20,593 results on '"Vascular Medicine"'
Search Results
2. Arterial Doppler Waveforms Analysis in PAD (APP-Wave-PAD)
- Author
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French Society of Vascular Medicine
- Published
- 2019
3. Feasibility Study of Unfractionated Heparin in Acute Chest Syndrome
- Author
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Vascular Medicine Institute and Craig Seaman, Assistant Professor of Medicine
- Published
- 2019
4. What Treatment for Patients With Phlebitis or Pulmonary Embolism ? (AntiCoagChoice)
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SFMV (French Society of Vascular Medicine)
- Published
- 2019
5. Practical Recommendations for Optimal Thromboprophylaxis in Patients with COVID-19: A Consensus Statement Based on Available Clinical Trials
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Konstantinos G. Kyriakoulis, Evangelos Dimakakos, Ioannis G. Kyriakoulis, Mariella Catalano, Alex C. Spyropoulos, Sam Schulman, James Douketis, Anna Falanga, Anthony Maraveyas, Dan-Mircea Olinic, Jill Belch, Grigorios Gerotziafas, Konstantinos Syrigos, Anastasios Kollias, and COVID-19 Thrombosis Collaborative Group, Endorsed by VAS-European Independent Foundation in Angiology/Vascular Medicine, UEMS Division of Angiology/Vascular Medicine/and ESVM-European Society of Vascular Medicine and Supported by the Balkan Working Group
- Subjects
anticoagulation ,COVID-19 ,COVID-19 therapeutics ,dosage ,mortality ,thromboprophylaxis ,Medicine - Abstract
Coronavirus disease 2019 (COVID-19) has been shown to be strongly associated with increased risk for venous thromboembolism events (VTE) mainly in the inpatient but also in the outpatient setting. Pharmacologic thromboprophylaxis has been shown to offer significant benefits in terms of reducing not only VTE events but also mortality, especially in acutely ill patients with COVID-19. Although the main source of evidence is derived from observational studies with several limitations, thromboprophylaxis is currently recommended for all hospitalized patients with acceptable bleeding risk by all national and international guidelines. Recently, high quality data from randomized controlled trials (RCTs) further support the role of thromboprophylaxis and provide insights into the optimal thromboprophylaxis strategy. The aim of this statement is to systematically review all the available evidence derived from RCTs regarding thromboprophylaxis strategies in patients with COVID-19 in different settings (either inpatient or outpatient) and provide evidence-based guidance to practical questions in everyday clinical practice. Clinical questions accompanied by practical recommendations are provided based on data derived from 20 RCTs that were identified and included in the present study. Overall, the main conclusions are: (i) thromboprophylaxis should be administered in all hospitalized patients with COVID-19, (ii) an optimal dose of inpatient thromboprophylaxis is dependent upon the severity of COVID-19, (iii) thromboprophylaxis should be administered on an individualized basis in post-discharge patients with COVID-19 with high thrombotic risk, and (iv) thromboprophylaxis should not be routinely administered in outpatients. Changes regarding the dominant SARS-CoV-2 variants, the wide immunization status (increasing rates of vaccination and reinfections), and the availability of antiviral therapies and monoclonal antibodies might affect the characteristics of patients with COVID-19; thus, future studies will inform us about the thrombotic risk and the optimal therapeutic strategies for these patients.
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- 2022
- Full Text
- View/download PDF
6. PTA-Registry, a Prospective, Multicenter Study With 24-Month Follow-up (PTAReg)
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BVMed - The German Medical Technology Association, German Society for Angiology - Society for Vascular Medicine (DGA), and Prof. Dr. K.-L. Schulte, Head of Vascular Center Berlin
- Published
- 2017
7. Classification tree analysis of postal questionnaire data to identify risk of excessive gestational weight gain
- Author
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Fuller-Tyszkiewicz, Matthew, Skouteris, Helen, Hill, Briony, Teede, Helena, and McPhie, Skye
- Published
- 2016
- Full Text
- View/download PDF
8. Evaluation of lipoprotein(a) in the prevention and management of atherosclerotic cardiovascular disease: A survey among the Lipid Clinics Network
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Catapano, Alberico L, Tokgözoğlu, Lale, Banach, Maciej, Gazzotti, Marta, Olmastroni, Elena, Casula, Manuela, Ray, Kausik K, the Lipid Clinics Network, Alaa ABDELRAZIK (University Hospital of North Midland, United Kingdom), Alberto MELLO E SILVA (Sociedade Portuguesa de Aterosclerose, Portugal), Alexander VONBANK (VIVIT Institute, Austria), Alexandros, D TSELEPIS (Dept of Chemistry, Atherothrombosis Research Center, University of Ioannina, Greece), Alper SONMEZ (Department of Endocrinology and Metabolism, Ankara Guven Hospital, Turkey), Angelina PASSARO (Department of Translational Medicine, University of Ferrara &, Center for the Study and Treatment of Metabolic Diseases, Atherosclerosis, and Clinical Nutrition, University Hospital of Ferrara Arcispedale Sant’Anna, Italy), Anja VOGT (Medizinische Klinik und Poliklinik IV, Klinikum der Universit¨at München, Germany), Ann MERTENS (Clinical and Experimental Endocrinology, Leuven, Ku, Leuven, Belgium), Ann VERHAEGEN (Antwerp University Hospital, Belgium), Arman, S POSTADZHIYAN (Medical University of Sofia, Saint Anna University Hospital, Departement of Cardiology, Bulgaria), BAHADIR KIRILMAZ (Canakkale Onsekiz Mart University, Medical Faculty Cardiology Dept, Baris GUNGOR (University of Health Sciences Dr. Siyami Ersek Hospital, Turkey), Berit S HEDEGAARD (Aalborg University, Denmark), Bertrand CARIOU (Nantes Universit´e, Chu, Nantes, Cnrs, Inserm, l’institut du thorax, Nantes, France), Britta OTTE (Universit¨atsklinikum Münster, Lipidambulanz, Germany), Bu˘gra ¨OZKAN (Mersin University, Turkey), of cardiology, Christ BERGE (Dept., Unversity Hopsital, Haukeland., Norway), F EBENBICHLER (Department for Internal Medicine I, Christoph, Medical University Innsbruck, Austria), Christoph J BINDER (Medical University of Vienna, Austria), Christoph OLIVIER (Department of Cardiology and Angiology, University Heart Center Freiburg-Bad Krozingen, Faculty of Medicine, University of Freiburg, Conrad AZZOPARDI (Mater Dei Hospital, Malta), Cristina SOLER (Lipid Unit, Hospital de Sta Caterina, Spain), Dan GAITA (Universitatea de Medicina si Farmacie Victor Babes din Timisoara &, Clinica de Cardiologie, Institutul de Boli Cardiovasculare Timisoara, Romania), Daniel WEGHUBER (Department of Pediatrics, Paracelsus Medical University, Dilek URAL (Koç University School of Medicine Department of Cardiology, Turkey), Diogo CRUZ (Hospital de Cascais - Dr. Jos´e de Almeida, Portugal), Dragos VINEREANU (University of Medicine and Pharmacy, University and Emergency Hospital, Bucharest, Romania), Elena D PENCU (Grand Hˆopital de Charleroi GHDC, Belgium), Emil HAGSTR¨OM (Dept of medical sciences, Uppsala, University, Sweden), Erik B SCHMIDT (Aalborg University, Denmark), Erik, S STROES (Dept of vascular medicine, Amsterdamumc, The, Netherlands), Evangelos LIBEROPOULOS (1st Department of Propedeutic Medicine, School of Medicine, National and Kapodistrian University of Athens, General Hospital of Athens Laiko, Fabian DEMEURE (CHU UCL Namur - Site Godinne, Belgium), Fabio FIMIANI (Azienda Ospedaliera di Rilievo Nazionale AORN Dei Colli, Monaldi', 'V., Unit of Inherited and Rare Cardiovascular Diseases, Italy, ), Fabio PELLEGATTA (Center for the Study of Atherosclerosis. Bassini Hospital. Cinisello Balsamo, Italy), Fahri BAYRAM (Erciyes University, Turkey), Finn L HENRIKSEN (Department of Cardiology Odense University Hospital, Denmark), Florian H¨OLLERL (1st Medical Department, Landstrasse, Clinic, Vienna Health Association, Francesco CIPOLLONE (Clinica Medica Institute of, Department of Medicine and Aging Sciences, d’Annunzio' University, 'G., Francisco ARAÚJO (Hospital Lusíadas, Portugal), Franck BOCCARA (Sorbonne Universit´e, Groupe de Recherche Clinique number 22, C2MV—Complications Cardiovasculaires et M´etaboliques chez les Patients Vivant avec le Virus de l’Immunod´eficience Humaine, Institut National de la Sant´e et de la Recherche M´edicale Unit´e Mixte de Recherche, S 938, Centre de Recherche Saint-Antoine, Institut Hospital Universitaire de Cardiom ´etabolisme et Nutrition Cardiologie, Hˆopital Saint Antoine Assistance Publique–Hˆopitaux de Paris, Paris, France), François PAILLARD (Cardiologie et Centre Clinico-Biologique des Lipides et Ath´eroscl´erose, Chu, Rennes, France), Imre University Teaching Hospital, Gabor SIMONYI (DBC St., Metabolic, Center, Lipid, Center, Hungary), Gabriella IANNUZZO (Department of Clinical Medicine and Surgery. University of Naples Federico II, Italy), Giuseppe MANDRAFFINO (Department of Clinical and Experimental Medicine, - Lipid Center, University of Messina, Graham BAYLY (Dept Clinical Biochemistry, University Hospitals Bristol, United, Kingdom), Gustavs LATKOVSKIS (Institute of Cardiology and Regenerative Medicine, University of Latvia &, Latvian Center of Cardiology, Pauls Stradins Clinical University Hospital &, University of Latvia, Latvia), Gy¨orgy PARAGH (Division of Metabolic Disorders, Department of Internal Medicine, University of Debrecen, Debrecen, Hungary), Hana ROSOLOVA (Charles University Prague Medical Hospital in Pilsen, Czech Republic), Handrean SORAN (Central Manchester University Hospital NHS Foundation Trust, United Kingdom), Helle KANSTRUP (Department of cardiology, Aarhus University hospital, Denmark), Hermann TOPLAK (Department of Medicine, Division of Endocrinology and Diabetology, Medical University Graz, Hülya ÇIÇEKÇIO ˘GLU (ankara bilkent city hospital, Turkey), Inanc ARTAC (Department of Cardiology, Kafkas University Hospital, Ioanna GOUNI-BERTHOLD (Center for Endocrinology, Diabetes and Preventive Medicine, University of Cologne, Faculty of Medicine and University Hospital Cologne, Irfan, V DUZEN (Gaziantep University, Cardiology, Department, Isabel M PALMA (CHUPORTO - Centro Hospitalar Universit ´ario do Porto, Portugal), Istvan REIBER (Szent Gyorgy University Teaching Hospital of Fejer County, Hungary), Iveta DZIVITE-KRISANE (Children’s University Hospital, Latvia), Jeanine, E ROETERS VAN LENNEP (Department of Internal medicine, Erasmus MC University Medical Center, Jean-Luc, J BALLIGAND (Institut de Recherche Exp´erimentale et Clinique, Universite catholique de Louvain, Bruxelles), Joao C PORTO (CHUC, Portugal), Jo˜ao, S DUARTE (Hospital Egas Moniz, Lisboa, Portugal), Johan DE SUTTER (AZ Maria Middelares Hospital Gent, Belgium), Jos´e L´OPEZ-MIRANDA (Lipid and Arteriosclerosis Unit. Department of Internal Medicine. Hospital Universitario Reina Sofia. IMIBIC. University of Cordoba. CiberOBN, Spain), Jose M MOSTAZA (Hospital La Paz-Carlos III, Spain), Jurgita PLISIENE (Lithuanian University of Health sciences, Lithuania), Kadir, U MERT (Eskis ¸ehir Osmangazi University, Department of Cardiology, Kirsten, B HOLVEN (Department of Nutrition, University of Oslo and National Advisory unit on FH, Oslo University Hospital, Kjetil RETTERSTØL (The Lipid Clinic, Oslo University Hospital and Department of Nutrition, University of Oslo, Kristian, K THOMSEN (University Hospital of South Denmark, Esbjerg, Denmark), Lale TOKGOZOGLU (Hacettepe University, Turkey), Laszlo BAJNOK (1st Department of Medicine, Medical, School, University of Pecs, Lia E BANG (Copenhagen University Hospital, Denmark), Liliana GRIGORE (IRCCS Multimedica, Italy), Lluís MASANA (Hospital Universitari Sant Joan. Universitat Rovira i Virgili. CIBERDEM. Reus, Spain), Loukianos S RALLIDIS (University General Hospital Attikon, Greece), Maciej BANACH (Department of Preventive Cardiology and Lipidology, Medical University of Lodz, Poland), Małgorzata WALU´S-MIARKA (Jagiellonian University Medical College, Of Metabolic Diseases and Diabetology, Dept., Manuel CASTRO CABEZAS (Franciscus Gasthuis &, Vlietland Rotterdam, The Netherlands), Marcello ARCA (Sapienza University of Rome, Italy), Margus VIIGIMAA (North Estonia Medical Centre, Tallinn University of Technology, Estonia), Martin, P BOGSRUD (Unit for Cardiac and Cardiovascular Genetics, Matej MLINARIˇC (Department of Endocrinology, Diabetes and Metabolism, University Children’s Hospital, University Medical Centre Ljubljana, Slovenia), Matteo PIRRO (Section of Internal Medicine, Angiology and Arteriosclerosis Diseases, Maurizio AVERNA (Department PROMISE-University