3,066 results on '"Munich Heart Alliance"'
Search Results
2. Biomarkers in patients with heart failure and central sleep apnoea : findings from the SERVE-HF trial
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Marie Pia d'Ortho, Erland Erdmann, Karl Wegscheider, Faiez Zannad, Wolfgang Koenig, João Pedro Ferreira, Anita K. Simonds, Martin R. Cowie, Helmut Teschler, Virend K. Somers, Christiane E. Angermann, Holger Woehrle, Patrick Rossignol, Kevin Duarte, Patrick Levy, Centre d'investigation clinique plurithématique Pierre Drouin [Nancy] (CIC-P), Centre d'investigation clinique [Nancy] (CIC), Université de Lorraine (UL)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM), Défaillance Cardiovasculaire Aiguë et Chronique (DCAC), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Cardiovascular and Renal Clinical Trialists [Vandoeuvre-les-Nancy] (INI-CRCT), Institut Lorrain du Coeur et des Vaisseaux Louis Mathieu [Nancy], French-Clinical Research Infrastructure Network - F-CRIN [Paris] (Cardiovascular & Renal Clinical Trialists - CRCT ), ResMed Science Center, ResMed Germany Inc., Martinsried, Faculty of Medicine, Imperial College London, Department of Medical Biometry and Epidemiology, University Medical Center Hamburg-Eppendorf, Faculty of Medicine I and Comprehensive Heart Failure Center, University Hospital and University of Würzburg, Hôpital Bichat, Explorations Fonctionnelles, DHU FIRE, AP-HP, Paris, UFR de Médicine, Sorbonne Paris Cité, Paris Diderot University, Paris, Heart Center, University of Cologne, Inserm, HP2 lab. CHU Grenoble, Université de Grenoble Alpes, Respiratory Medicine, Royal Brompton Hospital, London, Cardiovascular Facility and the Sleep Facility, Mayo Clinic and Mayo Foundation, Rochester, Department of Pneumology, Ruhrlandklinik, Essen, West German Lung Centre, Essen University Hospital, Essen, University Duisburg-EssenDepartment of Pneumology, Essen, Deutsches Herzzentrum München, Technische Universität München, Munich, Munich Heart Alliance, German Centre for Cardiovascular Research, partner site Munich Heart Alliance, Munich, J. P. F., P. R., and F. Z. are supported by a public grant overseen by the French National Research Agency (ANR) aspart of the second ‘Investissements d’Avenir’ programme (ANR-15-RHU-0004)., ANR-15-RHUS-0004,FIGHT-HF,Combattre l'insuffisance cardiaque(2015), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), University of Cologne, BOZEC, Erwan, and Combattre l'insuffisance cardiaque - - FIGHT-HF2015 - ANR-15-RHUS-0004 - RHUS - VALID
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Male ,Cardiac & Cardiovascular Systems ,Circulating biomarkers ,Medizin ,030204 cardiovascular system & hematology ,RISK STRATIFICATION ,0302 clinical medicine ,Original Research Articles ,Medicine ,Original Research Article ,030212 general & internal medicine ,1102 Cardiorespiratory Medicine and Haematology ,Adaptive servo‐ventilation ,education.field_of_study ,Ejection fraction ,Middle Aged ,GROWTH-DIFFERENTIATION FACTOR-15 ,Loop diuretic ,Prognosis ,Sleep Apnea, Central ,[SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system ,3. Good health ,PROGNOSTIC VALUE ,Cardiology ,Biomarker (medicine) ,Female ,Cardiology and Cardiovascular Medicine ,Life Sciences & Biomedicine ,medicine.medical_specialty ,Adaptive servo-ventilation ,medicine.drug_class ,Population ,Heart failure ,PRESSURE ,DIAGNOSIS ,MECHANISMS ,03 medical and health sciences ,Sleep Apnea Syndromes ,[SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system ,Internal medicine ,Diabetes mellitus ,Humans ,Diseases of the circulatory (Cardiovascular) system ,SOLUBLE ST2 ,education ,Aged ,Science & Technology ,business.industry ,MORTALITY ,Stroke Volume ,medicine.disease ,VENTILATION ,Blood pressure ,RC666-701 ,Cardiovascular System & Cardiology ,GDF15 ,business ,REDUCED EJECTION FRACTION ,Biomarkers - Abstract
International audience; Aims: The Treatment of Sleep-Disordered Breathing with Predominant Central Sleep Apnoea by Adaptive Servo Ventilation in Patients with Heart Failure trial investigated the effects of adaptive servo-ventilation (ASV) (vs. control) on outcomes of 1325 patients with heart failure and reduced ejection fraction (HFrEF) and central sleep apnoea (CSA). The primary outcome (a composite of all-cause death or unplanned HF hospitalization) did not differ between the two groups. However, all-cause and cardiovascular (CV) mortality were higher in the ASV group. Circulating biomarkers may help in better ascertain patients’ risk, and this is the first study applying a large set of circulating biomarkers in patients with both HFrEF and CSA.Methods and results: Circulating protein-biomarkers (n = 276) ontologically involved in CV pathways, were studied in 749 (57% of the trial population) patients (biomarker substudy), to investigate their association with the study outcomes (primary outcome, CV death and all-cause death). The mean age was 69 ± 10 years, and > 90% were male. The groups (ASV vs. control and biomarker substudy vs. no biomarker) were well balanced. The “best” clinical prognostic model included male sex, systolic blood pressure < 120 mmHg, diabetes, loop diuretic, cardiac device, 6-min walking test distance, and N-terminal pro BNP as the strongest prognosticators. On top of the “best” clinical prognostic model, the biomarkers that significantly improved both the discrimination (c-index) and the net reclassification index (NRI) of the model were soluble suppression of tumorigenicity 2 for the primary outcome; neurogenic locus notch homolog protein 3 (Notch-3) for CV-death and all-cause death; and growth differentiation factor 15 (GDF-15) for all-cause death only.Conclusions: We studied 276 circulating biomarkers in patients with HFrEF and central sleep apnoea; of these biomarkers, three added significant prognostic information on top of the best clinical model: soluble suppression of tumorigenicity 2 (primary outcome), Notch-3 (CV and all-cause death), and GDF-15 (all-cause death).
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- 2020
3. Impact of denoising on precision and accuracy of saturation-recovery-based myocardial T 1 mapping
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Bustin, Aurélien, Ferry, Pauline, Codreanu, Andrei, Beaumont, Marine, Liu, Shufang, Burschka, Darius, Felblinger, Jacques, Brau, Anja C.S., Menini, Anne, Odille, Freddy, Imagerie Adaptative Diagnostique et Interventionnelle (IADI), Université de Lorraine (UL)-Institut National de la Santé et de la Recherche Médicale (INSERM), General Electric Global Research Center, Munich, Technische Universität München [München] (TUM), Centre Hospitalier de Luxembourg [Luxembourg] (CHL), Centre d'Investigation Clinique - Innovation Technologique [Nancy] (CIC-IT), Centre d'investigation clinique [Nancy] (CIC), Université de Lorraine (UL)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM), Munich Heart Alliance, German Centre for Cardiovascular Research, partner site Munich Heart Alliance, Munich, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), and Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM)
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myocardial T1 mapping ,accuracy ,[SDV.IB.IMA]Life Sciences [q-bio]/Bioengineering/Imaging ,cardiac MRI ,denoising ,precision - Abstract
International audience; Purpose: To evaluate the impact of a novel postprocessing denoising technique on accuracy and precision in myocardial T1 mapping.Materials and methods: This study introduces a fast and robust denoising method developed for magnetic resonance T1 mapping. The technique imposes edge-preserving regularity and exploits the co-occurence of spatial gradients in the acquired T1 -weighted images. The proposed approach was assessed in simulations, ex vivo data and in vivo imaging on a cohort of 16 healthy volunteers (12 males, average age 39 ± 8 years, 62 ± 9 bpm) both in pre- and postcontrast injection. The method was evaluated in myocardial T1 mapping at 3T with a saturation-recovery technique that is accurate but sensitive to noise. ROIs in the myocardium and left-ventricle blood pool were analyzed by an experienced reader. Mean T1 values and standard deviation were extracted and compared in all studies.Results: Simulations on synthetic phantom showed signal-to-noise ratio and sharpness improvement with the proposed method in comparison with conventional denoising. In vivo results demonstrated that our method preserves accuracy, as no difference in mean T1 values was observed in the myocardium (precontrast: 1433/1426 msec, 95%CI: [-40.7, 55.9], p = 0.75, postcontrast: 766/759 msec, 95%CI: [-60.7, 77.2], p = 0.8). Meanwhile, precision was improved with standard deviations of T1 values being significantly decreased (precontrast: 223/151 msec, 95%CI: [27.3, 116.5], p = 0.003, postcontrast: 176/135 msec, 95%CI: [5.5, 77.1], p = 0.03).Conclusion: The proposed denoising method preserves accuracy and improves precision in myocardial T1 mapping, with the potential to offer better map visualization and analysis.Level of evidence: 3 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2017;46:1377-1388.
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- 2017
4. The level of hepatic ABCC6 expression determines the severity of calcification after cardiac injury
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Brampton, Christopher, Aherrahrou, Zouhair, Chen, Li-Hsieh, Martin, Ludovic, Bergen, Arthur A B, Gorgels, Theo G M F, Erdmann, Jeannette, Erdfdi, Jeannette, Schunkert, Heribert, Szabó, Zalán, Váradi, András, Le Saux, Olivier, University of Hawaii, Universität zu Lübeck [Lübeck], Biologie Neurovasculaire et Mitochondriale Intégrée (BNMI), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Netherlands Institute for Neuroscience (NIN), Royal Netherlands Academy of Arts and Sciences (KNAW), Munich Heart Alliance, German Centre for Cardiovascular Research, partner site Munich Heart Alliance, Munich, Hungarian Academy of Sciences (MTA), MUMC+: *AB Onderzoekers (9), RS: MHeNs - R3 - Neuroscience, Oogheelkunde, Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université d'Angers (UA), ANS - Amsterdam Neuroscience, Human Genetics, and Other departments
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Liver/metabolism ,Pathology ,medicine.medical_specialty ,Heart Injury ,Calcinosis/metabolism ,Osteopontin/metabolism ,[SDV]Life Sciences [q-bio] ,Blotting, Western ,Myocardial Ischemia ,Inbred C57BL ,Real-Time Polymerase Chain Reaction ,Mineralization (biology) ,Extracellular Matrix Proteins/metabolism ,Pathology and Forensic Medicine ,Mice ,Calcium-Binding Proteins/metabolism ,Calcinosis ,Calcium-binding protein ,Matrix gla protein ,medicine ,Animals ,Humans ,Osteopontin ,ATP-Binding Cassette Transporters/metabolism ,Multidrug Resistance-Associated Proteins/metabolism ,Extracellular Matrix Proteins ,biology ,Blotting ,Animal ,Calcium-Binding Proteins ,Myocardial Ischemia/metabolism/pathology ,Regular Article ,medicine.disease ,Immunohistochemistry ,Mice, Inbred C57BL ,Disease Models, Animal ,Heart Injuries ,Liver ,Heart Injuries/metabolism/pathology ,Disease Models ,biology.protein ,Osteocalcin ,ATP-Binding Cassette Transporters ,Multidrug Resistance-Associated Proteins ,Western ,Calcification - Abstract
International audience; Because vascular or cardiac mineralization is inversely correlated with morbidity and long-term survival, we investigated the role of ABCC6 in the calcification response to cardiac injury in mice. By using two models of infarction, nonischemic cryoinjury and the pathologically relevant coronary artery ligation, we confirmed a large propensity to acute cardiac mineralization in Abcc6-/- mice. Furthermore, when the expression of ABCC6 was reduced to approximately 38% of wild-type levels in Abcc6+/- mice, no calcium deposits in injured cardiac tissue were observed. In addition, we used a gene therapy approach to deliver a functional human ABCC6 via hydrodynamic tail vein injection to approximately 13% of mouse hepatocytes, significantly reducing the calcification response to cardiac cryoinjury. We observed that the level and distribution of known regulators of mineralization, such as osteopontin and matrix Gla protein, but not osteocalcin, were concomitant to the level of hepatic expression of human and mouse ABCC6. We notably found that undercarboxylated matrix Gla protein precisely colocalized within areas of mineralization, whereas osteopontin was more diffusely distributed in the area of injury, suggesting a prominent association for matrix Gla protein and osteopontin in ABCC6-related dystrophic cardiac calcification. This study showed that the expression of ABCC6 in liver is an important determinant of calcification in cardiac tissues in response to injuries and is associated with changes in the expression patterns of regulators of mineralization.
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- 2014
5. Optical coherence tomography in coronary atherosclerosis assessment and intervention
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Makoto Araki, Seung-Jung Park, Harold L. Dauerman, Shiro Uemura, Jung-Sun Kim, Carlo Di Mario, Thomas W. Johnson, Giulio Guagliumi, Adnan Kastrati, Michael Joner, Niels Ramsing Holm, Fernando Alfonso, William Wijns, Tom Adriaenssens, Holger Nef, Gilles Rioufol, Nicolas Amabile, Geraud Souteyrand, Nicolas Meneveau, Edouard Gerbaud, Maksymilian P. Opolski, Nieves Gonzalo, Guillermo J. Tearney, Brett Bouma, Aaron D. Aguirre, Gary S. Mintz, Gregg W. Stone, Christos V. Bourantas, Lorenz Räber, Sebastiano Gili, Kyoichi Mizuno, Shigeki Kimura, Toshiro Shinke, Myeong-Ki Hong, Yangsoo Jang, Jin Man Cho, Bryan P. Yan, Italo Porto, Giampaolo Niccoli, Rocco A. Montone, Vikas Thondapu, Michail I. Papafaklis, Lampros K. Michalis, Harmony Reynolds, Jacqueline Saw, Peter Libby, Giora Weisz, Mario Iannaccone, Tommaso Gori, Konstantinos Toutouzas, Taishi Yonetsu, Yoshiyasu Minami, Masamichi Takano, O. Christopher Raffel, Osamu Kurihara, Tsunenari Soeda, Tomoyo Sugiyama, Hyung Oh Kim, Tetsumin Lee, Takumi Higuma, Akihiro Nakajima, Erika Yamamoto, Krzysztof L. Bryniarski, Luca Di Vito, Rocco Vergallo, Francesco Fracassi, Michele Russo, Lena M. Seegers, Iris McNulty, Sangjoon Park, Marc Feldman, Javier Escaned, Francesco Prati, Eloisa Arbustini, Fausto J. Pinto, Ron Waksman, Hector M. Garcia-Garcia, Akiko Maehara, Ziad Ali, Aloke V. Finn, Renu Virmani, Annapoorna S. Kini, Joost Daemen, Teruyoshi Kume, Kiyoshi Hibi, Atsushi Tanaka, Takashi Akasaka, Takashi Kubo, Satoshi Yasuda, Kevin Croce, Juan F. Granada, Amir Lerman, Abhiram Prasad, Evelyn Regar, Yoshihiko Saito, Mullasari Ajit Sankardas, Vijayakumar Subban, Neil J. Weissman, Yundai Chen, Bo Yu, Stephen J. Nicholls, Peter Barlis, Nick E. J. West, Armin Arbab-Zadeh, Jong Chul Ye, Jouke Dijkstra, Hang Lee, Jagat Narula, Filippo Crea, Sunao Nakamura, Tsunekazu Kakuta, James Fujimoto, Valentin Fuster, Ik-Kyung Jang, CarMeN, laboratoire, Massachusetts General Hospital [Boston, MA, USA], Harvard Medical School [Boston] (HMS), Asan Medical Center [Seoul, South Korea] (AMC), University of Vermont [Burlington], Kawasaki Medical School [Okayama, Japan] (KMS), Yonsei University College of Medicine [Seoul, South Korea] (YUCM), Azienda Ospedaliero-Universitaria Careggi [Firenze] (AOUC), University Hospitals Bristol, Azienda Ospedaliera Ospedale Papa Giovanni XXIII [Bergamo, Italy], Technische Universität München = Technical University of Munich (TUM), Munich Heart Alliance [Munich, Allemagne] (MHA), German Heart Center = Deutsches Herzzentrum München [Munich, Germany] (GHC), Aarhus University Hospital [Skejby, Denmark] (AUH), Hospital Universitario de La Princesa, National University of Ireland [Galway] (NUI Galway), University Hospitals Leuven [Leuven], Technische Hochschule Mittelhessen - University of Applied Sciences [Giessen] (THM), Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Hospices Civils de Lyon (HCL), Université de Lyon, Institut Mutualiste de Montsouris (IMM), CHU Clermont-Ferrand, Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Centre de recherche Cardio-Thoracique de Bordeaux [Bordeaux] (CRCTB), Université Bordeaux Segalen - Bordeaux 2-CHU Bordeaux [Bordeaux]-Institut National de la Santé et de la Recherche Médicale (INSERM), National Institute of Cardiology [Warsaw, Poland] (NIC), Instituto de Investigación Sanitaria del Hospital Clínico San Carlos [Madrid, Spain] (IdISSC), Massachusetts General Hospital [Boston], Cardiovascular Research Foundation [New York, NY, USA] (CRF), Icahn School of Medicine at Mount Sinai [New York] (MSSM), Barts Health NHS Trust [London, UK], Queen Mary University of London (QMUL), Bern University Hospital [Berne] (Inselspital), Centro Cardiologico Monzino [Milan, Italy] (2CM), Istituti di Ricovero e Cura a Carattere Scientifico (IRCCS), Mitsukoshi Health and Welfare Foundation [Tokyo, Japan] (MHWF), Yokohama Minami Kyosai Hospital [Kanagawa, Japan] (YMKH), Showa University Hospital [Tokyo, Japan] (SUH), Kyung Hee University [Seoul, South Korea] (KHU), The Chinese University of Hong Kong [Hong Kong], Università degli studi di Genova = University of Genoa (UniGe), Università degli studi di Parma = University of Parma (UNIPR), Catholic University of the Sacred Heart [Rome, Italy] (CUSH), University Hospital [Ioannina, Greece] (UH), New York University School of Medicine (NYU Grossman School of Medicine), Vancouver General Hospital [Vancouver, British Columbia, Canada] (VGH), University of British Columbia (UBC), Brigham and Women’s Hospital [Boston, MA], New York Presbyterian Hospital, Columbia University Medical Center (CUMC), Columbia University [New York], Ospedale San Giovanni Bosco [Turin, Italy] (OSGB), Johannes Gutenberg - Universität Mainz = Johannes Gutenberg University (JGU), National and Kapodistrian University of Athens (NKUA), Tokyo Medical and Dental University [Japan] (TMDU), Kitasato University, Nippon Medical School Chiba Hokusoh Hospital [Chiba, Japan] (NMSC2H), The Prince Charles Hospital, Nara Medical University [Nara, Japan] (NMU), Tsuchiura Kyodo General Hospital [Ibaraki, Japan] (TKGH), Japanese Red Cross Musashino Hospital [Tokyo], St. Marianna University School of Medicine [Kanagawa, Japan], Kyoto University Graduate School of Medicine [Kyoto, Japan] (KUGSM), Jagiellonian University - Medical College (JUMC), Uniwersytet Jagielloński w Krakowie = Jagiellonian University (UJ), Mazzoni Hospital [Ascoli Piceno, Italy] (MH), Korea Advanced Institute of Science and Technology (KAIST), University of Texas Health Science Center, The University of Texas Health Science Center at Houston (UTHealth), Saint Camillus International University of Health Sciences [Rome, Italy] (SCIUHS), Fondazione IRCCS Policlinico San Matteo [Pavia], Università degli Studi di Pavia = University of Pavia (UNIPV), Universidade de Lisboa = University of Lisbon (ULISBOA), MedStar Washington Hospital Center [Washington, DC, USA] (MedStar WHC), CV Path Institute [Gaithersburg, MD, USA] (CV-PI), Erasmus University Medical Center [Rotterdam] (Erasmus MC), Yokohama City University (YCU), Wakayama University, Tohoku University [Sendai], Mayo Clinic [Rochester, MN, USA], Mayo Clinic [Rochester], University hospital of Zurich [Zurich], Gifu University Graduate School of Medicine, Madras Medical Mission [Chennai, India] (3M), MedStar Health Research Institute [Washington, DC, USA] (MedStar-HRI), Chinese People's Liberation Army General Hospital [Beijing, China] (CPLAGH), Harbin Medical University [China] (HMU), Monash university, University of Melbourne, Royal Papworth Hospital [Cambridge, UK] (RPH), Johns Hopkins University (JHU), Leiden University Medical Center (LUMC), The Open University of Japan [Chiba] (OUJ), and Massachusetts Institute of Technology (MIT)
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[SDV] Life Sciences [q-bio] ,[SDV]Life Sciences [q-bio] ,Cardiology and Cardiovascular Medicine - Abstract
Optical coherence tomography (OCT) has been widely adopted in research on coronary atherosclerosis and adopted clinically to optimize percutaneous coronary intervention. In this Review, Jang and colleagues summarize this rapidly progressing field, with the aim of standardizing the use of OCT in coronary atherosclerosis.Since optical coherence tomography (OCT) was first performed in humans two decades ago, this imaging modality has been widely adopted in research on coronary atherosclerosis and adopted clinically for the optimization of percutaneous coronary intervention. In the past 10 years, substantial advances have been made in the understanding of in vivo vascular biology using OCT. Identification by OCT of culprit plaque pathology could potentially lead to a major shift in the management of patients with acute coronary syndromes. Detection by OCT of healed coronary plaque has been important in our understanding of the mechanisms involved in plaque destabilization and healing with the rapid progression of atherosclerosis. Accurate detection by OCT of sequelae from percutaneous coronary interventions that might be missed by angiography could improve clinical outcomes. In addition, OCT has become an essential diagnostic modality for myocardial infarction with non-obstructive coronary arteries. Insight into neoatherosclerosis from OCT could improve our understanding of the mechanisms of very late stent thrombosis. The appropriate use of OCT depends on accurate interpretation and understanding of the clinical significance of OCT findings. In this Review, we summarize the state of the art in cardiac OCT and facilitate the uniform use of this modality in coronary atherosclerosis. Contributions have been made by clinicians and investigators worldwide with extensive experience in OCT, with the aim that this document will serve as a standard reference for future research and clinical application.
