3,083 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. Distinct Genetic Risk Profile in Aortic Stenosis Compared With Coronary Artery Disease.
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Trenkwalder T, Maj C, Al-Kassou B, Debiec R, Doppler SA, Musameh MD, Nelson CP, Dasmeh P, Grover S, Knoll K, Naamanka J, Mordi IR, Braund PS, Dreßen M, Lahm H, Wirth F, Baldus S, Kelm M, von Scheidt M, Krefting J, Ellinghaus D, Small AM, Peloso GM, Natarajan P, Thanassoulis G, Engert JC, Dufresne L, Franke A, Görg S, Laudes M, Nowak-Göttl U, Vaht M, Metspalu A, Stoll M, Berger K, Pellegrini C, Kastrati A, Hengstenberg C, Lang CC, Kessler T, Hovatta I, Nickenig G, Nöthen MM, Krane M, Schunkert H, Samani NJ, Schumacher J, Kals M, Reigo A, Teder-Laving M, Gehlen J, Webb TR, Giel AS, Koebbe LL, Feirer N, Billmann M, Srinivasan S, Zimmer S, Palmer CNA, Li L, Yang C, Borisov O, Adam M, Veulemans V, Joner M, and Xhepa E
- Abstract
Importance: Aortic stenosis (AS) and coronary artery disease (CAD) frequently coexist. However, it is unknown which genetic and cardiovascular risk factors might be AS-specific and which could be shared between AS and CAD., Objective: To identify genetic risk loci and cardiovascular risk factors with AS-specific associations., Design, Setting, and Participants: This was a genomewide association study (GWAS) of AS adjusted for CAD with participants from the European Consortium for the Genetics of Aortic Stenosis (EGAS) (recruited 2000-2020), UK Biobank (recruited 2006-2010), Estonian Biobank (recruited 1997-2019), and FinnGen (recruited 1964-2019). EGAS participants were collected from 7 sites across Europe. All participants were of European ancestry, and information on comorbid CAD was available for all participants. Follow-up analyses with GWAS data on cardiovascular traits and tissue transcriptome data were also performed. Data were analyzed from October 2022 to July 2023., Exposures: Genetic variants., Main Outcomes and Measures: Cardiovascular traits associated with AS adjusted for CAD. Replication was performed in 2 independent AS GWAS cohorts., Results: A total of 18 792 participants with AS and 434 249 control participants were included in this GWAS adjusted for CAD. The analysis found 17 AS risk loci, including 5 loci with novel and independently replicated associations (RNF114A, AFAP1, PDGFRA, ADAMTS7, HAO1). Of all 17 associated loci, 11 were associated with risk specifically for AS and were not associated with CAD (ALPL, PALMD, PRRX1, RNF144A, MECOM, AFAP1, PDGFRA, IL6, TPCN2, NLRP6, HAO1). Concordantly, this study revealed only a moderate genetic correlation of 0.15 (SE, 0.05) between AS and CAD (P = 1.60 × 10-3). Mendelian randomization revealed that serum phosphate was an AS-specific risk factor that was absent in CAD (AS: odds ratio [OR], 1.20; 95% CI, 1.11-1.31; P = 1.27 × 10-5; CAD: OR, 0.97; 95% CI 0.94-1.00; P = .04). Mendelian randomization also found that blood pressure, body mass index, and cholesterol metabolism had substantially lesser associations with AS compared with CAD. Pathway and transcriptome enrichment analyses revealed biological processes and tissues relevant for AS development., Conclusions and Relevance: This GWAS adjusted for CAD found a distinct genetic risk profile for AS at the single-marker and polygenic level. These findings provide new targets for future AS research.
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- 2024
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21. 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
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- Humans, Male, Female, Aged, Middle Aged, Coronary Angiography, Prognosis, Treatment Outcome, Time Factors, Risk Factors, Recovery of Function, Retrospective Studies, Percutaneous Coronary Intervention adverse effects, Stroke Volume physiology, Coronary Artery Disease physiopathology, Coronary Artery Disease mortality, Coronary Artery Disease therapy, Coronary Artery Disease diagnostic imaging, Coronary Artery Disease diagnosis, Ventricular Function, Left physiology
- 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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22. Physiologists as medical scientists: An early warning from the German academic system.