of Palermo &, Istituto di Biofisica, Consiglio Nazionale delle Ricerche, Palermo, Italy), Meral KAYIKCIOGLU (Ege University Medical School Department of Cardiology, Turkey), Merete HEITMANN (Bispebjerg-Frederiksberg University Hospital, Denmark), Mette MOURIDSEN (Department of Cardiology, Herlev and Gentofte Hospital, University of Copenhagen, Michal VRABLIK (3rd Department of Internal Medicine, General University Hospital and 1st Medical Faculty, Charles, University, Prague, Czech, Republic), Michel FARNIER (PEC2, University of Bourgogne Franche-Comt´e, Laboratory Medicine, Michel R LANGLOIS (Dept., Jan Hospital, AZ St., Belgium), Milad KHEDR (Department of Clinical Biochemistry and Metabolic Medicine, Royal Liverpool University Hospital, Muge ILDIZLI DEMIRBAS (Kartal Kosuyolu Research and Training Hospital, Turkey), Myra TILNEY (Lipid Clinic, Mater Dei Hospital &, Dept of Medicine, University of Malta Medical School, Malta), Nadia CITRONI (Internal Medicine, APSS Trento Hospital, Of Internal Medicine, Niels P RIKSEN (Dept., Radboud university medical center, Nikolay M RUNEV (UMHAT Alexandrovska, Bulgaria), Nora KUPSTYTEKRISTAPONE (Hospital of Lithuanian University of Health Sciences Kaunas Clinics, Lithuania), Olena MITCHENKO (NSC, Clinical and Regenerative Medicine of the NAMS of Ukraine, Ukraine), Oliver WEING¨ARTNER (Universit¨atsklinikum Jena, Department of Internal Medicine, I, Oner OZDOGAN (University of Health Sciences, Izmir Faculty of Medicine, Tepecik Training and Research Hospital, Ovidio MU˜NIZGRIJALVO (Hospital Virgen del Rocío, Spain), Ozcan BASARAN (Mugla Sitki Kocman University, Pankaj GUPTA (University Hospitals of Leicester, United Kingdom), Paolo PARINI (Cardio Metabolic Unit, Karolinska, Institutet, and Theme Inflammation and Ageing, Karolinska University Hospital Huddinge, Patrizia SUPPRESSA (Department of Internal Medicine and rare disease Centre, Bari, Italy), Paul DOWNIE (Salisbury NHS Foundation trust, United Kingdom), Pavel JESINA (Metabolic Center General University Hospital, Czech Republic), of Internal Medicine, Pavel KRAML (Dept., Third Faculty of Medicine, Charles University and Kr´alovsk´e Vinohrady University Hospital Prague, Pawel BURCHARDT (Department of Cardiology, Cardiovascular, Unit, Hospital, J. Stru´s., Pozna´n, &, Department of Hypertension, Angiology and Internal Medicine, Poznan University of Medical Sciences, Pozna´n, Poland), Pedro VALDIVIELSO (Hospital VIRGEN DE LA VICTORIA, Spain), Pedro VON HAFE (Instituto Cuf, Portugal), Dept, Peter FASCHING (5th Med., Clinic, Ottakring, Philippe MOULIN (Hospices civils de Lyon/INSERM/Universit ´e Lyon1, Hˆopital Louis Pradel, F´ed´eration, D’Endocrinologie, Quit´eria RATO (Sociedade Portuguesa de Aterosclerose, Portugal), Reinhold INNERHOFER (Medical University Vienna, Austria), Renata C´IFKOV´A (Center for Cardiovascular Prevention, Charles University in Prague, First Faculty of Medicine and Thomayer University Hospital, Rene VALERO (Aix Marseille Univ, Aphm, Inserm, Inrae, C2vn, University Hospital La Conception, Department of Nutrition, Metabolic Diseases and Endocrinology, Scicali, Roberto, Robin URB´ANEK (Internal medicine, Obezita-Ormiga, s. r. o., Roma KAVALIAUSKIENE (Klaip˙ eda Seamen’s Hospital, Lituania), Roman CIBULKA (Department of paramedic science, medical diagnostics studies and public health, Faculty of Health Care Studies, University of West Bohemia, Sabina ZAMBON (Department of Medicine, - DIMED, University of Padova, Sergio D’ADDATO (University of Bologna. IRCCS S. Orsola Bologna, Italy), Stanislav ZEMEK (Lipidova ambulance, Czech Republic), Stefano ROMEO (Gothenburg University, Sweden), Stephanie K¨ONEMANN (Department of Internal Medicine, B, University Medicine Greifswald, DZHK (German Centre for Cardiovascular Research), Susanne GREBER-PLATZER (Clinical Division of Pediatric Pulmonology, Allergology and Endocrinology, Department of Pediatrics and Adolescent Medicine, Medical University Vienna, Thomas STULNIG (Clinical Division of Endocrinology and Metabolism, Department of Medicine III, Medical University Vienna &, Third Medical Department and Karl Landsteiner Institute for Metabolic Diseases and Nephrology, Clinic, Hietzing, Vienna, Austria), Thomas MUHR (Dept of Cardiology, Link¨oping University Hospital, Tina, Z KHAN (Consultant Cardiologist, Royal Brompton and Harefield Hospitals Part of Guy’s and St Thomas’ NHS Foundation Trust, Tomas FREIBERGER (Centre of Cardiovascular Surgery and Transplantation, Brno &, Medical, Faculty, Masaryk, University, Brno, Tom´aˇs ˇS´ALEK (Metabolic Clinic, Tomas Bata Hospital, Zlín, Tomas VASYLIUS (Republican Panevezys hospital, Of Cardiology, Dep., Lithuania), Ulrich LAUFS (Klinik und Poliklinik für Kardiologie, Universit ¨atsklinikum Leipzig, Ulrike SCHATZ (University Hospital Carl Gustav Carus Dresden at the Technical University Dresden, Department of Internal Medicine III, Urh GROSELJ (UMC, - University Children’s Hospital Ljubljana, University of Ljubljana, Victoria MARCO-BENEDI (Hospital Universitario Miguel Servet, Iisa, Cibercv, Vincent MAHER (Advanced Lipid Management and Research ALMAR centre, Tallaght University Hospital, Ireland), Vladimír BLAHA (University Hospital Hradec Kr´alov´e and Charles University, Faculty of Medicine in Hradec Kr´alov´e, 3rd Department of Internal Medicine, - Metabolism and Gerontology, Vladimir SOSKA (Department of Clinical Biochemistry, St. Anne’s University Hospital Brno, 2nd Clinic of Internal Medicine, Masaryk University Brno, Volker JJ SCHETTLER (Centre of Nephrology G¨ottingen, Germany), Wolfgang REINHARDT (SUS Malmoe, Sweden), Xavier PINT´O (Hospital Universitari de Bellvitge-Idibell-UB-CiberObn, Spain), Yoto YOTOV (Second Cardiology Clinic, Marina, University Hospital Sv., Medical University of Varna, Zaneta PETRULIONIENE (Vilnius University Medical Faculty, Vilnius University Hospital Santaros klinikos, Lithuania), ˇZeljko REINER (Department for Metabolic Diseases, University Hospital Center Zagreb, and Croatia, ).
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Clinicians ,Clinical evaluation ,Cardiology and Cardiovascular Medicine ,Cardiovascular risk ,Lipoprotein(a) - Published
- 2023
9. T-13-20: Adults with severe or moderately severe haemophilia B receiving etranacogene dezaparvovec in the HOPE-B phase 3 trial experience a stable increase in mean Factor IX activity levels and durable haemostatic protection after 24 months' follow-up.
- Author
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Pipe, S. W., Leebeek, F. W.G., Recht, M., Key4 University of of North Carolina, Chapel Hill, USA, N. S., Lattimore5 Oregon Health & Science University, Portland, USA, S., Castaman6 Center for Bleeding Disorders and Coagulation,Careggi University Hospital, Florence, Italy, G., Coppens7 Department of Vascular Medicine, AmsterdamCardiovascular Sciences, Amsterdam UMC, University ofAmsterdam, Amsterdam, Netherlands, M., Cooper, D., Gut, R., Slawka, S., Verweij, S., Dolmetsch, R., Li, Y., Monahan, P. E., and Miesbach, W.
- Published
- 2023
- Full Text
- View/download PDF
10. Laboratory and Clinical Data in Antiphospholipid Patients (APSregistry)
- Author
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Pr Denis WAHL, Head of Vascular Medicine Division, Principal Investigator, Professor of Vascular Medicine
- Published
- 2021
11. Rate Control Efficacy in Atrial Fibrillation With Rheumatic Mitral Stenosis: Lenient vs Strict Rate Control Strategies (RACE-MS)
- Author
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Saiful Anwar Hospital and Ardian Rizal, Ardian Rizal, MD, FIHA. Assistant Professor of Arrhythmia, Department of Cardiology and Vascular Medicine, Faculty of Medicine.
- Published
- 2024
12. Predictors of death and stroke after carotid angioplasty and stenting: a subgroup analysis of the Pro-CAS data.
- Author
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Theiss W, Hermanek P, Mathias K, Brückmann H, Dembski J, Hoffmann FJ, Kerner R, Leisch F, Mudra H, Schulte KL, Sievert H, German Society of Angiology/Vascular Medicine, Theiss, Wolfram, Hermanek, Peter, Mathias, Klaus, Brückmann, Hartmut, Dembski, Jürgen, Hoffmann, Franz-Josef, Kerner, Rüdiger, and Leisch, Franz
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- 2008
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13. Retinal arterial changes correlate with cerebral small-vessel disease.
- Author
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Kwa, V I H, van der Sande, J J, Stam, J, Tijmes, N, Vrooland, J L, and Amsterdam Vascular Medicine Group
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- 2002
- Full Text
- View/download PDF
14. Presyncopal sympathetic withdrawal is the same in patients with vasodepressor syncope and controls who faint on head-up tilting
- Author
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From Monash University Department of Medicine, Monash Medical Centre., Unit, Vascular Medicine, Prinz-Zaiss, M., Yeap, A., Moguilevski, V., Trigg, L., and McGrath, B.P.
- Abstract
Head-up tilt provokes vasodepressor syncope in patients with this disorder but may also cause fainting in unaffected subjects. The aims of this study were to examine autonomic function and sequential changes in heart rate variability and plasma catecholamines during graded head-up tilt in patients with vasodepressor syncope compared with healthy subjects. Studies were performed in 10 patients and 15 control subjects. Eight negative controls completed the study; presyncope or syncope developed in seven positive controls and all 10 patients. The negative control group showed a progressive increase in mid-frequency from the supine position to end tilt. Patients and positive controls showed significant and similar falls in mid-frequency in the presyncope period. The rise in plasma norepinephrine was blunted in patients and positive controls, whereas plasma epinephrine increased more in these groups compared with the negative control group. In conclusion, the patterns of heart rate variability and catecholamine changes could not be distinguished in patients and positive control subjects. (Am Heart J 1997;133:230-9.)
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- 1997
- Full Text
- View/download PDF
15. OKL-1111, A modified cyclodextrin as a potential universal reversal agent for anticoagulants
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Joost C.M. Meijers, Kamran Bakhtiari, Alex Zwiers, Stephan L.M. Peters, Experimental Vascular Medicine, Vascular Medicine, ACS - Pulmonary hypertension & thrombosis, and ACS - Amsterdam Cardiovascular Sciences
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Cyclodextrins ,Anticoagulants ,Hematology ,Anticoagulation reversal ,Factor Xa inhibitors ,Antithrombins - Abstract
Background: Antithrombotic therapy is inevitably associated with a risk for bleeding and these bleeding complications can be life-threatening. Recently, specific reversal agents were developed for the direct factor Xa and thrombin inhibitors (DOACs). However, next to the fact that these agents are relatively expensive, the use of selective reversal agents complicates treatment of bleeding patients in practice. In a series of screening experiments, we discovered a class of cyclodextrins with procoagulant properties. In this study we characterize a lead compound, OKL-1111, and demonstrate its potential use as a universal reversal agent. Objectives: To assess the anticoagulant reversal properties of OKL-1111, in vitro and in vivo. Methods: The effect of OKL-1111 on coagulation in the absence and presence of DOACs was investigated in a thrombin generation assay. Its reversal effect on a variety of anticoagulants in vivo was investigated in a rat tail cut bleeding model. A possible prothrombotic action of OKL-1111 was assessed in a Wessler model in rabbits. Results: OKL-1111 concentration-dependently reversed the in vitro anticoagulant effects of dabigatran, rivaroxaban, apixaban and edoxaban in the thrombin generation assay. Also in the absence of a DOAC, OKL-1111 concentration-dependently accelerated coagulation in this assay, but did not initiate coagulation. The reversal effect was also seen for all DOACs in the rat tail cut bleeding model. In addition, when tested with other anticoagulants, OKL-1111 also reversed the anticoagulant effect of the vitamin K antagonist warfarin, the low molecular weight heparin enoxaparin, the pentasaccharide fondaparinux and the platelet inhibitor clopidogrel in vivo. OKL-1111 did not have prothrombotic effects in the Wessler model. Conclusion: OKL-1111 is a procoagulant cyclodextrin with a currently unknown working mechanism that has potential to become a universal reversal agent for anticoagulants and platelet inhibitors.