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- 2022
6. Pregnancy Outcomes in Women After Arterial Switch Operation for Transposition of the Great Arteries: Results From ROPAC (Registry of Pregnancy and Cardiac Disease) of the European Society of Cardiology EURObservational Research Programme
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Oktay Tutarel, Karishma P. Ramlakhan, Lucia Baris, Maria T. Subirana, Judith Bouchardy, Attila Nemes, Niels G. Vejlstrup, Olga A. Osipova, Mark R. Johnson, Roger Hall, Jolien W. Roos‐Hesselink, Christopher Peter Gale, Branko Beleslin, Andrzej Budaj, Ovidiu Chioncel, Nikolaos Dagres, Nicolas Danchin, David Erlinge, Jonathan Emberson, Michael Glikson, Alastair Gray, Meral Kayikcioglu, Aldo Maggioni, Klaudia Vivien Nagy, Aleksandr Nedoshivin, Anna‐Sonia Petronio, Jolien Roos‐Hesselink, Lars Wallentin, Uwe Zeymer, Joerg Stein, William Anthony Parsonage, Werner Budts, Julie De Backer, Jasmin Grewal, Ariane Marelli, Harald Kaemmerer, Guillaume Jondeau, Mark Johnson, Aldo P. Maggioni, Luigi Tavazzi, Ulf Thilen, Uri Elkayam, Catherine Otto, Karen Sliwa, A. Aquieri, A. Saad, H. Ruda Vega, J. Hojman, J. M. Caparros, M. Vazquez Blanco, M. Arstall, C. M. Chung, G. Mahadavan, E. Aldridge, M. Wittwer, Y. Y. Chow, W. A. Parsonage, K. Lust, N. Collins, G. Warner, R. Hatton, A. Gordon, E. Nyman, J. Stein, E. Donhauser, H. Gabriel, A. Bahshaliyev, F. Guliyev, I. Hasanova, T. Jahangirov, Z. Gasimov, A. Salim, C. M. Ahmed, F. Begum, M. H. Hoque, M. Mahmood, M. N. Islam, P. P. Haque, S. K. Banerjee, T. Parveen, M. Morissens, J. De Backer, L. Demulier, M. de Hosson, W. Budts, M. Beckx, M. Kozic, M. Lovric, T. Kovacevic‐Preradovic, N. Chilingirova, P. Kratunkov, N. Wahab, S. McLean, E. Gordon, L. Walter, A. Marelli, A. R. Montesclaros, G. Monsalve, C. Rodriguez, F. Balthazar, V. Quintero, W. Palacio, L. A. Mejía Cadavid, E. Munoz Ortiz, F. Fortich Hoyos, E. Arevalo Guerrero, J. Gandara Ricardo, J. Velasquez Penagos, Z. Vavera, J. Popelova, N. Vejlstrup, L. Grønbeck, M. Johansen, A. Ersboll, Y. Elrakshy, K. Eltamawy, M. Gamal Abd‐El Aziz, A. El Nagar, H. Ebaid, H. Abo Elenin, M. Saed, S. Farag, W. Makled, K. Sorour, Z. Ashour, G. El‐Sayed, M. Abdel Meguid Mahdy, N. Taha, A. Dardeer, M. Shabaan, M. Ali, P. Moceri, G. Duthoit, M. Gouton, J. Nizard, L. Baris, S. Cohen, M. Ladouceur, D. Khimoud, B. Iung, F. Berger, A. Olsson, U. Gembruch, W. M. Merz, E. Reinert, S. Clade, Y. Kliesch, C. Wald, C. Sinning, R. Kozlik‐Feldmann, S. Blankenberg, E. Zengin‐Sahm, G. Mueller, M. Hillebrand, P. Hauck, Y. von Kodolitsch, N. Zarniko, H. Baumgartner, R. Schmidt, A. Hellige, O. Tutarel, H. Kaemmerer, B. Kuschel, N. Nagdyman, R. Motz, D. Maisuradze, A. Frogoudaki, E. Iliodromitis, M. Anastasiou‐Nana, D. Triantafyllis, G. Bekiaris, H. Karvounis, G. Giannakoulas, D. Ntiloudi, S. A. Mouratoglou, A. Temesvari, H. Balint, D. Kohalmi, B. Merkely, C. Liptai, A. Nemes, T. Forster, A. Kalapos, K. Berek, K. Havasi, N. Ambrus, A. Shelke, R. Kawade, S. Patil, E. Martanto, T. M. Aprami, A. Purnomowati, C. J. Cool, M. Hasan, R. Akbar, S. Hidayat, T. I. Dewi, W. Permadi, D. A. Soedarsono, M. M. Ansari‐Ramandi, N. Samiei, A. Tabib, F. Kashfi, S. Ansari‐Ramandi, S. Rezaei, H. Ali Farhan, A. Al‐Hussein, G. Al‐Saedi, G. Mahmood, I. F. Yaseen, L. Al‐Yousuf, M. AlBayati, S. Mahmood, S. Raheem, T. AlHaidari, Z. Dakhil, P. Thornton, J. Donnelly, M. Bowen, A. Blatt, G. Elbaz‐Greener, A. Shotan, S. Yalonetsky, S. Goland, M. Biener, G. Egidy Assenza, M. Bonvicini, A. Donti, A. Bulgarelli, D. Prandstraller, C. Romeo, R. Crepaz, E. Sciatti, M. Metra, R. Orabona, L. Ait Ali, P. Festa, V. Fesslova, C. Bonanomi, M. Calcagnino, F. Lombardi, null Colli, M. W. Ossola, C. Gobbi, E. Gherbesi, L. Tondi, M. Schiavone, M. Squillace, M. G. Carmina, A. Maina, C. Macchi, E. Gollo, F. M. Comoglio, N. Montali, P. Re, R. Bordese, T. Todros, V. Donvito, W. Grosso Marra, G. Sinagra, B. D'Agata Mottolese, M. Bobbo, V. Gesuete, S. Rakar, F. Ramani, K. Niwa, D. Mekebekova, A. Mussagaliyeva, T. Lee, E. Mirrakhimov, S. Abilova, E. Bektasheva, K. Neronova, O. Lunegova, R. Žaliūnas, R. Jonkaitienė, J. Petrauskaitė, A. Laucevicius, D. Jancauskaite, L. Lauciuviene, L. Gumbiene, L. Lankutiene, S. Glaveckaite, M. Laukyte, S. Solovjova, V Rudiene, K. H. Chee, C. C.‐W. Yim, H. L. Ang, R. Kuppusamy, T. Watson, M. Caruana, M.‐E. Estensen, M. G. A. Mahmood Kayani, R. Munir, A. Tomaszuk‐Kazberuk, B. Sobkowicz, J. Przepiesc, A. Lesniak‐Sobelga, L. Tomkiewicz‐Pajak, M. Komar, M. Olszowska, P. Podolec, S. Wisniowska‐Smialek, M. Lelonek, U. Faflik, A. Cichocka‐Radwan, K. Plaskota, O. Trojnarska, N. Guerra, L. de Sousa, C. Cruz, V. Ribeiro, S. Jovanova, V. Petrescu, R. Jurcut, C. Ginghina, I. Mircea Coman, M. Musteata, O. Osipova, T. Golivets, I. Khamnagadaev, O. Golovchenko, A. Nagibina, I. Ropatko, I. R. Gaisin, L. Valeryevna Shilina, N. Sharashkina, E. Shlyakhto, O. Irtyuga, O. Moiseeva, E. Karelkina, I. Zazerskaya, A. Kozlenok, I. Sukhova, L. Jovovic, K. Prokšelj, M. Koželj, A. O. Askar, A. A. Abdilaahi, M. H. Mohamed, A. M. Dirir, K. Sliwa, P. Manga, A. Pijuan‐Domenech, L. Galian‐Gay, P. Tornos, M. T. Subirana, N. Murga, J. M. Oliver, B. Garcia‐Aranda Dominguez, I. Hernandez Gonzalez, J. F. Delgado Jimenez, P. Escribano Subias, A. Elbushi, A. Suliman, K. Jazzar, M. Murtada, N. Ahamed, M. Dellborg, E. Furenas, M. Jinesjo, K. Skoglund, P. Eriksson, T. Gilljam, U. Thilen, D. Tobler, K. Wustmann, F. Schwitz, M. Schwerzmann, T. Rutz, J. Bouchardy, M. Greutmann, B. M. Santos Lopes, L. Meier, M. Arrigo, K. de Boer, T. Konings, E. Wajon, L. J. Wagenaar, P. Polak, E. P. G. Pieper, J. Roos‐Hesselink, I. van Hagen, H. Duvekot, J. M. J. Cornette, C. De Groot, C. van Oppen, L. Sarac, O. Batukan Esen, S. Catirli Enar, C. Mondo, P. Ingabire, B. Nalwanga, T. Semu, B. T. Salih, W. A. R. Almahmeed, S. Wani, F. S. Mohamed Farook, Al Ain, F. Gerges, A. M. Komaranchath, F. Al bakshi, A. Al Mulla, A. H. Yusufali, E. I. Al Hatou, N. Bazargani, F. Hussain, L. Hudsmith, P. Thompson, S. Thorne, S. Bowater, A. Money‐Kyrle, P. Clifford, P. Ramrakha, S. Firoozan, J. Chaplin, N. Bowers, D. Adamson, F. Schroeder, R. Wendler, S. Hammond, P. Nihoyannopoulos, R. Hall, L. Freeman, G. Veldtman, J. Kerr, L. Tellett, N. Scott, A. B. Bhatt, D. DeFaria Yeh, M. A. Youniss, M. Wood, A. A. Sarma, S. Tsiaras, A. Stefanescu, J. M. Duran, L. Stone, D. S. Majdalany, J. Chapa, K. Chintala, P. Gupta, J. Botti, J. Ting, W. R. Davidson, G. Wells, D. Sparks, V. Paruchuri, K. Marzo, D. Patel, W. Wagner, S. N. Ahanya, L. Colicchia, T. Jentink, K. Han, M. Loichinger, M. Parker, C. Longtin, A. Yetman, K. Erickson, J. Cramer, S. Tsai, B. Fletcher, S. Warta, C. Cohen, C. Lindblade, R. Puntel, K. Nagaran, N. Croft, M. Gurvitz, C. Otto, C. Talluto, D. Murphy, M. G. Perlroth, ROPAC (Registry of Pregnancy and Cardiac Disease) Investigators Group, Gale, C.P., Beleslin, B., Budaj, A., Chioncel, O., Dagres, N., Danchin, N., Erlinge, D., Emberson, J., Glikson, M., Gray, A., Kayikcioglu, M., Maggioni, A., Nagy, K.V., Nedoshivin, A., Petronio, A.S., Roos-Hesselink, J., Wallentin, L., Zeymer, U., Hall, R., Stein, J., Parsonage, W.A., Budts, W., De Backer, J., Grewal, J., Marelli, A., Kaemmerer, H., Jondeau, G., Johnson, M., Maggioni, A.P., Tavazzi, L., Thilen, U., Elkayam, U., Otto, C., Sliwa, K., Aquieri, A., Saad, A., Ruda Vega, H., Hojman, J., Caparros, J.M., Vazquez Blanco, M., Arstall, M., Chung, C.M., Mahadavan, G., Aldridge, E., Wittwer, M., Chow, Y.Y., Lust, K., Collins, N., Warner, G., Hatton, R., Gordon, A., Nyman, E., Donhauser, E., Gabriel, H., Bahshaliyev, A., Guliyev, F., Hasanova, I., Jahangirov, T., Gasimov, Z., Salim, A., Ahmed, C.M., Begum, F., Hoque, M.H., Mahmood, M., Islam, M.N., Haque, P.P., Banerjee, S.K., Parveen, T., Morissens, M., Demulier, L., de Hosson, M., Beckx, M., Kozic, M., Lovric, M., Kovacevic-Preradovic, T., Chilingirova, N., Kratunkov, P., Wahab, N., McLean, S., Gordon, E., Walter, L., Montesclaros, A.R., Monsalve, G., Rodriguez, C., Balthazar, F., Quintero, V., Palacio, W., Mejía Cadavid, L.A., Munoz Ortiz, E., Fortich Hoyos, F., Arevalo Guerrero, E., Gandara Ricardo, J., Velasquez Penagos, J., Vavera, Z., Popelova, J., Vejlstrup, N., Grønbeck, L., Johansen, M., Ersboll, A., Elrakshy, Y., Eltamawy, K., Gamal Abd-El Aziz, M., El Nagar, A., Ebaid, H., Abo Elenin, H., Saed, M., Farag, S., Makled, W., Sorour, K., Ashour, Z., El-Sayed, G., Abdel Meguid Mahdy, M., Taha, N., Dardeer, A., Shabaan, M., Ali, M., Moceri, P., Duthoit, G., Gouton, M., Nizard, J., Baris, L., Cohen, S., Ladouceur, M., Khimoud, D., Iung, B., Berger, F., Olsson, A., Gembruch, U., Merz, W.M., Reinert, E., Clade, S., Kliesch, Y., Wald, C., Sinning, C., Kozlik-Feldmann, R., Blankenberg, S., Zengin-Sahm, E., Mueller, G., Hillebrand, M., Hauck, P., von Kodolitsch, Y., Zarniko, N., Baumgartner, H., Schmidt, R., Hellige, A., Tutarel, O., Kuschel, B., Nagdyman, N., Motz, R., Maisuradze, D., Frogoudaki, A., Iliodromitis, E., Anastasiou-Nana, M., Triantafyllis, D., Bekiaris, G., Karvounis, H., Giannakoulas, G., Ntiloudi, D., Mouratoglou, S.A., Temesvari, A., Balint, H., Kohalmi, D., Merkely, B., Liptai, C., Nemes, A., Forster, T., Kalapos, A., Berek, K., Havasi, K., Ambrus, N., Shelke, A., Kawade, R., Patil, S., Martanto, E., Aprami, T.M., Purnomowati, A., Cool, C.J., Hasan, M., Akbar, R., Hidayat, S., Dewi, T.I., Permadi, W., Soedarsono, D.A., Ansari-Ramandi, M.M., Samiei, N., Tabib, A., Kashfi, F., Ansari-Ramandi, S., Rezaei, S., Ali Farhan, H., Al-Hussein, A., Al-Saedi, G., Mahmood, G., Yaseen, I.F., Al-Yousuf, L., AlBayati, M., Mahmood, S., Raheem, S., AlHaidari, T., Dakhil, Z., Thornton, P., Donnelly, J., Bowen, M., Blatt, A., Elbaz-Greener, G., Shotan, A., Yalonetsky, S., Goland, S., Biener, M., Egidy Assenza, G., Bonvicini, M., Donti, A., Bulgarelli, A., Prandstraller, D., Romeo, C., Crepaz, R., Sciatti, E., Metra, M., Orabona, R., Ait Ali, L., Festa, P., Fesslova, V., Bonanomi, C., Calcagnino, M., Lombardi, F., Colli, C., Ossola, M.W., Gobbi, C., Gherbesi, E., Tondi, L., Schiavone, M., Squillace, M., Carmina, M.G., Maina, A., Macchi, C., Gollo, E., Comoglio, F.M., Montali, N., Re, P., Bordese, R., Todros, T., Donvito, V., Grosso Marra, W., Sinagra, G., D'Agata Mottolese, B., Bobbo, M., Gesuete, V., Rakar, S., Ramani, F., Niwa, K., Mekebekova, D., Mussagaliyeva, A., Lee, T., Mirrakhimov, E., Abilova, S., Bektasheva, E., Neronova, K., Lunegova, O., Žaliūnas, R., Jonkaitienė, R., Petrauskaitė, J., Laucevicius, A., Jancauskaite, D., Lauciuviene, L., Gumbiene, L., Lankutiene, L., Glaveckaite, S., Laukyte, M., Solovjova, S., Rudiene, V., Chee, K.H., Yim, C.C., Ang, H.L., Kuppusamy, R., Watson, T., Caruana, M., Estensen, M.E., Mahmood Kayani, MGA, Munir, R., Tomaszuk-Kazberuk, A., Sobkowicz, B., Przepiesc, J., Lesniak-Sobelga, A., Tomkiewicz-Pajak, L., Komar, M., Olszowska, M., Podolec, P., Wisniowska-Smialek, S., Lelonek, M., Faflik, U., Cichocka-Radwan, A., Plaskota, K., Trojnarska, O., Guerra, N., de Sousa, L., Cruz, C., Ribeiro, V., Jovanova, S., Petrescu, V., Jurcut, R., Ginghina, C., Mircea Coman, I., Musteata, M., Osipova, O., Golivets, T., Khamnagadaev, I., Golovchenko, O., Nagibina, A., Ropatko, I., Gaisin, I.R., Valeryevna Shilina, L., Sharashkina, N., Shlyakhto, E., Irtyuga, O., Moiseeva, O., Karelkina, E., Zazerskaya, I., Kozlenok, A., Sukhova, I., Jovovic, L., Prokšelj, K., Koželj, M., Askar, A.O., Abdilaahi, A.A., Mohamed, M.H., Dirir, A.M., Manga, P., Pijuan-Domenech, A., Galian-Gay, L., Tornos, P., Subirana, M.T., Murga, N., Oliver, J.M., Garcia-Aranda Dominguez, B., Hernandez Gonzalez, I., Delgado Jimenez, J.F., Escribano Subias, P., Elbushi, A., Suliman, A., Jazzar, K., Murtada, M., Ahamed, N., Dellborg, M., Furenas, E., Jinesjo, M., Skoglund, K., Eriksson, P., Gilljam, T., Tobler, D., Wustmann, K., Schwitz, F., Schwerzmann, M., Rutz, T., Bouchardy, J., Greutmann, M., Santos Lopes, B.M., Meier, L., Arrigo, M., de Boer, K., Konings, T., Wajon, E., Wagenaar, L.J., Polak, P., Pieper, EPG, van Hagen, I., Duvekot, H., Cornette, JMJ, De Groot, C., van Oppen, C., Sarac, L., Batukan Esen, O., Catirli Enar, S., Mondo, C., Ingabire, P., Nalwanga, B., Semu, T., Salih, B.T., Almahmeed, WAR, Wani, S., Mohamed Farook, F.S., Ain, A., Gerges, F., Komaranchath, A.M., Al Bakshi, F., Al Mulla, A., Yusufali, A.H., Al Hatou, E.I., Bazargani, N., Hussain, F., Hudsmith, L., Thompson, P., Thorne, S., Bowater, S., Money-Kyrle, A., Clifford, P., Ramrakha, P., Firoozan, S., Chaplin, J., Bowers, N., Adamson, D., Schroeder, F., Wendler, R., Hammond, S., Nihoyannopoulos, P., Freeman, L., Veldtman, G., Kerr, J., Tellett, L., Scott, N., Bhatt, A.B., DeFaria Yeh, D., Youniss, M.A., Wood, M., Sarma, A.A., Tsiaras, S., Stefanescu, A., Duran, J.M., Stone, L., Majdalany, D.S., Chapa, J., Chintala, K., Gupta, P., Botti, J., Ting, J., Davidson, W.R., Wells, G., Sparks, D., Paruchuri, V., Marzo, K., Patel, D., Wagner, W., Ahanya, S.N., Colicchia, L., Jentink, T., Han, K., Loichinger, M., Parker, M., Longtin, C., Yetman, A., Erickson, K., Cramer, J., Tsai, S., Fletcher, B., Warta, S., Cohen, C., Lindblade, C., Puntel, R., Nagaran, K., Croft, N., Gurvitz, M., Talluto, C., Murphy, D., Perlroth, M.G., Neurosurgery, Pediatrics, Cardiology, ACS - Heart failure & arrhythmias, Obstetrics and gynaecology, Amsterdam Reproduction & Development (AR&D), Institut Català de la Salut, [Tutarel O] Department of Congenital Heart Disease and Paediatric Cardiology German Heart Centre MunichTechnical University of Munich School of MedicineTechnical University of Munich Germany. DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance Munich Germany. [Ramlakhan KP, Baris L] Department of Cardiology Erasmus University Medical Center Rotterdam the Netherlands. [Subirana MT] Unitat de Cardiopaties congènites de l’adult, Vall d'Hebron Hospital Universitari, Barcelona Spain. Hospital Sant Pau, Barcelona Spain. [Bouchardy J] Service of Cardiology University Hospital Lausanne and University of Lausanne Switzerland. Service of Cardiology University of Geneva Switzerland. [Nemes A] 2nd Department of Medicine and Cardiology Centre Medical Faculty Albert Szent-Györgyi Clinical Center University of Szeged Hungary, Szeged, Hungary, and Vall d'Hebron Barcelona Hospital Campus
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Male ,Transposition of Great Vessels ,pregnancy outcomes ,enfermedades cardiovasculares::anomalías cardiovasculares::cardiopatías congénitas::transposición de los grandes vasos [ENFERMEDADES] ,Disease ,030204 cardiovascular system & hematology ,Sistema cardiovascular - Malalties ,Ventricular tachycardia ,Vasos sanguinis - Cirurgia ,0302 clinical medicine ,Pregnancy ,Clinical endpoint ,Registries ,030212 general & internal medicine ,Cardiovascular Diseases::Pregnancy Complications, Cardiovascular [DISEASES] ,Original Research ,Aortic dissection ,Pregnancy Outcome ,Congenital Heart Disease ,Other subheadings::Other subheadings::/surgery [Other subheadings] ,arterial switch operation ,pregnancy and cardiac disease ,transposition of the great arteries ,Europe ,Great arteries ,Cardiology ,enfermedades cardiovasculares::complicaciones cardiovasculares del embarazo [ENFERMEDADES] ,Female ,Maternal death ,Cardiology and Cardiovascular Medicine ,Adult ,medicine.medical_specialty ,diagnóstico::pronóstico::resultado del embarazo [TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS] ,Pregnancy Complications, Cardiovascular ,Embaràs - Complicacions ,Cardiovascular Diseases::Cardiovascular Abnormalities::Heart Defects, Congenital::Transposition of Great Vessels [DISEASES] ,Risk Assessment ,03 medical and health sciences ,SDG 3 - Good Health and Well-being ,Internal medicine ,medicine ,Humans ,Heart Failure ,business.industry ,Infant, Newborn ,Otros calificadores::Otros calificadores::/cirugía [Otros calificadores] ,Diagnosis::Prognosis::Pregnancy Outcome [ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES, AND EQUIPMENT] ,medicine.disease ,Arterial Switch Operation ,Heart failure ,Tachycardia, Ventricular ,business - Abstract
Embaràs i malaltia cardíaca; Resultats de l’embaràs; Transposició de les grans artèries Embarazo y enfermedad cardíaca; Resultados del embarazo; Transposición de las grandes arterias Pregnancy and cardiac disease; Pregnancy outcomes, Transposition of the great arteries Background In the past 3 decades, the arterial switch procedure has replaced the atrial switch procedure as treatment of choice for transposition of the great arteries. Although survival is superior after the arterial switch procedure, data on pregnancy outcomes are scarce and transposition of the great arteries after arterial switch is not yet included in the modified World Health Organization classification of maternal cardiovascular risk. Methods and Results The ROPAC (Registry of Pregnancy and Cardiac disease) is an international prospective registry of pregnant women with cardiac disease, part of the European Society of Cardiology EURObservational Research Programme. Pregnancy outcomes in all women after an arterial switch procedure for transposition of the great arteries are described. The primary end point was a major adverse cardiovascular event, defined as combined end point of maternal death, supraventricular or ventricular arrhythmias requiring treatment, heart failure, aortic dissection, endocarditis, ischemic coronary events, and thromboembolic events. Altogether, 41 pregnant women (mean age, 26.7±3.9 years) were included, and there was no maternal mortality. A major adverse cardiovascular event occurred in 2 women (4.9%): heart failure in one (2.4%) and ventricular tachycardia in another (2.4%). One woman experienced fetal loss, whereas no neonatal mortality was observed. Conclusions Women after an arterial switch procedure for transposition of the great arteries tolerate pregnancy well, with a favorable maternal and fetal outcome. During counseling, most women should be reassured that the risk of pregnancy is low. Classification as modified World Health Organization risk class II seems appropriate. Funding from “Zabawas Foundation” and “De Hoop Foundation” in addition to the support from EURObservational Research Programme (EORP) is greatly acknowledged. Since the start of EORP, the following companies have supported the program: Abbott Vascular Int (2011–2021), Amgen Cardiovascular (2009–2018), AstraZeneca (2014–2021), Bayer AG (2009–2018), Boehringer Ingelheim (2009–2019), Boston Scientific (2009–2012), The Bristol Myers Squibb and Pfizer Alliance (2011–2019), Daiichi Sankyo Europe GmbH (2011–2020), The Alliance Daiichi Sankyo Europe GmbH and Eli Lilly and Company (2014–2017), Edwards (2016–2019), Gedeon Richter Plc (2014–2016), Menarini Int Op (2009–2012), MSD‐Merck & Co (2011–2014), Novartis Pharma AG (2014–2020), ResMed (2014–2016), Sanofi (2009–2011), SERVIER (2009–2021), and Vifor (2019–2022).
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- 2021
7. Alcohol consumption is associated with widespread changes in blood DNA methylation: Analysis of cross-sectional and longitudinal data
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Daniel F. Schmidt, Rory P. Wilson, Melanie Waldenberger, Laura Baglietto, Harindra Jayasekara, Benjamin Lehne, Graham G. Giles, Pierre Antoine Dugué, Jaspal S. Kooner, Melissa C. Southey, Xiaochuan Wang, Annette Peters, Karl-Heinz Ladwig, Dallas R. English, John C Chambers, Jihoon E. Joo, Christian Gieger, Roger L. Milne, Chol-Hee Jung, Gianluca Severi, Enes Makalic, Cancer Epidemiology Centre & Cancer Council Victoria [Melbourne, Australia], University of Melbourne-Melbourne School for Population and Global Health, Melbourne School of Population and Global Health [Melbourne], University of Melbourne, German Research Center for Environmental Health - Helmholtz Center München (GmbH), Department of Epidemiology and Biostatistics, Imperial College London, St Mary's Campus, London, W2 1PG, Melbourne Bioinformatics [Australia], The University of MelbourneParkville, VIC, Australia., Department of Clinical and Experimental Medicine, University of Pisa, Centre de recherche en épidémiologie et santé des populations (CESP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris-Sud - Paris 11 (UP11)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), München, Technische Universität München, German Research Center for Cardiovascular Disease (DZHK), Partner site Munich Heart Alliance, Institute of Epidemiology and Medical Biometry, University of Ulm, Munich, Germany, Ealing Hospital, Imperial College Healthcare NHS Trust, Monash University [Clayton], Nanyang Technological University [Singapour], Imperial College Healthcare NHS Trust Oregon Department of Agriculture, ODA: 16/136/68 279143 Wellcome Trust, WT: 084723/Z/08/Z, 090532, RP‐PG‐0407‐10371, 098381 Cancer Council Victoria: 1026892, 1027505, 251553, 209057, 1050198, 1011618, 1074383, 504711, 1043616 Bundesministerium für Bildung und Forschung, BMBF VicHealth British Heart Foundation, BHF: SP/04/002 Münchner Zentrum für Gesundheitswissenschaften, Ludwig-Maximilians-Universität München National Institute for Health Research, NIHR National Health and Medical Research Council, NHMRC: 1088405 Horizon 2020 Framework Programme, H2020: 643774 ERAB: The European Foundation for Alcohol Research, ERAB: ERAB 2018 – EA1817 Medical Research Council, MRC: G0601966, G0700931 National Medical Research Council, NMRC: NMRC/STaR/0028/2017, and This work (MCCS) was supported by the Australian National Health and Medical Research Council (NHMRC) (Grant 1088405). MCCS cohort recruitment was funded by VicHealth and Cancer Council Victoria. The MCCS was further supported by Australian NHMRC Grants 209057, 251553, and 504711 and by infrastructure provided by Cancer Council Victoria. Cases were ascertained through the Victorian Cancer Registry (VCR) and the Australian Cancer Database (Australian Institute of Health and Welfare). The nested case‐control methylation studies were supported by the NHMRC Grants 1011618, 1026892, 1027505, 1050198, 1043616, and 1074383. M.C.S. is an NHMRC Senior Research Fellow (1061177). The KORA study was initiated and financed by the Helmholtz Zentrum München – German Research Center for Environmental Health, which is funded by the German Federal Ministry of Education and Research (BMBF) and by the State of Bavaria. Furthermore, KORA research has been supported within the Munich Center of Health Sciences (MC‐Health), Ludwig‐Maximilians‐Universität, as part of LMUinnovativ. This work has received funding from the European Foundation for Alcohol Research (ERAB 2018 – EA1817). We thank all members of field staffs who were involved in the planning and conduct of the MONICA/KORA Augsburg studies. The LOLIPOP study is supported by the National Institute for Health Research (NIHR) Comprehensive Biomedical Research Centre Imperial College Healthcare NHS Trust, the British Heart Foundation (SP/04/002), the Medical Research Council (G0601966, G0700931), the Wellcome Trust (084723/Z/08/Z, 090532, and 098381), the NIHR (RP‐PG‐0407‐10371), the NIHR Official Development Assistance (ODA, award 16/136/68), the European Union FP7 (EpiMigrant, 279143), and H2020 programs (iHealth‐T2D, 643774). We acknowledge support of the MRC‐PHE Centre for Environment and Health and the NIHR Health Protection Research Unit on Health Impact of Environmental Hazards. The work was carried out in part at the NIHR/Wellcome Trust Imperial Clinical Research Facility. The views expressed are those of the author(s) and not necessarily those of the Imperial College Healthcare NHS Trust, the NHS, the NIHR, or the Department of Health. We thank the participants and research staff who made the study possible. JC is supported by the Singapore Ministry of Health's National Medical Research Council under its Singapore Translational Research Investigator (STaR) Award (NMRC/STaR/0028/2017).