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Streckfuss-Bömeke K, Kränkel N, Maack C, Schnabel RB, Zelarayán LC, Frey N, Jezzard P, Krüger M, Lachmann N, Lutz S, Noack C, Schoger E, Schröder K, Sommerfeld LC, Steffens S, Winkels H, Würtz C, Zeller T, Rog-Zielinska EA, and Kohl P
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- Germany, Humans, Research Personnel, Biomedical Research, Physiology education
- Abstract
"Medical scientists" are postgraduate investigators who are engaged in biomedical research, and either hold a biomedical PhD or are qualified in medicine but do not participate in patient care. Medical scientists constitute ~40% of staff at medical faculties and >90% at nonuniversity medical research institutions in Germany. However, medical scientists in Germany face limited long-term career prospects and a lack of dedicated training and support programmes. They also face time limits on their career progression arising from national academic employment legislation, and imminent reforms by the German government are likely to make this worse. Nevertheless, recent developments in the educational landscape including the introduction of increasingly focused MSc, pre-PhD, and doctoral programmes to train medically aware basic scientists, as well as improved general recognition of the roles and relevance of medical scientists in health research, are encouraging. Physiologists have taken essential steps to improve the recognition of medical scientists in Germany by introducing a "specialist physiologist" qualification; this initiative could be applied to support medical scientists in other fields and countries. In this review, we describe the particular challenges facing medical scientists in Germany and make recommendations that may apply to other academic systems., (© 2024 The Author(s). Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.)
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- 2024
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23. [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
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- Humans, Female, Germany epidemiology, Male, Middle Aged, Aged, Heart Disease Risk Factors, Adult, Risk Factors, Cardiovascular Diseases prevention & control, Cardiovascular Diseases epidemiology
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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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24. Impact of residual mitral regurgitation after transcatheter edge-to-edge repair in atrial functional mitral regurgitation: Results from MITRA-PRO registry.
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Rottländer D, Hausleiter J, Schmitz T, Bufe A, Seyfarth M, von Bardeleben RS, Beucher H, Ouarrak T, Schneider S, and Boekstegers P
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- Humans, Male, Female, Treatment Outcome, Aged, Time Factors, Risk Factors, Aged, 80 and over, Patient Readmission, Atrial Function, Left, Recovery of Function, Europe, Heart Valve Prosthesis, Mitral Valve Insufficiency physiopathology, Mitral Valve Insufficiency diagnostic imaging, Mitral Valve Insufficiency surgery, Mitral Valve Insufficiency mortality, Registries, Cardiac Catheterization adverse effects, Cardiac Catheterization instrumentation, Mitral Valve physiopathology, Mitral Valve surgery, Mitral Valve diagnostic imaging, Heart Valve Prosthesis Implantation adverse effects, Heart Valve Prosthesis Implantation instrumentation, Heart Valve Prosthesis Implantation mortality
- Abstract
Background: Transcatheter edge-to-edge repair (TEER) has emerged to address symptomatic atrial functional mitral regurgitation (aFMR) in patients who are at high operative risk., Aims: No clinical data is available on the impact of residual mitral regurgitation (MR) following TEER in aFMR compared to ventricular functional MR (vFMR)., Methods: In the MITRA-PRO registry, 846 patients with FMR and MitraScore assessment for residual MR quantification were included (722 patients with vFMR and 124 patients with aFMR)., Results: Compared to vFMR similar procedural results in regard of residual MR following TEER were found in aFMR patients (MitraScore post TEER 2.5 ± 1.8 vs. 2.7 ± 1.9), while the amount of implanted TEER devices was increased in vFMR. 1-year survival was better in aFMR compared to vFMR regardless of relevant residual MR (MitraScore ≥ 4), while 1-year rehospitalization was comparable for both MR entities. Patients with aFMR and mild residual MR had a lower mortality rate (6.6% vs. 10.3%) and rehospitalization rate (29.1% vs. 46.2%) 1 year after mitral TEER. However, in contrast to vFMR a MitraScore ≥4 was no independent predictor of mortality in aFMR indicating a better tolerance toward residual MR., Conclusions: Residual MR is an independent predictor of 1-year mortality in vFMR patients, whereas in aFMR patients, a MitraScore of ≥4 is associated with higher mortality but is not an independent predictor in multivariate analysis. Therefore, minimizing MR through mitral TEER is crucial for survival in vFMR patients, while aFMR patients tolerate significant residual MR better 1 year after the procedure., (© 2024 The Author(s). Catheterization and Cardiovascular Interventions published by Wiley Periodicals LLC.)
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- 2024
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25. Expert opinion on design and endpoints for studies on catheter ablation of atrial fibrillation.