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- 2023
16. Effects of oral semaglutide on cardiovascular outcomes in individuals with type 2 diabetes and established atherosclerotic cardiovascular disease and/or chronic kidney disease
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Darren K. McGuire, Rodica P. Busui, John Deanfield, Silvio E. Inzucchi, Johannes F. E. Mann, Nikolaus Marx, Sharon L. Mulvagh, Neil Poulter, Mads D. M. Engelmann, G. Kees Hovingh, Maria Sejersten Ripa, Mette Gislum, Kirstine Brown‐Frandsen, John B. Buse, Experimental Vascular Medicine, Vascular Medicine, ACS - Atherosclerosis & ischemic syndromes, and ACS - Amsterdam Cardiovascular Sciences
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Endocrinology ,semaglutide ,cardiovascular disease ,Endocrinology, Diabetes and Metabolism ,Internal Medicine ,randomized trial ,type 2 diabetes ,GLP-1 - Abstract
Aim: To describe the design of the SOUL trial (Semaglutide cardiOvascular oUtcomes triaL) and the baseline clinical data of its participants. Materials and methods: In SOUL, the effects of oral semaglutide, the first oral glucagon-like peptide-1 receptor agonist, on the risk of cardiovascular (CV) events in individuals with type 2 diabetes and established atherosclerotic CV disease (ASCVD) and/or chronic kidney disease (CKD) will be assessed. SOUL is a randomized, double-blind, parallel-group, placebo-controlled CV outcomes trial comparing oral semaglutide (14 mg once daily) with placebo, both in addition to standard of care, in individuals aged ≥50 years with type 2 diabetes and evidence of ASCVD (coronary artery disease [CAD], cerebrovascular disease, symptomatic peripheral arterial disease [PAD]) and/or CKD (estimated glomerular filtration rate
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- 2023
17. Ursodeoxycholic Acid Use After Bariatric Surgery
- Author
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Maimoena S. S. Guman, Sylke Haal, Yair I. Z. Acherman, Arnold W. L. van de Laar, Max Nieuwdorp, Rogier P. Voermans, Victor E. A. Gerdes, Vascular Medicine, Gastroenterology and Hepatology, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, Paediatric Surgery, Experimental Vascular Medicine, ACS - Diabetes & metabolism, CCA - Cancer Treatment and Quality of Life, Internal medicine, and AGEM - Endocrinology, metabolism and nutrition
- Subjects
Bariatric surgery ,Metabolic markers ,Nutrition and Dietetics ,Adverse effects ,Ursodeoxycholic acid ,Endocrinology, Diabetes and Metabolism ,Beneficial effects ,Inflammatory markers ,Surgery ,Bile acid ,Gallstones ,Weight loss surgery - Abstract
Background In addition to the reduction of symptomatic gallstone disease, ursodeoxycholic acid (UDCA) might also have beneficial metabolic effects after bariatric surgery. We examined the impact of UDCA on liver enzymes, hemoglobin A1c (HbA1c), lipids, and inflammation markers. Methods Patients in the UPGRADE trial (placebo-controlled, double-blind) were randomized between UDCA 900 mg daily or placebo pills for 6 months after bariatric surgery. Patients without blood measurements pre- or 6 months postoperatively were excluded. The change in liver enzymes, Hba1c, lipids, and inflammation markers after surgery were compared between the UDCA and placebo group, followed by a postoperative cross-sectional comparison. Results In total, 513 patients were included (age [mean ± SD] 45.6 ± 10.7 years; 79% female). Preoperative blood values did not differ between UDCA (n = 266) and placebo (n = 247) groups. Increase of alkaline phosphatase (ALP) was greater in the UDCA group (mean difference 3.81 U/l [95%CI 0.50 7.12]). Change in other liver enzymes, HbA1c, lipids, and CRP levels did not differ. Postoperative cross-sectional comparison in 316 adherent patients also revealed a higher total cholesterol (mean difference 0.25 mg/dl [95%CI 0.07–0.42]), lower aspartate aminotransferase (mean difference −3.12 U/l [−5.16 – −1.08]), and lower alanine aminotransferase level (mean difference −5.89 U/l [−9.41 – −2.37]) in the UDCA group. Conclusion UDCA treatment leads to a higher, but clinically irrelevant increase in ALP level in patients 6 months after bariatric surgery. No other changes in metabolic or inflammatory markers were observed. Except for the reduction of gallstone formation, UDCA has no effects after bariatric surgery. Graphical Abstract
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- 2023
18. Proteomics and lipidomics in atherosclerotic cardiovascular disease risk prediction
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Nick S Nurmohamed, Jordan M Kraaijenhof, Manuel Mayr, Stephen J Nicholls, Wolfgang Koenig, Alberico L Catapano, Erik S G Stroes, Graduate School, Vascular Medicine, ACS - Amsterdam Cardiovascular Sciences, Experimental Vascular Medicine, and ACS - Atherosclerosis & ischemic syndromes
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Proteomics ,Lipidomics ,Risk score ,Cardiology and Cardiovascular Medicine ,Multiomics ,ASCVD - Abstract
Given the limited accuracy of clinically used risk scores such as the Systematic COronary Risk Evaluation 2 system and the Second Manifestations of ARTerial disease 2 risk scores, novel risk algorithms determining an individual’s susceptibility of future incident or recurrent atherosclerotic cardiovascular disease (ASCVD) risk are urgently needed. Due to major improvements in assay techniques, multimarker proteomic and lipidomic panels hold the promise to be reliably assessed in a high-throughput routine. Novel machine learning-based approaches have facilitated the use of this high-dimensional data resulting from these analyses for ASCVD risk prediction. More than a dozen of large-scale retrospective studies using different sets of biomarkers and different statistical methods have consistently demonstrated the additive prognostic value of these panels over traditionally used clinical risk scores. Prospective studies are needed to determine the clinical utility of a biomarker panel in clinical ASCVD risk stratification. When combined with the genetic predisposition captured with polygenic risk scores and the actual ASCVD phenotype observed with coronary artery imaging, proteomics and lipidomics can advance understanding of the complex multifactorial causes underlying an individual’s ASCVD risk.
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- 2023
19. Bempedoic acid lowers high-sensitivity C-reactive protein and low-density lipoprotein cholesterol
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Erik S.G. Stroes, Harold E. Bays, Maciej Banach, Alberico L. Catapano, P. Barton Duell, Ulrich Laufs, G.B. John Mancini, Kausik K. Ray, William J. Sasiela, Yang Zhang, Antonio M. Gotto, Experimental Vascular Medicine, Vascular Medicine, and ACS - Atherosclerosis & ischemic syndromes
- Subjects
Inflammation ,Hyperlipidemia ,Atherosclerotic cardiovascular disease ,Cardiology and Cardiovascular Medicine ,C-reactive protein - Abstract
Background and aims: High-sensitivity C-reactive protein (hsCRP), a marker for atherosclerotic cardiovascular disease risk, is reduced by bempedoic acid. We assessed the relationship between changes in low-density lipoprotein cholesterol (LDL-C) and hsCRP in relation to baseline statin use. Methods: Pooled data from four phase 3 trials (patients on maximally tolerated statins [Pool 1] and patients receiving no or low-dose statins [Pool 2]) were used to determine the proportion of patients with baseline hsCRP ≥2 mg/L who achieved hsCRP
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- 2023
20. Gender gaps in type 1 diabetes care
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Jessica C. G. Bak, Erik H. Serné, Harold W. de Valk, Niek K. Valk, Mark H. H. Kramer, Max Nieuwdorp, Carianne L. Verheugt, Vascular Medicine, Amsterdam Cardiovascular Sciences, Experimental Vascular Medicine, ACS - Diabetes & metabolism, Amsterdam Gastroenterology Endocrinology Metabolism, ACS - Heart failure & arrhythmias, Internal medicine, ACS - Microcirculation, and AGEM - Endocrinology, metabolism and nutrition
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Gender equality ,Endocrinology ,Endocrinology, Diabetes and Metabolism ,Outpatients ,Internal Medicine ,Type 1 diabetes mellitus ,General Medicine ,Registries - Abstract
Aims: Diabetes mellitus is one of the largest global health concerns of recent times. Women with diabetes mellitus have a higher excess risk of all-cause mortality and more vascular events than men. Focusing on type 1 diabetes, this could be caused by gender inequalities in delivered diabetes care. This study aims to assess gender differences in type 1 diabetes outpatient care, particularly diagnostics and outcomes. Methods: This cross-sectional cohort study included all adult type 1 diabetes patients in the Dutch Pediatric and Adult Registry of Diabetes (DPARD) visiting diabetes outpatient clinics between 2016–2021. The frequency of process measurements, including physical examination and laboratory testing, was assessed among both sexes after adjustment for age and body mass index. Gender differences in eGFR ≥ 60, BMI-, and control in blood pressure and LDL-cholesterol were evaluated. Hospital variation in achieving HbA1c targets of 53 mmol/mol and median HbA1c were assessed. Cardiovascular risk scores were calculated in men and women using the Systematic Coronary Risk Evaluation (SCORE) European low-risk chart. Results: Our study showed a 17% higher odds of reaching weight control and a 23% lower odds of achieving blood pressure targets in men than women. Gender-skewed cardiovascular mortality risk scores were found. Gender disparities in outcomes appear not to be caused by gender-biased attitudes in healthcare professionals since no gender differences were found in the performance of process measurements in type 1 diabetes care. In addition, hospitals appear to vary by extent of gender differences in achieving a target HbA1c of 53 mmol/mol. Conclusion: Gender equality exists in the diagnostic process of diabetes care. However, differences in weight control, blood pressure control, and cardiovascular mortality risk scores remain between both sexes, most likely due to multifactorial causes. Indications for interhospital variation in gender disparities in HbA1c control exist. Further focus on performance of process measurements between hospitals may identify areas for improvement of gender-skewed outcomes to further enhance Dutch diabetes care for both sexes.
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- 2023
21. Effect of evolocumab on fasting and post fat load lipids and lipoproteins in familial dysbetalipoproteinemia
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Britt E. Heidemann, Charlotte Koopal, Jeanine E. Roeters van Lennep, Erik S.G. Stroes, Niels P. Riksen, Monique T. Mulder, Leonie C. van Vark – van der Zee, Dee M. Blackhurst, A. David Marais, Frank L.J. Visseren, Internal Medicine, Experimental Vascular Medicine, Vascular Medicine, and ACS - Atherosclerosis & ischemic syndromes
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Clinical trial ,All institutes and research themes of the Radboud University Medical Center ,Nutrition and Dietetics ,SDG 3 - Good Health and Well-being ,Endocrinology, Diabetes and Metabolism ,Internal Medicine ,Vascular damage Radboud Institute for Molecular Life Sciences [Radboudumc 16] ,Non-HDL-cholesterol ,Cardiology and Cardiovascular Medicine ,Evolocumab ,Proprotein convertase subtilin kexin 9 ,Familial dysbetalipoproteinemia - Abstract
Contains fulltext : 291402.pdf (Publisher’s version ) (Open Access) BACKGROUND: Familial dysbetalipoproteinemia (FD) is the second most common monogenic lipid disorder (prevalence 1 in 850-3500), characterized by postprandial remnant accumulation and associated with increased cardiovascular disease (CVD) risk. Many FD patients do not achieve non-HDL-C treatment goals, indicating the need for additional lipid-lowering treatment options. OBJECTIVES: To evaluate the effect of the PCSK9 monoclonal antibody evolocumab added to standard lipid-lowering therapy on fasting and post fat load lipids and lipoproteins in patients with FD. METHODS: A randomized placebo-controlled double-blind crossover trial comparing evolocumab (140 mg subcutaneous every 2 weeks) with placebo during two 12-week treatment periods. At the start and end of each treatment period patients received an oral fat load. The primary endpoint was the 8-hour post fat load non-HDL-C area under the curve (AUC). Secondary endpoints included fasting and post fat load lipids and lipoproteins. RESULTS: In total, 28 patients completed the study. Mean age was 62±9 years and 93% had an Ɛ2Ɛ2 genotype. Evolocumab reduced the 8-hour post fat load non-HDL-C AUC with 49% (95%CI 42-55) and apolipoprotein B (apoB) AUC with 47% (95%CI 41-53). Other fasting and absolute post fat load lipids and lipoproteins including triglycerides and remnant-cholesterol were also significantly reduced by evolocumab. However, evolocumab did not have significant effects on the rise above fasting levels that occurred after consumption of the oral fat load. CONCLUSIONS: Evolocumab added to standard lipid-lowering therapy significantly reduced fasting and absolute post fat load concentrations of non-HDL-C, apoB and other atherogenic lipids and lipoproteins in FD patients. The clinically significant decrease in lipids and lipoproteins can be expected to translate into a reduction in CVD risk in these high-risk patients.
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- 2023
22. START-Register: Survey on Anticoagulated Patients Register
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Arianna Anticoagulazione Foundation and GUALTIERO PALARETI, Professor in Vascular Medicine
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- 2023
23. Nanobodies against factor XI apple 3 domain inhibit binding of factor IX and reveal a novel binding site for high molecular weight kininogen
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Awital Bar Barroeta, J. Arnoud Marquart, Kamran Bakhtiari, Alexander B. Meijer, Rolf T. Urbanus, Joost C.M. Meijers, Graduate School, Experimental Vascular Medicine, Vascular Medicine, ACS - Pulmonary hypertension & thrombosis, and ACS - Amsterdam Cardiovascular Sciences
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Factor IX ,Epitopes ,anticoagulants ,Binding Sites ,Kininogen, High-Molecular-Weight ,Humans ,hydrogen–deuterium exchange mass spectrometrynanobody ,Hematology ,Single-Domain Antibodies ,Deuterium ,factor XI ,high molecular weight kininogen - Abstract
Background: Factor XI (FXI) is a promising target for novel anticoagulants because it shows a strong relation to thromboembolic diseases, while fulfilling a mostly supportive role in hemostasis. Anticoagulants targeting FXI could therefore reduce the risk for thrombosis, without increasing the chance of bleeding side effects. Objectives: To generate nanobodies that can interfere with FXIa mediated activation of factor IX (FIX). Methods: Nanobodies were selected for binding to the apple 3 domain of FXI and their effects on FXI and coagulation were measured in purified protein systems as well as in plasma-based coagulation assays. Additionally, the binding epitope of selected nanobodies was assessed by hydrogen–deuterium exchange mass spectrometry. Results: We have identified five nanobodies that inhibit FIX activation by FXI by competing with the FIX binding site on FXI. Interestingly, a sixth nanobody was found to target a different binding epitope in the apple 3 domain, resulting in competition with the FXI–high molecular weight kininogen (HK) interaction. Conclusions: We have characterized a nanobody targeting the FXI apple 3 domain that elucidates the binding orientation of HK on FXI. Moreover, we have produced five nanobodies that can inhibit the FXI–FIX interaction.
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- 2022
24. Disentangling Genetic Risks for Metabolic Syndrome
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Eva S. van Walree, Iris E. Jansen, Nathaniel Y. Bell, Jeanne E. Savage, Christiaan de Leeuw, Max Nieuwdorp, Sophie van der Sluis, Danielle Posthuma, Complex Trait Genetics, Amsterdam Neuroscience - Neurodegeneration, Amsterdam Neuroscience - Complex Trait Genetics, Internal medicine, ACS - Diabetes & metabolism, AGEM - Endocrinology, metabolism and nutrition, Human genetics, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, Amsterdam Neuroscience - Compulsivity, Impulsivity & Attention, Amsterdam Reproduction & Development (AR&D), ARD - Amsterdam Reproduction and Development, Experimental Vascular Medicine, Vascular Medicine, and AGEM - Amsterdam Gastroenterology Endocrinology Metabolism
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Metabolic Syndrome ,Blood Glucose ,Endocrinology, Diabetes and Metabolism ,Cholesterol, HDL ,Blood Pressure ,Glucose ,Diabetes Mellitus, Type 2 ,Fenofibrate ,SDG 3 - Good Health and Well-being ,Risk Factors ,Internal Medicine ,Humans ,Waist Circumference ,Triglycerides ,Genome-Wide Association Study - Abstract
A quarter of the world’s population is estimated to meet the criteria for metabolic syndrome, a cluster of cardiometabolic risk factors that promote development of coronary artery disease and type II diabetes, leading to increased risk of premature death and significant health costs. In this study we investigate whether the genetics associated with metabolic syndrome components mirror their phenotypic clustering. A multivariate approach that leverages genetic correlations between fasting glucose, high-density lipoprotein cholesterol, systolic blood pressure, triglycerides, and waist circumference was used; which revealed that these genetic correlations are best captured by a genetic one factor model. The common genetic factor genome-wide association study (GWAS) detects 235 associated loci, 174 more than the largest GWAS on metabolic syndrome to date. Of these loci, 53 (22.5%) overlap with loci identified for two or more metabolic syndrome components, indicating that metabolic syndrome is a complex, heterogeneous disorder. Associated loci harbour genes that show increased expression in the brain, especially in GABAergic and dopaminergic neurons. A polygenic risk score drafted from the metabolic syndrome factor GWAS predicts 5.9% of the variance in metabolic syndrome. These results provide mechanistic insights in the genetics of metabolic syndrome and suggestions for drug targets, especially fenofibrate, which has the promise of tackling multiple metabolic syndrome components.