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Male ,longitudinal data ,[SDV]Life Sciences [q-bio] ,Medicine (miscellaneous) ,Physiology ,Alcohol ,Disease ,Epigenesis, Genetic ,Cohort Studies ,chemistry.chemical_compound ,0302 clinical medicine ,Medicine ,Prospective Studies ,education.field_of_study ,0303 health sciences ,DNA methylation ,Confounding ,Regression analysis ,Methylation ,Middle Aged ,epigenome-wide association study ,Substance abuse ,Psychiatry and Mental health ,030220 oncology & carcinogenesis ,Female ,Alcohol consumption ,Cohort study ,Adult ,Alcohol Drinking ,Longitudinal data ,alcohol consumption ,Population ,03 medical and health sciences ,Genetic ,cross-sectional data ,EWAS ,HM450 assay ,Aged ,CpG Islands ,Cross-Sectional Studies ,Genome-Wide Association Study ,Humans ,DNA Methylation ,Epigenetics ,education ,030304 developmental biology ,Pharmacology ,business.industry ,Alcohol Consumption ,Cross-sectional Data ,Dna Methylation ,Epigenome-wide Association Study ,Ewas ,Hm450 Assay ,Longitudinal Data ,medicine.disease ,030227 psychiatry ,chemistry ,business ,030217 neurology & neurosurgery ,Epigenesis - Abstract
Background:DNA methylation may be one of the mechanisms by which alcohol consumption is associated with the risk of disease. We conducted a large-scale, cross-sectional, genome-wide DNA methylation association study of alcohol consumption and a longitudinal analysis of repeated measurements taken several years apart.Methods:Using the Illumina Infinium HumanMethylation450 BeadChip, DNA methylation measures were determined using baseline peripheral blood samples from 5,606 adult Melbourne Collaborative Cohort Study (MCCS) participants. For a subset of 1,088 of them, these measures were repeated using blood samples collected at follow-up, a median of 11 years later. Associations between alcohol intake and blood DNA methylation were assessed using linear mixed-effects regression models adjusted for batch effects and potential confounders. Independent data from the LOLIPOP (N=4,042) and KORA (N=1,662) cohorts were used to replicate associations discovered in the MCCS.Results:Cross-sectional analyses identified 1,414 CpGs associated with alcohol intake at P-7, 1,243 of which had not been reported previously. Of these 1,243 novel associations, 1,078 were replicated (PConclusion:Our study indicates that, for middle-aged and older adults, alcohol intake is associated with widespread changes in DNA methylation across the genome. Longitudinal analyses showed that the methylation status of alcohol-associated CpGs may change with changes in alcohol consumption.
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- 2021
8. Ontogeny of arterial macrophages defines their functions in homeostasis and inflammation
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Weinberger, Tobias, Esfandyari, Dena, Messerer, Denise, Percin, Gulce, Schleifer, Christian, Thaler, Raffael, Liu, Lulu, Stremmel, Christopher, Schneider, Vanessa, Vagnozzi, Ronald J., Schwanenkamp, Jennifer, Fischer, Maximilian, Busch, Katrin, Klapproth, Kay, Ishikawa-Ankerhold, Hellen, Klösges, Lukas, Titova, Anna, Molkentin, Jeffery D., Kobayashi, Yasuhiro, Engelhardt, Stefan, Massberg, Steffen, Waskow, Claudia, Perdiguero, Elisa Gomez, Schulz, Christian, Klinikum der Universitat Munchen, Ludwig-Maximilians-Universität München (LMU), DZHK site Munich Heart Alliance, Institute of pharmacology and toxicology, Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM), Leibniz Institute on Aging - Fritz Lipmann Institute (FLI), Leibniz Association, Cincinnati Children's Hospital Medical Center, German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), Institute for Oral Science, Matsumoto Dental University, Friedrich-Schiller-Universität = Friedrich Schiller University Jena [Jena, Germany], Macrophages et Cellules endothéliales / Macrophages and Endothelial Cells, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), This study was supported by the SFB 1123,projects A07 (C.Schu.) and B06 (S.M.), and the SFB914, projects A10 (C.Schu.), B02(S.M.), and Z01 (H.I.-A.), as well as the DZHK (German Centre for CardiovascularResearch) and the BMBF (German Ministry of Education and Research) (grants81Z0600204 to C.Schu., 81X2600252 to T.W. and 81X2600256 to M.F.). C.Str. wassupported by a Gerok position of the SFB914. M.F. is supported by the DFG-fundedClinician Scientist ProgramPRIME. S.M. was supported by the Leducq FoundationTransatlantic Network'Clonal hematopoiesis and atherosclerosis'. C.W. was supported by FOR2033-A03, TRR127-A5, WA2837/6-1, and WA2837/7-1. E.G.P. was supported by ANR-10-LABX-73 and 2016-StG-715320, ANR-10-LABX-0073,REVIVE,Stem Cells in Regenerative Biology and Medicine(2010), European Project: 715320,ERC-2016-STG,ResidentMacroPhage(2016), Technical University of Munich (TUM), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), and Walter-Brendel-Center for Experimental Medicine, LMU
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Male ,Aging ,Science ,Systems analysis ,Mice, Transgenic ,Article ,Mice ,[SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system ,Bone Marrow ,Animals ,Homeostasis ,Humans ,Regeneration ,Cell Lineage ,RNA-Seq ,lcsh:Science ,Monocytes and macrophages ,Bone Marrow Transplantation ,Arteritis ,Transplantation Chimera ,Angiotensin II ,Macrophages ,Cell Differentiation ,Arteries ,Hematopoietic Stem Cells ,Cardiovascular biology ,Disease Models, Animal ,Haematopoiesis ,embryonic structures ,[SDV.IMM]Life Sciences [q-bio]/Immunology ,lcsh:Q ,Female ,Single-Cell Analysis - Abstract
Arterial macrophages have different developmental origins, but the association of macrophage ontogeny with their phenotypes and functions in adulthood is still unclear. Here, we combine macrophage fate-mapping analysis with single-cell RNA sequencing to establish their cellular identity during homeostasis, and in response to angiotensin-II (AngII)-induced arterial inflammation. Yolk sac erythro-myeloid progenitors (EMP) contribute substantially to adventitial macrophages and give rise to a defined cluster of resident immune cells with homeostatic functions that is stable in adult mice, but declines in numbers during ageing and is not replenished by bone marrow (BM)-derived macrophages. In response to AngII inflammation, increase in adventitial macrophages is driven by recruitment of BM monocytes, while EMP-derived macrophages proliferate locally and provide a distinct transcriptional response that is linked to tissue regeneration. Our findings thus contribute to the understanding of macrophage heterogeneity, and associate macrophage ontogeny with distinct functions in health and disease., Arterial macrophages develop from either yolk sac or bone marrow progenitors. Here, the author show that ageing-induced reduction of arterial macrophages is not replenished by bone marrow-derived cells, but under inflammatory conditions circulating monocytes are recruited to maintain homeostasis, while arterial macrophages of yolk sac origin carry out tissue repair.
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- 2020
9. Association of Insulin-like Growth Factor 1 Concentrations with Risk for and Prognosis of Amyotrophic Lateral Sclerosis - Results from the ALS Registry Swabia
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Dietrich Rothenbacher, Angela Rosenbohm, Wolfgang Koenig, Albert C. Ludolph, Gabriele Nagel, Raphael Simon Peter, Luc Dupuis, Institute of Epidemiology and Medical Biometry [Ulm, Allemagne], Universität Ulm - Ulm University [Ulm, Allemagne], Department of Neurology [Ulm, Allemagne], Deutsches Herzzentrum München [Munich, Allemagne] (DHM), Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM), German Center for Cardiovascular Research (DZHK), Berlin Institute of Health (BIH), Munich Heart Alliance [Munich, Allemagne] (MHA), Mécanismes Centraux et Périphériques de la Neurodégénérescence, Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), The ALS registry Swabia and this study have been supported by the German Research Council (DFG)., and Bodescot, Myriam
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Male ,medicine.medical_treatment ,[SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology ,lcsh:Medicine ,Cohort Studies ,Prognostic markers ,Insulin-like growth factor ,0302 clinical medicine ,Germany ,Registries ,Insulin-Like Growth Factor I ,Amyotrophic lateral sclerosis ,lcsh:Science ,0303 health sciences ,Multidisciplinary ,Middle Aged ,Prognosis ,Survival Rate ,Quartile ,Female ,Cohort study ,Risk ,medicine.medical_specialty ,Article ,03 medical and health sciences ,Internal medicine ,medicine ,Humans ,Survival rate ,Aged ,Proportional Hazards Models ,030304 developmental biology ,business.industry ,Proportional hazards model ,Amyotrophic Lateral Sclerosis ,lcsh:R ,Case-control study ,[SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology ,medicine.disease ,Serum samples ,Logistic Models ,Risk factors ,[SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie ,Case-Control Studies ,lcsh:Q ,[SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie ,business ,Biomarkers ,030217 neurology & neurosurgery ,Follow-Up Studies - Abstract
We investigated the associations of serum concentration of insulin-like growth factor 1 (IGF1) with risk and prognosis of ALS in the ALS registry (October 2010–June 2014, median follow-up 67.6 months) in a case-control and cohort study, respectively. Serum samples were measured for IGF-1. Information on covariates was collected by standardized questionnaire. We applied conditional logistic regression to appraise the risk and Cox proportional hazards models to appraise the prognostic value of IGF-1. Data of 294 ALS patients (mean age 65.4 (SD 11.0) years, 60.2% men) and 504 controls were included in the case-control study. Median serum IGF-1 concentrations were slightly higher in ALS cases than in controls (101 vs. 99.5 ng/ml). IGF-1 concentrations were not associated with ALS risk in the fully adjusted model (top vs. bottom quartile: OR 1.16; 95%-CI 0.73–1.84, p for trend = 0.44). Among 293 ALS cases (mean age 65.5 (SD 10.5) years, 56.8% men) 243 died during follow-up. We found a statistically significant inverse association between continuous IGF-1 concentrations and survival (p = 0.01). Very high values IGF-1 were associated with a better prognosis of ALS suggesting that functions related to IGF-1 could be involved in survival.
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- 2020
10. Efficacy and safety of low-dose colchicine after myocardial infarction
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Lucie Blondeau, Mylène Provencher, Olivier F. Bertrand, Aldo P. Maggioni, José López-Sendón, Jean-Claude Tardif, François Roubille, Simon Kouz, Wolfgang Koenig, Marie-Pierre Dubé, Rafael Diaz, Andreas Orfanos, Reda Ibrahim, Denis Angoulvant, Petr Ostadal, Fausto J. Pinto, Jean Grégoire, Ghassan S. Kiwan, Marie-Claude Guertin, David D. Waters, Marc-André Lavoie, David Rhainds, Colin Berry, Habib Gamra, Philippe L. L’Allier, Montreal Heart Institute Coordinating Centre (MHICC), Université de Montréal (UdeM), Montreal Heart Institute, Montreal, Canada, Université Laval [Québec] (ULaval), Division of Cardiology, Zuckerberg San Francisco General Hospital, Department of Medicine, University of California, San Francisco, USA., Institut de Cardiologie et Pneumologie de Québec, Quebec City, ECLAEstudios Clínicos Latino América & Instituto Cardiovascular de Rosario), Rosario, Argentina, Research Center [Associazione Nazionale Medici Cardiologi Ospedalieri] (ANMCO Research Center), Associazione Nazionale Medici Cardiologi Ospedalieri [Firenze] (ANMCO), Cardiology Department, CHULN, Centro Cardiovascular da Universidade de Lisboa, Faculdade de Medicina da Universidade de Lisboa, Lisboa, Portugal, Montrea l Heart Institute, Université de Montréal, Montreal, Canada, CHU Fattouma Bourguiba [Monastir] (HFB), Bellevue Medical Center, Beirut, Lebanon, Institute of Cardiovascular and Medical Sciences, University of Glasgow, British Heart Foundation Glasgow Cardiovascular Research Centre (BHF GCRC), University of Glasgow-NHS Greater Glasgow and Clyde, Cardiology department Hospital Universitario La Paz. UAM. IdiPaz. CIBER-CV, Madrid, Spain, Department of Cardiology Cardiovascular Center, NaHomolce Hospital, Prague, Czech Republic, Department of Internal Medicine II – Cardiology, Universität Ulm - Ulm University [Ulm, Allemagne], München, Technische Universität München, German Research Center for Cardiovascular Disease (DZHK), Partner site Munich Heart Alliance, Institute of Epidemiology and Medical Biometry, University of Ulm, Munich, Germany, Cellules Dendritiques, Immunomodulation et Greffes, Université de Tours (UT), Centre Hospitalier Universitaire (CHU) de Tours and Équipe d'Accueil 4245 Transplantation Immunité Inflammation Loire Valley Cardiovascular Collaboration, Tours University, Tours, Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Montreal Heart Institute - Institut de Cardiologie de Montréal, Montreal Health Innovations Coordinating Center [Montreal Heart Institute] (MHICC), Montreal Health Innovation Coordination Center, Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046] (PhyMedExp), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), MORNET, Dominique, Repositório da Universidade de Lisboa, Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Tours, and Centre Hospitalier Régional Universitaire de Tours (CHRU TOURS)
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Male ,medicine.medical_treatment ,[SDV]Life Sciences [q-bio] ,Myocardial Infarction ,Anti-Inflammatory Agents ,Inflammation ,Kaplan-Meier Estimate ,030204 cardiovascular system & hematology ,Pharmacology ,Medical and Health Sciences ,law.invention ,Angina Pectoris ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Percutaneous Coronary Intervention ,Randomized controlled trial ,Double-Blind Method ,law ,Recurrence ,General & Internal Medicine ,medicine ,Colchicine ,Humans ,030212 general & internal medicine ,Myocardial infarction ,Proportional Hazards Models ,Aged ,Intention-to-treat analysis ,business.industry ,Incidence ,Low dose ,Percutaneous coronary intervention ,General Medicine ,Middle Aged ,medicine.disease ,3. Good health ,Intention to Treat Analysis ,Stroke ,[SDV] Life Sciences [q-bio] ,C-Reactive Protein ,chemistry ,Clinical evidence ,Cardiovascular Diseases ,Female ,medicine.symptom ,business ,Biomarkers - Abstract
Copyright © 2019 Massachusetts Medical Society. All rights reserved., Background: Experimental and clinical evidence support the role of inflammation in atherosclerosis and its complications. Colchicine is an orally administered, potent antiinflammatory medication that is indicated for the treatment of gout and pericarditis. Methods: We performed a randomized, double-blind trial involving patients recruited within 30 days after a myocardial infarction. The patients were randomly assigned to receive either low-dose colchicine (0.5 mg once daily) or placebo. The primary efficacy end point was a composite of death from cardiovascular causes, resuscitated cardiac arrest, myocardial infarction, stroke, or urgent hospitalization for angina leading to coronary revascularization. The components of the primary end point and safety were also assessed. Results: A total of 4745 patients were enrolled; 2366 patients were assigned to the colchicine group, and 2379 to the placebo group. Patients were followed for a median of 22.6 months. The primary end point occurred in 5.5% of the patients in the colchicine group, as compared with 7.1% of those in the placebo group (hazard ratio, 0.77; 95% confidence interval [CI], 0.61 to 0.96; P = 0.02). The hazard ratios were 0.84 (95% CI, 0.46 to 1.52) for death from cardiovascular causes, 0.83 (95% CI, 0.25 to 2.73) for resuscitated cardiac arrest, 0.91 (95% CI, 0.68 to 1.21) for myocardial infarction, 0.26 (95% CI, 0.10 to 0.70) for stroke, and 0.50 (95% CI, 0.31 to 0.81) for urgent hospitalization for angina leading to coronary revascularization. Diarrhea was reported in 9.7% of the patients in the colchicine group and in 8.9% of those in the placebo group (P = 0.35). Pneumonia was reported as a serious adverse event in 0.9% of the patients in the colchicine group and in 0.4% of those in the placebo group (P = 0.03). Conclusions: Among patients with a recent myocardial infarction, colchicine at a dose of 0.5 mg daily led to a significantly lower risk of ischemic cardiovascular events than placebo. (Funded by the Government of Quebec and others; COLCOT ClinicalTrials.gov number, NCT02551094.).
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- 2019
11. Exome-wide association study reveals novel susceptibility genes to sporadic dilated cardiomyopathy
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Esslinger, U, Garnier, S, Korniat, A, Proust, C, Kararigas, G, Mueller-Nurasyid, M, Empana, J-P, Morley, MP, Perret, C, Stark, K, Bick, AG, Prasad, SK, Kriebel, J, Li, J, Tiret, L, Strauch, K, O'Regan, DP, Marguiles, KB, Seidman, JG, Boutouyrie, P, Lacolley, P, Jouven, X, Hengstenberg, C, Komajda, M, Hakonarson, H, Isnard, R, Arbustini, E, Grallert, H, Cook, SA, Seidman, CE, Regitz-Zagrosek, V, Cappola, TP, Charron, P, Cambien, F, Villard, E, Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière] (IHU ICAN), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Helmholtz Zentrum München = German Research Center for Environmental Health, Ludwig-Maximilians-Universität München (LMU), German Center for Cardiovascular Research (DZHK), Berlin Institute of Health (BIH), Munich Heart Alliance [Munich, Allemagne] (MHA), Paris-Centre de Recherche Cardiovasculaire (PARCC (UMR_S 970/ U970)), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), University of Pennsylvania, University of Regensburg, Harvard Medical School [Boston] (HMS), Royal Brompton Hospital, German Center for Diabetes Research - Deutsches Zentrum für Diabetesforschung [Neuherberg] (DZD), Children’s Hospital of Philadelphia (CHOP ), Imperial College London, Howard Hughes Medical Institute [Chevy Chase] (HHMI), Howard Hughes Medical Institute (HHMI), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Défaillance Cardiovasculaire Aiguë et Chronique (DCAC), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM), Fondazione IRCCS Policlinico San Matteo [Pavia], Università degli Studi di Pavia = University of Pavia (UNIPV), National Heart Centre Singapore (NHCS), Duke-NUS Medical School [Singapore], Howard Hughes Medical Institute [Boston] (HHMI), Howard Hughes Medical Institute (HHMI)-Harvard Medical School [Boston] (HMS), Hôpital Ambroise Paré [AP-HP], LACOLLEY, Patrick, Ludwig-Maximilians University [Munich] (LMU), Technische Universität München = Technical University of Munich (TUM), Garnier, Sophie, Fondation Leducq, National Institute for Health Research, British Heart Foundation, Wellcome Trust, and Department of Health
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[SDV]Life Sciences [q-bio] ,PROTEIN ,Biochemistry ,Heat Shock Response ,Myofibrils ,Animal Cells ,Medicine and Health Sciences ,Cellular Stress Responses ,ARCHITECTURE ,Computer-Aided Drug Design ,COMMON VARIANTS ,Genomics ,Precipitation Techniques ,Multidisciplinary Sciences ,[SDV] Life Sciences [q-bio] ,DIFFERENTIATION ,Cell Processes ,Science & Technology - Other Topics ,HEART-FAILURE ,Medicine ,HSPB7 ,Cellular Types ,Anatomy ,Cardiomyopathies ,Research Article ,Sarcomeres ,Drug Research and Development ,General Science & Technology ,Science ,Cardiology ,Muscle Tissue ,Research and Analysis Methods ,MD Multidisciplinary ,Genetics ,Genome-Wide Association Studies ,Immunoprecipitation ,SKELETAL-MUSCLES ,Pharmacology ,Muscle Cells ,Science & Technology ,MUTATIONS ,Biology and Life Sciences ,Computational Biology ,Proteins ,Human Genetics ,Cell Biology ,Genome Analysis ,Co-Immunoprecipitation ,Chaperone Proteins ,Biological Tissue ,Genetic Loci ,Drug Design ,FHOD3 ,P19CL6 CELLS - Abstract
International audience; Aims: Dilated cardiomyopathy (DCM) is an important cause of heart failure with a strong familial component. We performed an exome-wide array-based association study (EWAS) to assess the contribution of missense variants to sporadic DCM.Methods and results: 116,855 single nucleotide variants (SNVs) were analyzed in 2796 DCM patients and 6877 control subjects from 6 populations of European ancestry. We confirmed two previously identified associations with SNVs in BAG3 and ZBTB17 and discovered six novel DCM-associated loci (Q-value
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- 2017
12. Bleeding-Related Deaths in Relation to the Duration of Dual-Antiplatelet Therapy After Coronary Stenting
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Abdourahmane Diallo, Bo Xu, Giuseppe Biondi-Zoccai, Seung-Jung Park, Jung-Min Ahn, Philippe Généreux, Gregg W. Stone, Yaling Han, Gilles Montalescot, Hyo-Soo Kim, Stefanie Schüpke, Diego Della Riva, Alexandre Abizaid, Deepak L. Bhatt, Adnan Kastrati, Philippe Gabriel Steg, Martine Gilard, Letizia Bacchi Reggiani, Marco Valgimigli, Yangsoo Jang, Marie Claude Morice, Tullio Palmerini, Myeong Ki Hong, Mattia Romanello, Eric Vicaut, Alaide Chieffo, Gérard Helft, Antonio Colombo, Byeong Keuk Kim, Kyung Woo Park, Fausto Feres, Palmerini, Tullio, Bacchi Reggiani, Letizia, Della Riva, Diego, Romanello, Mattia, Feres, Fausto, Abizaid, Alexandre, Gilard, Martine, Morice, Marie-Claude, Valgimigli, Marco, Hong, Myeong-Ki, Kim, Byeong-Keuk, Jang, Yangsoo, Kim, Hyo-Soo, Park, Kyung Woo, Colombo, Antonio, Chieffo, Alaide, Ahn, Jung-Min, Park, Seung-Jung, Schüpke, Stefanie, Kastrati, Adnan, Montalescot, Gille, Steg, Philippe Gabriel, Diallo, Abdourahmane, Vicaut, Eric, Helft, Gerard, Biondi-Zoccai, Giuseppe, Xu, Bo, Han, Yaling, Genereux, Philippe, Bhatt, Deepak L., Stone, Gregg W, Morice, Marie claude, Hong, Myeong ki, Kim, Byeong keuk, Kim, Hyo soo, Ahn, Jung min, Park, Seung jung, Schã¼pke, Stefanie, Biondi zoccai, Giuseppe, Stone, Gregg W., University of Bologna/Università di Bologna, Instituto de Cardiologia Dante Pazzanese (IDPC), Université de Brest (UBO), Institut Cardiovasculaire Paris Sud [Massy] (ICPS), Inselspital Bern, Yonsei University, Seoul National University [Seoul] (SNU), IRCCS San Raffaele Scientific Institute [Milan, Italie], University of Ulsan, Deutsches Zentrum für Herz-Kreislauf-Forschung partner site, Munich Heart Alliance, German Heart Center = Deutsches Herzzentrum München [Munich, Germany] (GHC), Institut de cardiologie [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière] (IHU ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de cardiologie [CHU Bichat], AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot, Sorbonne Paris Cité, Unité de Recherche Clinique (Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [APHP]), Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière] (IHU ICAN), Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome] (UNIROMA), Fuwai Hospital of Chinese Academy of Medical Sciences [Beijing, China] (FH-CAMS), General Hospital of Shenyang Military Region [Shenyang, China] (GH-SMR), New York Presbyterian Hospital, Columbia University Medical Center (CUMC), Columbia University [New York], Brigham and Women’s Hospital [Boston, MA], Harvard Medical School [Boston] (HMS), and Lesnik, Philippe
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medicine.medical_specialty ,Multivariate analysis ,animal structures ,[SDV]Life Sciences [q-bio] ,medicine.medical_treatment ,Population ,MEDLINE ,Hemorrhage ,030204 cardiovascular system & hematology ,Lower risk ,law.invention ,03 medical and health sciences ,0302 clinical medicine ,Percutaneous Coronary Intervention ,Randomized controlled trial ,law ,Internal medicine ,medicine ,Drug-Eluting Stent ,drug-eluting stent ,dual antiplatelet therapy ,030212 general & internal medicine ,dual antiplatelet therapy ,mortality ,drug-eluting stents ,hemorrhage ,humans ,percutaneous coronary intervention ,platelet aggregation inhibitors ,postoperative complications ,randomized controlled trials as topic ,cardiology and cardiovascular medicine ,education ,Randomized Controlled Trials as Topic ,education.field_of_study ,business.industry ,Platelet Aggregation Inhibitor ,Hazard ratio ,Confidence interval ,Surgery ,[SDV] Life Sciences [q-bio] ,Drug-eluting stent ,Postoperative Complication ,business ,Cardiology and Cardiovascular Medicine ,Human - Abstract
Background Although some randomized controlled trials (RCTs) and meta-analyses have suggested that prolonged dual-antiplatelet therapy (DAPT) may be associated with increased mortality, the mechanistic underpinnings of this association remain unclear. Objectives The aim of this study was to analyze the associations among bleeding, mortality, and DAPT duration after drug-eluting stent implantation in a meta-analysis of RCTs. Methods RCTs comparing different DAPT durations after drug-eluting stent placement were sought through the MEDLINE, Embase, and Cochrane databases and the proceedings of international meetings. Deaths were considered possibly bleeding related if occurring within 1 year of the episodes of bleeding. Primary analysis was by intention-to-treat. Secondary analysis was performed in a modified intention-to-treat population in which events occurring when all patients were on DAPT were excluded. Results Individual patient data were obtained for 6 RCTs, and aggregate data were available for 12 RCTs. Patients with bleeding had significantly higher rates of mortality compared with those without, and in a time-adjusted multivariate analysis, bleeding was an independent predictor of mortality occurring within 1 year of the bleeding episode (hazard ratio: 6.93; 95% confidence interval: 4.53 to 10.60; p< 0.0001). Shorter DAPT was associated with lower rates of all-cause death compared with longer DAPT (hazard ratio: 0.85; 95% confidence interval: 0.73 to 1.00; p= 0.05), which was driven by lower rates of bleeding-related deaths with shorter DAPT compared with prolonged DAPT (hazard ratio: 0.65; 95% confidence interval: 0.43 to 0.99; p= 0.04). Mortality unrelated to bleeding was comparable between the 2groups. Similar results were apparent in the modified intention-to-treat population. Conclusions Bleeding was strongly associated with the occurrence of mortality within 1 year after the bleeding event. Shorter compared with longer DAPT was associated with lower risk for bleeding-related death, a finding that mayunderlie the lower all-cause mortality with shorter DAPT in the RCTs of different DAPT durations after DES.
