research [Stanford], Stanford Medicine, Stanford University-Stanford University, Pirogov Russian National Reasearch Medical University Moscow, National Academy of Medical Sciences of Ukraine, Shupyk National Medical Academy of Postgraduate Education [Kiev] (SNMAPE), Michael DeGroote School of Medicine [Hamilton, ON, Canada], Faculty of Health Sciences [Hamilton, ON, Canada], McMaster University [Hamilton, Ontario]-McMaster University [Hamilton, Ontario], KEMRI-Wellcome Trust Research Programme (KWTRP), Pius Branzeu Clinical Emergency Hospital (OncoGen), University of Manchester [Manchester], National and Kapodistrian University of Athens (NKUA), Ajou University, Nippon Medical School [Tokyo, Japon], Hietzing Hospital, Karl Landsteiner Institute for Dermatological Research, Landesklinikum St. Poelten, University of Giessen and Marburg Lung Center [Gießen, Germany] (UGMLC), German Center for Lung Research, University of Zimbawe [Harare] (UZ), University of Zimbawe, National University of Science and Technology [Bulawayo], 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), Southern Federal University [Rostov-on-Don] (SFEDU), Peking Union Medical College Hospital [Beijing] (PUMCH), Chinese Academy of Medical Sciences and Peking Union Medical College, National University of Singapore (NUS), Center of Allergology and Clinical Immunology, Dr von Hauner Children's Hospital [Munich, Germany], Ludwig-Maximilians-Universität München (LMU), Helmholtz Centre Munich, German Centre for Lung Research, National Cheng Kung University Hospital [Tainan], The Chinese University of Hong Kong [Hong Kong], Respiratory and Allergic Diseases [Golnik, Slovenia], University Clinic of Respiratory and Allergic Diseases Golnik, University of Ljubljana, and Karl Landsteiner University of Health Sciences - Karl Landsteiner Privatuniversität für Gesundheitswissenschaften [Krems an der Donau, Austria]
Subjects: 0301 basic medicine, Allergy, MESH: Asthma, Rhinovirus, Asthma treatment, CHILDREN, EPITOPE, Disease, Microarray, medicine.disease_cause, sopenje, alergeni, Personalization, Atopy, 0302 clinical medicine, immune system diseases, astma, Immunology and Allergy, MESH: Animals, Precision Medicine, RISK, MESH: Rhinovirus, respiratorni znaki in simptomi, analiza mikromrež, Allergen, alergija in imunologija, SENSITIZATION, personalizirana medicina, Wheeze, rhinovirus, allergy and immunology, INFECTIONS, 1107 Immunology, wheeze, ATOPY, [SDV.IMM]Life Sciences [q-bio]/Immunology, medicine.symptom, Life Sciences & Biomedicine, Bioquímica, medicine.medical_specialty, MESH: Allergens, [SDV.IMM] Life Sciences [q-bio]/Immunology, precision medicine, Immunology, udc:616-097, MESH: Precision Medicine, 03 medical and health sciences, [SDV.MHEP.PED] Life Sciences [q-bio]/Human health and pathology/Pediatrics, rinovirus, medicine, Animals, Humans, allergens, IMMUNOTHERAPY, Intensive care medicine, Asthma, [SDV.MHEP.PED]Life Sciences [q-bio]/Human health and pathology/Pediatrics, MESH: Humans, Science & Technology, business.industry, Allergens, asthma, respiratory, medicine.disease, respiratory tract diseases, signs and symptoms, 030104 developmental biology, ANTIBODY, 030228 respiratory system, Ciencias Médicas, MESH: Biomarkers, microarray analysis, business, Biomarkers, RESPONSES
Abstract: Asthma is a severe and chronic disabling disease affecting more than 300 million people worldwide. Although in the past few drugs for the treatment of asthma were available, new treatment options are currently emerging, which appear to be highly effective in certain subgroups of patients. Accordingly, there is a need for biomarkers that allow selection of patients for refined and personalized treatment strategies. Recently, serological chip tests based on microarrayed allergen molecules and peptides derived from the most common rhinovirus strains have been developed, which may discriminate 2 of the most common forms of asthma, that is, allergen- and virus-triggered asthma. In this perspective, we argue that classification of patients with asthma according to these common trigger factors may open new possibilities for personalized management of asthma., La lista completa de autores que integran el documento puede consultarse en el archivo., Facultad de Ciencias Exactas
Published: 2020