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- 2022
25. Lipoprotein(a) is associated with the onset but not the progression of aortic valve calcification
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Yannick Kaiser, Janine E van der Toorn, Sunny S Singh, Kang H Zheng, Maryam Kavousi, Eric J G Sijbrands, Erik S G Stroes, Meike W Vernooij, Yolanda B de Rijke, S Matthijs Boekholdt, Daniel Bos, Graduate School, Vascular Medicine, Experimental Vascular Medicine, ACS - Atherosclerosis & ischemic syndromes, Cardiology, Radiology and Nuclear Medicine, Epidemiology, Internal Medicine, Radiology & Nuclear Medicine, and Clinical Chemistry
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Male ,Calcinosis ,Aortic Valve Stenosis ,Middle Aged ,Aortic Valve/diagnostic imaging ,Aortic Valve ,Creatinine ,Humans ,Calcium ,Female ,Cardiology and Cardiovascular Medicine ,Aortic Valve Stenosis/epidemiology ,Aged ,Lipoprotein(a) - Abstract
Aim Lipoprotein(a) [Lp(a)] is a potential causal factor in the pathogenesis of aortic valve disease. However, the relationship of Lp(a) with new onset and progression of aortic valve calcium (AVC) has not been studied. The purpose of the study was to assess whether high serum levels of Lp(a) are associated with AVC incidence and progression. Methods and results A total of 922 individuals from the population-based Rotterdam Study (mean age 66.0±4.2 years, 47.7% men), whose Lp(a) measurements were available, underwent non-enhanced cardiac computed tomography imaging at baseline and after a median follow-up of 14.0 [interquartile range (IQR) 13.9–14.2] years. New-onset AVC was defined as an AVC score >0 on the follow-up scan in the absence of AVC on the first scan. Progression was defined as the absolute difference in AVC score between the baseline and follow-up scan. Logistic and linear regression analyses were performed to evaluate the relationship of Lp(a) with baseline, new onset, and progression of AVC. All analyses were corrected for age, sex, body mass index, smoking, hypertension, dyslipidaemia, and creatinine. AVC progression was analysed conditional on baseline AVC score expressed as restricted cubic splines. Of the 702 individuals without AVC at baseline, 415 (59.1%) developed new-onset AVC on the follow-up scan. In those with baseline AVC, median annual progression was 13.5 (IQR = 5.2–37.8) Agatston units (AU). Lipoprotein(a) concentration was independently associated with baseline AVC [odds ratio (OR) 1.43 for each 50 mg/dL higher Lp(a); 95% confidence interval (CI) 1.15–1.79] and new-onset AVC (OR 1.30 for each 50 mg/dL higher Lp(a); 95% CI 1.02–1.65), but not with AVC progression (β: −71 AU for each 50 mg/dL higher Lp(a); 95% CI −117; 35). Only baseline AVC score was significantly associated with AVC progression (P < 0.001). Conclusion In the population-based Rotterdam Study, Lp(a) is robustly associated with baseline and new-onset AVC but not with AVC progression, suggesting that Lp(a)-lowering interventions may be most effective in pre-calcific stages of aortic valve disease.
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- 2022
26. Cognitive function with evolocumab in pediatric heterozygous familial hypercholesterolemia
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Daniel Gaudet, Andrea Ruzza, Ian Bridges, Paul Maruff, Adrian Schembri, Andrew Hamer, François Mach, Jean Bergeron, Isabelle Gaudet, Julie St Pierre, John J.P. Kastelein, G. Kees Hovingh, Albert Wiegman, Frederick J. Raal, Raul D. Santos, Vascular Medicine, ACS - Atherosclerosis & ischemic syndromes, ACS - Pulmonary hypertension & thrombosis, Experimental Vascular Medicine, Amsterdam Cardiovascular Sciences, Paediatric Metabolic Diseases, ACS - Diabetes & metabolism, Amsterdam Gastroenterology Endocrinology Metabolism, ACS - Heart failure & arrhythmias, and Pediatrics
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Adult ,Nutrition and Dietetics ,Anticholesteremic Agents ,Endocrinology, Diabetes and Metabolism ,Familial hypercholesterolemia ,Evolocumab ,FH ,LDL ,Hyperlipoproteinemia Type II ,PCSK9 ,Treatment Outcome ,Cholesterol ,Cognition ,Cognitive dysfunction ,Internal Medicine ,Humans ,Proprotein Convertase 9 ,Cardiology and Cardiovascular Medicine ,Child - Abstract
Background: Evolocumab is a fully human monoclonal antibody inhibitor of PCSK9 approved for lowering low-density lipoprotein cholesterol in adults and pediatric patients with familial hypercholesterolemia (FH). The cognitive safety of evolocumab has been established in adults but has not yet been described in pediatric patients. Objective: To determine the effects of evolocumab on cognitive function in pediatric heterozygous FH. Methods: Cognitive function was assessed during a 24-week, randomized, double-blind, placebo-controlled study (HAUSER-RCT) evaluating the efficacy, safety, and tolerability of 24 weeks of monthly subcutaneous injections of evolocumab in pediatric patients with FH. Cognitive safety endpoints included changes from baseline to week 24 in test scores in domains of psychomotor function, attention, visual learning, and executive function. Between-group differences in age-standardized mean test score changes were analyzed using analysis of covariance models and point estimates with 95% confidence interval (CI). Magnitudes of difference between treatment groups (Cohen's d) and reliable change indices were calculated for each cognitive function test. Results: At week 24, changes from baseline in age-standardized cognitive test scores were similar between the treatment groups. Differences (95% CI) between the evolocumab and placebo groups in mean test score changes for the Groton Maze Learning, One-Card Learning, Identification, and Detection tests were 0.1 (–0.2, 0.4), –0.1 (–0.5, 0.4), 0.3 (0.0, 0.7), 0.3 (–0.1, 0.8), respectively. For all tests, abnormal and clinically important cognitive decline occurred with lesser frequency in the evolocumab group. Conclusion: In pediatric patients with FH, 24-week treatment with evolocumab did not negatively influence cognition. Funding: This study was funded and designed by Amgen.
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- 2022
27. Joint Genetic Inhibition of PCSK9 and CETP and the Association With Coronary Artery Disease
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Arjen J. Cupido, Laurens F. Reeskamp, Aroon D. Hingorani, Chris Finan, Folkert W. Asselbergs, G. Kees Hovingh, Amand F. Schmidt, Graduate School, Vascular Medicine, ACS - Atherosclerosis & ischemic syndromes, ACS - Amsterdam Cardiovascular Sciences, Experimental Vascular Medicine, and ACS - Heart failure & arrhythmias
- Subjects
Male ,Proprotein Convertase 9/genetics ,Coronary Artery Disease/genetics ,Genetic Variation ,Cholesterol, LDL ,Coronary Artery Disease ,Mendelian Randomization Analysis ,Middle Aged ,Cholesterol Ester Transfer Proteins ,LDL/blood ,Macular Degeneration ,Cholesterol ,Cholesterol, LDL/blood ,Diabetes Mellitus, Type 2 ,Diabetes Mellitus ,Humans ,Female ,Proprotein Convertase 9 ,Cardiology and Cardiovascular Medicine ,Type 2 ,Cholesterol Ester Transfer Proteins/genetics - Abstract
IMPORTANCE: Cholesteryl ester transfer protein inhibition (CETP) has been shown to increase levels of high-density lipoprotein cholesterol (HDL-C) and reduce levels of low-density lipoprotein cholesterol (LDL-C). Current LDL-C target attainment is low, and novel phase 3 trials are underway to investigate whether CETP inhibitors result in reduction of cardiovascular disease risk in high-risk patients who may be treated with PCSK9-inhibiting agents. OBJECTIVE: To explore the associations of combined reduction of CETP and PCSK9 concentrations with risk of coronary artery disease (CAD) and other clinical and safety outcomes. DESIGN, SETTING, AND PARTICIPANTS: Two-sample 2 × 2 factorial Mendelian randomization study in a general population sample that includes data for UK Biobank participants of European ancestry. EXPOSURES: Separate genetic scores were constructed for CETP and PCSK9 plasma protein concentrations, which were combined to determine the associations of combined genetically reduced CETP and PCSK9 concentrations with disease. MAIN OUTCOMES AND MEASURES: Blood lipid and lipoprotein concentrations, blood pressure, CAD, age-related macular degeneration, type 2 diabetes, any stroke and ischemic stroke, Alzheimer disease, vascular dementia, heart failure, atrial fibrillation, chronic kidney disease, asthma, and multiple sclerosis. RESULTS: Data for 425 354 UKB participants were included; the median (IQR) age was 59 years (51-64), and 229 399 (53.9%) were female. The associations of lower CETP and lower PCSK9 concentrations with CAD are similar when scaled per 10-mg/dL reduction in LDL-C concentrations (CETP: odds ratio [OR], 0.74; 95% CI, 0.67 to 0.81; PCSK9: OR, 0.75; 95% CI, 0.71 to 0.79). Combined exposure to lower CETP and PCSK9 concentrations was associated with an additive magnitude with lipids and all outcomes, and we did not observe any nonadditive interactions, most notably for LDL-C (CETP: effect size, -1.11 mg/dL; 95% CI, -1.40 to -0.82; PCSK9: effect size, -2.13 mg/dL; 95% CI, -2.43 to -1.84; combined: effect size, -3.47 mg/dL; 95% CI, -3.76 to -3.18; P = .34 for interaction) and CAD (CETP: OR, 0.96; 95% CI, 0.94 to 1.00; PCSK9: OR, 0.94; 95% CI, 0.91 to 0.97; combined: OR, 0.90; 95% CI, 0.87 to 0.93; P = .83 for interaction). In addition, when corrected for multiple testing, lower CETP concentrations were associated with increased age-related macular degeneration (OR, 1.11; 95% CI, 1.04 to 1.19). CONCLUSIONS AND RELEVANCE: Our results suggest that joint inhibition of CETP and PCSK9 has additive effects on lipid traits and disease risk, including a lower risk of CAD. Further research may explore whether a combination of CETP- and PCSK9-related therapeutics can benefit high-risk patients who are unable to reach treatment targets with existing options.
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- 2022
28. Hyperinsulinemia Is Highly Associated With Markers of Hepatocytic Senescence in Two Independent Cohorts
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Abraham S. Meijnikman, Casper C. van Olden, Ömrüm Aydin, Hilde Herrema, Dorota Kaminska, Dimitra Lappa, Ville Männistö, Valentina Tremaroli, Louise E. Olofsson, Maurits de Brauw, Arnold van de Laar, Joanne Verheij, Victor E.A. Gerdes, Thue W. Schwartz, Jens Nielsen, Fredrik Bäckhed, Päivi Pajukanta, Jussi Pihlajamäki, Tamar Tchkonia, James L. Kirkland, Folkert Kuipers, Max Nieuwdorp, Albert K. Groen, Pathology, Internal medicine, ACS - Diabetes & metabolism, AGEM - Endocrinology, metabolism and nutrition, Center for Liver, Digestive and Metabolic Diseases (CLDM), Graduate School, Vascular Medicine, ACS - Atherosclerosis & ischemic syndromes, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, and Experimental Vascular Medicine
- Subjects
Diabetes Mellitus, Type 2 ,Liver ,Non-alcoholic Fatty Liver Disease ,Endocrinology, Diabetes and Metabolism ,Hyperinsulinism ,Internal Medicine ,Humans ,Insulin ,Insulin Resistance ,Biomarkers - Abstract
Cellular senescence is an essentially irreversible growth arrest that occurs in response to various cellular stressors and may contribute to development of type 2 diabetes and Non-Alcoholic Fatty Liver Disease (NAFLD). Here, we investigated whether chronically elevated insulin levels are associated with cellular senescence in the human liver. In 107 individuals undergoing bariatric surgery, hepatic senescence markers were assessed by immunohistochemistry as well as transcriptomics. A subset of 180 participants from the ongoing Finnish Kuopio OBesity Surgery (KOBS) study was used as validation cohort. We found plasma insulin to be highly associated with various markers of cellular senescence in liver tissue. The liver transcriptome of individuals with high insulin revealed significant upregulation of several genes associated with senescence: p21, TGFβ, PI3K, HLA-G, IL8, p38, Ras, and E2F. Insulin associated with hepatic senescence independently of NAFLD and plasma glucose. By using transcriptomic data from the KOBS study, we could validate the association of insulin with p21 in the liver. Our results support a potential role for hyperinsulinemia in induction of cellular senescence in the liver. These findings suggest possible benefits of lowering insulin levels in obese individuals with insulin resistance.