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- 2017
13. Immunochip analysis identifies association of the RAD50/IL13 region with human longevity
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Martina Müller-Nurasyid, Amke Caliebe, Céline Derbois, Friederike Flachsbart, Carsten Büning, Anette Peters, Pilar Galan, Per Hoffmann, Marianne Nygaard, Stephan Brand, Stefan Schreiber, Femke-Anouska Heinsen, Almut Nebel, Andre Franke, Markus M. Nöthen, Wolfgang Lieb, Liljana Gentschew, Kaare Christensen, David Ellinghaus, Lene Christiansen, Hélène Blanché, Konstantin Strauch, Jean-François Deleuze, Institute of Clinical Molecular Biology, Kiel University, Christian-Albrechts University of Kiel, University of Southern Denmark (SDU), Department of Clinical Genetics, Odense University Hospital, Odense University Hospital (OUH), Centre d'Etude du Polymorphisme Humain (CEPH), Fondation Jean Dausset-Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7), Centre National de Génotypage (CNG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Centre de Recherche Épidémiologie et Statistique Sorbonne Paris Cité (CRESS (U1153 / UMR_A_1125 / UMR_S_1153)), Université Paris Diderot - Paris 7 (UPD7)-Université Sorbonne Paris Cité (USPC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Recherche Agronomique (INRA), Université Sorbonne Paris Cité (COMUE) (USPC), Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Ludwig Maximilians University of Munich, Institute of Epidemiology, Helmholtz-Zentrum München (HZM), Munich Heart Alliance, German Center for Diabetes Research - Deutsches Zentrum für Diabetesforschung [Neuherberg] (DZD), German Research Center for Environmental Health - Helmholtz Center München (GmbH), Institute of Human Genetics, Universität Ulm - Ulm University [Ulm, Allemagne], Department of Genomics, Life and Brain Center, University of Bonn, Department of Biomedicine, University of Bergen (UiB), University Hospital Basel [Basel], University Medical Center Schleswig-Holstein, RESOLVE project [FP7-HEALTH-F4-2008-202047], Deutsche Forschungsgemeinschaft (DFG) Cluster of Excellence 'Inflammation at Interfaces', German Federal Ministry of Education and Research (BMBF) [01ZX1306A], German Ministry for Education and Research [01EY1103], German Federal Ministry for Education and Research within the context of the National Genome Research Network 2 [NGFN-2], National Genome Research Network plus (NGFNplus), Integrated Genome Research Network (IG) MooDS [01GS08144, 01GS08147], INTER-REG4A program Syddanmark-Schleswig-K.E.R.N, EU funds from the European Regional Development Fund, VELUX Foundation, Danish National Research Foundation, US National Institutes of Health-National Institute on Aging [P01 AG08761], Danish Agency for Science, Technology and Innovation [09-070081], French Institut National de la Sante et de la Recherche Medicale, Institut National de la Recherche Agronomique, the Universite Paris 13, Helmholtz Zentrum Munchen-German Research Center for Environmental Health, German Federal Ministry of Education and Research, State of Bavaria, Munich Center of Health Sciences (MC Health), Ludwig-Maximilians-University Munich, as part of LMUinnovativ, DFG [BR1912/6-1], Else-Kroner-Fresenius-Stiftung [2010_EKES.32], Alfried Krupp von Bohlen und Halbach-Stiftung, Heinz Nixdorf Foundation (Germany), German Ministry of Education and Science, German Research Council (DFG) [SI 236/8-1, SI236/9-1, ER 155/61], Université Paris Diderot - Paris 7 (UPD7)-Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Fondation Jean Dausset, Institut National de la Recherche Agronomique (INRA)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Ludwig-Maximilians University [Munich] (LMU), Helmholtz Zentrum München = German Research Center for Environmental Health, Universität Bonn = University of Bonn, ProdInra, Migration, Flachsbart, Friederike, and Ellinghaus, David
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0301 basic medicine ,Il13 ,Rad50 ,5q31.1 ,Immunochip ,Genetic Association ,Human Longevity ,Aging ,IL 13 ,genetic association ,media_common.quotation_subject ,[SDV]Life Sciences [q-bio] ,Longevity ,Locus (genetics) ,Single-nucleotide polymorphism ,Genome-wide association study ,030105 genetics & heredity ,Biology ,Danish ,03 medical and health sciences ,Humans ,SNP ,chromosome ,5q31 ,human longevity ,IL13 ,RAD50 ,longévité ,Oligonucleotide Array Sequence Analysis ,media_common ,Genetic association ,Short Takes ,Genetics ,Interleukin-13 ,Short Take ,Cell Biology ,language.human_language ,Acid Anhydride Hydrolases ,3. Good health ,DNA-Binding Proteins ,[SDV] Life Sciences [q-bio] ,DNA Repair Enzymes ,030104 developmental biology ,Genetic Loci ,Multiple comparisons problem ,language ,Chromosomes, Human, Pair 5 ,Genome-Wide Association Study - Abstract
Human longevity is characterized by a remarkable lack of confirmed genetic associations. Here, we report on the identification of a novel locus for longevity in the RAD50/IL13 region on chromosome 5q31.1 using a combined European sample of 3208 long-lived individuals (LLI) and 8919 younger controls. First, we performed a large-scale association study on 1458 German LLI (mean age 99.0 years) and 6368 controls (mean age 57.2 years) by targeting known immune-associated loci covered by the Immunochip. The analysis of 142 136 autosomal single nucleotide polymorphisms (SNPs) revealed an Immunochip-wide significant signal (PI mmunochip = 7.01 × 10-9 ) for the SNP rs2075650 in the TOMM40/APOE region, which has been previously described in the context of human longevity. To identify novel susceptibility loci, we selected 15 markers with PI mmunochip < 5 × 10-4 for replication in two samples from France (1257 LLI, mean age 102.4 years; 1811 controls, mean age 49.1 years) and Denmark (493 LLI, mean age 96.2 years; 740 controls, mean age 63.1 years). The association at SNP rs2706372 replicated in the French study collection and showed a similar trend in the Danish participants and was also significant in a meta-analysis of the combined French and Danish data after adjusting for multiple testing. In a meta-analysis of all three samples, rs2706372 reached a P-value of PI mmunochip+Repl = 5.42 × 10-7 (OR = 1.20; 95% CI = 1.12-1.28). SNP rs2706372 is located in the extended RAD50/IL13 region. RAD50 seems a plausible longevity candidate due to its involvement in DNA repair and inflammation. Further studies are needed to identify the functional variant(s) that predispose(s) to a long and healthy life. Human longevity is characterized by a remarkable lack of confirmed genetic associations. Here, we report on the identification of a novel locus for longevity in the RAD50/IL13 region on chromosome 5q31.1 using a combined European sample of 3208 long-lived individuals (LLI) and 8919 younger controls. First, we performed a large-scale association study on 1458 German LLI (mean age 99.0 years) and 6368 controls (mean age 57.2 years) by targeting known immune-associated loci covered by the Immunochip. The analysis of 142 136 autosomal single nucleotide polymorphisms (SNPs) revealed an Immunochip-wide significant signal (PI mmunochip = 7.01 × 10(-9) ) for the SNP rs2075650 in the TOMM40/APOE region, which has been previously described in the context of human longevity. To identify novel susceptibility loci, we selected 15 markers with PI mmunochip < 5 × 10(-4) for replication in two samples from France (1257 LLI, mean age 102.4 years; 1811 controls, mean age 49.1 years) and Denmark (493 LLI, mean age 96.2 years; 740 controls, mean age 63.1 years). The association at SNP rs2706372 replicated in the French study collection and showed a similar trend in the Danish participants and was also significant in a meta-analysis of the combined French and Danish data after adjusting for multiple testing. In a meta-analysis of all three samples, rs2706372 reached a P-value of PI mmunochip+Repl = 5.42 × 10(-7) (OR = 1.20; 95% CI = 1.12-1.28). SNP rs2706372 is located in the extended RAD50/IL13 region. RAD50 seems a plausible longevity candidate due to its involvement in DNA repair and inflammation. Further studies are needed to identify the functional variant(s) that predispose(s) to a long and healthy life.
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- 2016
14. Defects in TRPM7 channel function deregulate thrombopoiesis through altered cellular Mg2+ homeostasis and cytoskeletal architecture
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Masayuki Matsushita, Stephanie Burger-Stritt, Harald Schulze, Michael Laffan, Susanna Zierler, Rémi Favier, Michele P. Lambert, Paola Ballerini, Simon Stritt, Silvia Ferioli, Lorenz Mittermeier, Paquita Nurden, Sanjeev K. Gotru, Bernhard Nieswandt, Marie Favier, Thomas Gudermann, Judith M.M. van Eeuwijk, Alan T. Nurden, Ernest Turro, Attila Braun, Vladimir Chubanov, University of Würzburg, CHU Bordeaux [Bordeaux], CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut Gustave Roussy (IGR), Hématopoïèse normale et pathologique (U1170 Inserm), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Nutrition, obésité et risque thrombotique (NORT), Aix Marseille Université (AMU)-Institut National de la Recherche Agronomique (INRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Ludwig Maximilians University of Munich, Hôpital Xavier Arnozan, Children’s Hospital of Philadelphia (CHOP ), University of Pennsylvania, Department of Haematology, Queens Elizabeth Hospital [Birmingham], NHS Blood and Transplant, Medical Research Council, NIHR BioResource - Rare Diseases, Cambridge University Hospitals (CUH), University Hospital of Würzburg, University of the RyuKyus, Partenaires INRAE, Imperial College London, Centre for Haematology, Hammersmith Campus, Munich Heart Alliance, German Center for Lung Research, Deutsche Forschungsgemeinschaft [SFB 688, TRR 152], German Excellence Initiative to the Graduate School of Life Sciences, University of Wurzburg, European Commission, NIHR, BHF [RP-PG-0310-1002, RG/09/12/28096], Imperial College London Biomedical Research Centre, Institut National de la Recherche Agronomique (INRA)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Ludwig-Maximilians University [Munich] (LMU), ProdInra, Migration, and Medical Research Council (MRC)
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0301 basic medicine ,[SDV]Life Sciences [q-bio] ,General Physics and Astronomy ,DISEASE ,Transient receptor potential channel ,Mice ,Megakaryocyte ,ACTOMYOSIN CONTRACTILITY ,Homeostasis ,Platelet ,Magnesium ,Thrombopoiesis ,Cytoskeleton ,Multidisciplinary ,Nonmuscle Myosin Type IIA ,KINASE TRPM7 ,3. Good health ,Cell biology ,Multidisciplinary Sciences ,[SDV] Life Sciences [q-bio] ,MEGAKARYOCYTE ,medicine.anatomical_structure ,Science & Technology - Other Topics ,Megakaryocytes ,Blood Platelets ,MIGRATION ,Platelet disorder ,Science ,TRPM Cation Channels ,PLATELET DISORDERS ,Biology ,Protein Serine-Threonine Kinases ,General Biochemistry, Genetics and Molecular Biology ,Article ,03 medical and health sciences ,TRPM7 ,MD Multidisciplinary ,medicine ,Animals ,Humans ,ddc:610 ,PROPLATELET FORMATION ,Science & Technology ,MUTATIONS ,General Chemistry ,Thrombocytopenia ,030104 developmental biology ,Mutant Proteins - Abstract
Mg2+ plays a vital role in platelet function, but despite implications for life-threatening conditions such as stroke or myocardial infarction, the mechanisms controlling [Mg2+]i in megakaryocytes (MKs) and platelets are largely unknown. Transient receptor potential melastatin-like 7 channel (TRPM7) is a ubiquitous, constitutively active cation channel with a cytosolic α-kinase domain that is critical for embryonic development and cell survival. Here we report that impaired channel function of TRPM7 in MKs causes macrothrombocytopenia in mice (Trpm7fl/fl-Pf4Cre) and likely in several members of a human pedigree that, in addition, suffer from atrial fibrillation. The defect in platelet biogenesis is mainly caused by cytoskeletal alterations resulting in impaired proplatelet formation by Trpm7fl/fl-Pf4Cre MKs, which is rescued by Mg2+ supplementation or chemical inhibition of non-muscle myosin IIA heavy chain activity. Collectively, our findings reveal that TRPM7 dysfunction may cause macrothrombocytopenia in humans and mice., Although Mg2+ is vital for platelet activation and aggregation, its regulation in these cells is still largely unknown. Here, the authors show that TRPM7, a cation channel and a protein kinase, regulates thrombopoiesis and platelet size by affecting the cytoskeleton of these cells in mice and humans.
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- 2016
15. Genetic fine mapping and genomic annotation defines causal mechanisms at type 2 diabetes susceptibility loci
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Laura J. Scott, Neil Robertson, Anders Hamsten, Domenico Palli, Susanne Moebus, Bernhard O. Boehm, Gunnar Sigurðsson, Paul W. Franks, C. N. A. Palmer, Sonali Pechlivanis, Katharine R. Owen, Michael E. Reschen, Sarah Edkins, Jason Carey, Christopher A. O’Callaghan, Norman Klopp, Caroline S. Fox, Petter Storm, N. William Rayner, Johan G. Eriksson, Thomas Illig, Anubha Mahajan, Erik Ingelsson, Allan Linneberg, Andrew R. Wood, Oddgeir L. Holmen, Nicola L. Beer, Mark I. McCarthy, Frank B. Hu, Peter Almgren, Heiner Boeing, Peter Donnelly, Carl Platou, Veikko Salomaa, Karl-Heinz Jöcke, Wen-Hong L. Kao, Lori L. Bonnycastle, Denis Rybin, Benjamin F. Voight, Peter Kraft, Inês Barroso, Claudia Langenberg, Teresa Ferreira, Peter Kovacs, Anne Raimondo, Christian Theil Have, Ulf de Faire, Torben Hansen, Han Chen, James B. Meigs, Timothy M. Frayling, Noël P. Burtt, Gerald Steinbach, Eric Boerwinkle, Michael Stumvoll, Stefan Gustafsson, Lars Lind, Andrew D. Morris, Alena Stančáková, Panagiotis Deloukas, Kari Stefansson, Augustine Kong, Hans A. Kestler, Andrew T. Hattersley, Beverley Balkau, Lorenzo Pasquali, Yingchang Lu, Nicola D. Kerrison, George B. Grant, Eeva Korpi-Hyövälti, Steven Wiltshire, Karl Gertow, Jorge Ferrer, Barbara Thorand, Inga Prokopenko, Matthias Blüher, Yvonne T. van der Schouw, Olga McLeod, Oluf Pedersen, Leena Peltonen, Anil Chalisey, Eleftheria Zeggini, Joseph Trakalo, Eric J.G. Sijbrands, Rainer Rauramaa, Guillaume Charpentier, Satu Männistö, Cordelia Langford, Lewin Eisele, Damiano Baldassarre, Lennart C. Karssen, Rona J. Strawbridge, Ghazala Mirza, Peter S. Chines, Roman Wennauer, Sara M. Willems, Erwin P. Bottinger, Timo Saaristo, Stéphane Cauchi, Ching-Ti Liu, Martijn van de Bunt, Valgerdur Steinthorsdottir, David Altshuler, Hyun Min Kang, Michael Boehnke, Jaakko Tuomilehto, Peter M. Nilsson, Kyle J. Gaulton, Jian'an Luan, Loic Yengo, David Couper, Reedik Mägi, Harald Grallert, Simone Wahl, Juha Saltevo, Phoenix Kwan, Cecilia M. Lindgren, Peter Lichtner, Richard N. Bergman, Andrew Crenshaw, João Fadista, Michael Roden, Annette Peters, Robert A. Scott, Unnur Thorsteinsdottir, James S. Pankow, Yeji Lee, Cornelia M. van Duijn, Samuli Ripatti, Francis S. Collins, Stéphane Lobbens, Niels Grarup, Ruth J. F. Loos, Julia Meyer, Marit E. Jørgensen, Christian Herder, Inger Njølstad, John R. B. Perry, Markus M. Nöthen, Man Li, Martina Müller-Nurasyid, Valeriya Lyssenko, Pierre Fontanillas, Michael D. Linderman, Leena Kinnunen, Jana K. Rundle, Elena Tremoli, Marilyn C. Cornelis, Tanya M. Teslovich, Todd Green, Raimund Erbel, Elisabeth M. van Leeuwen, Bengt Sennblad, Olle Melander, Sirkka Keinänen-Kiukaanniemi, Markku Laakso, Eero Lindholm, Alex S. F. Doney, Anke Tönjes, Maija Hassinen, Thomas W. Mühleisen, Gonçalo R. Abecasis, Nancy L. Pedersen, Thomas Sparsø, Johanna Kuusisto, Dorothée Thuillier, Qi Sun, Ian Dunham, Himanshu Chheda, Adam E. Locke, Philippe Froguel, Nicholas J. Wareham, Bruna Gigante, Jose C. Florez, Mozhgan Dorkhan, Omri Gottesman, Liming Liang, Anna Jonsson, Tiinamaija Tuomi, Leif Groop, Steve E. Humphries, Heikki A. Koistinen, Kristian Hveem, Astradur B. Hreidarsson, Jason Flannick, Torben Jørgensen, Clement Ma, Mattias Frånberg, Ewan Birney, Andrew P. Morris, Timo A. Lakka, Rob M. van Dam, Heather M. Stringham, Christian Gieger, Elodie Eury, Konstantin Strauch, Anna L. Gloyn, Rafn Benediktsson, Andres Metspalu, David J. Hunter, Karen L. Mohlke, Gudmar Thorleifsson, Josée Dupuis, Emmi Tikkanen, Christian Fuchsberger, Evelin Mihailov, Christopher J. Groves, Soren K. Thomsen, Tõnu Esko, Anne U. Jackson, Karin Leander, Douglas M. Ruderfer, Nikolay Oskolkov, Sekar Kathiresan, Robert Sladek, Lu Qi, Jasmina Kravic, Carmen Navarro, Epidemiology, Dermatology, Internal Medicine, ACS - Amsterdam Cardiovascular Sciences, Vascular Medicine, Cardiology, Wellcome Trust, Imperial College Healthcare NHS Trust- BRC Funding, Medical Research Council (MRC), [ 1 ] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England [ 2 ] Stanford Univ, Dept Genet, Stanford, CA 94305 USA [ 3 ] Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA [ 4 ] Univ Oxford, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England [ 5 ] Univ Tartu, Estonian Genome Ctr, EE-50090 Tartu, Estonia [ 6 ] Univ Oxford, Nuffield Dept Med, Ctr Cellular & Mol Physiol, Oxford, England [ 7 ] Wellcome Trust Sanger Inst, Hinxton, England [ 8 ] Univ Cambridge, Sch Clin Med, Inst Metab Sci, Med Res Council MRC Epidemiol Unit, Cambridge, England [ 9 ] Univ London Imperial Coll Sci Technol & Med, Genom Common Dis, London, England [ 10 ] Broad Inst Harvard & MIT, Cambridge, MA USA [ 11 ] Univ Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn Ctr Basic Metab Res, Copenhagen, Denmark [ 12 ] European Genom Inst Diabet, Lille Inst Biol, Lille, France [ 13 ] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Res Unit Mol Epidemiol, Neuherberg, Germany [ 14 ] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Epidemiol 2, Neuherberg, Germany [ 15 ] German Ctr Diabet Res, Neuherberg, Germany [ 16 ] Karolinska Inst, Dept Med Solna, Atherosclerosis Res Unit, Stockholm, Sweden [ 17 ] Sci Life Lab, Stockholm, Sweden [ 18 ] Stockholm Univ, Dept Numer Anal & Comp Sci, S-10691 Stockholm, Sweden [ 19 ] Fritz Lipmann Inst, Leibniz Inst Age Res, Jena, Germany [ 20 ] Univ Ulm, Med Syst Biol, D-89069 Ulm, Germany [ 21 ] Finnish Inst Mol Med, Helsinki, Finland [ 22 ] Univ Hosp Essen, Inst Med Informat Biometry & Epidemiol, Essen, Germany [ 23 ] Uppsala Univ, Dept Med Sci, Mol Epidemiol & Sci Life Lab, Uppsala, Sweden [ 24 ] deCODE Genet Amgen Inc, Reykjavik, Iceland [ 25 ] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA [ 26 ] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA [ 27 ] Brigham & Womens Hosp, Dept Med, Channing Div Network Med, Boston, MA 02115 USA [ 28 ] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA [ 29 ] Tulane Univ, Sch Publ Hlth & Trop Med, Dept Epidemiol, New Orleans, LA USA [ 30 ] Erasmus Univ, Med Ctr, Dept Epidemiol, Rotterdam, Netherlands [ 31 ] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA [ 32 ] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA [ 33 ] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA [ 34 ] Icahn Sch Med Mt Sinai, Icahn Inst Genom & Multiscale Biol, New York, NY 10029 USA [ 35 ] Icahn Sch Med Mt Sinai, Genet Obes & Related Metab Traits Program, New York, NY 10029 USA [ 36 ] Univ Penn, Perelman Sch Med, Dept Pharmacol, Philadelphia, PA 19104 USA [ 37 ] Lund Univ, Scania Univ Hosp, Dept Clin Sci Malmo, Ctr Diabet, Malmo, Sweden [ 38 ] IRCCS, Ctr Cardiol Monzino, Milan, Italy [ 39 ] Univ Milan, Dipartimento Sci Farmacol & Biomol, Milan, Italy [ 40 ] Ctr Rech Epidemiol & Sante Populat CESP, INSERM, U1018, Villejuif, France [ 41 ] Univ Paris 11, UMRS 1018, Villejuif, France [ 42 ] Univ Iceland, Fac Med, Reykjavik, Iceland [ 43 ] Landspitali Univ Hosp, Reykjavik, Iceland Organization-Enhanced Name(s) Landspitali National University Hospital [ 44 ] Univ Leipzig, Integrated Treatment & Res IFB Ctr Adipos Dis, D-04109 Leipzig, Germany [ 45 ] Univ Leipzig, Dept Med, D-04109 Leipzig, Germany [ 46 ] German Inst Human Nutr, Potsdam, Germany [ 47 ] NHGRI, US NIH, Bethesda, MD 20892 USA [ 48 ] Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, New York, NY 10029 USA [ 49 ] Corbeil Essonnes Hosp, Endocrinol Diabetol Unit, Corbeil Essonnes, France [ 50 ] Northwestern Univ, Feinberg Sch Med, Dept Prevent Med, Chicago, IL 60611 USA [ 51 ] Univ N Carolina, Dept Biostat, Collaborat Studies Coordinating Ctr, Chapel Hill, NC USA [ 52 ] Natl Univ Singapore, Saw Swee Hock Sch Publ Hlth, Singapore 117548, Singapore [ 53 ] Univ Dundee, Ninewells Hosp, Biomed Res Inst, Ctr Diabet Res, Dundee, Scotland [ 54 ] Univ Dundee, Ninewells Hosp, Biomed Res Inst, Pharmacogen Ctr, Dundee, Scotland [ 55 ] Lund Univ, Ctr Diabet, Dept Clin Sci Malmo, Novo Nordisk Scandinavia, Malmo, Sweden [ 56 ] Natl Inst Hlth & Welf, Dept Chron Dis Prevent, Helsinki, Finland [ 57 ] Univ Helsinki, Dept Gen Practice & Primary Hlth Care, Helsinki, Finland [ 58 ] Univ Helsinki, Cent Hosp, Unit Gen Practice, Helsinki, Finland [ 59 ] Folkhalsan Res Ctr, Helsinki, Finland [ 60 ] Childrens Hosp, Div Endocrinol, Boston, MA 02115 USA [ 61 ] Broad Inst Harvard & MIT, Program Med & Populat Genet, Cambridge, MA USA [ 62 ] CNRS, UMR 8199, Inst Biol, Lille, France [ 63 ] Univ Lille 2, Inst Pasteur, Lille, France [ 64 ] NHLBI, Framingham Heart Study, Framingham, MA USA [ 65 ] Brigham & Womens Hosp, Div Endocrinol & Metab, Boston, MA 02115 USA [ 66 ] Harvard Univ, Sch Med, Boston, MA USA [ 67 ] Lund Univ, Dept Clin Sci, Malmo, Sweden [ 68 ] Umea Univ, Dept Publ Hlth & Clin Med, Umea, Sweden [ 69 ] Karolinska Inst, Inst Environm Med, Div Cardiovasc Epidemiol, S-10401 Stockholm, Sweden [ 70 ] Kuopio Res Inst Exercise Med, Kuopio, Finland [ 71 ] Univ Dusseldorf, Leibniz Ctr Diabet Res, German Diabet Ctr, Inst Clin Diabetol, Dusseldorf, Germany [ 72 ] Partner Site Dusseldorf, German Ctr Diabet Res, Dusseldorf, Germany [ 73 ] Norwegian Univ Sci & Technol, Dept Publ Hlth & Gen Practice, Nord Trondelag Hlth Study HUNT Res Ctr, Levanger, Norway [ 74 ] UCL, Inst Cardiovasc Sci, British Heart Fdn BHF Labs, Cardiovasc Genet, London, England [ 75 ] Harvard Univ, Sch Publ Hlth, Program Genet Epidemiol & Stat Genet, Boston, MA 02115 USA [ 76 ] Steno Diabet Ctr, DK-2820 Gentofte, Denmark [ 77 ] Capital Reg Denmark, Res Ctr Prevent & Hlth, Copenhagen, Denmark [ 78 ] Univ Copenhagen, Fac Hlth & Med Sci, Copenhagen, Denmark [ 79 ] Aalborg Univ, Fac Med, Aalborg, Denmark [ 80 ] Hannover Med Sch, Hannover Unified Biobank, Hannover, Germany [ 81 ] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Human Genet, Neuherberg, Germany [ 82 ] Rigshosp, Copenhagen Univ Hosp, DK-2100 Copenhagen, Denmark [ 83 ] Univ Copenhagen, Fac Hlth & Med Sci, Dept Clin Med, Copenhagen, Denmark [ 84 ] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Genet Epidemiol, Neuherberg, Germany [ 85 ] Guys & St Thomas Natl Hlth Serv NHS Fdn Trust, Guys & St Thomas Hosp, Genom Core Facil, Biomed Res Ctr, London, England [ 86 ] Univ Bonn, Inst Human Genet, Bonn, Germany [ 87 ] Univ Bonn, Life & Brain Ctr, Dept Genom, Bonn, Germany [ 88 ] Res Ctr Julich, Inst Neurosci & Med INM 1, Julich, Germany [ 89 ] Univ Munich, Univ Hosp Grosshadern, Dept Med 1, Munich, Germany [ 90 ] Univ Munich, Chair Genet Epidemiol, Inst Med Informat Biometry & Epidemiol, Neuherberg, Germany [ 91 ] Partner Site Munich Heart Alliance, DZHK German Ctr Cardiovasc Res, Munich, Germany [ 92 ] Inst Murciano Invest Biosanitaria Virgen de la Ar, Murcia Reg Hlth Council, Dept Epidemiol, Murcia, Spain [ 93 ] CIBERESP, Madrid, Spain [ 94 ] Univ Murcia, Dept Hlth & Social Sci, Murcia, Spain [ 95 ] Churchill Hosp, Biomed Res Ctr, Oxford Natl Inst Hlth Res, Oxford OX3 7LJ, England [ 96 ] Canc Res & Prevent Inst ISPO, Florence, Italy [ 97 ] Nord Trondelag Hlth Trust, Levanger Hosp, Dept Internal Med, Levanger, Norway [ 98 ] Univ Hosp Dusseldorf, Dept Endocrinol & Diabetol, Dusseldorf, Germany [ 99 ] Icahn Sch Med Mt Sinai, Dept Psychiat, Div Psychiat Genom, New York, NY 10029 USA [ 100 ] Boston Univ, Data Coordinating Ctr, Boston, MA 02215 USA [ 101 ] Univ Med Ctr Utrecht, Utrecht, Netherlands [ 102 ] Iceland Heart Assoc, Kopavogur, Iceland [ 103 ] Univ Eastern Finland, Dept Med, Kuopio, Finland [ 104 ] Kuopio Univ Hosp, SF-70210 Kuopio, Finland [ 105 ] Univ Ulm, Dept Clin Chem & Cent Lab, D-89069 Ulm, Germany [ 106 ] Univ Helsinki, Dept Publ Hlth, Hjelt Inst, Helsinki, Finland [ 107 ] Helsinki Univ Hosp, Abdominal Ctr, Dept Endocrinol, Helsinki, Finland [ 108 ] Univ Helsinki, Res Program Diabet & Obes, Helsinki, Finland [ 109 ] Erasmus Univ, Med Ctr, Dept Internal Med, Rotterdam, Netherlands [ 110 ] Univ Exeter, Sch Med, Genet Complex Traits, Exeter, Devon, England [ 111 ] European Mol Biol Lab, EBI, Hinxton, England [ 112 ] Germans Trias & Pujol Univ Hosp & Res Inst, Div Endocrinol, Badalona, Spain [ 113 ] Josep Carreras Leukaemia Res Inst, Badalona, Spain [ 114 ] CIBERDEM, Barcelona, Spain [ 115 ] Univ London Imperial Coll Sci Technol & Med, Dept Med, London, England [ 116 ] Inst Invest Biomed August Pi & Sunyer, Ctr Esther Koplowitz, Barcelona, Spain [ 117 ] Icahn Sch Med Mt Sinai, Mindich Child Hlth & Dev Inst, New York, NY 10029 USA [ 118 ] Harvard Univ, Sch Med, Dept Med, Boston, MA USA [ 119 ] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA [ 120 ] Massachusetts Gen Hosp, Diabet Res Ctr, Boston, MA 02114 USA [ 121 ] Univ Texas Hlth Sci Ctr Houston, Human Genet Ctr, Houston, TX 77030 USA [ 122 ] Baylor Coll Med, Human Genome Sequencing Ctr, Houston, TX 77030 USA [ 123 ] Univ Minnesota, Div Epidemiol & Community Hlth, Minneapolis, MN USA [ 124 ] Netherlands Consortium Hlth Ageing, Netherlands Genom Initiat, Rotterdam, Netherlands [ 125 ] Ctr Med Syst Biol, Rotterdam, Netherlands [ 126 ] Massachusetts Gen Hosp, Gen Med Div, Boston, MA 02114 USA [ 127 ] Univ Eastern Finland, Inst Biomed Physiol, Kuopio, Finland [ 128 ] Kuopio Univ Hosp, Dept Clin Physiol & Nucl Med, SF-70210 Kuopio, Finland [ 129 ] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden [ 130 ] Univ Uppsala Hosp, Dept Med Sci, Uppsala, Sweden [ 131 ] Univ Oulu, Inst Hlth Sci, Fac Med, Oulu, Finland [ 132 ] Oulu Univ Hosp, Unit Gen Practice, Oulu, Finland [ 133 ] South Ostrobothnia Cent Hosp, Seinajoki, Finland [ 134 ] Finnish Diabet Assoc, Tampere, Finland [ 135 ] Pirkanmaa Dist Hosp, Tampere, Finland [ 136 ] Cent Finland Cent Hosp, Dept Med, Jyvasklya, Finland [ 137 ] Univ Tartu, Inst Mol & Cell Biol, EE-50090 Tartu, Estonia [ 138 ] Univ Duisdurg Essen, Univ Hosp Essen, West German Heart Ctr, Clin Cardiol, Essen, Germany [ 139 ] Natl Inst Hlth & Welf, Publ Hlth Genom Unit, Helsinki, Finland [ 140 ] Univ Med Ctr Ulm, Dept Internal Med, Div Endocrinol & Diabet, Ulm, Germany [ 141 ] Univ London Imperial Coll Sci Technol & Med, Lee Kong Chian Sch Med, London SW7 2AZ, England [ 142 ] Nanyang Technol Univ, Singapore 639798, Singapore [ 143 ] Cedars Sinai Med Ctr, Diabet & Obes Res Inst, Los Angeles, CA 90048 USA [ 144 ] Univ N Carolina, Dept Genet, Chapel Hill, NC USA [ 145 ] Univ Helsinki, Cent Hosp, Dept Med, Div Endocrinol, Helsinki, Finland [ 146 ] Minerva Fdn, Helsinki, Finland [ 147 ] Hosp Univ La Paz, Inst Invest Sanitaria, Madrid, Spain [ 148 ] Danube Univ Krems, Ctr Vasc Prevent, Krems, Austria [ 149 ] King Abdulaziz Univ, Diabet Res Grp, Jeddah 21413, Saudi Arabia [ 150 ] Univ Tromso, Fac Hlth Sci, Dept Community Med, Tromso, Norway [ 151 ] Queen Mary Univ London, Barts & London Sch Med & Dent, William Harvey Res Inst, London, England [ 152 ] Univ Oxford, Dept Stat, Oxford OX1 3TG, England [ 153 ] Univ Exeter, Sch Med, Inst Biomed & Clin Sci, Exeter, Devon, England [ 154 ] Ctr Hosp Univ Montreal, Ctr Rech, Montreal Diabet Res Ctr, Montreal, PQ, Canada [ 155 ] McGill Univ, Montreal, PQ, Canada [ 156 ] Genome Quebec Innovat Ctr, Montreal, PQ, Canada [ 157 ] Univ Southern Denmark, Fac Hlth Sci, Odense, Denmark [ 158 ] Univ Edinburgh, Usher Inst Populat Hlth Sci & Informat, Edinburgh, Midlothian, Scotland [ 159 ] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA [ 160 ] Univ Cambridge, Metab Res Labs, Wellcome Trust MRC Inst Metab Sci, Cambridge, England [ 161 ] Cambridge Biomed Res Ctr, Natl Inst Hlth Res, Cambridge, England [ 162 ] Harvard Univ, Sch Med, Dept Genet, Boston, MA USA [ 163 ] Harvard Univ, Sch Med, Dept Mol Biol, Boston, MA USA [ 164 ] Univ Liverpool, Dept Biostat, Liverpool L69 3BX, Merseyside, England [ 165 ] Univ Liverpool, Dept Mol & Clin Pharmacol, Liverpool L69 3BX, Merseyside, England, Luan, Jian'an [0000-0003-3137-6337], Perry, John [0000-0001-6483-3771], Barroso, Ines [0000-0001-5800-4520], Langenberg, Claudia [0000-0002-5017-7344], Wareham, Nicholas [0000-0003-1422-2993], and Apollo - University of Cambridge Repository