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Lewalter T, Blomström-Lundqvist C, Lakkireddy D, Packer D, Meyer R, Kuniss M, Ladwig KH, Jilek C, Diener HC, Boriani G, Turakhia MP, Schneider S, Svennberg E, Albers B, Andrade JG, de Melis M, and Brachmann J
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- Humans, Treatment Outcome, Consensus, Atrial Fibrillation surgery, Atrial Fibrillation physiopathology, Atrial Fibrillation diagnosis, Catheter Ablation adverse effects, Catheter Ablation standards, Research Design, Endpoint Determination standards
- Abstract
Introduction: Catheter ablation of atrial fibrillation (AF) is frequently studied in randomized trials, observational and registry studies. The aim of this expert opinion is to provide guidance for clinicians and industry regarding the development of future clinical studies on catheter ablation of AF, implement lessons learned from previous studies, and promote a higher degree of consistency across studies., Background: Studies on catheter ablation of AF may benefit from well-described definitions of endpoints and consistent methodology and documentation of outcomes related to efficacy, safety and cost-effectiveness. The availably of new, innovative technologies warrants further consideration about their application and impact on study design and the choice of endpoints. Moreover, recent insights gained from AF ablation studies suggest a reconsideration of some methodological aspects., Methods: A panel of clinical experts on catheter ablation of AF and designing and conducting clinical studies developed an expert opinion on the design and endpoints for studies on catheter ablation of AF. Discussions within the expert panel with the aim to reach consensus on predefined topics were based on outcomes reported in the literature and experiences from recent clinical trials., Results: A comprehensive set of recommendations is presented. Key elements include the documentation of clinical AF, medication during the study, repeated ablations and their effect on endpoint assessments, postablation blanking and the choice of rhythm-related and other endpoints., Conclusion: This expert opinion provides guidance and promotes consistency regarding design of AF catheter ablation studies and identified aspects requiring further research to optimize study design and methodology., Condensed Abstract: Recent insights from studies on catheter ablation of atrial fibrillation (AF) and the availability of new innovative technologies warrant reconsideration of methodological aspects related to study design and the choice and assessment of endpoints. This expert opinion, developed by clinical experts on catheter ablation of AF provides a comprehensive set of recommendations related to these methodological aspects. The aim of this expert opinion is to provide guidance for clinicians and industry regarding the development of clinical studies, implement lessons learned from previous studies, and promote a higher degree of consistency across studies., (© 2024 The Author(s). Journal of Cardiovascular Electrophysiology published by Wiley Periodicals LLC.)
- Published
- 2024
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26. Optical coherence tomography characterization of degradation kinetics between second- and third-generation resorbable magnesium scaffold.
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Seguchi M, Baumann-Zumstein P, Fubel A, Pritsch M, Aytekin A, Nicol P, Altevogt J, and Joner M
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- Animals, Time Factors, Materials Testing, Sus scrofa, Predictive Value of Tests, Kinetics, Cardiovascular Agents administration & dosage, Cardiovascular Agents pharmacokinetics, Tomography, Optical Coherence, Absorbable Implants, Magnesium, Prosthesis Design, Coronary Vessels diagnostic imaging, Models, Animal
- Abstract
Aims: This preclinical study aimed to establish optical coherence tomography (OCT)-derived parameters that could be used in the clinical setting for assessing strut degradation in the third-generation drug-eluting resorbable magnesium scaffold (DREAMS-3G), and characterize the comparative degradation profile against its precursor device (Magmaris
TM scaffold)., Methods and Results: Twelve DREAMS-3G and 10 MagmarisTM scaffolds were implanted in juvenile pigs, and OCT images obtained at baseline and follow-up (6 or 12 months). Strut degradation was assessed by planimetric analysis and compared with OCT-derived indices to validate their diagnostic accuracy. A total of 3327 struts of DREAMS-3G and 2995 struts of the MagmarisTM scaffold were delineated by OCT. DREAMS-3G exhibited a significantly higher number of visible struts per analyzed frame at 6 months than the MagmarisTM scaffold, in the absence of significant differences at 12 months. Attenuation index (AtI) analysis indicated DREAMS-3G degradation was less advanced at 6 months but more advanced at 12 months compared to the MagmarisTM scaffold. These OCT-derived indices significantly correlated with the results of the planimetric analysis., Conclusion: The current preclinical study validated OCT indices that may serve as clinical surrogate markers for scaffold degradation. AtI analysis indicated that DREAMS-3G showed less degradation at 6 months but more advanced degradation at 12 months compared to the MagmarisTM scaffold, which corroborates the findings from planimetric analysis., (© 2024 Wiley Periodicals LLC.)- Published
- 2024
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27. Comparative long-term efficacy and safety of two paclitaxel-coated balloons with different coating strategies for the treatment of drug-eluting coronary stent restenosis.