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- 2022
29. Lipoprotein(a) in atherosclerotic cardiovascular disease and aortic stenosis: a European Atherosclerosis Society consensus statement
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Kronenberg, Florian, Mora, Samia, Stroes, Erik S G, Ference, Brian A, Arsenault, Benoit J, Berglund, Lars, Dweck, Marc R, Koschinsky, Marlys, Lambert, Gilles, Mach, François, McNeal, Catherine J, Moriarty, Patrick M, Natarajan, Pradeep, Nordestgaard, Børge G, Parhofer, Klaus G, Virani, Salim S, von Eckardstein, Arnold, Watts, Gerald F, Stock, Jane K, Ray, Kausik K, Tokgözoğlu, Lale S, Catapano, Alberico L, University of Zurich, Experimental Vascular Medicine, Vascular Medicine, and ACS - Atherosclerosis & ischemic syndromes
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Adult ,Consensus ,Aortic stenosis ,Testing ,Calcinosis ,610 Medicine & health ,Aortic Valve Stenosis ,Cholesterol, LDL ,Cardiovascular risk ,Atherosclerosis ,2705 Cardiology and Cardiovascular Medicine ,Model of care ,Treatment ,Cardiovascular Diseases ,Risk Factors ,Clinical guidance ,540 Chemistry ,Humans ,Cardiology and Cardiovascular Medicine ,10038 Institute of Clinical Chemistry ,Lipoprotein(a) - Abstract
This 2022 European Atherosclerosis Society lipoprotein(a) [Lp(a)] consensus statement updates evidence for the role of Lp(a) in atherosclerotic cardiovascular disease (ASCVD) and aortic valve stenosis, provides clinical guidance for testing and treating elevated Lp(a) levels, and considers its inclusion in global risk estimation. Epidemiologic and genetic studies involving hundreds of thousands of individuals strongly support a causal and continuous association between Lp(a) concentration and cardiovascular outcomes in different ethnicities; elevated Lp(a) is a risk factor even at very low levels of low-density lipoprotein cholesterol. High Lp(a) is associated with both microcalcification and macrocalcification of the aortic valve. Current findings do not support Lp(a) as a risk factor for venous thrombotic events and impaired fibrinolysis. Very low Lp(a) levels may associate with increased risk of diabetes mellitus meriting further study. Lp(a) has pro-inflammatory and pro-atherosclerotic properties, which may partly relate to the oxidized phospholipids carried by Lp(a). This panel recommends testing Lp(a) concentration at least once in adults; cascade testing has potential value in familial hypercholesterolaemia, or with family or personal history of (very) high Lp(a) or premature ASCVD. Without specific Lp(a)-lowering therapies, early intensive risk factor management is recommended, targeted according to global cardiovascular risk and Lp(a) level. Lipoprotein apheresis is an option for very high Lp(a) with progressive cardiovascular disease despite optimal management of risk factors. In conclusion, this statement reinforces evidence for Lp(a) as a causal risk factor for cardiovascular outcomes. Trials of specific Lp(a)-lowering treatments are critical to confirm clinical benefit for cardiovascular disease and aortic valve stenosis.
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- 2022
30. The Influence of Plasma Prekallikrein Oligonucleotide Antisense Therapy on Coagulation and Fibrinolysis Assays: A Post-hoc Analysis
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Lauré M. Fijen, Remy S. Petersen, Joost C. M. Meijers, Laura Bordone, Marcel Levi, Danny M. Cohn, Graduate School, Vascular Medicine, ACS - Atherosclerosis & ischemic syndromes, Amsterdam Cardiovascular Sciences, Experimental Vascular Medicine, and ACS - Pulmonary hypertension & thrombosis
- Subjects
alpha-2-Antiplasmin ,Fibrinolysis ,Prekallikrein ,Oligonucleotides ,Humans ,Fibrinolysin ,Hematology ,Blood Coagulation - Abstract
Background Congenital prekallikrein deficiency has been associated with increased risk of thrombosis in a few uncontrolled studies. Prekallikrein levels were reduced by 36-94% (median 75%) in a phase 2 study with the prekallikrein specific antisense oligonucleotide, donidalorsen, in patients with hereditary angioedema (HAE). Objectives To estimate the effects of plasma prekallikrein reduction on coagulation and fibrinolysis. Methods Plasma samples were obtained from 16 HAE patients treated with donidalorsen and six placebo-treated patients. Calibrated automated thrombogram (CAT), clot lysis time, high-molecular-weight kininogen activity, factor XI activity, prothrombin fragment 1+2 (F1+2), thrombin-antithrombin complexes, D-dimer, plasminogen activity, plasmin-α2-antiplasmin complexes, and α2-antiplasmin activity were measured before and after four months of treatment. Results No significant changes following donidalorsen treatment were observed between baseline and after four months of treatment: CAT lag time 3.0 min and 3.0 min, CAT peak thrombin concentration 109% and 129%, CAT endogenous thrombin potential 98% and 108%, factor XI activity 110% and 115%, F1+2 levels 251 pMol/L and 161 pMol/L, thrombin-antithrombin complexes 2.6 μg/L and 1.9 μg/L, high-molecular-weight kininogen activity 87% and 93%, clot lysis time 92% and 99%, D-dimer levels 0.65 μg/L and 0.36 μg/L, plasminogen activity 116% and 125%, plasmin-α2-antiplasmin complexes 533 ng/mL and 328 ng/mL, and α2-antiplasmin activity 122% and 127%, respectively. There were also no differences between donidalorsen and placebo treatment. Conclusions Reduction of plasma prekallikrein by donidalorsen in HAE patients neither affected thrombin formation nor fibrinolytic activity. Our data suggest that partial plasma prekallikrein reduction does not influence thrombotic risk.
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- 2022
31. Gut microbial characteristics in poor appetite and undernutrition
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Kristina S. Fluitman, Mark Davids, Louise E. Olofsson, Madelief Wijdeveld, Valentina Tremaroli, Bart J.F. Keijser, Marjolein Visser, Fredrik Bäckhed, Max Nieuwdorp, Richard G. IJzerman, Center of Experimental and Molecular Medicine, Graduate School, Vascular Medicine, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, Experimental Vascular Medicine, ACS - Diabetes & metabolism, Internal medicine, AGEM - Endocrinology, metabolism and nutrition, Amsterdam Gastroenterology Endocrinology Metabolism, Preventive Dentistry, Nutrition and Health, APH - Societal Participation & Health, APH - Aging & Later Life, and APH - Health Behaviors & Chronic Diseases
- Subjects
Male ,Microbiota ,Body Weight ,Malnutrition ,Appetite ,Undernutrition ,Gut microbiota ,Gastrointestinal Microbiome ,Cohort Studies ,Mice ,Cross-Sectional Studies ,Microbiota transfer experiment ,RNA, Ribosomal, 16S ,Physiology (medical) ,Older adults ,Weight Loss ,SDG 1 - No Poverty ,Animals ,Humans ,Orthopedics and Sports Medicine ,SDG 2 - Zero Hunger ,Germ-free mice - Abstract
Background: Older adults are particularly prone to the development of poor appetite and undernutrition. Possibly, this is partly due to the aged gut microbiota. We aimed to evaluate the gut microbiota in relation to both poor appetite and undernutrition in community-dwelling older adults. Furthermore, we studied the causal effects of the microbiota on body weight and body composition by transferring faecal microbiota from cohort participants into germ-free mice. Methods: First, we conducted a cross-sectional cohort study of 358 well-phenotyped Dutch community-dwelling older adults from the Longitudinal Aging Study Amsterdam. Data collection included body measurements, a faecal and blood sample, as well as extensive questionnaires on appetite, dietary intake, and nutritional status. Appetite was assessed by the Council of Nutrition Appetite Questionnaire (CNAQ) and undernutrition was defined by either a low body mass index (BMI) (BMI 2 if 2 if ≥70 years) or >5% body weight loss averaged over the last 2 years. Gut microbiota composition was determined with 16S rRNA sequencing. Next, we transferred faecal microbiota from 12 cohort participants with and without low BMI or recent weight loss into a total of 41 germ-free mice to study the potential causal effects of the gut microbiota on host BMI and body composition. Results: The mean age (range) of our cohort was 73 (65–93); 58.4% was male. Seventy-seven participants were undernourished and 21 participants had poor appetite (CNAQ
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- 2022
32. Glucose-mediated insulin secretion is improved in FHL2-deficient mice and elevated FHL2 expression in humans is associated with type 2 diabetes
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Jayron J. Habibe, Maria P. Clemente-Olivo, Torsten P. M. Scheithauer, Elena Rampanelli, Hilde Herrema, Mariska Vos, Arnout Mieremet, Max Nieuwdorp, Daniel H. van Raalte, Etto C. Eringa, Carlie J. M. de Vries, Fysiologie, RS: Carim - H08 Experimental atrial fibrillation, Internal medicine, ACS - Diabetes & metabolism, AGEM - Endocrinology, metabolism and nutrition, Amsterdam Gastroenterology Endocrinology Metabolism, Physiology, Graduate School, Vascular Medicine, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, Experimental Vascular Medicine, Medical Biochemistry, ACS - Atherosclerosis & ischemic syndromes, and ACS - Heart failure & arrhythmias
- Subjects
GENES ,FHL2 ,Endocrinology, Diabetes and Metabolism ,LIM-Homeodomain Proteins ,Pancreatic islets ,Muscle Proteins ,Islets of Langerhans ,Mice ,Insulin-Secreting Cells ,Four and a half LIM domains protein 2 ,Insulin Secretion ,Internal Medicine ,Animals ,Humans ,Insulin ,Aged ,COACTIVATOR ,Forkhead Box Protein O1 ,Glucose-stimulated insulin secretion ,GSIS ,MAFA ,TRANSCRIPTION FACTORS ,Basic-Leucine Zipper Transcription Factors ,Glucose ,Diabetes Mellitus, Type 2 ,Glucose tolerance test ,ONLY PROTEIN FHL2 ,ISLETS ,GTT ,Gene expression ,MIN6 ,Reactive Oxygen Species ,REGULATOR - Abstract
Aims/hypothesis The general population is ageing, involving an enhanced incidence of chronic diseases such as type 2 diabetes. With ageing, DNA methylation of FHL2 increases, as well as expression of the four and a half LIM domains 2 (FHL2) protein in human pancreatic islets. We hypothesised that FHL2 is actively involved in glucose metabolism. Methods Publicly available microarray datasets from human pancreatic islets were analysed for FHL2 expression. In FHL2-deficient mice, we studied glucose clearance and insulin secretion. Gene expression analysis and glucose-stimulated insulin secretion (GSIS) were determined in isolated murine FHL2-deficient islets to evaluate insulin-secretory capacity. Moreover, knockdown and overexpression of FHL2 were accomplished in MIN6 cells to delineate the underlying mechanism of FHL2 function. Results Transcriptomics of human pancreatic islets revealed that individuals with elevated levels of HbA1c displayed increased FHL2 expression, which correlated negatively with insulin secretion pathways. In line with this observation, FHL2-deficient mice cleared glucose more efficiently than wild-type littermates through increased plasma insulin levels. Insulin sensitivity was comparable between these genotypes. Interestingly, pancreatic islets isolated from FHL2-deficient mice secreted more insulin in GSIS assays than wild-type mouse islets even though insulin content and islet size was similar. To support this observation, we demonstrated increased expression of the transcription factor crucial in insulin secretion, MAF BZIP transcription factor A (MafA), higher expression of GLUT2 and reduced expression of the adverse factor c-Jun in FHL2-deficient islets. The underlying mechanism of FHL2 was further delineated in MIN6 cells. FHL2-knockdown led to enhanced activation of forkhead box protein O1 (FOXO1) and its downstream genes such as Mafa and Pdx1 (encoding pancreatic and duodenal homeobox 1), as well as increased glucose uptake. On the other hand, FHL2 overexpression in MIN6 cells blocked GSIS, increased the formation of reactive oxygen species and increased c-Jun activity. Conclusions/interpretation Our data demonstrate that FHL2 deficiency improves insulin secretion from beta cells and improves glucose tolerance in mice. Given that FHL2 expression in humans increases with age and that high expression levels of FHL2 are associated with beta cell dysfunction, we propose that enhanced FHL2 expression in elderly individuals contributes to glucose intolerance and the development of type 2 diabetes. Data availability The human islet microarray datasets used are publicly available and can be found on https://www.ncbi.nlm.nih.gov/geo/. Graphical abstract
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- 2022
33. Peripheral Ischemia Imprints Epigenetic Changes in Hematopoietic Stem Cells to Propagate Inflammation and Atherosclerosis
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Emilie Coppin, Xinyi Zhang, Lee Ohayon, Ebin Johny, Ankush Dasari, Kang H. Zheng, Lotte Stiekema, Eugenia Cifuentes-Pagano, Patrick J. Pagano, Srilakshmi Chaparala, Erik S. Stroes, Partha Dutta, Vascular Medicine, ACS - Atherosclerosis & ischemic syndromes, and Experimental Vascular Medicine
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inflammation ,epigenomics ,atherosclerosis ,myelopoiesis ,Cardiology and Cardiovascular Medicine ,peripheral artery disease ,hematopoiesis ,hematopoietic stem cells - Abstract
Background: Peripheral ischemia caused by peripheral artery disease is associated with systemic inflammation, which may aggravate underlying comorbidities such as atherosclerosis and heart failure. However, the mechanisms of increased inflammation and inflammatory cell production in patients with peripheral artery disease remain poorly understood. Methods: We used peripheral blood collected from patients with peripheral artery disease and performed hind limb ischemia (HI) in Apoe −/− mice fed a Western diet and C57BL/6J mice with a standard laboratory diet. Bulk and single-cell RNA sequencing analysis, whole-mount microscopy, and flow cytometry were performed to analyze hematopoietic stem and progenitor cell (HSPC) proliferation, differentiation, and relocation. Results: We observed augmented numbers of leukocytes in the blood of patients with peripheral artery disease and Apoe −/− mice with HI. RNA sequencing and whole-mount imaging of the bone marrow revealed HSPC migration into the vascular niche from the osteoblastic niche and their exaggerated proliferation and differentiation. Single-cell RNA sequencing demonstrated alterations in the genes responsible for inflammation, myeloid cell mobilization, and HSPC differentiation after HI. Heightened inflammation in Apoe −/− mice after HI aggravated atherosclerosis. Surprisingly, bone marrow HSPCs expressed higher amounts of the receptors for IL (interleukin)-1 and IL-3 after HI. Concomitantly, the promoters of Il1r1 and Il3rb had augmented H3K4me3 and H3K27ac marks after HI. Genetic and pharmacological inhibition of these receptors resulted in suppressed HSPC proliferation, reduced leukocyte production, and ameliorated atherosclerosis. Conclusions: Our findings demonstrate increased inflammation, HSPC abundance in the vascular niches of the bone marrow, and elevated IL-3Rb and IL-1R1 (IL-1 receptor 1) expression in HSPC following HI. Furthermore, the IL-3Rb and IL-1R1 signaling plays a pivotal role in HSPC proliferation, leukocyte abundance, and atherosclerosis aggravation after HI.