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endocrine system diseases ,Medizin ,Genome-wide association study ,Glucose homeostasis ,WIDE ASSOCIATION ,Association mapping ,Non-U.S. Gov't ,Genome-Wide Association Study ,Regulation of gene expression ,Genetics ,Genetics & Heredity ,LARGE-SCALE ASSOCIATION ,Research Support, Non-U.S. Gov't ,COMMON VARIANTS ,Chromosome Mapping ,11 Medical And Health Sciences ,Genomics ,3. Good health ,TRANSCRIPTION FACTORS ,Liver ,Hepatocyte Nuclear Factor 3-beta ,Medical Genetics ,Life Sciences & Biomedicine ,Chromatin Immunoprecipitation ,endocrine system ,European Continental Ancestry Group/genetics ,Biology ,GENOTYPE IMPUTATION ,Research Support ,INSULIN-SECRETION ,Polymorphism, Single Nucleotide ,Article ,N.I.H ,Sykursýki ,Islets of Langerhans ,SDG 3 - Good Health and Well-being ,Research Support, N.I.H., Extramural ,HUMAN PANCREATIC-ISLETS ,GLYCEMIC TRAITS ,Journal Article ,SNP ,Humans ,Genetic Predisposition to Disease ,Comparative Study ,Enhancer ,Medicinsk genetik ,Science & Technology ,Binding Sites ,DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) Consortium ,Receptor, Melatonin, MT2 ,Extramural ,Molecular Sequence Annotation ,Arfgengi ,06 Biological Sciences ,Genetic Predisposition to Disease/genetics ,BETA-CELL ,Diabetes Mellitus, Type 2/genetics ,Diabetes Mellitus, Type 2 ,Gene Expression Regulation ,Genetic Loci ,Case-Control Studies ,Gene-Environment Interaction ,GLUCOSE-HOMEOSTASIS ,Chromatin immunoprecipitation ,Developmental Biology - Abstract
To access publisher's full text version of this article click on the hyperlink at the bottom of the page We performed fine mapping of 39 established type 2 diabetes (T2D) loci in 27,206 cases and 57,574 controls of European ancestry. We identified 49 distinct association signals at these loci, including five mapping in or near KCNQ1. 'Credible sets' of the variants most likely to drive each distinct signal mapped predominantly to noncoding sequence, implying that association with T2D is mediated through gene regulation. Credible set variants were enriched for overlap with FOXA2 chromatin immunoprecipitation binding sites in human islet and liver cells, including at MTNR1B, where fine mapping implicated rs10830963 as driving T2D association. We confirmed that the T2D risk allele for this SNP increases FOXA2-bound enhancer activity in islet- and liver-derived cells. We observed allele-specific differences in NEUROD1 binding in islet-derived cells, consistent with evidence that the T2D risk allele increases islet MTNR1B expression. Our study demonstrates how integration of genetic and genomic information can define molecular mechanisms through which variants underlying association signals exert their effects on disease. cademy of Finland 77299 102318 10493 118065 123885 124243 129293 129680 136895 139635 211119 213506 251217 263836 Agence National de la Recherche Association de Langue Francaise pour l'Etude du Diabete et des Maladies Metaboliques Association Diabeete Risque Vasculaire Association Francaise des Diabetiques Association of Danish Pharmacies Augustinus Foundation Becket Foundation British Diabetes Association (BDA) Research British Heart Foundation Central Norway Health Authority Central Finland Hospital District Center for Inherited Disease Research (CIDR) City of Kuopio City of Leutkirch Copenhagen County Danish Centre for Evaluation and Health Technology Assessment Danish Council for Independent Research Danish Heart Foundation Danish Research Councils Deutsche Forschungsgemeinschaft ER 155/6-2 Diabetes Research Foundation Diabetes UK Doris Duke Charitable Foundation Erasmus Medical Center Erasmus University Estonian government SF0180142s08 European Commission ENGAGE HEALTH-F4-2007-201413 FP7-201413 FP7-245536 EXGENESIS LSHM-CT-2004-005272 FP6 LSHM_CT_2006_037197 LSHM-CT-2007-037273 C-Public Health 2004310 European Regional Development Fund Federal Ministry of Education and Research, Germany FKZ 01GI1128 FKZ 01EO1001 Federal Ministry of Health, Germany Finnish Diabetes Association Finnish Diabetes Research Foundation Finnish Foundation for Cardiovascular Research Finnish Medical Society Folkhalsan Research Foundation Foundation for Life and Health in Finland Foundation for Old Servants Fredrick och Ingrid Thuring Foundation French region of Nord-Pas-de-Calais (Contrat de Projets Etat-Region) German Center for Diabetes Research German Research Council GRK1041 German National Genome Research Network Groupe d'Etude des Maladies Metaboliques et Systemiques Health Care Centers in Vasa, Narpes and Korsholm, Finland Health Foundation Heinz Nixdorf Foundation Helmholtz Zentrum Munchen Helsinki University Central Hospital Research Foundation Hospital District of Southwest Finland Ib Henriksens Foundation IngaBritt and Arne Lundberg's Research Foundation 359 Karolinska Institutet Knut and Alice Wallenberg Foundation KAW 2009.0243 Kuopio University Hospital Lundbeck Foundation Magnus Bergvall Foundation Medical Faculty of University Duisburg-Essen Medical Research Council, UK G0000649 G0601261 Ministry for Health, Welfare and Sports, the Netherlands Ministry of Education and Culture, Finland 722 627 Ministry of Education, Culture and Science, the Netherlands Ministry of Health and Prevention, Denmark Ministry of Social Affairs and Health, Finland Ministry of Innovation, Science, Research and Technology of North Rhine-Westphalia, Germany Munich Center of Health Sciences Municipal Health Care Center and Hospital in Jakobstad, Finland municipality of Rotterdam, the Netherlands Narpes Health Care Foundation National Health Screening Service of Norway National Heart, Lung, and Blood Institute, USA HHSN268201100005C HHSN268201100006C HHSN268201100007C HHSN268201100008C HHSN268201100009C HHSN268201100010C HHSN268201100011C HHSN268201100012C N01HC25195 N02HL64278 R01HL087641 R01HL59367 R01HL086694 National Human Genome Research Institute, USA U01HG004402 N01HG65403 National Institute for Diabetes and Digestive and Kidney Diseases, USA R01DK078616 U01DK085526 K24DK080140 R01DK073490 National Institute for Health and Welfare, Finland National Institutes of Health, USA HHSN268200625226C UL1RR025005 R01DK062370 R01DK072193 1Z01HG000024 AG028555 AG08724 AG04563 AG10175 AG08861 U01HG004399 DK58845 CA055075 DK085545 DK098032 Netherlands Genomics Initiative Netherlands Organisation for Health Research and Development Netherlands Organisation of Scientific Research NOW Investments 175.010.2005.011 911-03-012 050-060-810 Nord-Trondelag County Council Nordic Center of Excellence in Disease Genetics Norwegian Institute of Public Health Norwegian Research Council Novo Nordisk Foundation Ollquist Foundation Oxford National Institute for Health Research (NIHR) Biomedical Research Centre Paavo Nurmi Foundation Paivikki and Sakari Sohlberg Foundation Perklen Foundation Pirkanmaa Hospital District, Finland Programme Hospitalier de Recherche Clinique Programme National de Recherche sur la Diabete Research Institute for Diseases in the Elderly 014-93-015 Robert Dawson Evans Endowment, Department of Medicine, Boston University School of Medicine and Boston Medical Center Royal Swedish Academy of Sciences Sarstedt, Germany Signe and Ane Gyllenberg Foundation Sigrid Juselius Foundation Slottery Machine Association, Finland Social Insurance Institution of Finland South OstroBothnia Hospital District state of Baden-Wurttemberg, Germany Stockholm County Council 560183 Swedish Cultural Foundation, Finland Swedish Diabetes Foundation Swedish e-science Research Center Swedish Foundation for Strategic Research Swedish Heart-Lung Foundation Swedish Research Council SFO EXODIAB 2009-1039 521-2010-3490 521-2007-4037 521-2008-2974 ANDIS 825-2010-5983 LUDC 349-2008-6589 8691 Swedish Society of Medicine Tore Nilsson Foundation Torsten and Ragnar Soderbergs Stiftelser MT33/09 University Hospital Essen University of Tromso University College London NIHR Biomedical Research Centre UK NIHR Cambridge Biomedical Research Centre Uppsala University Uppsala University Hospital Vaasa Hospital District Velux Foundation Wellcome Trust GR072960 076113 083948 090367 090532 083270 086596 098017 095101 098051 098381
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- 2015
16. Mutations in GTPBP3 cause a mitochondrial translation defect associated with hypertrophic cardiomyopathy, lactic acidosis, and encephalopathy
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Rosalba Carrozzo, Abraham Lorber, Kei Murayama, Michal Minczuk, Tom Sante, Björn Menten, Joél Smet, Massimo Zeviani, Dominique Chretien, Marlène Rio, Sarah F. Pearce, Joanna Rorbach, Yoshimi Tokuzawa, Thomas Schwarzmayr, Daniele Ghezzi, Agnès Rötig, Patrick F. Chinnery, Asaad Khoury, Yoshihito Kishita, Ellen Crushell, François Feillet, Enrico Bertini, Peter Freisinger, Robert W. Taylor, Ewen W. Sommerville, Thomas Meitinger, Luc Régal, Arnold Munnich, Thomas Wieland, Thomas Klopstock, Robert Kopajtich, Johannes A. Mayr, Holger Prokisch, Bénédict Mousson de Camaret, Rudy Van Coster, Tim M. Strom, Hanna Mandel, Yasushi Okazaki, Zahra Assouline, Angela Pyle, Arnaud Vanlander, Tobias B. Haack, Masakazu Kohda, Metodi D. Metodiev, Thomas J. Nicholls, Christopher A. Powell, Akira Ohtake, Federica Invernizzi, Klaus Marquard, Eleonora Lamantea, Ann Saada, Helmholtz-Zentrum München (HZM), MRC Mitochondrial Biology Unit, University of Cambridge [UK] (CAM), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Reutlingen University, Rambam Health Care Campus, Department of Pediatric Neurology and Metabolism [Ghent], Ghent University Hospital, Fondazione IRCCS Istituto Neurologico 'Carlo Besta', Dipartimento di Neuroscienze [IRCCS Gesù Roma], IRCCS Ospedale Pediatrico Bambino Gesù [Roma], Wellcome Trust Centre for Mitochondrial Research, Newcastle University [Newcastle]-International Centre for Life-Institute of Genetic Medicine, Klinikum Stuttgart, Department of Metabolism [Chiba], Children's Hospital Chiba, Institute of Human Genetics, Technische Universität München [München] (TUM)-Helmholtz-Zentrum München (HZM)-German Research Center for Environmental Health, Paracelsus Medical University and Universitätsklinikum Salzburg, Department of Genetics and Metabolic Diseases and the Monique and Jacques Roboh Department of Genetic Research, Hadassah Hebrew University Medical Center [Jerusalem], Saitama Medical University, National Centre for Inherited Metabolic Disorders [Dublin], Temple Street Children's University Hospital [Dublin], Saitama University, Service de Génétique Médicale [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP], Nutrition-Génétique et Exposition aux Risques Environnementaux (NGERE), Université de Lorraine (UL)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Médecine Infantile I [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Service des Maladies Héréditaires du Métabolisme, Hospices Civils de Lyon (HCL)-Centre de Biologie et de pathologie Est, Center for Medical Genetics [Ghent], Hôpitaux universitaires de Louvain, German Center for Cardiovascular Research (DZHK), Berlin Institute of Health (BIH), Munich Heart Alliance, Munich Cluster for systems neurology [Munich] (SyNergy), Technische Universität München [München] (TUM)-Ludwig-Maximilians-Universität München (LMU), German Research Center for Neurodegenerative Diseases - Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Friedrich-Baur Institute, Ludwig-Maximilians-Universität München (LMU), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM)-Helmholtz-Zentrum München (HZM)-German Research Center for Environmental Health, CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Centre de Biologie et de pathologie Est-Hospices Civils de Lyon (HCL), and Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM)-Ludwig-Maximilians-Universität München (LMU)
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Male ,Mitochondrial translation ,[SDV]Life Sciences [q-bio] ,Respiratory chain ,medicine.disease_cause ,Consanguinity ,RNA, Transfer ,pathology [Brain] ,Genetics(clinical) ,Child ,metabolism [GTP-Binding Proteins] ,metabolism [RNA, Transfer] ,Genetics (clinical) ,Genetics ,Mutation ,physiopathology [Acidosis, Lactic] ,Brain Diseases ,genetics [Cardiomyopathy, Hypertrophic] ,Lactic ,Respiratory chain complex ,genetics [Brain Diseases] ,Brain ,3. Good health ,Pedigree ,genetics [Acidosis, Lactic] ,Lactic acidosis ,Child, Preschool ,genetics [RNA, Transfer] ,Acidosis, Lactic ,Female ,RNA Interference ,GTPBP3 ,Acidosis ,GTPBP3 protein, human ,Mitochondrial DNA ,genetics [GTP-Binding Proteins] ,Cardiomyopathy ,Molecular Sequence Data ,Biology ,Human mitochondrial genetics ,Cell Line ,GTP-Binding Proteins ,ddc:570 ,Report ,medicine ,Humans ,Amino Acid Sequence ,Preschool ,Protein Processing ,physiopathology [Cardiomyopathy, Hypertrophic] ,Post-Translational ,Infant, Newborn ,Infant ,Cardiomyopathy, Hypertrophic ,Fibroblasts ,medicine.disease ,Newborn ,Transfer ,Protein Biosynthesis ,Sequence Alignment ,Protein Processing, Post-Translational ,Hypertrophic ,physiopathology [Brain Diseases] ,RNA - Abstract
International audience; Respiratory chain deficiencies exhibit a wide variety of clinical phenotypes resulting from defective mitochondrial energy production through oxidative phosphorylation. These defects can be caused by either mutations in the mtDNA or mutations in nuclear genes coding for mitochondrial proteins. The underlying pathomechanisms can affect numerous pathways involved in mitochondrial physiology. By whole-exome and candidate gene sequencing, we identified 11 individuals from 9 families carrying compound heterozygous or homozygous mutations in GTPBP3, encoding the mitochondrial GTP-binding protein 3. Affected individuals from eight out of nine families presented with combined respiratory chain complex deficiencies in skeletal muscle. Mutations in GTPBP3 are associated with a severe mitochondrial translation defect, consistent with the predicted function of the protein in catalyzing the formation of 5-taurinomethyluridine (τm(5)U) in the anticodon wobble position of five mitochondrial tRNAs. All case subjects presented with lactic acidosis and nine developed hypertrophic cardiomyopathy. In contrast to individuals with mutations in MTO1, the protein product of which is predicted to participate in the generation of the same modification, most individuals with GTPBP3 mutations developed neurological symptoms and MRI involvement of thalamus, putamen, and brainstem resembling Leigh syndrome. Our study of a mitochondrial translation disorder points toward the importance of posttranscriptional modification of mitochondrial tRNAs for proper mitochondrial function.
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- 2014
17. Constitutive Activation of PKA Catalytic Subunit in Adrenal Cushing's Syndrome
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Ulrike Zabel, Thomas Wieland, Martin J. Lohse, Fabio R. Faucz, Annalisa Vetro, Andrea Osswald, Guillaume Assié, Cristina L. Ronchi, Thomas Schwarzmayr, Susanne Diener, Caroline Kisker, Bruno Allolio, Tim M. Strom, Silviu Sbiera, Olivia Barreau, Martin Reincke, Delphine Vezzosi, Felix Beuschlein, Jérôme Bertherat, Orsetta Zuffardi, Antonella Forlino, Thomas Meitinger, Martin Fassnacht, Katrin Schaak, Eva Szarek, Constantine A. Stratakis, Anett Schmittfull, Paraskevi Salpea, Davide Calebiro, Marthe Rizk-Rabin, Medizinische Klinik und Poliklinik IV, Ludwig-Maximilians-Universität München (LMU), Department of Medicine I, University Hospital, Institut Cochin (UMR_S567 / UMR 8104), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5), Institute of Pharmacology and Toxicology, Julius-Maximilians-Universität Würzburg [Wurtzbourg, Allemagne] (JMU)-University Hospital of Würzburg-Rudolf Virchow Center for Experimental Biomedicine, Julius-Maximilians-Universität Würzburg [Wurtzbourg, Allemagne] (JMU), Section on Endocrinology and Genetics, National Institutes of Health (NIH)-National Institute of Child Health and Human Development, Comprehensive Cancer Center Mainfranken, Institute of Human Genetics, Helmholtz-Zentrum München (HZM)-Deutsches Forschungszentrum für Gesundheit und Umwelt (GmbH), University Hospital of Würzburg, Technische Universität München [München] (TUM)-German Research Center for Environmental Health-Helmholtz-Zentrum München (HZM), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Department of Molecular Medicine [Pavia, Italy] (Unit of Biochemistry), University of Pavia, Human Genetics, Biologia Generale e Genetica Medica, Università degli Studi di Pavia, Deutsche Forschungsgemeinschaft Research Center for Experimental Biomedicine, Internal Medicine III, Universität Ulm - Ulm University [Ulm, Allemagne], German Center for Cardiovascular Research (DZHK), Berlin Institute of Health (BIH), Medizinische Klinik - Innenstadt, Department of Psychiatry, Ludwig-Maximilians-Universität München, Comprehensive Heart Failure Center, University of Würzburg-University Hospital of Würzburg-Rudolf Virchow Center for Experimental Biomedicine, Endocrine and Diabetes Unit, Institut Cochin ( UMR_S567 / UMR 8104 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Service d'Endocrinologie, Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Cochin [AP-HP]-Centre de Référence pour les Maladies Rares, University of Würzburg, Helmholtz-Zentrum München ( HZM ) -Deutsches Forschungszentrum für Gesundheit und Umwelt (GmbH), Dipartimento di Medicina Molecolare, Biotechnology Research Laboratory, Istituti di Ricovero e Cura a Carattere Scientifico ( IRCCS ) -Fondazione I.R.C.C.S. - Policlinico San Matteo, Deutsches Zentrum für Herz-Kreislauf-Forschung partner site, Munich Heart Alliance, Supported by a grant (FP7/2007-2013) from the European Com - mission Seventh Framework Program under grant agreement 259735 (to Drs. Beuschlein, Fassnacht, Bertherat, and Allolio) and, in part, by grants from the Wilhelm Sander-Stiftung (2012.095.1, to Dr. Allolio), the Else Kröner-Fresenius-Stiftung (2012_A103, to Dr. Reincke), Bundesministerium für Bildung und Forschung (BMBF 01EO1004-D2, to Drs. Fassnacht and Allolio), the COMETE Network (Programme Hospitalier de Recherche Clinique grant AOM95201), the Institut National du Cancer Recherche Transla - tionelle 2009-RT-02, INSERM (with Dr. Assié a recipient of a Contrat d'Interface), the Conny-Maeva Charitable Foundation, the European Research Council (Advanced Grant TOPAS, to Dr. Lohse), the Deutsche Forschungsgemeinschaft (DFG) (Ru - dolf Virchow Center and DFG Research Center for Experimen - tal Biomedicine FZT82, to Drs. Kisker and Lohse, and DFG grant CA1014/1-1, to Dr. Calebiro), the Fondazione Telethon 2010 (GGP10121, to Dr. Zuffardi), and the Intramural Research Pro - gram of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)., Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre de Référence pour les Maladies Rares, Istituti di Ricovero e Cura a Carattere Scientifico (IRCCS)-Fondazione I.R.C.C.S. - Policlinico San Matteo, Julius-Maximilians-Universität Würzburg (JMU)-University Hospital of Würzburg-Rudolf Virchow Center for Experimental Biomedicine, Julius-Maximilians-Universität Würzburg (JMU), Helmholtz Zentrum München = German Research Center for Environmental Health-Deutsches Forschungszentrum für Gesundheit und Umwelt (GmbH), Università degli Studi di Pavia = University of Pavia (UNIPV), Bos, Mireille, Technische Universität München [München] (TUM)-Helmholtz-Zentrum München (HZM)-German Research Center for Environmental Health, and Università di Pavia
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MESH: Adrenal Hyperplasia, Congenital ,MESH: Sequence Analysis, DNA ,Hydrocortisone ,Protein Conformation ,MESH : Adrenal Hyperplasia, Congenital ,MESH : Germ-Line Mutation ,[SDV]Life Sciences [q-bio] ,Adrenal Gland Neoplasms ,MESH: Catalytic Domain ,MESH: Cushing Syndrome ,Cushing syndrome ,0302 clinical medicine ,MESH: Protein Conformation ,Catalytic Domain ,MESH: Germ-Line Mutation ,Exome ,Cushing Syndrome ,Exome sequencing ,MESH : Protein Conformation ,MESH : Cushing Syndrome ,ComputingMilieux_MISCELLANEOUS ,0303 health sciences ,MESH: Exome ,MESH: Middle Aged ,Adrenal cortex ,MESH : Catalytic Domain ,General Medicine ,Middle Aged ,MESH : Adult ,MESH: Hydrocortisone ,3. Good health ,MESH : Cyclic AMP-Dependent Protein Kinases ,medicine.anatomical_structure ,MESH : Mutation ,hormones, hormone substitutes, and hormone antagonists ,medicine.drug ,Adenoma ,Adult ,endocrine system ,MESH: Mutation ,MESH : Adrenal Gland Neoplasms ,Adrenal Gland Neoplasm ,030209 endocrinology & metabolism ,MESH: Cyclic AMP-Dependent Protein Kinases ,[SDV.BC]Life Sciences [q-bio]/Cellular Biology ,Article ,03 medical and health sciences ,[SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology ,medicine ,Humans ,[SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology ,MESH : Middle Aged ,[ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology ,Germ-Line Mutation ,030304 developmental biology ,MESH: Adenoma ,MESH: Humans ,Adrenal Hyperplasia, Congenital ,business.industry ,MESH : Humans ,MESH : Exome ,MESH: Adult ,Sequence Analysis, DNA ,medicine.disease ,Cyclic AMP-Dependent Protein Kinases ,MESH: Adrenal Gland Neoplasms ,PRKACA ,MESH : Adenoma ,Mutation ,Cancer research ,business ,MESH : Hydrocortisone ,MESH : Sequence Analysis, DNA - Abstract
International audience; BACKGROUND: Corticotropin-independent Cushing's syndrome is caused by tumors or hyperplasia of the adrenal cortex. The molecular pathogenesis of cortisol-producing adrenal adenomas is not well understood. METHODS: We performed exome sequencing of tumor-tissue specimens from 10 patients with cortisol-producing adrenal adenomas and evaluated recurrent mutations in candidate genes in an additional 171 patients with adrenocortical tumors. We also performed genomewide copy-number analysis in 35 patients with cortisol-secreting bilateral adrenal hyperplasias. We studied the effects of these genetic defects both clinically and in vitro. RESULTS: Exome sequencing revealed somatic mutations in PRKACA, which encodes the catalytic subunit of cyclic AMP-dependent protein kinase (protein kinase A [PKA]), in 8 of 10 adenomas (c.617A→C in 7 and c.595_596insCAC in 1). Overall, PRKACA somatic mutations were identified in 22 of 59 unilateral adenomas (37%) from patients with overt Cushing's syndrome; these mutations were not detectable in 40 patients with subclinical hypercortisolism or in 82 patients with other adrenal tumors. Among 35 patients with cortisol-producing hyperplasias, 5 (including 2 first-degree relatives) carried a germline copy-number gain (duplication) of the genomic region on chromosome 19 that includes PRKACA. In vitro studies showed impaired inhibition of both PKA catalytic subunit mutants by the PKA regulatory subunit, whereas cells from patients with germline chromosomal gains showed increased protein levels of the PKA catalytic subunit; in both instances, basal PKA activity was increased. CONCLUSIONS: Genetic alterations of the catalytic subunit of PKA were found to be associated with human disease. Germline duplications of this gene resulted in bilateral adrenal hyperplasias, whereas somatic PRKACA mutations resulted in unilateral cortisol-producing adrenal adenomas. (Funded by the European Commission Seventh Framework Program and others.).