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Koch T, Lenz T, Rheude T, Cassese S, Xhepa E, Joner M, Mehilli J, Schunkert H, Kastrati A, and Kufner S
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- Humans, Male, Female, Middle Aged, Aged, Time Factors, Treatment Outcome, Risk Factors, Prosthesis Design, Myocardial Infarction etiology, Iohexol adverse effects, Iohexol analogs & derivatives, Iohexol administration & dosage, Citric Acid administration & dosage, Citric Acid adverse effects, Coronary Thrombosis etiology, Prospective Studies, Contrast Media adverse effects, Contrast Media administration & dosage, Paclitaxel administration & dosage, Paclitaxel adverse effects, Coated Materials, Biocompatible, Coronary Restenosis etiology, Coronary Restenosis diagnostic imaging, Cardiovascular Agents administration & dosage, Cardiovascular Agents adverse effects, Drug-Eluting Stents, Angioplasty, Balloon, Coronary instrumentation, Angioplasty, Balloon, Coronary adverse effects, Cardiac Catheters, Percutaneous Coronary Intervention instrumentation, Percutaneous Coronary Intervention adverse effects, Coronary Artery Disease therapy, Coronary Artery Disease diagnostic imaging, Coronary Artery Disease mortality
- Abstract
Background: We previously showed non-inferiority of a low-dose paclitaxel-coated balloon (PCB) with citrate excipient (Agent PCB) as compared to normal-dose iopromide excipient (SeQuent Please PCB) in terms of angiographic and clinical endpoints at 12 months. The long-term clinical efficacy and safety of Agent PCB is not defined., Methods: 262 patients (323 DES-ISR lesions) were enrolled in this study and treated with either Agent PCB (125 patients, 151 lesions) in the ISAR-DESIRE 3a trial or with SeQuent Please PCB (137 patients, 172 lesions) in the setting of the randomized ISAR-DESIRE 3 trial with similar in- and exclusion criteria serving as historical control arm. The follow-up period was extended to 7 years. The efficacy and safety endpoints of this analysis were target-lesion revascularization (TLR), death, myocardial infarction (MI) and target lesion thrombosis (TLT) at 7 years., Results: At 7 years, 206 patients (78.6%) were alive. The risks of TLR (hazard ratio [HR]: 1.29, 95% confidence interval [CI]: 0.87-1.90; p = 0.205), death (HR: 1.38, 95% CI: 0.82-2.35; p = 0.227), MI (HR: 1.10, 95% CI: 0.39-3.15; p = 0.852) and TLT (HR: 2.18, 95% CI: 0.20-24.10; p = 0.523) were comparable between Agent PCB and SeQuent PCB. Multivariate analysis showed comparable risks of TLR, death and MI between both PCB devices., Conclusions: In patients treated for DES-ISR by angioplasty with Agent PCB and SeQuent Please PCB, there was no statistically significant difference in TLR at 7 years. Randomized trials with standardized lesion preparation and long-term follow-up are warranted to further evaluate comparative efficacy of both devices. (ClinicalTrials. gov Identifier: NCT02367495)., (© 2024 The Author(s). Catheterization and Cardiovascular Interventions published by Wiley Periodicals LLC.)
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- 2024
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28. IF1 is a cold-regulated switch of ATP synthase hydrolytic activity to support thermogenesis in brown fat.
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Brunetta HS, Jung AS, Valdivieso-Rivera F, de Campos Zani SC, Guerra J, Furino VO, Francisco A, Berçot M, Moraes-Vieira PM, Keipert S, Jastroch M, Martinez LO, Sponton CH, Castilho RF, Mori MA, and Bartelt A
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- Animals, Mice, Hydrolysis, Mitochondria metabolism, Mice, Inbred C57BL, Male, Adipocytes, Brown metabolism, Membrane Potential, Mitochondrial, Energy Metabolism, Thermogenesis genetics, Adipose Tissue, Brown metabolism, Cold Temperature, ATPase Inhibitory Protein, Mitochondrial Proton-Translocating ATPases metabolism, Mitochondrial Proton-Translocating ATPases genetics
- Abstract
While mechanisms controlling uncoupling protein-1 (UCP1) in thermogenic adipocytes play a pivotal role in non-shivering thermogenesis, it remains unclear whether F
1 Fo-ATP synthase function is also regulated in brown adipose tissue (BAT). Here, we show that inhibitory factor 1 (IF1, encoded by Atp5if1), an inhibitor of ATP synthase hydrolytic activity, is a critical negative regulator of brown adipocyte energy metabolism. In vivo, IF1 levels are diminished in BAT of cold-adapted mice compared to controls. Additionally, the capacity of ATP synthase to generate mitochondrial membrane potential (MMP) through ATP hydrolysis (the so-called "reverse mode" of ATP synthase) is increased in brown fat. In cultured brown adipocytes, IF1 overexpression results in an inability of mitochondria to sustain the MMP upon adrenergic stimulation, leading to a quiescent-like phenotype in brown adipocytes. In mice, adeno-associated virus-mediated IF1 overexpression in BAT suppresses adrenergic-stimulated thermogenesis and decreases mitochondrial respiration in BAT. Taken together, our work identifies downregulation of IF1 upon cold as a critical event for the facilitation of the reverse mode of ATP synthase as well as to enable energetic adaptation of BAT to effectively support non-shivering thermogenesis., (© 2024. The Author(s).)- Published
- 2024
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29. Inhibition of complement factor C5a or C5aR for cholesterol crystal embolism-related vascular thrombosis with microvascular injury and its consequences.