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- 2023
34. Anti-high-mobility group box-1 treatment strategies improve trauma-induced coagulopathy in a mouse model of trauma and shock
- Author
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Sloos, Pieter H., Maas, M. Adrie W., Meijers, Joost C.M., Nieuwland, Rienk, Roelofs, Joris J.T.H., Juffermans, Nicole P., Kleinveld, Derek J.B., Pathology, Graduate School, Intensive Care Medicine, Surgery, Experimental Vascular Medicine, Vascular Medicine, ACS - Pulmonary hypertension & thrombosis, ACS - Amsterdam Cardiovascular Sciences, Laboratory Specialized Diagnostics & Research, ACS - Microcirculation, CCA - Cancer biology and immunology, CCA - Imaging and biomarkers, ACS - Diabetes & metabolism, AII - Inflammatory diseases, AII - Infectious diseases, and Anesthesiology
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Anesthesiology and Pain Medicine ,trauma ,inflammation ,platelets ,thromboelastometry ,thrombomodulin ,HMGB-1 ,coagulopathy - Abstract
Background: Trauma-induced coagulopathy is associated with platelet dysfunction and contributes to early mortality after traumatic injury. Plasma concentrations of the damage molecule high-mobility group box-1 (HMGB-1) increase after trauma, which may contribute to platelet dysfunction. We hypothesised that inhibition of HMGB-1 with a monoclonal antibody (mAb) or with recombinant thrombomodulin (rTM) improves trauma-induced coagulopathy in a murine model of trauma and shock. Methods: Male 129S2/SvPasOrlRJ mice were anaesthetised, mechanically ventilated, and randomised into five groups: (i) ventilation control (VENT), (ii) trauma/shock (TS), (iii) TS+anti-HMGB-1 mAb (TS+AB), (iv) TS+rTM (TS+TM), and (v) TS+anti-HMGB-1 mAb+rTM (TS+COMBI). Primary outcome was rotational thromboelastometry EXTEM. Secondary outcomes included tail bleeding time, platelet count, plasma HMGB-1 concentration, and platelet activation. Results: Trauma and shock resulted in a hypocoagulable thromboelastometry profile, increased plasma HMGB-1, and increased platelet activation markers. TS+AB was associated with improved clot firmness after 5 min compared with TS (34 [33–37] vs 32 [29–34] mm; P=0.043). TS+COMBI was associated with decreased clot formation time (98 [92–125] vs 122 [111–148] s; P=0.018) and increased alpha angle (77 [72–78] vs 69 [64–71] degrees; P=0.003) compared with TS. TS+COMBI also reduced tail bleeding time compared with TS (P=0.007). The TS+TM and TS+COMBI groups had higher platelet counts compared with TS (P=0.044 and P=0.041, respectively). Conclusions: Inhibition of HMGB-1 early after trauma in a mouse model improves clot formation and strength, preserves platelet count, and decreases bleeding time.
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- 2023
35. The efficacy of flexor tenotomy to prevent recurrent diabetic foot ulcers (DIAFLEX trial):Study protocol for a randomized controlled trial
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M.A. Mens, T.E. Busch-Westbroek, S.A. Bus, J.J. van Netten, R.H.H. Wellenberg, G.J. Streekstra, M. Maas, M. Nieuwdorp, G.M.M.J. Kerkhoffs, S.A.S. Stufkens, Radiology and nuclear medicine, Internal medicine, ACS - Diabetes & metabolism, AGEM - Endocrinology, metabolism and nutrition, Rehabilitation medicine, AMS - Rehabilitation & Development, Biomedical Engineering and Physics, Radiology and Nuclear Medicine, ACS - Microcirculation, AMS - Musculoskeletal Health, AMS - Sports, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, Experimental Vascular Medicine, Vascular Medicine, Orthopedic Surgery and Sports Medicine, and AMS - Ageing & Vitality
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Pharmacology ,Foot ulcer ,Prevention ,Toe deformity ,General Medicine ,Flexor tenotomy - Abstract
Foot ulcers are a frequent and costly problem in people with diabetes mellitus and can lead to amputations. Prevention of these ulcers is therefore of paramount importance. Claw/hammer toe deformities are commonly seen in people with diabetes. These deformities increase the risk of ulcer development specifically at the (tip of) the toe. Percutaneous needle tenotomy of the tendon of the m. flexor digitorum longus (tendon tenotomy) can be used to reduce the severity of claw/hammer toe deformity with the goal to prevent ulcer recurrence. The main objective of this randomized controlled trial is to assess the efficacy of flexor tenotomy to prevent recurrence of toe ulcers in people with diabetes and a history of toe (pre-)ulcers. Additionally, we aim to assess interphalangeal joints (IPJ) and metatarsophalangeal joint (MTPJ) angles in a weight-bearing and non-weight-bearing position, barefoot plantar pressure during walking, cost-effectiveness and quality of life before and after the intervention and compare intervention and control study groups. Sixty-six subjects with diabetes and claw/hammer toe deformity and a recent history of (pre-)ulceration on the tip of the toe will be included and randomized between flexor tenotomy of claw/hammer toes (intervention) versus standard of care including orthosis and shoe offloading (controls) in a mono-center randomized controlled trial. Clinicaltrials.gov registration: NCT05228340.
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- 2023
36. Lipoproteins act as vehicles for lipid antigen delivery and activation of invariant natural killer T cells
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Suzanne E. Engelen, Francesca A. Ververs, Angela Markovska, B. Christoffer Lagerholm, Jordan M. Kraaijenhof, Laura I.E. Yousif, Yasemin-Xiomara Zurke, Can M.C. Gulersonmez, Sander Kooijman, Michael Goddard, Robert J. van Eijkeren, Peter J. Jervis, Gurdyal S. Besra, Saskia Haitjema, Folkert W. Asselbergs, Eric Kalkhoven, Hidde L. Ploegh, Marianne Boes, Vincenzo Cerundolo, G.K. Hovingh, Mariolina Salio, Edwin C.A. Stigter, Patrick C.N. Rensen, Claudia Monaco, Henk S. Schipper, Graduate School, Vascular Medicine, Cardiology, ACS - Heart failure & arrhythmias, Experimental Vascular Medicine, ACS - Atherosclerosis & ischemic syndromes, and ACS - Amsterdam Cardiovascular Sciences
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NKT cells ,Lipoproteins ,Immunology ,General Medicine - Abstract
Invariant natural killer T (iNKT) cells act at the interface between lipid metabolism and immunity because of their restriction to lipid antigens presented on CD1d by antigen-presenting cells (APCs). How foreign lipid antigens are delivered to APCs remains elusive. Since lipoproteins routinely bind glycosylceramides structurally similar to lipid antigens, we hypothesized that circulating lipoproteins form complexes with foreign lipid antigens. In this study, we used 2-color fluorescence correlation spectroscopy to show, for the first time to our knowledge, stable complex formation of lipid antigens α-galactosylceramide (αGalCer), isoglobotrihexosylceramide, and OCH, a sphingosine-truncated analog of αGalCer, with VLDL and/or LDL in vitro and in vivo. We demonstrate LDL receptor-mediated (LDLR-mediated) uptake of lipoprotein-αGalCer complexes by APCs, leading to potent complex-mediated activation of iNKT cells in vitro and in vivo. Finally, LDLR-mutant PBMCs of patients with familial hypercholesterolemia showed impaired activation and proliferation of iNKT cells upon stimulation, underscoring the relevance of lipoproteins as a lipid antigen delivery system in humans. Taken together, circulating lipoproteins form complexes with lipid antigens to facilitate their transport and uptake by APCs, leading to enhanced iNKT cell activation. This study thereby reveals a potentially novel mechanism of lipid antigen delivery to APCs and provides further insight into the immunological capacities of circulating lipoproteins.
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- 2023
37. Inflammatory Effects of Triglycerides: Relevant or Redundant?
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Kraaijenhof, Jordan M., Stroes, Erik S. G., Graduate School, Vascular Medicine, Experimental Vascular Medicine, and ACS - Atherosclerosis & ischemic syndromes
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high saturated fat diet ,low saturated fat diet ,hypertriglyceridemia ,monocyte ,atherosclerotic cardiovascular disease - Published
- 2023
38. Plasma Lipoprotein Lipase Is Associated with Risk of Future Major Adverse Cardiovascular Events in Patients Following Carotid Endarterectomy
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Joost M. Mekke, Maarten C. Verwer, Erik S.G. Stroes, Jeffrey Kroon, Leo Timmers, Gerard Pasterkamp, Gert J. de Borst, Sander W. van der Laan, Dominique P.V. de Kleijn, Experimental Vascular Medicine, Vascular Medicine, ACS - Atherosclerosis & ischemic syndromes, ACS - Microcirculation, and AGEM - Amsterdam Gastroenterology Endocrinology Metabolism
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Proteomics ,Carotid endarterectomy ,Surgery ,MACE ,Cardiology and Cardiovascular Medicine ,Atherosclerosis ,Lipoprotein lipase - Abstract
INTRODUCTION: Carotid plaque intraplaque haemorrhage (IPH) is associated with future cardiovascular events. It was hypothesised that plasma proteins associated with carotid plaque IPH are also likely to be associated with major adverse cardiovascular events (MACE) after carotid endarterectomy (CEA). METHODS: In pre-operative blood samples from patients undergoing CEA within the Athero-Express biobank, proteins involved in cardiovascular disease were measured using three OLINK proteomics immunoassays. The association between proteins and IPH was analysed using logistic regression analyses. Subsequently, the association between the IPH associated plasma proteins and the three year post-operative risk of MACE (including stroke, myocardial infarction, or cardiovascular death) was analysed. RESULTS: Within the three year follow up, 130 patients (18.9%) of 688 symptomatic and asymptomatic patients undergoing CEA developed MACE. Six of 276 plasma proteins were found to be significantly associated with IPH, from which only lipoprotein lipase (LPL) was associated with the post-operative risk of MACE undergoing CEA. Within the 30 day peri-operative period, high plasma LPL was independently associated with an increased risk of MACE (adjusted hazard ratio [HR] per standard deviation [SD] 1.60, 1.10 - 2.30), p = .014). From 30 days to three years, however, high LPL was associated with a lower risk of MACE (adjusted HR per SD 0.80, 0.65 - 0.99, p= .036). CONCLUSION: High LPL concentrations were found to be associated with a higher risk of MACE in the first 30 post-operative days but with a lower risk MACE between 30 days and three years, meaning that LPL has different hazards at different time points. ispartof: EUROPEAN JOURNAL OF VASCULAR AND ENDOVASCULAR SURGERY vol:65 issue:5 pages:700-709 ispartof: location:England status: published
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- 2023
39. The secondary bile acid isoursodeoxycholate correlates with post-prandial lipemia, inflammation, and appetite and changes post-bariatric surgery
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Louca, Panayiotis, Meijnikman, Abraham S., Nogal, Ana, Asnicar, Francesco, Attaye, Ilias, Vijay, Amrita, Kouraki, Afroditi, Visconti, Alessia, Wong, Kari, Berry, Sarah E., Leeming, Emily R., Mompeo, Olatz, Tettamanzi, Francesca, Baleanu, Andrei-Florin, Falchi, Mario, Hadjigeorgiou, George, Wolf, Jonathan, Acherman, Yair I. Z., van de Laar, Arnold W., Gerdes, Victor E. A., Michelotti, Gregory A., Franks, Paul W., Segata, Nicola, Mangino, Massimo, Spector, Tim D., Bulsiewicz, William J., Nieuwdorp, Max, Valdes, Ana M., Menni, Cristina, Graduate School, Vascular Medicine, ACS - Atherosclerosis & ischemic syndromes, ACS - Diabetes & metabolism, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, ACS - Amsterdam Cardiovascular Sciences, Experimental Vascular Medicine, Internal medicine, and AGEM - Endocrinology, metabolism and nutrition
- Subjects
bile acids ,post-prandial ,liver function ,bariatric surgery ,triglycerides ,General Biochemistry, Genetics and Molecular Biology - Abstract
Primary and secondary bile acids (BAs) influence metabolism and inflammation, and the gut microbiome modulates levels of BAs. We systematically explore the host genetic, gut microbial, and habitual dietary contribution to a panel of 19 serum and 15 stool BAs in two population-based cohorts (TwinsUK, n = 2,382; ZOE PREDICT-1, n = 327) and assess changes post-bariatric surgery and after nutritional interventions. We report that BAs have a moderately heritable genetic component, and the gut microbiome accurately predicts their levels in serum and stool. The secondary BA isoursodeoxycholate (isoUDCA) can be explained mostly by gut microbes (area under the receiver operating characteristic curve [AUC] = ∼80%) and associates with post-prandial lipemia and inflammation (GlycA). Furthermore, circulating isoUDCA decreases significantly 1 year after bariatric surgery (β = −0.72, p = 1 × 10 −5) and in response to fiber supplementation (β = −0.37, p < 0.03) but not omega-3 supplementation. In healthy individuals, isoUDCA fasting levels correlate with pre-meal appetite (p < 1 × 10 −4). Our findings indicate an important role for isoUDCA in lipid metabolism, appetite, and, potentially, cardiometabolic risk.