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- 2014
18. A regulatory variant in CCR6 is associated with susceptibility to antitopoisomerase-positive systemic sclerosis
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Koumakis, E., Bouaziz, M., Dieude, P., Ruiz, B., Riemekasten, G., Airo, P., Muller Nurasyid, M., Cusi, D., Matucci Cerinic, M., Melchers, I., Salvi, E., Strauch, K., Peters, A., Cuomo, G., Hachulla, E., Diot, E., Hunzelmann, N., Caramaschi, P., Riccieri, Valeria, Distler, J. H., Tarner, I., Avouac, J., Letenneur, L., Amouyel, P., Lambert, J. C., Chiocchia, G., Boileau, C., Allanore, Y., Institut Cochin (IC UM3 (UMR 8104 / U1016)), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), UMR 1152 Statistique et Génome, Institut National de la Recherche Agronomique (INRA), U699, Institut National de la Santé et de la Recherche Médicale (INSERM), Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Leibniz Association, Civil Hospital, Ludwig Maximilians University of Munich, Helmholtz Zentrum für Umweltforschung = Helmholtz Centre for Environmental Research (UFZ), University Hospital, Università degli Studi di Milano [Milano] (UNIMI), Università degli Studi di Firenze = University of Florence [Firenze] (UNIFI), University of Freiburg [Freiburg], Munich Heart Alliance, Munich, Germany, Partenaires INRAE, Helmholtz-Zentrum München (HZM), Università degli studi di Napoli Federico II, Université de Lille, Droit et Santé, University of Cologne, Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome], Justus-Liebig-Universität Gießen (JLU), Kerckhoff clinic, U 897, Epidémiologie des maladies chroniques : impact des interactions gène environnement sur la santé des populations, Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Droit et Santé, Université Paris Descartes - Paris 5 (UPD5), Hôpital Ambroise Paré [AP-HP], Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Actelion, Bayer, GlaxoSmithKline, Bristol-Myers Squibb, UCB, Celgene, JB Therapeutics, Boehringer Ingelheim, Novartis, RuiYi, Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire Statistique et Génome (SG), Institut National de la Recherche Agronomique (INRA)-Université d'Évry-Val-d'Essonne (UEVE)-Centre National de la Recherche Scientifique (CNRS), Ludwig-Maximilians University [Munich] (LMU), Università degli Studi di Milano = University of Milan (UNIMI), Università degli Studi di Firenze = University of Florence (UniFI), Helmholtz Zentrum München = German Research Center for Environmental Health, University of Naples Federico II = Università degli studi di Napoli Federico II, Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome] (UNIROMA), Justus-Liebig-Universität Gießen = Justus Liebig University (JLU), Koumakis, E, Bouaziz, M, Dieudé, P, Ruiz, B, Riemekasten, G, Airo, P, Müller Nurasyid, M, Cusi, D, Matucci Cerinic, M, Melchers, I, Salvi, E, Strauch, K, Peters, A, Cuomo, Giovanna, Hachulla, E, Diot, E, Hunzelmann, N, Caramaschi, P, Riccieri, V, Distler, Jh, Tarner, I, Avouac, J, Letenneur, L, Amouyel, P, Lambert, Jc, Chiocchia, G, Boileau, C, and Allanore, Y.
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Adult ,Male ,Receptors, CCR6 ,Scleroderma, Systemic ,antitopoisomerase ,Genotype ,[SDV]Life Sciences [q-bio] ,Polymorphism, Single Nucleotide ,autoantibodies ,genetic regulatory variant ,systemic sclerosis ,White People ,Systemic sclerosi ,Humans ,Female ,Genetic Predisposition to Disease ,Alleles ,DNA Topoisomerases ,Genetic Association Studies ,Autoantibodies - Abstract
International audience; Objective: Recognition of the well-known pleiotropism of autoimmune genes supports the concept of a shared pathogenesis across autoimmune diseases such as rheumatoid arthritis (RA) and systemic sclerosis (SSc). Studies have reproducibly demonstrated an association between susceptibility to RA and polymorphisms of the CCR6 gene, a surface marker for Th17 cells, and the causal variant was recently identified. The present study was thus undertaken to investigate whether CCR6 polymorphisms could also be associated with susceptibility to SSc. Methods: Twelve tag single-nucleotide polymorphisms (SNPs) of CCR6, including the known RA-associated SNP rs3093023, were genotyped in a total of 2,411 SSc patients and 7,084 healthy individuals from 3 European populations (France, Italy, and Germany). Meta-analyses of the data were performed to assess whether an association exists between CCR6 polymorphisms and susceptibility to SSc or its main subtypes. Direct sequencing of DNA was performed to ascertain whether the functional dinucleotide polymorphism of CCR6 previously identified in RA (CCR6DNP) was also present in SSc. Results: Combined analyses revealed an association between the rs10946216 SNP and SSc susceptibility (odds ratio [OR] 1.13, 95% confidence interval [95% CI] 1.05-1.21, adjusted P [P-adj] = 0.026). The rs3093023 A allele and rs10946216 T allele were in high linkage disequilibrium, and both were found to confer disease susceptibility in the antitopoisomerase-positive subset of SSc patients (OR 1.27, 95% CI 1.13-1.42, P-adj = 1.5 x 10(-3) and OR 1.32, 95% CI 1.17-1.48, P-adj = 9.0 x 10(-5), respectively, relative to healthy controls). Direct sequencing of the DNA of 78 individuals supported the hypothesis that the regulatory dinucleotide CCR6DNP could be the causal variant in SSc. Conclusion: The results of this study establish CCR6 as a new susceptibility factor for antitopoisomerase-positive SSc, as demonstrated in 3 European Caucasian populations, confirming the notion that SSc and RA could conceivably share autoimmune risk alleles. The results also suggest a potential role of the interleukin-17 pathway in SSc.
- Published
- 2013
19. Marine Le Pen mise sur une crise terminale de la droite classique
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Monnot, Caroline, Schneider, Vanessa, Perrineau, Pascal, Sciences Po Institutional Repository, Spire, DZHK site Munich Heart Alliance, Klinikum der Universitat Munchen, Ludwig-Maximilians-Universität München (LMU), Centre de recherches politiques de Sciences Po (Sciences Po, CNRS) (CEVIPOF), and Sciences Po (Sciences Po)-Centre National de la Recherche Scientifique (CNRS)
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[SHS.SCIPO] Humanities and Social Sciences/Political science ,[SHS.SCIPO]Humanities and Social Sciences/Political science - Published
- 2012
20. Mitral valve edge-to-edge repair under scrutiny: what can we learn from transoesophageal echocardiographic follow-up?
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Hausleiter J and Stolz L
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- 2024
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21. Specific calcium deposition on pre-procedural CCTA at the time of percutaneous coronary intervention predicts in-stent restenosis in symptomatic patients.
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Adolf R, Krinke I, Datz J, Cassese S, Kastrati A, Joner M, Schunkert H, Wall W, Hadamitzky M, and Engel LC
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Purpose: To characterize preprocedural coronary atherosclerotic lesions derived from CCTA and assess their association with in-stent restenosis (ISR) after percutaneous coronary intervention (PCI)., Materials and Methods: This retrospective cohort-study included patients who underwent CCTA for suspected coronary artery disease, subsequent index angiography including PCI and surveillance angiography within 6-8 months after the index procedure. We performed a plaque analysis of culprit lesions on CCTA using a dedicated plaque analysis software including assessment of the surrounding pericoronary fat attenuation index (FAI) and compared findings between lesions with and without ISR at surveillance angiography after stenting., Results: Overall 278 coronary lesions in 209 patients were included. Of these lesions, 43 (15.5 %) had ISR at surveillance angiography after stenting while 235 (84.5 %) did not. Likewise, plaque composition such as volume of calcification [129.8 mm
3 (83.3-212.6) vs. 94.4 mm3 (60.4-160.5) p = 0.06] and lipid-rich and fibrous plaque volume [38.4 mm3 (19.4-71.2) vs. 38.0 mm3 (14.0-59.1), p = 0.11 and 50.4 mm3 (26.1-77.6) vs. 42.1 mm3 (31.1-60.3), p = 0.16] between lesion with and without ISR were not statistically significant. However lesions associated with ISR were more eccentric (n = 37, 86.0 % versus n = 159, 67,7 %; p = 0.03) and more frequently demonstrated calcified portions on opposite sides on the vessel wall on cross-sectional datasets (n = 24, 55.8 % versus n = 55, 23.4 %, p = 0.001). FAIlesion was significantly different in lesions with ISR as compared to those without ISR [-76.5 (-80.1 to -73.6) vs. -80.9 (-88.9 to -74.0), p = 0.02]. There was no difference with respect to FAIRCA between the two groups [-77.4 (-81.9 to -75.6) vs. -78.5 (-86.0 to -71.0), p = 0.41]., Conclusion: Coronary lesions associated with ISR at surveillance angiography demonstrated differences in the arrangement of calcified portions as well as an increased lesion-specific pericoronary fat attenuation index at baseline CCTA. This latter finding suggests that perivascular inflammation at baseline may play a major role in the development of in-stent restenosis., Competing Interests: Declaration of competing interest On behalf of the co-authors, I declare that there are no conflicts of interests associated with our manuscript., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)- Published
- 2024
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22. Gpr55 deficiency crucially alters cardiomyocyte homeostasis and counteracts angiotensin II induced maladaption in female mice.
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Schopohl B, Kohlhaas M, Nickel AG, Schiuma AF, Maas SL, van der Vorst EPC, Shia YX, Maack C, Steffens S, and Puhl SL
- Abstract
Background and Purpose: Cannabis stimulates several G-protein-coupled-receptors and causes bradycardia and hypotension upon sustained consumption. Moreover, in vitro studies suggest an interference of cannabinoid-signalling with cardiomyocyte contractility and hypertrophy. We aimed at revealing a functional contribution of the cannabinoid-sensitive receptor GPR55 to cardiomyocyte homeostasis and neurohumorally induced hypertrophy in vivo., Experimental Approach: Gpr55
-/- and wild-type (WT) mice were characterized after 28-day angiotensin II (AngII; 1·μg·kg-1 min-1 ) or vehicle infusion. In isolated adult Gpr55-/- and WT cardiomyocytes, mitochondrial function was assessed under naïve conditions, while cytosolic Ca2+ handling was additionally determined following application of the selective GPR55 antagonist CID16020046., Key Results: Gpr55 deficiency did not affect angiotensin II (AngII) mediated hypertrophic growth, yet, especially in females, it alleviated maladaptive pro-hypertrophic and -inflammatory gene expression and improved inotropy and adrenergic responsiveness compared to WT. In-depth analyses implied increased cytosolic Ca2+ concentrations and transient amplitudes, and accelerated sarcomere contraction kinetics in Gpr55-/- myocytes, which could be mimicked by GPR55 blockade with CID16020046 in female WT cells. Moreover, Gpr55 deficiency up-regulated factors involved in glucose and fatty acid transport independent of the AngII challenge, accelerated basal mitochondrial respiration and reduced basal protein kinase (PK) A, G and C activity and phospholemman (PLM) phosphorylation., Conclusions and Implications: Our study suggests GPR55 as crucial regulator of cardiomyocyte hypertrophy and homeostasis presumably by regulating PKC/PKA-PLM and PKG signalling, and identifies the receptor as potential target to counteract maladaptation, adrenergic desensitization and metabolic shifts as unfavourable features of the hypertrophied heart in females., (© 2024 The Author(s). British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)- Published
- 2024
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23. Left Ventricular Ejection Fraction Change Following Percutaneous Coronary Intervention: Correlates and Association With Prognosis.
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Ndrepepa G, Cassese S, Byrne RA, Bevapi B, Joner M, Sager HB, Kufner S, Xhepa E, Ibrahim T, Laugwitz KL, Schunkert H, and Kastrati A
- Abstract
Background: The association between left ventricular ejection fraction (LVEF) change (ΔLVEF) following percutaneous coronary intervention (PCI) and the long-term mortality rate in patients with coronary artery disease is incompletely investigated. We aimed to assess the impact of PCI on LVEF and the association of ΔLVEF after PCI with the long-term mortality rate., Methods and Results: This observational study included 8181 patients with paired angiographic LVEF measurements performed at baseline and 6 to 8 months following the index PCI. ΔLVEF was defined as LVEF measured on the 6- to 8-month angiography minus LVEF measured on the baseline angiography. LVEF change was classified according to the following categories: reduced (ΔLVEF <0), mildly improved (ΔLVEF >0% to <10%) and largely improved (ΔLVEF ≥10%). The primary outcome was the 5-year mortality rate. In patients with baseline LVEF <40%, 40% to <50% and ≥50%, ΔLVEF (median [25th-75th percentiles]) was 6.0% [0.0% to 14.0%], 4.0% [-1.0% to 11.0%] and 0.0% [-4.0% to 3.0%], respectively ( P <0.001). In patients with reduced, mildly improved, and largely improved ΔLVEF, the 5-year mortality rate (n=712) was 29.1%, 23.1%, and 16.5%, respectively, in patients with baseline LVEF <40%; 17.0%, 12.2% and 9.8%, respectively, in patients with baseline LVEF 40% to <50%; and 7.8%, 7.1%, and 5.6%, respectively, in patients with baseline LVEF ≥50% (adjusted hazard ratio [HR], 0.91 [95% CI, 0.86-0.96]; P <0.001) for all-cause death and adjusted (HR, 0.86 [95% CI, 0.81-0.92]; P <0.001) for cardiac death, calculated for 5% higher ΔLVEF., Conclusions: In patients with coronary artery disease undergoing PCI, improvement of LVEF following PCI was associated with a reduced long-term mortality rate in patients with reduced LVEF but not in patients with preserved LVEF before intervention.
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- 2024
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24. Oxidative stress initiates hemodynamic change in CKD-induced heart disease.
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Sen P, Hamers J, Sittig T, Shashikadze B, d'Ambrosio L, Stöckl JB, Bierschenk S, Zhang H, d'Alessio C, Zandbergen LM, Pauly V, Clauss S, Wolf E, Dendorfer A, Fröhlich T, and Merkus D
- Abstract
Chronic kidney disease (CKD) predisposes to cardiac remodeling and coronary microvascular dysfunction. Studies in swine identified changes in microvascular structure and function, as well as changes in mitochondrial structure and oxidative stress. However, CKD was combined with metabolic derangement, thereby obscuring the contribution of CKD alone. Therefore, we studied the impact of CKD on the heart and combined proteome studies with measurement of cardiac function and perfusion to identify processes involved in cardiac remodeling in CKD. CKD was induced in swine at 10-12 weeks of age while sham-operated swine served as controls. 5-6 months later, left ventricular (LV) function and coronary flow reserve were measured. LC-MS-MS-based proteomic analysis of LV tissue was performed. LV myocardium and kidneys were histologically examined for interstitial fibrosis and oxidative stress. Renal embolization resulted in mild chronic kidney injury (increased fibrosis and urinary NGAL). PV loops showed LV dilation and increased wall stress, while preload recruitable stroke work was impaired in CKD. Quantitative proteomic analysis of LV myocardium and STRING pre-ranked functional analysis showed enrichments in pathways related to contractile function, reactive oxygen species, and extracellular matrix (ECM) remodeling, which were confirmed histologically and associated with impaired total anti-oxidant capacity. H
2 O2 exposure of myocardial slices from CKD, but not normal swine, impaired contractile function. Furthermore, in CKD, mitochondrial proteins were downregulated suggesting mitochondrial dysfunction which was associated with higher basal coronary blood flow. Thus, mild CKD induces alterations in mitochondrial proteins along with contractile proteins, oxidative stress and ECM remodeling, that were associated with changes in cardiac function and perfusion., (© 2024. The Author(s).)- Published
- 2024
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25. Association between Long-Term Exposure to Traffic-Related Air Pollution and Cardio-Metabolic Phenotypes: An MRI Data-Based Analysis.
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Woeckel M, Rospleszcz S, Wolf K, Breitner-Busch S, Ingrisch M, Bamberg F, Ricke J, Schlett CL, Storz C, Schneider A, Stoecklein S, and Peters A
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- Humans, Middle Aged, Female, Male, Air Pollutants, Environmental Exposure, Cross-Sectional Studies, Phenotype, Particulate Matter, Aged, Vehicle Emissions, Magnetic Resonance Imaging, Air Pollution
- Abstract
Long-term exposure to traffic-related air pollution (TRAP) is associated with cardiometabolic disease; however, its role in subclinical stages of disease development is unclear. Thus, we aimed to explore this association in a cross-sectional analysis, with cardiometabolic phenotypes derived from magnetic resonance imaging (MRI). Phenotypes of the left (LV) and right cardiac ventricle, whole-body adipose tissue (AT), and organ-specific AT were obtained by MRI in 400 participants of the KORA cohort. Land-use regression models were used to estimate residential long-term exposures to TRAP, e.g., nitrogen dioxides (NO
2 ) or particle number concentration (PNC). Associations between TRAP and MRI phenotypes were modeled using linear regression. Participants' mean age was 56 ± 9 years, and 42% were female. Long-term exposure to TRAP was associated with decreased LV wall thickness; a 6.0 μg/m3 increase in NO2 was associated with a -1.9% [95% confidence interval: -3.7%; -0.1%] decrease in mean global LV wall thickness. Furthermore, we found associations between TRAP and increased cardiac AT. A 2,242 n/cm3 increase in PNC was associated with a 4.3% [-1.7%; 10.4%] increase in mean total cardiac AT. Associations were more pronounced in women and in participants with diabetes. Our exploratory study indicates that long-term exposure to TRAP is associated with subclinical cardiometabolic disease states, particularly in metabolically vulnerable subgroups.- Published
- 2024
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26. Myeloid cannabinoid CB1 receptor deletion confers atheroprotection in male mice by reducing macrophage proliferation in a sex-dependent manner.
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Wang Y, Li G, Chen B, Shakir G, Volz M, van der Vorst EPC, Maas SL, Geiger M, Jethwa C, Bartelt A, Li Z, Wettich J, Sachs N, Maegdefessel L, Nazari Jahantigh M, Hristov M, Lacy M, Lutz B, Weber C, Herzig S, Guillamat Prats R, and Steffens S
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- Animals, Female, Humans, Male, Aortic Diseases genetics, Aortic Diseases pathology, Aortic Diseases prevention & control, Aortic Diseases metabolism, Aortic Diseases enzymology, Carotid Artery Diseases genetics, Carotid Artery Diseases pathology, Carotid Artery Diseases metabolism, Carotid Artery Diseases prevention & control, Estradiol pharmacology, Estrogen Receptor alpha metabolism, Estrogen Receptor alpha genetics, Estrogen Receptor alpha deficiency, Mice, Inbred C57BL, Mice, Knockout, Phenotype, Sex Factors, Tumor Suppressor Protein p53 metabolism, Tumor Suppressor Protein p53 genetics, Tumor Suppressor Protein p53 deficiency, Atherosclerosis genetics, Atherosclerosis pathology, Atherosclerosis metabolism, Atherosclerosis prevention & control, Atherosclerosis enzymology, Cell Proliferation, Disease Models, Animal, Macrophages metabolism, Macrophages pathology, Plaque, Atherosclerotic, Receptor, Cannabinoid, CB1 metabolism, Receptor, Cannabinoid, CB1 genetics, Signal Transduction
- Abstract
Aims: Although the cannabinoid CB1 receptor has been implicated in atherosclerosis, its cell-specific effects in this disease are not well understood. To address this, we generated a transgenic mouse model to study the role of myeloid CB1 signalling in atherosclerosis., Methods and Results: Here, we report that male mice with myeloid-specific Cnr1 deficiency on atherogenic background developed smaller lesions and necrotic cores than controls, while only minor genotype differences were observed in females. Male Cnr1-deficient mice showed reduced arterial monocyte recruitment and macrophage proliferation with less inflammatory phenotype. The sex-specific differences in proliferation were dependent on oestrogen receptor (ER)α-oestradiol signalling. Kinase activity profiling identified a CB1-dependent regulation of p53 and cyclin-dependent kinases. Transcriptomic profiling further revealed chromatin modifications, mRNA processing, and mitochondrial respiration among the key processes affected by CB1 signalling, which was supported by metabolic flux assays. Chronic administration of the peripherally restricted CB1 antagonist JD5037 inhibited plaque progression and macrophage proliferation, but only in male mice. Finally, CNR1 expression was detectable in human carotid endarterectomy plaques and inversely correlated with proliferation, oxidative metabolism, and inflammatory markers, suggesting a possible implication of CB1-dependent regulation in human pathophysiology., Conclusion: Impaired macrophage CB1 signalling is atheroprotective by limiting their arterial recruitment, proliferation, and inflammatory reprogramming in male mice. The importance of macrophage CB1 signalling appears to be sex-dependent., Competing Interests: Conflict of interest: none declared., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)
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- 2024
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27. Inclisiran administration potently and durably lowers LDL-C over an extended-term follow-up: the ORION-8 trial.