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Zhao D, Han C, Mammadova-Bach E, Watanabe-Kusunoki K, Bandeira Honda TS, Li Y, Li C, Li Q, Long H, Lyubenov L, Shi C, Santovito D, Weber C, Boor P, Droste P, Parikh S, Shapiro J, De Chiara L, Carangelo G, Romagnani P, Klussmann S, Hoehlig K, Vater A, and Anders HJ
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- Animals, Male, Mice, Kidney pathology, Kidney immunology, Kidney blood supply, Kidney drug effects, Mice, Inbred C57BL, Mice, Knockout, Microvessels immunology, Microvessels drug effects, Microvessels pathology, Necrosis, Thrombosis etiology, Thrombosis immunology, Thrombosis prevention & control, Complement C3 metabolism, Complement C3 antagonists & inhibitors, Complement C3 immunology, Complement C5a antagonists & inhibitors, Complement C5a immunology, Complement C5a metabolism, Disease Models, Animal, Embolism, Cholesterol complications, Embolism, Cholesterol diagnosis, Receptor, Anaphylatoxin C5a antagonists & inhibitors, Receptor, Anaphylatoxin C5a genetics, Receptor, Anaphylatoxin C5a metabolism
- Abstract
Cholesterol crystal embolism (CCE) implies immunothrombosis, tissue necrosis, and organ failure but no specific treatments are available. As CCE involves complement activation, we speculated that inhibitors of the C5a/C5aR axis would be sufficient to attenuate the consequences of CCE like that with systemic vasculitis. Cholesterol microcrystal injection into the kidney artery of wild-type mice initiated intra-kidney immunothrombosis within a few hours followed by a sudden drop of glomerular filtration rate and ischemic kidney necrosis after 24 hours. Genetic deficiency of either C3 or C5aR prevented immunothrombosis, glomerular filtration rate drop, and ischemic necrosis at 24 hours as did preemptive treatment with inhibitors of either C5a or C5aR. Delayed C5a blockade after crystal injection still resolved crystal clots and prevented all consequences. Thus, selective blockade of C5a or C5aR is sufficient to attenuate the consequences of established CCE and prospective inhibition in high-risk patients may be clinically feasible and safe., (Copyright © 2024 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)
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- 2024
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30. Impact of Patient-Prosthesis Mismatch on Long-term Outcomes After Aortic Valve Replacement.
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Graser M, Bleiziffer S, Zittermann A, Mayr B, Sideris K, Puluca N, Krane M, and Prinzing A
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- Humans, Male, Female, Aged, Retrospective Studies, Treatment Outcome, Middle Aged, Aortic Valve surgery, Aortic Valve diagnostic imaging, Time Factors, Follow-Up Studies, Bioprosthesis, Prosthesis Design, Survival Rate trends, Aortic Valve Stenosis surgery, Postoperative Complications epidemiology, Risk Factors, Heart Valve Prosthesis, Reoperation statistics & numerical data, Heart Valve Prosthesis Implantation adverse effects
- Abstract
Background: Patient-prosthesis mismatch (PPM) after aortic valve replacement potentially affects the outcome after the operation. This study sought to determine whether PPM has an impact on long-term mortality and reoperation rates., Methods: We included 645 patients who underwent biologic aortic valve replacement between 2000 and 2007. Based on echocardiographic examinations at postoperative month 6, the incidence of PPM was determined according to an indexed effective orifice area <0.85 cm
2 /m2 . Survival and reoperation status were analyzed during 15 years of follow-up., Results: PPM was present in 256 patients (40%), of whom 175 had moderate PPM and 81 had severe PPM. In multivariable adjusted analysis, survival was not statistically significantly impaired in patients with moderate PPM compared with patients with no PPM, whereas patients with severe PPM showed a marginally significant impairment of survival (hazard ratio [HR], 1.40; 95% CI, 0.99-1.97; P = .054). Risk factors for survival were higher age (HR, 1.12; 95% CI, 1.10-1.14; P < .001), arterial hypertension (HR, 1.78; 95% CI, 1.38-2.31; P < .001), and diabetes mellitus (HR, 1.67; 95% CI, 1.31-2.14; P < .001). In patients with no, moderate, and severe PPM, there were 10.1, 8.5, and 14.8 events of reoperation/1000 patient-years, respectively. The corresponding 10-year cumulative incidence of reoperation was 8.3%, 6.7%, and 12.1%, respectively. In multivariable adjusted analysis, PPM category was not significantly associated with the risk of reoperation (P > .2)., Conclusions: In our study with directly measured effective orifice area, PPM was only marginally related to long-term survival and was not statistically significantly associated with the risk of reintervention., Competing Interests: Disclosures Sabine Bleiziffer reports a relationship with Abbott that includes: speaking and lecture fees; with Boston Scientific Corp that includes: speaking and lecture fees; with Edwards Lifesciences Corporation that includes: speaking and lecture fees; and with Medtronic that includes: speaking and lecture fees. Markus Krane reports a relationship with JOMDD that includes: board membership and consulting or advisory; with Peter Duschek that includes: consulting or advisory; with Evotec that includes: consulting or advisory; with Moderna Inc that includes: consulting or advisory; with Medtronic that includes: speaking and lecture fees; and with Terumo that includes: speaking and lecture fees. The other authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)- Published
- 2024
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31. Targeting immune cell recruitment in atherosclerosis.