50. Heart failure treatment up‐titration and outcome and age: an analysis of BIOSTAT‐CHF

Author: Kenneth Dickstein, Faiez Zannad, Adriaan A. Voors, Marco Metra, Ify R. Mordi, John G.F. Cleland, Nilesh J. Samani, Stefan D. Anker, Dirk J. van Veldhuisen, Chim C. Lang, Leong L. Ng, Wouter Ouwerkerk, Ninewells Hospital and Medical School [Dundee], University of Dundee, National Heart Centre Singapore (NHCS), Amsterdam UMC - Amsterdam University Medical Center, Charité Campus Virchow-Klinikum (CVK), 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), National Heart and Lung Institute [London] (NHLI), Imperial College London-Royal Brompton and Harefield NHS Foundation Trust, Imperial College London, University of Bergen (UiB), Stavanger University Hospital, Università degli Studi di Brescia = University of Brescia (UniBs), Civic Hospital of Brescia, University of Leicester, University Hospitals Leicester, University Medical Center Groningen [Groningen] (UMCG), Centre d'investigation clinique plurithématique Pierre Drouin [Nancy] (CIC-P), Centre d'investigation clinique [Nancy] (CIC), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Défaillance Cardiovasculaire Aiguë et Chronique (DCAC), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), 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 ), NHS Education for Scotland/Chief Scientist Office Postdoctoral Clinical Lectureship. Grant Number: PCL/17/07, European Commission: FP7-242209-BIOSTAT-CHF, European Project: 242209,EC:FP7:HEALTH,FP7-HEALTH-2009-single-stage,BIOSTAT-CHF(2010), Cardiovascular Centre (CVC), Epidemiology and Data Science, and Dermatology
Subjects: Male, medicine.medical_specialty, medicine.drug_class, Adrenergic beta-Antagonists, Angiotensin-Converting Enzyme Inhibitors, 030204 cardiovascular system & hematology, DIAGNOSIS, MORBIDITY, Angiotensin Receptor Antagonists, 03 medical and health sciences, Elderly, Up-titration, 0302 clinical medicine, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, ACE inhibitor, Internal medicine, Humans, Medicine, ESC GUIDELINES, Beta-blocker, cardiovascular diseases, Angiotensin receptor blocker, ELDERLY-PATIENTS, Beta blocker, Aged, Heart Failure, Ejection fraction, business.industry, BETA-BLOCKERS, MORTALITY, Incidence (epidemiology), Hazard ratio, Stroke Volume, Atrial fibrillation, medicine.disease, RANDOMIZED-TRIAL, Confidence interval, Treatment Outcome, HOSPITALIZATION, Heart failure, SYSTOLIC DYSFUNCTION, ATRIAL-FIBRILLATION, Cardiology, Female, Cardiology and Cardiovascular Medicine, business, medicine.drug
Abstract: Aims:\ud Several studies have shown that older patients with heart failure with reduced ejection fraction (HFrEF) are undertreated. The aim of this study was to evaluate the association of up‐titration of angiotensin‐converting enzyme inhibitors (ACEI), angiotensin receptor blockers (ARB) and beta‐blockers on outcome across the age spectrum in HFrEF patients.\ud \ud Methods and results:\ud We analysed HFrEF patients on sub‐optimal doses of ACEI/ARB and/or beta‐blockers from the BIOSTAT‐CHF study stratified by age. Patients underwent a 3‐month up‐titration period. We used inverse probability weighting to adjust for the likelihood of successful up‐titration to determine the association of achieved dose with mortality and/or heart failure hospitalisation, testing for an interaction with age. Over a median follow‐up of 21 months in 1720 HFrEF patients (76.5% male, mean age 67 years), the primary outcome occurred in 558 patients. Increased percentage of target dose of ACEI/ARB and beta‐blocker achieved at 3 months were both significantly associated with reduced incidence of the primary outcome, [ACEI‐ARB: hazard ratio (HR) per 12.5% increase in dose: 0.92, 95% confidence interval (CI) 0.91–0.94, P
Published: 2020

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