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Wright RS, Raal FJ, Koenig W, Landmesser U, Leiter LA, Vikarunnessa S, Lesogor A, Maheux P, Talloczy Z, Zang X, Schwartz GG, and Ray KK
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- Humans, Male, Middle Aged, Female, Treatment Outcome, Aged, Time Factors, Anticholesteremic Agents adverse effects, Anticholesteremic Agents therapeutic use, Anticholesteremic Agents administration & dosage, Down-Regulation, PCSK9 Inhibitors, Proprotein Convertase 9, RNA, Small Interfering, Cholesterol, LDL blood, Biomarkers blood, Hyperlipoproteinemia Type II blood, Hyperlipoproteinemia Type II drug therapy, Hyperlipoproteinemia Type II diagnosis, Hyperlipoproteinemia Type II genetics
- Abstract
Aims: Data describing the long-term efficacy and tolerability of inclisiran are limited. This was explored in ORION-8, an open-label extension of preceding Phase 2 and Phase 3 placebo-controlled and open-label extension trials., Methods and Results: Following completion of the parent trial, adult patients with atherosclerotic cardiovascular disease (ASCVD), ASCVD risk equivalent, or heterozygous familial hypercholesterolaemia received open-label inclisiran twice yearly (after initial and 3-month doses) until Day 990, followed by an end-of-study visit at Day 1080 or ≥ 90 days after the last dose. The study endpoints included the proportion of patients achieving pre-specified low-density lipoprotein cholesterol (LDL-C) goals [ASCVD: < 1.8 mmol/L (< 70 mg/dL); ASCVD risk equivalent: < 2.6 mmol/L (< 100 mg/dL)], percentage and absolute changes in LDL-C at end-of-study, and safety of inclisiran. Of 3274 patients, 2446 (74.7%) were followed until end-of-study. Mean age was 64.9 ± 9.9 years, 82.7% (n = 2709) had ASCVD, and mean baseline LDL-C was 2.9 ± 1.2 mmol/L. Mean cumulative exposure to inclisiran (including parent trials) was 3.7 years; maximum exposure was 6.8 years. With inclisiran, 78.4% [95% confidence interval (CI): 76.8, 80.0] of patients achieved pre-specified LDL-C goals and mean percentage change in LDL-C was -49.4% (95% CI: -50.4, -48.3). No attenuation of LDL-C lowering over time was observed. Treatment-emergent adverse events at injection site (all mild/moderate) occurred in 5.9% of the patients. Inclisiran-associated anti-drug antibodies were infrequent (5.5%) and had no impact on the efficacy or safety of inclisiran. No new safety signals were identified., Conclusion: In the largest and longest follow-up to date with >12 000 patient-years exposure, inclisiran demonstrated consistent and effective LDL-C lowering with a favourable long-term safety and tolerability profile., Trial Registration Number: ClinicalTrials.gov identifier: NCT03814187., Competing Interests: Conflict of interest: R.S.W. reports receiving advisory board fees from Boehringer Ingelheim and past fees for consulting on lipid issues with The Medicines Company; F.J.R. reports receiving advisory board fees and lecture fees from Amgen, Sanofi-Aventis, Regeneron Pharmaceuticals, Novartis, and LIB Therapeutics; W.K. reports receiving consulting fees and lecture fees from AstraZeneca, Novartis, and Amgen; consulting fees from Pfizer, The Medicines Company, Novartis, DalCor Pharmaceuticals, Kowa, Corvidia Therapeutics, Esperion, Genentech, OMEICOS, Novo Nordisk, LIB Therapeutics, Daiichi Sankyo, New Amsterdam Pharma, and TenSixteen Bio; lecture fees from Berlin-Chemie, Bristol-Myers Squibb, and Sanofi; and grant support and provision of reagents from Singulex, Abbott, Roche Diagnostics, and Dr Beckmann Pharma; U.L. reports receiving grant support from Amgen, Bayer, and Novartis and advisory board fee from Novartis; L.A.L. reports grant support paid to his institution and advisory board fees and fees for CME from Amgen and Novartis; grant support paid to his institution and fees for serving on a steering committee from Kowa, The Medicines Company and Novartis; and advisory board fees and fees for CME from Amarin, AstraZeneca, HLS, Merck, New Amsterdam, Pfizer, and Sanofi; G.G.S. reports receiving research support paid to his institution from AstraZeneca, Sanofi, Silence Therapeutics, and The Medicines Company and a patent (62/806313) on a method for reducing cardiovascular risk assigned in full to the University of Colorado; K.K.R. reports receiving support from the National Institute for Health Research (NIHR) Imperial Biomedical Research Centre; his institution (Imperial College London) receives support from the NIHR Applied Research Collaboration Northwest London. K.K.R. also reports receiving lecture fees from Aegerion Pharmaceuticals, Kowa, Cipla, Algorithm, and Zuelling Pharma; grant support paid to his institution; lecture fees and advisory board fees from Amgen, Regeneron Pharmaceuticals/Sanofi, and Pfizer; lecture fees and fees for serving on steering committees for trials from AstraZeneca and Eli Lilly; fees for serving on steering committees for trials from Cerenis Therapeutics, The Medicines Company, and Esperion; advisory board fees from Akcea Therapeutics, Novartis, Silence Therapeutics, Bayer, and Daiichi Sankyo; lecture fees and advisory board fees from Takeda, Boehringer Ingelheim, and Dr Reddy’s Laboratories; grant support and advisory board fees from Merck Sharp & Dohme; fees for serving on a clinical events adjudication committee from AbbVie; and fees for serving as principal investigator for a trial from Resverlogix; Z.T., S.V., and X.Z. are all employees of Novartis Pharmaceuticals Corp, East Hanover, New Jersey, USA and hold shares in Novartis; A.L. is employee of Novartis Pharma AG, Basel, Switzerland; P.M. was an employee of Novartis Pharma AG, Basel, Switzerland, at the time of conducting this study., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)
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- 2024
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28. The DanGer Shock trial: a new dawn but much to uncover.
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Lüsebrink E, Binzenhöfer L, and Thiele H
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- Humans, Shock, Cardiogenic therapy, Randomized Controlled Trials as Topic
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- 2024
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29. Cardiac troponin elevation and mortality in takotsubo syndrome: New insights from the international takotsubo registry.
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Stähli BE, Schindler M, Schweiger V, Cammann VL, Szawan KA, Niederseer D, Würdinger M, Schönberger A, Schönberger M, Koleva I, Mercier JC, Petkova V, Mayer S, Citro R, Vecchione C, Bossone E, Gili S, Neuhaus M, Franke J, Meder B, Jaguszewski M, Noutsias M, Knorr M, Jansen T, D'Ascenzo F, Dichtl W, von Lewinski D, Burgdorf C, Kherad B, Tschöpe C, Sarcon A, Shinbane J, Rajan L, Michels G, Pfister R, Cuneo A, Jacobshagen C, Karakas M, Koenig W, Pott A, Meyer P, Roffi M, Banning A, Wolfrum M, Cuculi F, Kobza R, Fischer TA, Vasankari T, Airaksinen KEJ, Napp LC, Dworakowski R, MacCarthy P, Kaiser C, Osswald S, Galiuto L, Chan C, Bridgman P, Beug D, Delmas C, Lairez O, Gilyarova E, Shilova A, Gilyarov M, El-Battrawy I, Akin I, Poledniková K, Toušek P, Winchester DE, Massoomi M, Galuszka J, Ukena C, Poglajen G, Carrilho-Ferreira P, Hauck C, Paolini C, Bilato C, Kobayashi Y, Kato K, Ishibashi I, Himi T, Din J, Al-Shammari A, Prasad A, Rihal CS, Liu K, Schulze PC, Bianco M, Jörg L, Rickli H, Pestana G, Nguyen TH, Böhm M, Maier LS, Pinto FJ, Widimský P, Felix SB, Braun-Dullaeus RC, Rottbauer W, Hasenfuß G, Pieske BM, Schunkert H, Budnik M, Opolski G, Thiele H, Bauersachs J, Horowitz JD, Di Mario C, Kong W, Dalakoti M, Imori Y, Liberale L, Montecucco F, Münzel T, Crea F, Lüscher TF, Bax JJ, Ruschitzka F, Ghadri JR, Di Vece D, and Templin C
- Abstract
Background: The clinical relevance of cardiac troponin (cTn) elevation in takotsubo syndrome (TTS) remains uncertain. The present study sought to investigate the role of cardiac troponin (cTn) elevations in mortality prediction of patients with Takotsubo syndrome (TTS)., Methods: Patients enrolled in the International Takotsubo (InterTAK) Registry from January 2011 to February 2020 with available data on peak cTn levels were included in the analysis. Peak cTn levels during the index hospitalization were used to define clinically relevant myocardial injury. The threshold at which clinically relevant myocardial injury drives mortality at 1 year was identified using restricted cubic spline analysis., Results: Out of 2'938 patients, 222 (7.6%) patients died during 1-year follow-up. A more than 28.8-fold increase of cTn above the upper reference limit was identified as threshold for clinically relevant myocardial injury. The presence of clinically relevant myocardial injury was significantly associated with an increased risk of mortality at 5 years (adjusted HR 1.58, 95% CI 1.18-2.12, p =.002). Clinically relevant myocardial injury was related to an increased 5-year mortality risk in patients with apical TTS (adjusted HR 1.57, 95% CI 1.21-2.03, p =.001), in presence of physical stressors (adjusted HR 1.60, 95% CI 1.22-2.11, p =.001), and in absence of emotional stressors (adjusted HR 1.49, 95% CI, 1.17-1.89, p =.001)., Conclusion: This study for the first time determined a troponin threshold for the identification of TTS patients at excess risk of mortality. These findings advance risk stratification in TTS and assist in identifying patients in need for close monitoring and follow-up., (© 2024 Stichting European Society for Clinical Investigation Journal Foundation. Published by John Wiley & Sons Ltd.)
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- 2024
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30. Associations of Circulating ANGPTL3, C-Terminal Domain-Containing ANGPTL4, and ANGPTL3/8 and ANGPTL4/8 Complexes with LPL Activity, Diabetes, Inflammation, and Cardiovascular Mortality.
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Silbernagel G, Chen YQ, Li H, Lemen D, Wen Y, Zhen EY, Rief M, Kleber ME, Delgado G, Sarzynski MA, Qian YW, Schmidt B, Erbel R, Trampisch U, Moissl AP, Rudolf H, Schunkert H, Stang A, März W, Trampisch HJ, Scharnagl H, and Konrad RJ
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Background: ANGPTL3/4/8 (angiopoietin-like proteins 3, 4, and 8) are important regulators of LPL (lipoprotein lipase). ANGPTL8 forms complexes with ANGPTL3 and ANGPTL4. ANGPTL4/8 complex formation converts ANGPTL4 from a furin substrate to a plasmin substrate, and both cleavages generate similar C-terminal domain-containing (CD)-ANGPTL4 fragments. Whereas several studies have investigated associations of free ANGPTL proteins with cardiovascular risk, there are no data describing associations of the complexes and CD-ANGPTL4 with outcomes or describing the effects of the complexes on LPL bound to GPIHBP1 (glycosylphosphatidylinositol HDL-binding protein 1)., Methods: Recombinant protein assays were used to study ANGPTL protein and complex effects on GPIHBP1-LPL activity. ANGPTL3/8, ANGPTL3, ANGPTL4/8, and CD-ANGPTL4 were measured with dedicated immunoassays in 2394 LURIC (Ludwigshafen Risk and Cardiovascular Health) study participants undergoing coronary angiography and 6188 getABI study (German Epidemiological Trial on Ankle Brachial Index) participants undergoing ankle brachial index measurement. There was a follow-up for cardiovascular death with a median (interquartile range) duration of 9.80 (8.75-10.40) years in the LURIC study and 7.06 (7.00-7.14) years in the getABI study., Results: ANGPTL3/8 potently inhibited GPIHBP1-LPL activity and showed positive associations with LDL-C (low-density lipoprotein cholesterol) and triglycerides (both P <0.001). However, in neither study did ANGPTL3/8 correlate with cardiovascular death. Free ANGPTL3 was positively associated with cardiovascular death in the getABI study but not the LURIC study. ANGPTL4/8 and especially CD-ANGPTL4 were positively associated with the prevalence of diabetes, CRP (C-reactive protein; all P <0.001), and cardiovascular death in both studies. In the LURIC and getABI studies, respective hazard ratios for cardiovascular mortality comparing the third with the first ANGPTL4/8 tertile were 1.47 (1.15-1.88) and 1.68 (1.25-2.27) when adjusted for sex, age, body mass index, and diabetes. For CD-ANGPTL4, these hazard ratios were 2.44 (1.86-3.20) and 2.76 (2.00-3.82)., Conclusions: ANGPTL3/8 potently inhibited GPIHBP1-LPL enzymatic activity, consistent with its positive association with serum lipids. However, ANGPTL3/8, LDL-C, and triglyceride levels were not associated with cardiovascular death in the LURIC and getABI cohorts. In contrast, concentrations of ANGPTL4/8 and particularly CD-ANGPTL4 were positively associated with inflammation, the prevalence of diabetes, and cardiovascular mortality.
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- 2024
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31. [Cardiovascular prevention in Saxony-Anhalt : Necessity and new perspectives].
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Müller P, Herzog M, Duderstadt Y, Kunz M, Lechner K, Meyer F, Schmeißer A, Meißler S, Ahrens D, Neumann K, Mattern H, Speck O, Behme D, Dunay IR, Seeland U, Schreiber S, and Braun-Dullaeus R
- Abstract
Cardiovascular risk factors (high blood pressure, smoking, overweight, type 2 diabetes, dyslipidemia, physical inactivity) substantially rise with increasing age, particularly after middle age, whereby women are affected to a much greater extent. In the population of Saxony-Anhalt the prevalence of cardiovascular risk factors is clearly increased and the population structure in Saxony-Anhalt is particularly characterized by a high average age as well as high morbidity and mortality rates due to cardiovascular diseases. Saxony-Anhalt therefore provides a model character for the demographic development in Europe. This review article discusses strategies for the implementation of target group-specific cardiovascular preventive strategies in the Federal State of Saxony-Anhalt with special consideration of age and sex. When preventive medicine facilities are established and innovative treatment possibilities for patients with cardiovascular risks are created, prevention should also become available in rural areas., (© 2024. The Author(s).)
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- 2024
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32. Prediction of individual lifetime cardiovascular risk and potential treatment benefit: development and recalibration of the LIFE-CVD2 model to four European risk regions.
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Hageman SHJ, Kaptoge S, de Vries TI, Lu W, Kist JM, van Os HJA, Numans ME, Läll K, Bobak M, Pikhart H, Kubinova R, Malyutina S, Pająk A, Tamosiunas A, Erbel R, Stang A, Schmidt B, Schramm S, Bolton TR, Spackman S, Bakker SJL, Blaha M, Boer JMA, Bonnefond A, Brenner H, Brunner EJ, Cook NR, Davidson K, Dennison E, Donfrancesco C, Dörr M, Floyd JS, Ford I, Fu M, Gansevoort RT, Giampaoli S, Gillum RF, Gómez-de-la-Cámara A, Håheim LL, Hansson PO, Harms P, Humphries SE, Ikram MK, Jukema JW, Kavousi M, Kiechl S, Kucharska-Newton A, Pablos DL, Matsushita K, Meyer HE, Moons KGM, Mortensen MB, Muilwijk M, Nordestgaard BG, Packard C, Pamieri L, Panagiotakos D, Peters A, Potier L, Providencia R, Psaty BM, Ridker PM, Rodriguez B, Rosengren A, Sattar N, Schöttker B, Schwartz JE, Shea S, Shipley MJ, Sofat R, Thorand B, Verschuren WMM, Völzke H, Wareham NJ, Westbury L, Willeit P, Zhou B, Danesh J, Visseren FLJ, Di Angelantonio E, Pennells L, and Dorresteijn JAN
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- Humans, Risk Assessment, Female, Male, Europe epidemiology, Middle Aged, Aged, Adult, Time Factors, Decision Support Techniques, Prognosis, Risk Factors, Cardiovascular Diseases prevention & control, Cardiovascular Diseases epidemiology, Heart Disease Risk Factors
- Abstract
Aims: The 2021 European Society of Cardiology prevention guidelines recommend the use of (lifetime) risk prediction models to aid decisions regarding initiation of prevention. We aimed to update and systematically recalibrate the LIFEtime-perspective CardioVascular Disease (LIFE-CVD) model to four European risk regions for the estimation of lifetime CVD risk for apparently healthy individuals., Methods and Results: The updated LIFE-CVD (i.e. LIFE-CVD2) models were derived using individual participant data from 44 cohorts in 13 countries (687 135 individuals without established CVD, 30 939 CVD events in median 10.7 years of follow-up). LIFE-CVD2 uses sex-specific functions to estimate the lifetime risk of fatal and non-fatal CVD events with adjustment for the competing risk of non-CVD death and is systematically recalibrated to four distinct European risk regions. The updated models showed good discrimination in external validation among 1 657 707 individuals (61 311 CVD events) from eight additional European cohorts in seven countries, with a pooled C-index of 0.795 (95% confidence interval 0.767-0.822). Predicted and observed CVD event risks were well calibrated in population-wide electronic health records data in the UK (Clinical Practice Research Datalink) and the Netherlands (Extramural LUMC Academic Network). When using LIFE-CVD2 to estimate potential gain in CVD-free life expectancy from preventive therapy, projections varied by risk region reflecting important regional differences in absolute lifetime risk. For example, a 50-year-old smoking woman with a systolic blood pressure (SBP) of 140 mmHg was estimated to gain 0.9 years in the low-risk region vs. 1.6 years in the very high-risk region from lifelong 10 mmHg SBP reduction. The benefit of smoking cessation for this individual ranged from 3.6 years in the low-risk region to 4.8 years in the very high-risk region., Conclusion: By taking into account geographical differences in CVD incidence using contemporary representative data sources, the recalibrated LIFE-CVD2 model provides a more accurate tool for the prediction of lifetime risk and CVD-free life expectancy for individuals without previous CVD, facilitating shared decision-making for cardiovascular prevention as recommended by 2021 European guidelines., Competing Interests: Conflict of interest: Due to the very long author list, these will be provided per author using ICMJE forms at the revision stage, if applicable., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)
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- 2024
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33. Activating the NFE2L1-ubiquitin-proteasome system by DDI2 protects from ferroptosis.
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Ofoghi A, Kotschi S, Lemmer IL, Haas DT, Willemsen N, Bayer B, Jung AS, Möller S, Haberecht-Müller S, Krüger E, Krahmer N, and Bartelt A
- Abstract
Ferroptosis is an iron-dependent, non-apoptotic form of cell death initiated by oxidative stress and lipid peroxidation. Recent evidence has linked ferroptosis to the action of the transcription factor Nuclear factor erythroid-2 derived,-like-1 (NFE2L1). NFE2L1 regulates proteasome abundance in an adaptive fashion, maintaining protein quality control to secure cellular homeostasis, but the regulation of NFE2L1 during ferroptosis and the role of the ubiquitin-proteasome system (UPS) herein are still unclear. In the present study, using an unbiased proteomic approach charting the specific ubiquitylation sites, we show that induction of ferroptosis leads to recalibration of the UPS. RSL3-induced ferroptosis inhibits proteasome activity and leads to global hyperubiquitylation, which is linked to NFE2L1 activation. As NFE2L1 resides in the endoplasmic reticulum tethered to the membrane, it undergoes complex posttranslational modification steps to become active and induce the expression of proteasome subunit genes. We show that proteolytic cleavage of NFE2L1 by the aspartyl protease DNA-damage inducible 1 homolog 2 (DDI2) is a critical step for the ferroptosis-induced feed-back loop of proteasome function. Cells lacking DDI2 cannot activate NFE2L1 in response to RSL3 and show global hyperubiquitylation. Genetic or chemical induction of ferroptosis in cells with a disrupted DDI2-NFE2L1 pathway diminishes proteasomal activity and promotes cell death. Also, treating cells with the clinical drug nelfinavir, which inhibits DDI2, sensitized cells to ferroptosis. In conclusion, our results provide new insight into the importance of the UPS in ferroptosis and highlight the role of the DDI2-NFE2L1 as a potential therapeutic target. Manipulating DDI2-NFE2L1 activity through chemical inhibition might help sensitizing cells to ferroptosis, thus enhancing existing cancer therapies., (© 2024. The Author(s).)
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- 2024
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34. Mex3a Protects Against Atherosclerosis: Evidence From Mice and Humans.
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Santovito D, Henderson JM, Bidzhekov K, Triantafyllidou V, Jansen Y, Chen Z, Farina FM, Diagel A, Aslani M, Blanchet X, Schunkert H, Megens RTA, Döring Y, Sattler M, and Weber C
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- Animals, Humans, Mice, Mice, Knockout, Atherosclerosis prevention & control, RNA-Binding Proteins genetics, RNA-Binding Proteins metabolism
- Abstract
Competing Interests: None.
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- 2024
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35. Real-world experience in initiation of treatment with the selective cardiomyosin inhibitor mavacamten in an outpatient clinic cohort during the 12-week titration period.
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Becker F, Novotny J, Jansen N, Clauß S, Möller-Dyrna F, Specht B, Orban M, Massberg S, Kääb S, and Reichart D
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Introduction: Lately, mavacamten emerged as a new therapeutic option for symptomatic patients with obstructive hypertrophic cardiomyopathy (oHCM). Clinical trials revealed reduction of serum biomarkers, and left ventricular outflow tract (LVOT) obstruction, as well as an improvement in clinical symptoms and exercise capacity. Nevertheless, clinical experience and manageability of patients in a real-world setting is still lacking., Material and Methods: 22 patients with symptomatic oHCM (54.5% male, age 58.5 ± 16.2 years) and elevated LVOT gradients were started on mavacamten between March 2023 and June 2024. All patients were New York Heart Association (NYHA) class II or higher. Seven patients were excluded from primary analysis due to comedication with Angiotensin-converting-enzyme-inhibitors or Angiotensin-II receptor blockers. Cardiac imaging, laboratory work-up and clinical evaluation were assessed at three visits during the 12 weeks initiation phase; Dosing of mavacamten was adjusted according to manufacturer's recommendations., Results: At 12 weeks, the majority of patients described a significant improvement of their quality of life. Work-up at 12 weeks revealed a significant reduction of serum biomarkers and LVOT gradients. In four patients, mavacamten needed to be temporarily paused due to clinical complaints or transient left ventricular ejection fraction deterioration below 50% with subsequent full recovery., Conclusion: We provide first insights into the usage of mavacamten in oHCM patients during the titration period in a real-world setting. Clinical findings are in line with previous clinical trials. In accordance with current recommendations, we highlight the need for standardized follow-up of patients on mavacamten treatment., (© 2024. The Author(s).)
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- 2024
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36. A Prospective, Randomized Trial of Bioresorbable Polymer Drug-Eluting Stents versus Fully Bioresorbable Scaffolds in Patients Undergoing Coronary Stenting.
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Wiebe J, Byrne RA, Bradaric C, Kuna C, Kessler T, Pfleiderer M, Kufner S, Xhepa E, Hoppmann P, Joner M, Schunkert H, Laugwitz KL, Kastrati A, and Cassese S
- Abstract
Background: The performance of an everolimus-eluting bioresorbable scaffold (BRS) was inferior to an everolimus-eluting metallic drug-eluting stent (DES) with permanent polymer, mainly due the mechanical features of BRS technology. The performance of BRS as compared to metallic DES with bioresorbable polymers remains unstudied. Methods: This prospective, randomized, multicenter, clinical trial enrolled patients who underwent coronary stenting for de novo coronary lesions. Patients were randomly assigned to bioresorbable polymer everolimus-eluting stents (BP-EES) or everolimus-eluting BRS. The primary endpoint was percentage diameter stenosis (in-device) at 6- to 8-month angiographic surveillance. The main secondary endpoint was the device-oriented composite endpoint (DOCE) of cardiac death/target vessel-myocardial infarction/target lesion revascularization assessed after 12 months and 5 years. Results: The trial was prematurely terminated after the enrollment of 117 of 230 patients (BP-EES, n = 60; BRS, n = 57) due to safety issues associated with BRS technology. The primary endpoint of in-device diameter stenosis at angiographic surveillance was 12.5 ± 7.7% with BP-EES versus 19.3 ± 16.5% with BRS ( p = 0.01). The DOCE occurred in 5.0% in the BP-EES group versus 12.3% of patients in the BRS group (hazard ratio [HR] 2.48, 95% confidence interval [CI] 0.64-9.58, p = 0.19) after 12 months and in 11.7% in the BP-EES group versus 26.4% of patients in the BRS group (HR 2.38, 95% CI 0.97-5.84, p = 0.06) after 5 years. Conclusions: BP-EES showed superior mid-term angiographic performance compared with BRS. Clinical event rates did not differ significantly between the groups up to 5 years of follow-up. These results should be interpreted with caution in view of the premature discontinuation of the study.
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- 2024
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37. Non-Hotspot PIK3CA Variants Have Higher Variant Allele Frequency and are More Common in Syndromic Vascular Malformations.
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Andreoti TA, Maiolo M, Tuleja A, Döring Y, Schaller A, Vassella E, Boon LM, Baumgartner I, Bernhard SM, Zweier C, Vikkula M, and Rössler J
- Abstract
PIK3CA variants are known to cause vascular malformations. We were interested in studying the phenotypic spectrum, the location within the PIK3CA gene, and the variant allele frequency (VAF) of somatic PI3KCA variants in vascular malformations. Clinical data of consecutive patients with extracranial/extraspinal vascular malformations were collected in the context of the VASCOM cohort (2008-2022, n = 558). Starting October 2020, biopsy samples were tested with the TSO500 gene panel (Illumina). All consenting patients with PIK3CA variants were included in this study. Eighty-nine patients had available genetic results by June 2022. PIK3CA variants (n = 25) were found in 16 simple/combined (nonsyndromic) vascular malformations and in nine vascular malformations associated with other anomalies (syndromic). Four hotspot variants in exons 9 and 20 (c.1624G>A, c.1633G>A, c.3140A>G, c.3140A>T) were identified in 16/25 patients (VAF 0.9%-9.7%). Six non-hotspot variants (c.328_330del, c.323_337del, c.353G>A, c.1258T>C, c.3132T>A, c.3195_3203delinsT) were detected in nine patients (VAF 3.6%-31.7%). Non-hotspot variants were more frequent in syndromic than nonsyndromic vascular malformations (p = 0.0034) and exhibited a higher VAF than hotspot variants (p = 0.0253). Our study contributes to the growing body of knowledge of the genetic background in vascular malformations. Further studies will enrich the ever-growing list of pathogenic PIK3CA variants associated with vascular malformations., (© 2024 The Author(s). American Journal of Medical Genetics Part A published by Wiley Periodicals LLC.)
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- 2024
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38. Effects of epileptic seizures on the quality of biosignals recorded from wearables.
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Böttcher S, Zabler N, Jackson M, Bruno E, Biondi A, Epitashvili N, Vieluf S, Dümpelmann M, Richardson MP, Brinkmann BH, Loddenkemper T, and Schulze-Bonhage A
- Abstract
Objective: Wearable nonelectroencephalographic biosignal recordings captured from the wrist offer enormous potential for seizure monitoring. However, signal quality remains a challenging factor affecting data reliability. Models trained for seizure detection depend on the quality of recordings in peri-ictal periods in performing a feature-based separation of ictal periods from interictal periods. Thus, this study aims to investigate the effect of epileptic seizures on signal quality, ensuring accurate and reliable monitoring., Methods: This study assesses the signal quality of wearable data during peri-ictal phases of generalized tonic-clonic and focal to bilateral tonic-clonic seizures (TCS), focal motor seizures (FMS), and focal nonmotor seizures (FNMS). We evaluated accelerometer (ACC) activity and the signal quality of electrodermal activity (EDA) and blood volume pulse (BVP) data. Additionally, we analyzed the influence of peri-ictal movements as assessed by ACC (ACC activity) on signal quality and examined intraictal subphases of focal to bilateral TCS., Results: We analyzed 386 seizures from 111 individuals in three international epilepsy monitoring units. BVP signal quality and ACC activity levels differed between all seizure types. We found the largest decrease in BVP signal quality and increase in ACC activity when comparing the ictal phase to the pre- and postictal phases for TCS. Additionally, ACC activity was strongly negatively correlated with BVP signal quality for TCS and FMS, and weakly for FNMS. Intraictal analysis revealed that tonic and clonic subphases have the lowest BVP signal quality and the highest ACC activity., Significance: Motor elements of seizures significantly impair BVP signal quality, but do not have significant effect on EDA signal quality, as assessed by wrist-worn wearables. The results underscore the importance of signal quality assessment methods and careful selection of robust modalities to ensure reliable seizure detection. Future research is needed to explain whether seizure detection models' decisions are based on signal responses induced by physiological processes as opposed to artifacts., (© 2024 The Author(s). Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)
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- 2024
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39. Baseline Platelet Count Predicts Infarct Size and Mortality after Acute Myocardial Infarction.