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- 2023
40. Genetic evidence implicating natriuretic peptide receptor-3 in cardiovascular disease risk: a Mendelian randomization study
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Héléne T. Cronjé, Ville Karhunen, G. Kees Hovingh, Ken Coppieters, Jens O. Lagerstedt, Michael Nyberg, Dipender Gill, Experimental Vascular Medicine, Vascular Medicine, ACS - Atherosclerosis & ischemic syndromes, and ACS - Amsterdam Cardiovascular Sciences
- Subjects
Blood pressure ,Mendelian randomization ,Genetic epidemiology ,NPR3 ,General Medicine ,Cardiovascular disease ,NPR2 ,C-type natriuretic peptide - Abstract
BackgroundC-type natriuretic peptide (CNP) is a known target for promoting growth and has been implicated as a therapeutic opportunity for the prevention and treatment of cardiovascular disease (CVD). This study aimed to explore the effect of CNP on CVD risk using the Mendelian randomization (MR) framework.MethodsInstrumental variables mimicking the effects of pharmacological intervention on CNP were identified as uncorrelated genetic variants located in the genes coding for its primary receptors, natriuretic peptide receptors-2 and 3 (NPR2 and NPR3), that associated with height. We performed MR and colocalization analyses to investigate the effects of NPR2 signalling and NPR3 function on CVD outcomes and risk factors. MR estimates were compared to those obtained when considering height variants from throughout the genome.ResultsGenetically-proxied reduced NPR3 function was associated with a lower risk of CVD, with odds ratio (OR) 0.74 per standard deviation (SD) higher NPR3-predicted height, and 95% confidence interval (95% CI) 0.64–0.86. This effect was greater in magnitude than observed when considering height variants from throughout the genome. For CVD subtypes, similar MR associations for NPR3-predicted height were observed when considering the outcomes of coronary artery disease (0.75, 95% CI 0.60–0.92), stroke (0.69, 95% CI 0.50–0.95) and heart failure (0.77, 95% CI 0.58–1.02). Consideration of CVD risk factors identified systolic blood pressure (SBP) as a potential mediator of the NPR3-related CVD risk lowering. For stroke, we found that the MR estimate for NPR3 was greater in magnitude than could be explained by a genetically predicted SBP effect alone. Colocalization results largely supported the MR findings, with no evidence of results being driven by effects due to variants in linkage disequilibrium. There was no MR evidence supporting effects of NPR2 on CVD risk, although this null finding could be attributable to fewer genetic variants being identified to instrument this target.ConclusionsThis genetic analysis supports the cardioprotective effects of pharmacologically inhibiting NPR3 receptor function, which is only partly mediated by an effect on blood pressure. There was unlikely sufficient statistical power to investigate the cardioprotective effects of NPR2 signalling. Background: C-type natriuretic peptide (CNP) is a known target for promoting growth and has been implicated as a therapeutic opportunity for the prevention and treatment of cardiovascular disease (CVD). This study aimed to explore the effect of CNP on CVD risk using the Mendelian randomization (MR) framework. Methods: Instrumental variables mimicking the effects of pharmacological intervention on CNP were identified as uncorrelated genetic variants located in the genes coding for its primary receptors, natriuretic peptide receptors-2 and 3 (NPR2 and NPR3), that associated with height. We performed MR and colocalization analyses to investigate the effects of NPR2 signalling and NPR3 function on CVD outcomes and risk factors. MR estimates were compared to those obtained when considering height variants from throughout the genome. Results: Genetically-proxied reduced NPR3 function was associated with a lower risk of CVD, with odds ratio (OR) 0.74 per standard deviation (SD) higher NPR3-predicted height, and 95% confidence interval (95% CI) 0.64–0.86. This effect was greater in magnitude than observed when considering height variants from throughout the genome. For CVD subtypes, similar MR associations for NPR3-predicted height were observed when considering the outcomes of coronary artery disease (0.75, 95% CI 0.60–0.92), stroke (0.69, 95% CI 0.50–0.95) and heart failure (0.77, 95% CI 0.58–1.02). Consideration of CVD risk factors identified systolic blood pressure (SBP) as a potential mediator of the NPR3-related CVD risk lowering. For stroke, we found that the MR estimate for NPR3 was greater in magnitude than could be explained by a genetically predicted SBP effect alone. Colocalization results largely supported the MR findings, with no evidence of results being driven by effects due to variants in linkage disequilibrium. There was no MR evidence supporting effects of NPR2 on CVD risk, although this null finding could be attributable to fewer genetic variants being identified to instrument this target. Conclusions: This genetic analysis supports the cardioprotective effects of pharmacologically inhibiting NPR3 receptor function, which is only partly mediated by an effect on blood pressure. There was unlikely sufficient statistical power to investigate the cardioprotective effects of NPR2 signalling.
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- 2023
41. Healthcare expenditure and technology use in pediatric diabetes care
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de Vries, Silvia A. G., Bak, Jessica C. G., Verheugt, Carianne L., Stangenberger, Vincent A., Mul, Dick, Wouters, Michel W. J. M., Nieuwdorp, Max, Sas, Theo C. J., Graduate School, Vascular Medicine, ACS - Amsterdam Cardiovascular Sciences, ACS - Heart failure & arrhythmias, Experimental Vascular Medicine, ACS - Diabetes & metabolism, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, Internal medicine, Obstetrics and gynaecology, Amsterdam Reproduction & Development (AR&D), AGEM - Endocrinology, metabolism and nutrition, and Pediatrics
- Subjects
Healthcare utilization ,Technology ,Diabetes mellitus ,SDG 3 - Good Health and Well-being ,Endocrinology, Diabetes and Metabolism ,Continuous glucose monitor ,General Medicine ,SDG 12 - Responsible Consumption and Production ,Hospital costs ,Children - Abstract
Background Diabetes mellitus is one of the most common chronic diseases in childhood. With more advanced care options including ever-evolving technology, allocation of resources becomes increasingly important to guarantee equal care for all. Therefore, we investigated healthcare resource utilization, hospital costs, and its determinants in Dutch children with diabetes. Methods We conducted a retrospective, observational analysis with hospital claims data of 5,474 children with diabetes mellitus treated in 64 hospitals across the Netherlands between 2019–2020. Results Total hospital costs were €33,002,652 per year, and most of these costs were diabetes-associated (€28,151,381; 85.3%). Mean annual diabetes costs were €5,143 per child, and treatment-related costs determined 61.8%. Diabetes technology significantly increased yearly diabetes costs compared to no technology: insulin pumps € 4,759 (28.7% of children), Real-Time Continuous Glucose Monitoring € 7,259 (2.1% of children), and the combination of these treatment modalities € 9,579 (27.3% of children). Technology use increased treatment costs significantly (5.9 – 15.3 times), but lower all-cause hospitalisation rates were observed. In all age groups, diabetes technology use influenced healthcare consumption, yet in adolescence usage decreased and consumption patterns changed. Conclusions These findings suggest that contemporary hospital costs of children with diabetes of all ages are driven primarily by the treatment of diabetes, with technology use as an important additive factor. The expected rise in technology use in the near future underlines the importance of insight into resource use and cost-effectiveness studies to evaluate if improved outcomes balance out these short-term costs of modern technology.
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- 2023
42. Acute Effects of Insulin Infusion on Kidney Hemodynamic Function in People With Type 2 Diabetes and Normal Kidney Function
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Michaël J.B. van Baar, Erik J.M. van Bommel, Daan J. Touw, Max Nieuwdorp, Jaap A. Joles, Merle M. Krebber, Petter Bjornstad, Daniël H. van Raalte, Pharmaceutical Analysis, Critical care, Anesthesiology, Peri-operative and Emergency medicine (CAPE), Biopharmaceuticals, Discovery, Design and Delivery (BDDD), Groningen Research Institute for Asthma and COPD (GRIAC), Medicinal Chemistry and Bioanalysis (MCB), Experimental Vascular Medicine, Vascular Medicine, ACS - Diabetes & metabolism, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, Internal medicine, AGEM - Endocrinology, metabolism and nutrition, and Amsterdam Gastroenterology Endocrinology Metabolism
- Subjects
glomerular filtration rate ,Nephrology ,insulin infusion ,kidney hemodynamics ,Research Letter ,kidney perfusion ,renal vascular resistance ,diabetic kidney disease - Published
- 2023
43. Effect of Prior Antibiotic Use on Culture Results in People with Diabetes and Foot Osteomyelitis
- Author
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Meryl Cinzía Tila Tamara Gramberg, Jarne Marijn Van Hattem, Jacob Albert Dijkstra, Emma Dros, Max Nieuwdorp, Louise Willy Elizabeth Sabelis, Edgar Josephus Gerardus Peters, Medical Microbiology and Infection Prevention, Experimental Vascular Medicine, Vascular Medicine, ACS - Diabetes & metabolism, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, Internal medicine, AGEM - Endocrinology, metabolism and nutrition, Rehabilitation medicine, Amsterdam Movement Sciences - Restoration and Development, Amsterdam Movement Sciences, AII - Infectious diseases, AII - Inflammatory diseases, and AMS - Rehabilitation & Development
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Microbiology (medical) ,diabetic foot osteomyelitis ,ulcer bed biopsy ,bone biopsy ,bacterial cultures ,antibiotics ,antibiotic resistance ,Infectious Diseases ,Pharmacology (medical) ,General Pharmacology, Toxicology and Pharmaceutics ,Biochemistry ,Microbiology - Abstract
Background: Antibiotic use prior to biopsy acquisition in people with diabetes and osteomyelitis of the foot (DFO) might influence bacterial yield in cultures or induce bacterial resistance. Obtaining reliable culture results is pivotal to guide antibiotics for conservative treatment of DFO. Methods: We prospectively analysed cultures of ulcer bed and percutaneous bone biopsies of people with DFO and investigated if antibiotics administered prior to (
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- 2023
44. Microbial influencers: treating diabetes through the gut
- Author
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Snelson, Matthew, Rampanelli, Elena, Nieuwdorp, Max, Hanssen, Nordin M. J., Coughlan, Melinda T., Internal medicine, ACS - Diabetes & metabolism, AGEM - Endocrinology, metabolism and nutrition, Vascular Medicine, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, Experimental Vascular Medicine, and ACS - Atherosclerosis & ischemic syndromes
- Subjects
Dietary Fiber ,SCFAs ,Immune regulation ,Research ,Microbiota ,Immunology ,Starch ,Autoimmunity ,Cell Biology ,Dietary-metabolites ,Type 1 diabetes ,Diabetes Mellitus ,Humans ,Immunology and Allergy - Abstract
Background Short-chain fatty acids (SCFAs) produced by the gut microbiota have beneficial anti-inflammatory and gut homeostasis effects and prevent type 1 diabetes (T1D) in mice. Reduced SCFA production indicates a loss of beneficial bacteria, commonly associated with chronic autoimmune and inflammatory diseases, including T1D and type 2 diabetes. Here, we addressed whether a metabolite-based dietary supplement has an impact on humans with T1D. We conducted a single-arm pilot-and-feasibility trial with high-amylose maize-resistant starch modified with acetate and butyrate (HAMSAB) to assess safety, while monitoring changes in the gut microbiota in alignment with modulation of the immune system status. Results HAMSAB supplement was administered for 6 weeks with follow-up at 12 weeks in adults with long-standing T1D. Increased concentrations of SCFA acetate, propionate, and butyrate in stools and plasma were in concert with a shift in the composition and function of the gut microbiota. While glucose control and insulin requirements did not change, subjects with the highest SCFA concentrations exhibited the best glycemic control. Bifidobacterium longum, Bifidobacterium adolescentis, and vitamin B7 production correlated with lower HbA1c and basal insulin requirements. Circulating B and T cells developed a more regulatory phenotype post-intervention. Conclusion Changes in gut microbiota composition, function, and immune profile following 6 weeks of HAMSAB supplementation were associated with increased SCFAs in stools and plasma. The persistence of these effects suggests that targeting dietary SCFAs may be a mechanism to alter immune profiles, promote immune tolerance, and improve glycemic control for the treatment of T1D. Trial registration ACTRN12618001391268. Registered 20 August 2018, https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=375792 Video Abstract Supplementary Information The online version contains supplementary material available at 10.1186/s40168-021-01193-9.
- Published
- 2022
45. Effects of Dapagliflozin and Combination Therapy With Exenatide on Food-Cue Induced Brain Activation in Patients With Type 2 Diabetes
- Author
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Charlotte C van Ruiten, Dick J Veltman, Anouk Schrantee, Liselotte van Bloemendaal, Frederik Barkhof, Mark H H Kramer, Max Nieuwdorp, Richard G IJzerman, Internal medicine, ACS - Diabetes & metabolism, Anatomy and neurosciences, Psychiatry, Amsterdam Neuroscience - Brain Imaging, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, Radiology and nuclear medicine, Amsterdam Neuroscience - Neuroinfection & -inflammation, AGEM - Endocrinology, metabolism and nutrition, Amsterdam Gastroenterology Endocrinology Metabolism, Radiology and Nuclear Medicine, APH - Personalized Medicine, Amsterdam Neuroscience - Compulsivity, Impulsivity & Attention, Experimental Vascular Medicine, Vascular Medicine, and APH - Mental Health
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Blood Glucose ,obesity ,GLP-1 receptor agonist ,Endocrinology, Diabetes and Metabolism ,exenatide ,Clinical Biochemistry ,functional neuroimaging ,Biochemistry ,body weight ,Endocrinology ,Double-Blind Method ,Glucosides ,Weight Loss ,satiety and reward circuits ,Humans ,Hypoglycemic Agents ,Benzhydryl Compounds ,Sodium-Glucose Transporter 2 Inhibitors ,Glycated Hemoglobin ,Biochemistry (medical) ,Brain ,SGLT2 inhibitor ,dapagliflozin ,Middle Aged ,central nervous system ,Diabetes Mellitus, Type 2 ,type 2 diabetes ,Cues - Abstract
Context Sodium-glucose cotransporter-2 inhibitors (SGLT2i) cause less weight loss than expected based on urinary calorie excretion. This may be explained by SGLT2i-induced alterations in central reward and satiety circuits, leading to increased appetite and food intake. Glucagon-like peptide-1 receptor agonists are associated with reduced appetite and body weight, mediated by direct and indirect central nervous system (CNS) effects. Objective We investigated the separate and combined effects of dapagliflozin and exenatide on the CNS in participants with obesity and type 2 diabetes. Methods This was a 16-week, double-blind, randomized, placebo-controlled trial. Obese participants with type 2 diabetes (n = 64, age 63.5 ± 0.9 years, BMI 31.7 ± 0.6 kg/m2) were randomized (1:1:1:1) to dapagliflozin 10 mg with exenatide-matched placebo, exenatide twice daily 10 µg with dapagliflozin-matched placebo, dapagliflozin and exenatide, or double placebo. Using functional MRI, the effects of treatments on CNS responses to viewing food pictures were assessed after 10 days and 16 weeks of treatment. Results After 10 days, dapagliflozin increased, whereas exenatide decreased CNS activation in the left putamen. Combination therapy had no effect on responses to food pictures. After 16 weeks, no changes in CNS activation were observed with dapagliflozin, but CNS activation was reduced with dapagliflozin-exenatide in right amygdala. Conclusion The early increase in CNS activation with dapagliflozin may contribute to the discrepancy between observed and expected weight loss. In combination therapy, exenatide blunted the increased CNS activation observed with dapagliflozin. These findings provide further insights into the weight-lowering mechanisms of SGLT2i and GLP-1 receptor agonists.