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Döring Y, van der Vorst EPC, and Weber C
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- Humans, Animals, Leukocytes immunology, Leukocytes metabolism, Inflammation immunology, Anti-Inflammatory Agents therapeutic use, Inflammation Mediators metabolism, Atherosclerosis immunology, Atherosclerosis drug therapy
- Abstract
Atherosclerosis is the primary underlying cause of myocardial infarction and stroke. Atherosclerotic cardiovascular disease is characterized by a chronic inflammatory reaction in medium-to-large-sized arteries, with its onset and perpetuation driven by leukocytes infiltrating the subendothelial space. Activation of endothelial cells triggered by hyperlipidaemia and lipoprotein retention in the arterial intima initiates the accumulation of pro-inflammatory leukocytes in the arterial wall, fostering the progression of atherosclerosis. This inflammatory response is coordinated by an array of soluble mediators, namely cytokines and chemokines, that amplify inflammation both locally and systemically and are complemented by tissue-specific molecules that regulate the homing, adhesion and transmigration of leukocytes. Despite abundant evidence from mouse models, only a few therapies targeting leukocytes in atherosclerosis have been assessed in humans. The major challenges for the clinical translation of these therapies include the lack of tissue specificity and insufficient selectivity of inhibition strategies. In this Review, we discuss the latest research on receptor-ligand pairs and interactors that regulate leukocyte influx into the inflamed artery wall, primarily focusing on studies that used pharmacological interventions. We also discuss mechanisms that promote the resolution of inflammation and highlight how major findings from these research areas hold promise as potential therapeutic strategies for atherosclerotic cardiovascular disease., (© 2024. Springer Nature Limited.)
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- 2024
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32. Differential Effects of Erythropoietin Administration and Overexpression on Venous Thrombosis in Mice.
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Stockhausen S, Kilani B, Schubert I, Steinsiek AL, Chandraratne S, Wendler F, Eivers L, von Brühl ML, Massberg S, Ott I, and Stark K
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- Animals, Mice, Splenectomy, Mice, Transgenic, Mice, Inbred C57BL, Blood Platelets metabolism, Blood Platelets drug effects, Male, Erythrocytes metabolism, Erythrocytes drug effects, Vena Cava, Inferior, Time Factors, Phenotype, Erythropoietin, Venous Thrombosis, Disease Models, Animal, Spleen metabolism, Spleen drug effects
- Abstract
Background: Deep vein thrombosis (DVT) is a common condition associated with significant mortality due to pulmonary embolism. Despite advanced prevention and anticoagulation therapy, the incidence of venous thromboembolism remains unchanged. Individuals with elevated hematocrit and/or excessively high erythropoietin (EPO) serum levels are particularly susceptible to DVT formation. We investigated the influence of short-term EPO administration compared to chronic EPO overproduction on DVT development. Additionally, we examined the role of the spleen in this context and assessed its impact on thrombus composition., Methods: We induced ligation of the caudal vena cava (VCC) in EPO-overproducing Tg(EPO) mice as well as wildtype mice treated with EPO for two weeks, both with and without splenectomy. The effect on platelet circulation time was evaluated through FACS analysis, and thrombus composition was analyzed using immunohistology., Results: We present evidence for an elevated thrombogenic phenotype resulting from chronic EPO overproduction, achieved by combining an EPO-overexpressing mouse model with experimental DVT induction. This increased thrombotic state is largely independent of traditional contributors to DVT, such as neutrophils and platelets. Notably, the pronounced prothrombotic effect of red blood cells (RBCs) only manifests during chronic EPO overproduction and is not influenced by splenic RBC clearance, as demonstrated by splenectomy. In contrast, short-term EPO treatment does not induce thrombogenesis in mice. Consequently, our findings support the existence of a differential thrombogenic effect between chronic enhanced erythropoiesis and exogenous EPO administration., Conclusion: Chronic EPO overproduction significantly increases the risk of DVT, while short-term EPO treatment does not. These findings underscore the importance of considering EPO-related factors in DVT risk assessment and potential therapeutic strategies., Competing Interests: None declared., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).)
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- 2024
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33. A randomized comparison of the treatment sequence of percutaneous coronary intervention and transcatheter aortic valve implantation: Rationale and design of the TAVI PCI trial.