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Dutsch A, Graesser C, Novacek S, Krefting J, Schories V, Niedermeier B, Voll F, Kufner S, Xhepa E, Joner M, Cassese S, Schunkert H, Ndrepepa G, Kastrati A, Kessler T, and Sager HB
- Abstract
Introduction: Platelets greatly contribute to cardiovascular diseases. We sought to explore the association of platelet counts with infarct size and outcome in patients presenting with acute ST-segment elevation MI (STEMI) treated with primary percutaneous coronary intervention (PPCI)., Methods and Results: In this retrospective study, we grouped 1,198 STEMI patients into tertiles (T) based on platelet count on admission: T1 = 102-206 [10
9 platelets/L] ( n = 402), T2 = 207-259 [109 platelets/L] ( n = 396), and T3 = 260-921 [109 platelets/L] ( n = 400). Primary endpoint was 1-year all-cause mortality. Patients with highest platelet counts on admission showed the greatest area at risk and infarct size: area at risk (median) was 22.0% (interquartile range [IQR]: 12.0-39.8%) in T1, 21.0% (IQR: 11.0-37.1%) in T2, and 26.0% (IQR: 14.9-45.0%) of the left ventricle in T3 ( p = 0.003); final infarct sizes after 7 to 14 days were as follows: 10.0% (IQR: 2.0-21.0%) in T1, 9.0% (IQR: 2.0-20.7%) in T2, and 12.0% (IQR: 3.0-27.3%) of the left ventricle in T3 ( p = 0.015) as serial imaging revealed. At 1 year, 16 all-cause deaths occurred in T1, 5 in T2, and 22 in T3 (log-rank test, p = 0.006). After adjustment, T1 and T3 were associated with all-cause 1-year mortality (T1: hazard ratio [HR] = 3.40, 95% confidence interval [CI] = 1.23-9.54, p = 0.02; T3: HR = 3.55, 95% CI = 1.23-9.78, p = 0.01) compared with T2. At 5 years, all-cause mortality remained numerically higher in the T1 and T3., Conclusions: In patients with STEMI undergoing PPCI, low and high blood platelet levels on admission were associated with increased long-term mortality (Fig. 1)., Competing Interests: None declared., (Thieme. All rights reserved.)- Published
- 2024
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40. Acute Alcohol Consumption and Arrhythmias in Young Adults: The MunichBREW II Study.
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Brunner S, Krewitz C, Winter R, von Falkenhausen AS, Kern A, Brunner D, and Sinner MF
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Background: and aims: Acute excessive alcohol intake may cause the holiday heart syndrome, characterized by cardiac arrhythmias including atrial fibrillation. Since underlying data are scarce, the study aimed to prospectively investigate the temporal course of occurring cardiac arrhythmias following binge drinking in young adults., Methods: A total of 202 volunteers planning acute alcohol consumption with expected peak breath alcohol concentrations (BAC) of ≥1.2 g/kg were enrolled. The study comprised 48-hour electrocardiogram (ECG) monitoring covering baseline (hour 0), 'drinking period' (hours 1-5), 'recovery period' (hours 6-19), and two control periods corresponding to 24 hours after the 'drinking' and 'recovery periods', respectively. Acute alcohol intake was monitored by BAC measurements during the 'drinking period'. ECGs were analyzed for mean heart rate, atrial tachycardia, premature atrial complexes (PAC), premature ventricular complexes (PVC), and heart rate variability (HRV) measures., Results: Data revealed an increase in heart rate and an excess of atrial tachycardias with increasing alcohol intake. HRV analysis indicated an autonomic modulation with sympathetic activation during alcohol consumption and the subsequent 'recovery period', followed by parasympathetic predominance thereafter. PACs occurred significantly more frequently in the 'control periods', whereas PVCs were more frequent in the 'drinking period'. Ten participants experienced notable arrhythmic episodes, including atrial fibrillation and ventricular tachycardias, primarily during the 'recovery period'., Conclusions: The study demonstrates the impact of binge drinking on heart rate alterations and increased atrial tachycardias during 'drinking period', and the occurrence of clinically relevant arrythmias during the 'recovery period', emphasizing the holiday heart syndrome as a health concern., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)
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- 2024
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41. 4D-Flow MRI and Vector Ultrasound in the In-Vitro Evaluation of Surgical Aortic Heart Valves - a Pilot Study.
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Stephan H, Grefen L, Clevert D, Onkes M, Ning J, Thierfelder N, Mela P, Hagl C, Curta A, and Grab M
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Introduction: The aim of this study was the initial investigation of 4D-Flow MRI and Vector Ultrasound as novel imaging techniques in the in-vitro analysis of hemodynamics in anatomical models. Specifically, by looking at the hemodynamic performance of state-of-the-art surgical heart valves in a 3D-printed aortic arch., Methods: The mock circulatory loop simulated physiological, pulsatile flow. Two mechanical and three biological aortic valves prostheses were compared in a 3D-printed aortic arch. 4D magnetic resonance imaging and vector flow Doppler ultrasound served as imaging methods. Hemodynamic parameters such as wall shear stress, flow velocities and pressure gradients were analyzed., Results: The flow analysis revealed characteristic flow-patterns in the 3D-printed aortic arch. The blood-flow in the arch presented complex patterns, including the formation of helixes and vortices. Higher proximal peak velocities and lower flow volumes were found for biological valves., Conclusion: The mock circulatory loop in combination with modern radiological imaging provides a sufficient basis for the hemodynamic comparison of aortic valves., (© 2024. The Author(s).)
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- 2024
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42. Lifetime cumulative activity burden is associated with symptomatic heart failure and arrhythmic risk in patients with arrhythmogenic right ventricular cardiomyopathy: a retrospective cohort study.
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Binzenhöfer L, Clauss S, Strauß K, Höpler J, Kraft M, Hoffmann S, Brunner S, Tomsits P, Schüttler D, Massberg S, Kääb S, and Lüsebrink E
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- Humans, Male, Female, Retrospective Studies, Adult, Middle Aged, Risk Assessment, Risk Factors, Exercise, Arrhythmias, Cardiac epidemiology, Arrhythmias, Cardiac physiopathology, Arrhythmias, Cardiac therapy, Arrhythmias, Cardiac diagnosis, Time Factors, Sports statistics & numerical data, Young Adult, Arrhythmogenic Right Ventricular Dysplasia physiopathology, Arrhythmogenic Right Ventricular Dysplasia complications, Arrhythmogenic Right Ventricular Dysplasia diagnosis, Arrhythmogenic Right Ventricular Dysplasia epidemiology, Heart Failure physiopathology, Heart Failure epidemiology
- Abstract
Aims: Sports-related physical activity is associated with an increased risk of ventricular dysfunction and arrhythmias in patients with arrhythmogenic right ventricular cardiomyopathy (ARVC). However, there are currently no standardized strategies for activity assessment. Thresholds for harmful levels of physical activity suggested by previous studies vary substantially and neither lifetime activity burden nor continuous modelling approaches were considered., Methods and Results: For this single-centre retrospective study, ARVC patients were interviewed to assess sports-related and non-sports-related physical activity between the age of 10 years and the last follow-up. Activity data were aggregated to the median metabolic equivalent of task-hours (METh) per week for each year. The association between cumulative physical activity burden and clinical study endpoints was investigated using Cox regression models. A total of 124 patients (median age: 39.5 years, 48% male) were included in the analysis, of whom 93 had been diagnosed with definite ARVC. Study participants reported a median overall activity of 202.3 METh/week, with 38.7 METh/week attributed to sports-related activity. In the continuous model, cumulative overall activity burden was associated with the occurrence of symptomatic heart failure [hazard ratio (HR) per 100 METh/week: 1.017, 95% CI (1.003, 1.032), P = 0.015], sustained ventricular tachycardia [HR: 1.021, 95% CI (1.006, 1.037), P = 0.007], and implantable cardioverter defibrillator interventions [HR: 1.017, 95%CI (1.000, 1.034), P = 0.048]. This finding was consistent when considering sports-related activity separately as a predictor variable, whereas the resulting hazard ratios did not show a significant association for non-sports-related physical activity., Conclusion: This study demonstrates for the first time that cumulative physical activity as a continuous predictor variable is associated with symptomatic heart failure and arrhythmic risk in ARVC patients. Collaborative research is required in larger cohorts to investigate the influence of potential confounders on event occurrence and to develop threshold recommendations for clinical practice., Competing Interests: Conflict of interest: none declared., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)
- Published
- 2024
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43. Randomized Trial of COBRA PzF Stenting to Reduce the Duration of Triple Therapy: The COBRA-REDUCE Trial.
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Byrne RA, Colleran R, Coughlan JJ, Jauhar R, Maillard L, De Labriolle A, Maeng M, Croft C, Brunner M, Leistner D, Zrenner B, Kollum M, Laugwitz KL, Xhepa E, Mayer K, Lahu S, Joner M, Kirtane A, Mehran R, Barakat M, Urban P, Cutlip DE, and Kastrati A
- Subjects
- Humans, Male, Female, Aged, Time Factors, Middle Aged, Treatment Outcome, Risk Factors, Administration, Oral, Thromboembolism prevention & control, Thromboembolism etiology, Drug Therapy, Combination, Dual Anti-Platelet Therapy adverse effects, Coronary Thrombosis etiology, Coronary Thrombosis prevention & control, Risk Assessment, Prospective Studies, Stents, Percutaneous Coronary Intervention adverse effects, Percutaneous Coronary Intervention instrumentation, Percutaneous Coronary Intervention mortality, Hemorrhage chemically induced, Platelet Aggregation Inhibitors administration & dosage, Platelet Aggregation Inhibitors adverse effects, Drug-Eluting Stents, Anticoagulants administration & dosage, Anticoagulants adverse effects, Coronary Artery Disease therapy, Coronary Artery Disease mortality, Coronary Artery Disease diagnostic imaging, Prosthesis Design, Drug Administration Schedule
- Abstract
Background: Patients with an indication for oral anticoagulation who undergo percutaneous coronary intervention require a combination of oral anticoagulation and antiplatelet therapy. The use of a coronary stent with a thromboresistant and pro-healing coating may allow an abbreviated duration of dual antiplatelet therapy (DAPT) without an increase in the risk of thromboembolic events., Methods: Patients with an indication for oral anticoagulation undergoing percutaneous coronary intervention were randomized to treatment with the COBRA polyzene F (PzF) stent followed by 14 days of DAPT or a Food and Drug Administration-approved new-generation drug-eluting stent followed by 3 or 6 months of DAPT. The bleeding coprimary end point was Bleeding Academic Research Consortium type ≥2 beyond 14 days (or after hospital discharge) until 6 months. The thromboembolic coprimary end point was the composite of all-cause death, myocardial infarction, definite or probable stent thrombosis, or ischemic stroke at 6 months. The trial hypothesis was that the COBRA PzF stent strategy would be superior with respect to bleeding events and noninferior with respect to thromboembolic events., Results: A total of 996 patients underwent randomization. The bleeding end point occurred in 37 of 475 patients (7.8%) in the COBRA PzF group and 47 of 482 patients (9.8%) in the control group (difference, -2.0 [95% CI, -5.6 to 1.6]; P =0.14). The thromboembolic end point occurred in 37 of 492 patients (7.5%) in the COBRA PzF group and 24 of 490 patients (4.9%) in the control group (difference, 2.6%; prespecified noninferiority margin 5%, upper limit of 1-sided 95% CI of the difference, 5.2%; P
noninferiority =0.07)., Conclusions: In patients with an indication for oral anticoagulation undergoing percutaneous coronary intervention, treatment with the COBRA PzF stent plus 14 days of DAPT was not superior with respect to bleeding events and was not noninferior with respect to thromboembolic events at 6 months compared with treatment with standard Food and Drug Administration-approved drug-eluting stent plus 3 to 6 months of DAPT., Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02594501., Competing Interests: Dr Byrne reports research or educational funding to the institution of current employment from Abbott Vascular, Biosensors, Boston Scientific, and Translumina. Dr Maeng is supported by a grant from the Novo Nordisk Foundation (grant number NNF22OC0074083), has received lecture and advisory board fees from Astra-Zeneca, Bayer, Boehringer-Ingelheim, Bristol-Myers Squibb, and Novo Nordisk, has received research grants from Philips, Bayer, and Novo Nordisk, has ongoing research contracts with Novo Nordisk and Philips, and is a minor shareholder in Eli Lilly and Novo Nordisk. Dr Brunner is a previous employee of CeloNova. Dr Urban reports personal consulting fees from and is a shareholder of MedAlliance, Nyon, Switzerland, outside of the submitted work. Dr Cutlip reports contracted research support paid to institution of current employment from Celonova. Dr Kirtane reports Institutional funding to Columbia University and/or Cardiovascular Research Foundation from Medtronic, Boston Scientific, Abbott Vascular, Amgen, CathWorks, Cardiovascular Systems Inc, Philips, ReCor Medical, Neurotronic, Biotronik, Chiesi, Bolt Medical, Magenta Medical, Canon, SoniVie, and Shockwave Medical. In addition to research grants, institutional funding includes fees paid to Columbia University and/or Cardiovascular Research Foundation for consulting and/or speaking engagements in which Dr Kirtane controlled the content. Personal: Travel Expenses/Meals from Amgen, Medtronic, Biotronik, Boston Scientific, Abbott Vascular, CathWorks, Edwards, Cardiovascular Systems Inc, Novartis, Philips, Abiomed, ReCor Medical, Chiesi, Zoll, Shockwave, and Regeneron. The other authors report no conflicts.- Published
- 2024
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44. Reduction of Cardiac Allograft Vasculopathy by PCI: Quantification and Correlation With Outcome After Heart Transplantation.
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Orban M, Kuehl A, Pechmajou L, Müller C, Sfeir M, Brunner S, Braun D, Hausleiter J, Bories MC, Martin AC, Ulrich S, Dalla Pozza R, Mehilli J, Jouven X, Hagl C, Karam N, and Massberg S
- Subjects
- Humans, Male, Female, Middle Aged, Retrospective Studies, Treatment Outcome, Coronary Artery Disease surgery, Adult, Follow-Up Studies, Cohort Studies, Postoperative Complications epidemiology, Postoperative Complications diagnosis, Risk Assessment methods, Aged, Heart Transplantation adverse effects, Percutaneous Coronary Intervention methods, Percutaneous Coronary Intervention adverse effects, Allografts
- Abstract
Background: Percutaneous coronary intervention (PCI) might improve outcome at severe stages of cardiac allograft vasculopathy (CAV) among patients after heart transplantation (HTx). Yet, risk stratification of HTx patients after PCI remains challenging., Aims: To assess whether the International Society for Heart and Lung Transplantation (ISHLT) CAV classification remains prognostic after PCI and whether risk-stratification models of non-transplanted patients extend to HTx patients with CAV., Methods: At 2 European academic centers, 203 patients were stratified in cohort 1 (ISHLT CAV1, without PCI, n = 126) or cohort 2 (ISHLT CAV2 and 3, with PCI). At first diagnosis of CAV or first PCI, respectively, ISHLT CAV grades, SYNTAX scores I and II (SXS-I, SXS-II) were used to quantify baseline and residual CAV (rISHLT, rSXS-I, rSXS-II). RSXS-I > 0 defined incomplete revascularization (IR)., Results: SXS-II predicted mortality in cohort 1 (P = 0.004), whereas SXS-I (P = 0.009) and SXS-II (P = 0.002) predicted mortality in cohort 2. Post-PCI, IR (P = 0.004), high rISHLT (P = 0.02) and highest tertile of rSXS-II (P = 0.006) were associated with higher 5-year mortality. In bivariable Cox analysis, baseline SXS-II, IR and rSXS-II remained predictors of 5-year mortality post-PCI. There was a strong inverse relationship between baseline and rSXS-I (r = -0.55; P < 0.001 and r = -0.50; P = 0.003, respectively) regarding the interval to first reintervention., Conclusion: People with ISHLT CAV classification could apply for risk stratification after PCI. SYNTAX scores could be complemental for risk stratification and individualization of invasive follow-up of HTx patients with CAV., Competing Interests: Disclosures DB reports speaker honoraria from Abbott Vascular outside the submitted work. JH reports grants and personal fees from Abbott Vascular and Edwards Lifescience outside the submitted work. A-CM reports grants and consulting fees from Bristol Myers Squibb, Bayer outside the submitted work. SU reports grants from Novartis and Astellas Pharma outside the submitted work. JM reports lecture fees from Daiichi Sankyo, SIS Medical, Biotronik, Astra Zeneca, and Bristol Myers Squibb outside the submitted work. SM reports grants from German Federal Ministry of Education and Research/German Centre for Cardiovascular Research, grants from German Research Foundation, grants from Boston Scientific and Foundation Leducq Transatlantic Network of Excellence outside the submitted work. All other authors declare no conflicts of interest., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Published
- 2024
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45. Ten-year clinical outcomes after drug-eluting stents implantation according to clinical presentation-Insights from the DECADE cooperation.
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Starnecker F, Coughlan JJ, Jensen LO, Bär S, Kufner S, Brugaletta S, Räber L, Maeng M, Ortega-Paz L, Heg D, Laugwitz KL, Sabaté M, Windecker S, Kastrati A, Olesen KKW, and Cassese S
- Abstract
Background: Investigations of very long-term outcomes after percutaneous coronary intervention (PCI) with drug-eluting stents (DES) according to clinical presentation are scarce. Here, we investigated the 10-year clinical outcomes of patients undergoing DES-PCI according to clinical presentation., Methods: Patient-level data from five randomized trials with 10-year follow-up after DES-PCI were pooled. Patients were dichotomized into acute coronary syndrome (ACS) or chronic coronary syndrome (CCS) groups as per clinical presentation. The primary outcome was all-cause death. Secondary outcomes were cardiovascular death, myocardial infarction (MI), definite stent thrombosis (ST) and repeat revascularization involving the target lesion (TLR), target vessel (TVR) or non-target vessel (nTVR)., Results: Of the 9700 patients included in this analysis, 4557 presented with ACS and 5143 with CCS. Compared with CCS patients, ACS patients had a higher risk of all-cause death and nTVR in the first year, but comparable risk thereafter. In addition, ACS patients had a higher risk of MI [adjusted hazard ratio 1.21, 95% confidence interval (1.04-1.41)] and definite ST [adjusted hazard ratio 1.48, 95% confidence interval (1.14-1.92)], while the risk of TLR and TVR was not significantly different up to 10-year follow-up., Conclusions: Compared to CCS patients, ACS patients treated with PCI and DES implantation have an increased risk of all-cause death and repeat revascularization of remote vessels up to 1 year, with no significant differences thereafter and up to 10-year follow-up. ACS patients have a consistently higher risk of MI and definite ST. Whether these differences persist with current antithrombotic and secondary prevention therapies requires further investigation., (© 2024 The Author(s). European Journal of Clinical Investigation published by John Wiley & Sons Ltd on behalf of Stichting European Society for Clinical Investigation Journal Foundation.)
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- 2024
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46. Correction to: Polygenic Risk Score: Clinically Useful Tool for Prediction of Cardiovascular Disease and Benefit from Lipid-Lowering Therapy?
- Author
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Arnold N and Koenig W
- Published
- 2024
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47. Myeloid cells take ischemic insult to heart.
- Author
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Nicolai L and Massberg S
- Subjects
- Humans, Animals, Interleukin-1beta metabolism, Interleukin-1beta immunology, Fibrosis, Immunologic Memory, Myocardial Ischemia immunology, Myocardium immunology, Myocardium pathology, Myeloid Cells immunology, Immunity, Innate
- Abstract
Morbidity and mortality associated with stroke cannot be attributed solely to the acute ischemic event, but are also rooted in long-term complications, including heart disease. Simats, Zhang, and colleagues now demonstrate that interleukin (IL)-1ß-mediated innate immune memory after brain ischemic stroke leads to proinflammatory changes in the heart causing myocardial fibrosis., Competing Interests: Declaration of interests No interests are declared., (Copyright © 2024. Published by Elsevier Ltd.)
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- 2024
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48. Vasodilator reactive oxygen species ameliorate perturbed myocardial oxygen delivery in exercising swine with multiple comorbidities.
- Author
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van Drie RWA, van de Wouw J, Zandbergen LM, Dehairs J, Swinnen JV, Mulder MT, Verhaar MC, MaassenVanDenBrink A, Duncker DJ, Sorop O, and Merkus D
- Subjects
- Animals, Female, Swine, Physical Conditioning, Animal, Diabetes Mellitus, Experimental metabolism, Diabetes Mellitus, Experimental physiopathology, Vasodilation drug effects, Coronary Circulation drug effects, Hypercholesterolemia metabolism, Hypercholesterolemia physiopathology, Oxygen metabolism, Comorbidity, Coronary Vessels metabolism, Coronary Vessels drug effects, Coronary Vessels physiopathology, Diet, High-Fat, Vasodilator Agents pharmacology, Reactive Oxygen Species metabolism, Oxidative Stress, Myocardium metabolism, Renal Insufficiency, Chronic metabolism, Renal Insufficiency, Chronic physiopathology
- Abstract
Multiple common cardiovascular comorbidities produce coronary microvascular dysfunction. We previously observed in swine that a combination of diabetes mellitus (DM), high fat diet (HFD) and chronic kidney disease (CKD) induced systemic inflammation, increased oxidative stress and produced coronary endothelial dysfunction, altering control of coronary microvascular tone via loss of NO bioavailability, which was associated with an increase in circulating endothelin (ET). In the present study, we tested the hypotheses that (1) ROS scavenging and (2) ET
A+B -receptor blockade improve myocardial oxygen delivery in the same female swine model. Healthy female swine on normal pig chow served as controls (Normal). Five months after induction of DM (streptozotocin, 3 × 50 mg kg-1 i.v.), hypercholesterolemia (HFD) and CKD (renal embolization), swine were chronically instrumented and studied at rest and during exercise. Sustained hyperglycemia, hypercholesterolemia and renal dysfunction were accompanied by systemic inflammation and oxidative stress. In vivo ROS scavenging (TEMPOL + MPG) reduced myocardial oxygen delivery in DM + HFD + CKD swine, suggestive of a vasodilator influence of endogenous ROS, while it had no effect in Normal swine. In vitro wire myography revealed a vasodilator role for hydrogen peroxide (H2 O2 ) in isolated small coronary artery segments from DM + HFD + CKD, but not Normal swine. Increased catalase activity and ceramide production in left ventricular myocardial tissue of DM + HFD + CKD swine further suggest that increased H2 O2 acts as vasodilator ROS in the coronary microvasculature. Despite elevated ET-1 plasma levels in DM + HFD + CKD swine, ETA+B blockade did not affect myocardial oxygen delivery in Normal or DM + HFD + CKD swine. In conclusion, loss of NO bioavailability due to 5 months exposure to multiple comorbidities is partially compensated by increased H2 O2 -mediated coronary vasodilation., (© 2024. The Author(s).)- Published
- 2024
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49. Population-based reference values for kidney function and kidney function decline in 25- to 95-year-old Germans without and with diabetes.
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Herold JM, Wiegrebe S, Nano J, Jung B, Gorski M, Thorand B, Koenig W, Zeller T, Zimmermann ME, Burkhardt R, Banas B, Küchenhoff H, Stark KJ, Peters A, Böger CA, and Heid IM
- Subjects
- Humans, Male, Female, Aged, Middle Aged, Reference Values, Cross-Sectional Studies, Adult, Aged, 80 and over, Germany epidemiology, Longitudinal Studies, Renal Insufficiency, Chronic physiopathology, Renal Insufficiency, Chronic blood, Renal Insufficiency, Chronic diagnosis, Renal Insufficiency, Chronic epidemiology, Diabetes Mellitus epidemiology, Diabetes Mellitus physiopathology, Diabetes Mellitus blood, Diabetes Mellitus diagnosis, Age Factors, Aging physiology, Biomarkers blood, Risk Factors, European People, Glomerular Filtration Rate, Cystatin C blood, Kidney physiopathology, Creatinine blood
- Abstract
Understanding normal aging of kidney function is pivotal to help distinguish individuals at particular risk for chronic kidney disease. Glomerular filtration rate (GFR) is typically estimated via serum creatinine (eGFRcrea) or cystatin C (eGFRcys). Since population-based age-group-specific reference values for eGFR and eGFR-decline are scarce, we aimed to provide such reference values from population-based data of a wide age range. In four German population-based cohorts (KORA-3, KORA-4, AugUR, DIACORE), participants underwent medical exams, interview, and blood draw up to five times within up to 25 years. We analyzed eGFRcrea and eGFRcys cross-sectionally and longitudinally (12,000 individuals, age 25-95 years). Cross-sectionally, we found age-group-specific eGFRcrea to decrease approximately linearly across the full age range, for eGFRcys up to the age of 60 years. Within age-groups, there was little difference by sex or diabetes status. Longitudinally, linear mixed models estimated an annual eGFRcrea decline of -0.80 [95% confidence interval -0.82, -0.77], -0.79 [-0.83, -0.76], and -1.20 mL/min/1.73m
2 [-1.33, -1.08] for the general population, "healthy" individuals, or individuals with diabetes, respectively. Reference values for eGFR using cross-sectional data were shown as percentile curves for "healthy" individuals and for individuals with diabetes. Reference values for eGFR-decline using longitudinal data were presented as 95% prediction intervals for "healthy" individuals and for individuals with diabetes, obesity, and/or albuminuria. Thus, our results can help clinicians to judge eGFR values in individuals seen in clinical practice according to their age and to understand the expected range of annual eGFR-decline based on their risk profile., (Copyright © 2024 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)- Published
- 2024
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50. Lack of Formyl-peptide Receptor 1 Mitigates Atherosclerosis in Hyperlipidemic Mice.
- Author
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Döring Y, Bender A, and Soehnlein O
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- Animals, Mice, Mice, Knockout, Mice, Inbred C57BL, Male, Receptors, Formyl Peptide metabolism, Mice, Knockout, ApoE, Atherosclerosis blood, Hyperlipidemias blood, Hyperlipidemias complications, Disease Models, Animal
- Abstract
Competing Interests: None declared.
- Published
- 2024
- Full Text
- View/download PDF
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