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- 2022
46. A Systematic Review and Meta-analysis of Dietary Interventions Modulating Gut Microbiota and Cardiometabolic Diseases—Striving for New Standards in Microbiome Studies
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Ilias Attaye, Moritz V. Warmbrunn, Aureline N.A.F. Boot, Suze C. van der Wolk, Barbara A. Hutten, Joost G. Daams, Hilde Herrema, Max Nieuwdorp, Internal medicine, ACS - Diabetes & metabolism, AGEM - Endocrinology, metabolism and nutrition, Graduate School, Vascular Medicine, ACS - Amsterdam Cardiovascular Sciences, Epidemiology and Data Science, APH - Aging & Later Life, APH - Health Behaviors & Chronic Diseases, Experimental Vascular Medicine, and AGEM - Amsterdam Gastroenterology Endocrinology Metabolism
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Gut Microbiome ,Metabolic Syndrome ,Hepatology ,Cardiovascular Diseases ,Risk Factors ,Cardiometabolic Diseases ,Dietary Intervention ,Gastroenterology ,Humans ,Blood Pressure ,Triglycerides ,Gastrointestinal Microbiome ,Type 2 Diabetes - Abstract
Background & Aims: Cardiometabolic diseases (CMDs) have shared properties and causes. Insulin resistance is a risk factor and characteristic of CMDs and has been suggested to be modulated by plasma metabolites derived from gut microbiota (GM). Because diet is among the most important modulators of GM, we performed a systematic review of the literature to assess whether CMDs can be modulated via dietary interventions targeting the GM. Methods: A systematic review of the literature for clinical studies was performed on Ovid MEDLINE and Ovid Embase. Studies were assessed for risk of bias and patterns of intervention effects. A meta-analysis with random effects models was used to evaluate the effect of dietary interventions on clinical outcomes. Results: Our search yielded 4444 unique articles, from which 15 randomized controlled trials and 6 nonrandomized clinical trials were included. The overall risk of bias was high in all studies. In general, most dietary interventions changed the GM composition, but no consistent effect could be found. Results of the meta-analyses showed that only diastolic blood pressure is decreased across interventions compared with controls (mean difference: −3.63 mm Hg; 95% confidence interval, −7.09 to −0.17; I2 = 0%, P = .04) and that a high-fiber diet was associated with reduced triglyceride levels (mean difference: −0.69 mmol/L; 95% confidence interval, −1.36 to −0.02; I2 = 59%, P = .04). Other CMD parameters were not affected. Conclusions: Dietary interventions modulate GM composition, blood pressure, and circulating triglycerides. However, current studies have a high methodological heterogeneity and risk of bias. Well-designed and controlled studies are thus necessary to better understand the complex interaction between diet, microbiome, and CMDs. PROSPERO: CRD42020188405
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- 2022
47. Targeted proteomics improves cardiovascular risk prediction in secondary prevention
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Nick S. Nurmohamed, João P. Belo Pereira, Renate M. Hoogeveen, Jeffrey Kroon, Jordan M. Kraaijenhof, Farahnaz Waissi, Nathalie Timmerman, Michiel J. Bom, Imo E. Hoefer, Paul Knaapen, Alberico L. Catapano, Wolfgang Koenig, Dominique de Kleijn, Frank L.J. Visseren, Evgeni Levin, Erik S.G. Stroes, Graduate School, Vascular Medicine, ACS - Atherosclerosis & ischemic syndromes, Experimental Vascular Medicine, ACS - Microcirculation, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, ACS - Heart failure & arrhythmias, ACS - Diabetes & metabolism, and Cardiology
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EXPRESSION ,Proteomics ,Cardiac & Cardiovascular Systems ,PROTEIN ,RATIONALE ,Risk Assessment ,VALIDATION ,ARTERIAL-DISEASE ,Brain Ischemia ,C-reactive protein ,NLRP3 ,Risk Factors ,Machine learning ,Secondary Prevention ,Humans ,Science & Technology ,VASCULAR EVENTS ,GROWTH-FACTOR-BETA ,MYELOPEROXIDASE ,Atherosclerosis ,Stroke ,ATHEROSCLEROSIS ,Cardiovascular Diseases ,Heart Disease Risk Factors ,Cardiovascular System & Cardiology ,Risk score ,INFARCTION ,Cardiology and Cardiovascular Medicine ,Life Sciences & Biomedicine ,ASCVD - Abstract
Aims Current risk scores do not accurately identify patients at highest risk of recurrent atherosclerotic cardiovascular disease (ASCVD) in need of more intensive therapeutic interventions. Advances in high-throughput plasma proteomics, analysed with machine learning techniques, may offer new opportunities to further improve risk stratification in these patients. Methods and results Targeted plasma proteomics was performed in two secondary prevention cohorts: the Second Manifestations of ARTerial disease (SMART) cohort (n = 870) and the Athero-Express cohort (n = 700). The primary outcome was recurrent ASCVD (acute myocardial infarction, ischaemic stroke, and cardiovascular death). Machine learning techniques with extreme gradient boosting were used to construct a protein model in the derivation cohort (SMART), which was validated in the Athero-Express cohort and compared with a clinical risk model. Pathway analysis was performed to identify specific pathways in high and low C-reactive protein (CRP) patient subsets. The protein model outperformed the clinical model in both the derivation cohort [area under the curve (AUC): 0.810 vs. 0.750; P < 0.001] and validation cohort (AUC: 0.801 vs. 0.765; P < 0.001), provided significant net reclassification improvement (0.173 in validation cohort) and was well calibrated. In contrast to a clear interleukin-6 signal in high CRP patients, neutrophil-signalling-related proteins were associated with recurrent ASCVD in low CRP patients. Conclusion A proteome-based risk model is superior to a clinical risk model in predicting recurrent ASCVD events. Neutrophil-related pathways were found in low CRP patients, implying the presence of a residual inflammatory risk beyond traditional NLRP3 pathways. The observed net reclassification improvement illustrates the potential of proteomics when incorporated in a tailored therapeutic approach in secondary prevention patients.
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- 2022
48. Pancreatic exocrine insufficiency after bariatric surgery
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Maimoena S.S. Guman, Nienke van Olst, Zehra G. Yaman, Rogier P. Voermans, Maurits L. de Brauw, Max Nieuwdorp, Victor E.A. Gerdes, Internal medicine, AGEM - Endocrinology, metabolism and nutrition, ACS - Diabetes & metabolism, Graduate School, Vascular Medicine, Gastroenterology and Hepatology, Amsterdam Gastroenterology Endocrinology Metabolism, and Experimental Vascular Medicine
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Adult ,Male ,Bariatric surgery ,Fecal elastase test ,technology, industry, and agriculture ,macromolecular substances ,Middle Aged ,Pancreatic Exocrine Insufficiency Questionnaire ,Surveys and Questionnaires ,Weight Loss ,Quality of Life ,Humans ,Pancreatic exocrine insufficiency ,Exocrine Pancreatic Insufficiency ,Female ,Surgery - Abstract
Background: Chronic abdominal complaints after bariatric surgery may be explained by pancreatic exocrine insufficiency (PEI). Objectives: We aimed to evaluate the clinical value of the Pancreatic Exocrine Insufficiency Questionnaire (PEI-Q) as a screening tool to identify patients with a high probability of having PEI. Setting: Outpatient clinic for bariatric surgery. Methods: Patients scheduled for a screening or follow-up appointment were asked to complete the PEI-Q and the Gastrointestinal Quality of Life Index questionnaire (GIQLI). Postoperative patients with a high PEI-Q score (0,6) were offered a fecalelastase (FE) test (abnormal if
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- 2022
49. Blood coagulation and beyond
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Asim Cengiz Akbulut, Ryanne A. Arisz, Constance C. F. M. J. Baaten, Gaukhar Baidildinova, Aarazo Barakzie, Rupert Bauersachs, Jur ten Berg, Wout W. A. van den Broek, H. C. de Boer, Amandine Bonifay, Vanessa Bröker, Richard J. Buka, Hugo ten Cate, Arina J. ten Cate-Hoek, S. Cointe, Ciro De Luca, Ilaria De Simone, Rocio Vacik Diaz, Françoise Dignat-George, Kathleen Freson, Giulia Gazzaniga, Eric C. M. van Gorp, Anxhela Habibi, Yvonne M. C. Henskens, Aaron F. J. Iding, Abdullah Khan, Gijsje H. Koenderink, Akhil Konkoth, Romaric Lacroix, Trisha Lahiri, Wilbur Lam, Rachel E. Lamerton, Roberto Lorusso, Qi Luo, Coen Maas, Owen J. T. McCarty, Paola E. J. van der Meijden, Joost C. M. Meijers, Adarsh K. Mohapatra, Neta Nevo, Alejandro Pallares Robles, Philippe Poncelet, Christoph Reinhardt, Wolfram Ruf, Ronald Saraswat, Claudia Schönichen, Roger Schutgens, Paolo Simioni, Stefano Spada, Henri M. H. Spronk, Karlygash Tazhibayeva, Jecko Thachil, L. Vallier, Alicia Veninga, Peter Verhamme, Chantal Visser, Steve P. Watson, Philip Wenzel, Ruth A. L. Willems, Anne Willers, Pengyu Zhang, Konstantinos Zifkos, Anton Jan van Zonneveld, Biochemie, RS: Carim - B02 Vascular aspects thrombosis and Haemostasis, RS: Carim - B04 Clinical thrombosis and Haemostasis, RS: Carim - B03 Cell biochemistry of thrombosis and haemostasis, Cardiologie, RS: Carim - B01 Blood proteins & engineering, MUMC+: MA Alg Interne Geneeskunde (9), MUMC+: HVC Trombosezorg (8), MUMC+: HVC Pieken Trombose (9), MUMC+: DA CDL Algemeen (9), Central Diagnostic Lab, MUMC+: HVC Trombosedienst (9), MUMC+: MA Cardiothoracale Chirurgie (3), RS: Carim - V04 Surgical intervention, CTC, MUMC+: MA Med Staf Spec CTC (9), MUMC+: MA Med Staf Artsass Cardiologie (9), MUMC+: MA Med Staf Artsass Interne Geneeskunde (9), MUMC+: MA Med Staf Artsass CTC (9), Experimental Vascular Medicine, Vascular Medicine, ACS - Pulmonary hypertension & thrombosis, and ACS - Amsterdam Cardiovascular Sciences
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Hematology - Abstract
The Fourth Maastricht Consensus Conference on Thrombosis included the following themes. Theme 1: The “coagulome” as a critical driver of cardiovascular disease. Blood coagulation proteins also play divergent roles in biology and pathophysiology, related to specific organs, including brain, heart, bone marrow, and kidney. Four investigators shared their views on these organ-specific topics. Theme 2: Novel mechanisms of thrombosis. Mechanisms linking factor XII to fibrin, including their structural and physical properties, contribute to thrombosis, which is also affected by variation in microbiome status. Virus infection-associated coagulopathies perturb the hemostatic balance resulting in thrombosis and/or bleeding. Theme 3: How to limit bleeding risks: insights from translational studies. This theme included state-of-the-art methodology for exploring the contribution of genetic determinants of a bleeding diathesis; determination of polymorphisms in genes that control the rate of metabolism by the liver of P2Y12 inhibitors, to improve safety of antithrombotic therapy. Novel reversal agents for direct oral anticoagulants are discussed. Theme 4: Hemostasis in extracorporeal systems: the value and limitations of ex vivo models. Perfusion flow chamber and nanotechnology developments are developed for studying bleeding and thrombosis tendencies. Vascularized organoids are utilized for disease modeling and drug development studies. Strategies for tackling extracorporeal membrane oxygenation-associated coagulopathy are discussed. Theme 5: Clinical dilemmas in thrombosis and antithrombotic management. Plenary presentations addressed controversial areas, i.e., thrombophilia testing, thrombosis risk assessment in hemophilia, novel antiplatelet strategies, and clinically tested factor XI(a) inhibitors, both possibly with reduced bleeding risk. Finally, COVID-19-associated coagulopathy is revisited.
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- 2023
50. FHL2 Genetic Polymorphisms and Pro-Diabetogenic Lipid Profile in the Multiethnic HELIUS Cohort
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Jayron J. Habibe, Ulrika Boulund, Maria P. Clemente-Olivo, Carlie J. M. de Vries, Etto C. Eringa, Max Nieuwdorp, Bart Ferwerda, Koos Zwinderman, Bert-Jan H. van den Born, Henrike Galenkamp, Daniel H. van Raalte, Fysiologie, RS: Carim - H08 Experimental atrial fibrillation, Graduate School, ACS - Diabetes & metabolism, Experimental Vascular Medicine, ACS - Amsterdam Cardiovascular Sciences, Medical Biochemistry, ACS - Heart failure & arrhythmias, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, Vascular Medicine, Epidemiology and Data Science, ANS - Neuroinfection & -inflammation, APH - Methodology, Public and occupational health, ACS - Atherosclerosis & ischemic syndromes, APH - Global Health, APH - Personalized Medicine, and APH - Health Behaviors & Chronic Diseases
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RISK ,FHL2 ,HELIUS ,Organic Chemistry ,dyslipidemia ,General Medicine ,Catalysis ,DISEASE ,Computer Science Applications ,polymorphism ,Inorganic Chemistry ,ONLY PROTEIN FHL2 ,cohort study ,TG ,Physical and Theoretical Chemistry ,LDL-C ,Molecular Biology ,Spectroscopy - Abstract
Type 2 diabetes mellitus (T2D) is a prevalent disease often accompanied by the occurrence of dyslipidemia. Four and a half LIM domains 2 (FHL2) is a scaffolding protein, whose involvement in metabolic disease has recently been demonstrated. The association of human FHL2 with T2D and dyslipidemia in a multiethnic setting is unknown. Therefore, we used the large multiethnic Amsterdam-based Healthy Life in an Urban Setting (HELIUS) cohort to investigate FHL2 genetic loci and their potential role in T2D and dyslipidemia. Baseline data of 10,056 participants from the HELIUS study were available for analysis. The HELIUS study contained individuals of European Dutch, South Asian Surinamese, African Surinamese, Ghanaian, Turkish, and Moroccan descent living in Amsterdam and were randomly sampled from the municipality register. Nineteen FHL2 polymorphisms were genotyped, and associations with lipid panels and T2D status were investigated. We observed that seven FHL2 polymorphisms associated nominally with a pro-diabetogenic lipid profile including triglyceride (TG), high-density and low-density lipoprotein-cholesterol (HDL-C and LDL-C), and total cholesterol (TC) concentrations, but not with blood glucose concentrations or T2D status in the complete HELIUS cohort upon correcting for age, gender, BMI, and ancestry. Upon stratifying for ethnicity, we observed that only two of the nominally significant associations passed multiple testing adjustments, namely, the association of rs4640402 with increased TG and rs880427 with decreased HDL-C concentrations in the Ghanaian population. Our results highlight the effect of ethnicity on pro-diabetogenic selected lipid biomarkers within the HELIUS cohort, as well as the need for more large multiethnic cohort studies.
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- 2023
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