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Stähli BE, Linke A, Westermann D, Van Mieghem NM, Leistner DM, Massberg S, Alber H, Mügge A, Musumeci G, Kesterke R, Schneider S, Kastrati A, Ford I, Ruschitzka F, and Kasel MA
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- Humans, Prospective Studies, Male, Female, Coronary Angiography, Treatment Outcome, Transcatheter Aortic Valve Replacement methods, Aortic Valve Stenosis surgery, Aortic Valve Stenosis complications, Percutaneous Coronary Intervention methods, Coronary Artery Disease surgery, Coronary Artery Disease complications, Coronary Artery Disease therapy
- Abstract
Background: About half of patients with severe aortic stenosis present with concomitant coronary artery disease. The optimal timing of percutaneous coronary intervention (PCI) and transcatheter aortic valve implantation (TAVI) in patients with severe aortic stenosis and concomitant coronary artery disease remains unknown., Study Design: The TAVI PCI trial is a prospective, international, multicenter, randomized, 2-arm, open-label study planning to enroll a total of 986 patients. It is designed to investigate whether the strategy "angiography-guided complete revascularization after (within 1-45 days) TAVI" is noninferior to the strategy "angiography-guided complete revascularization before (within 1-45 days) TAVI" using the Edwards SAPIEN 3 or 3 Ultra Transcatheter Heart Valve in patients with severe aortic stenosis and concomitant coronary artery disease. Patients are randomized in a 1:1 ratio to one of the 2 treatment strategies. The primary end point is a composite of all-cause death, nonfatal myocardial infarction, ischemia-driven revascularization, rehospitalization (valve- or procedure-related including heart failure), or life-threatening/disabling or major bleeding at 1 year., Conclusions: The TAVI PCI trial tests the hypothesis that the strategy "PCI after TAVI" is noninferior to the strategy "PCI before TAVI" in patients with severe aortic stenosis and concomitant coronary artery disease., Competing Interests: Declaration of competing interest TAVI PCI is supported as investigator-initiated research by Edwards Lifesciences (THV-I20-061)., (Copyright © 2024 Elsevier Inc. All rights reserved.)
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- 2024
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34. Beyond the Heartbeat: Single-Cell Omics Redefining Cardiovascular Research.
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Seeler S, Arnarsson K, Dreßen M, Krane M, and Doppler SA
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- Humans, Epigenomics, Transcriptome, Precision Medicine, Biomedical Research, Single-Cell Analysis methods, Genomics methods, Proteomics, Cardiovascular Diseases genetics
- Abstract
Purpose of Review: This review aims to explore recent advances in single-cell omics techniques as applied to various regions of the human heart, illuminating cellular diversity, regulatory networks, and disease mechanisms. We examine the contributions of single-cell transcriptomics, genomics, proteomics, epigenomics, and spatial transcriptomics in unraveling the complexity of cardiac tissues., Recent Findings: Recent strides in single-cell omics technologies have revolutionized our understanding of the heart's cellular composition, cell type heterogeneity, and molecular dynamics. These advancements have elucidated pathological conditions as well as the cellular landscape in heart development. We highlight emerging applications of integrated single-cell omics, particularly for cardiac regeneration, disease modeling, and precision medicine, and emphasize the transformative potential of these technologies to advance cardiovascular research and clinical practice., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)
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- 2024
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35. A cross-species foundation model for single cells.
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Traeuble K and Heinig M
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- 2024
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36. Comparison of strategies for vascular ACCESS closure after transcatheter aortic valve implantation: the ACCESS-TAVI randomized trial.
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Rheude T, Ruge H, Altaner N, Pellegrini C, Alvarez Covarrubias H, Mayr NP, Cassese S, Kufner S, Taniguchi Y, Thilo C, Klos M, Erlebach M, Schneider S, Jurisic M, Laugwitz KL, Lange R, Schunkert H, Kastrati A, Krane M, Xhepa E, and Joner M
- Abstract
Background and Aims: Data from randomized trials investigating different access closure strategies after transfemoral transcatheter aortic valve implantation (TF-TAVI) remain scarce. In this study, two vascular closure device (VCD) strategies to achieve hemostasis after TF-TAVI were compared., Methods: The ACCESS-TAVI (Comparison of Strategies for Vascular ACCESS Closure after Transcatheter Aortic Valve Implantation) is a prospective, multicenter trial in which patients undergoing TF-TAVI were randomly assigned to a strategy with a combined suture-/plug-based VCD strategy (suture/plug group) using one ProGlideTM/ProStyleTM (Abbott Vascular) and one Angio-Seal® (Terumo) versus a suture-based VCD strategy (suture-only group) using two ProGlidesTM/ProStylesTM. The primary endpoint was a composite of major or minor access site-related vascular complications during index hospitalization according to Valve Academic Research Consortium (VARC)-3 criteria. Key secondary endpoints included time to hemostasis, VARC-3 bleeding type ≥2 and all-cause mortality over 30 days., Results: Between September 2022 and April 2024, 454 patients were randomized. The primary endpoint occurred in 27% (62/230) in the suture/plug group and 54% (121/224) in the suture-only group (relative risk [RR] 0.55 [95% confidence interval: 0.44;0.68]; p<0.001). Time to hemostasis was significantly shorter in the suture/plug group compared to the suture-only group (108±208 s vs. 206±171 s; p <0.001). At 30 days, bleeding type ≥2 occurred less often in the suture/plug group compared to the sutureonly group (6.2% vs. 12.1%, RR 0.66 [0.43;1.02]; p=0.032), with no significant difference in mortality., Conclusions: With regard to the composite of major or minor access-related vascular complications, a combined suture-/plug-based VCD strategy was superior to a suturebased VCD strategy for vascular access closure in patients undergoing TF-TAVI., (© 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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37. Cardiac Repair after Myocardial Infarction is Controlled by a Complement C5a Receptor 1-Driven Signaling Cascade.
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Asare Y, Simsekyilmaz S, Köhncke J, Shagdarsuren G, Staudt M, Noels H, Klos A, Fischer JC, Bernhagen J, Zernecke A, Liehn EA, and Shagdarsuren E
- Abstract
Competing Interests: None declared.
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- 2024
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38. Association analysis between an epigenetic alcohol risk score and blood pressure.
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Bui H, Keshawarz A, Wang M, Lee M, Ratliff SM, Lin L, Birditt KS, Faul JD, Peters A, Gieger C, Delerue T, Kardia SLR, Zhao W, Guo X, Yao J, Rotter JI, Li Y, Liu X, Liu D, Tavares JF, Pehlivan G, Breteler MMB, Karabegovic I, Ochoa-Rosales C, Voortman T, Ghanbari M, van Meurs JBJ, Nasr MK, Dörr M, Grabe HJ, London SJ, Teumer A, Waldenberger M, Weir DR, Smith JA, Levy D, Ma J, and Liu C
- Subjects
- Humans, Female, Male, Middle Aged, Cross-Sectional Studies, Risk Factors, CpG Islands genetics, Aged, Adult, Epigenesis, Genetic, Alcohol Drinking genetics, Alcohol Drinking adverse effects, Blood Pressure genetics, Hypertension genetics, Hypertension epidemiology, DNA Methylation genetics, Genome-Wide Association Study methods
- Abstract
Background: Epigenome-wide association studies have identified multiple DNA methylation sites (CpGs) associated with alcohol consumption, an important lifestyle risk factor for cardiovascular diseases. This study aimed to test the hypothesis that an alcohol consumption epigenetic risk score (ERS) is associated with blood pressure (BP) traits., Results: We implemented an ERS based on a previously reported epigenetic signature of 144 alcohol-associated CpGs in meta-analysis of participants of European ancestry. We found a one-unit increment of ERS was associated with eleven drinks of alcohol consumed per day, on average, across several cohorts (p < 0.0001). We examined the association of the ERS with systolic blood pressure (SBP), diastolic blood pressure (DBP), and hypertension (HTN) in 3,898 Framingham Heart Study (FHS) participants. Cross-sectional analyses in FHS revealed that a one-unit increment of the ERS was associated with 1.93 mm Hg higher SBP (p = 4.64E-07), 0.68 mm Hg higher DBP (p = 0.006), and an odds ratio of 1.78 for HTN (p < 2E-16). Meta-analysis of the cross-sectional association of the ERS with BP traits in eight independent external cohorts (n = 11,544) showed similar relationships with BP levels, i.e., a one-unit increase in ERS was associated with 0.74 mm Hg (p = 0.002) higher SBP and 0.50 mm Hg (p = 0.0006) higher DBP, but not with HTN. Longitudinal analyses in FHS (n = 3260) and five independent external cohorts (n = 4021) showed that the baseline ERS was not associated with a change in BP over time or with incident HTN., Conclusions: Our findings demonstrate that the ERS has potential clinical utility in assessing lifestyle factors related to cardiovascular risk, especially when self-reported behavioral data (e.g., alcohol consumption) are unreliable or unavailable., (© 2024. The Author(s).)
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- 2024
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39. Subphenotypes of adult-onset diabetes: Data-driven clustering in the population-based KORA cohort.
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Dong Q, Xi Y, Brandmaier S, Fuchs M, Huemer MT, Waldenberger M, Niu J, Herder C, Rathmann W, Roden M, Koenig W, Bönhof GJ, Gieger C, Thorand B, Peters A, Rospleszcz S, and Grallert H
- Abstract
Aims: A data-driven cluster analysis in a cohort of European individuals with type 2 diabetes (T2D) has previously identified four subgroups based on clinical characteristics. In the current study, we performed a comprehensive statistical assessment to (1) replicate the above-mentioned original clusters; (2) derive de novo T2D subphenotypes in the Kooperative Gesundheitsforschung in der Region Augsburg (KORA) cohort and (3) describe underlying genetic risk and diabetes complications., Methods: We used data from n = 301 individuals with T2D from KORA FF4 study (Southern Germany). Original cluster replication was assessed forcing k = 4 clusters using three different hyperparameter combinations. De novo clusters were derived by open k-means analysis. Stability of de novo clusters was assessed by assignment congruence over different variable sets and Jaccard indices. Distribution of polygenic risk scores and diabetes complications in the respective clusters were described as an indication of underlying heterogeneity., Results: Original clusters did not replicate well, indicated by substantially different assignment frequencies and cluster characteristics between the original and current sample. De novo clustering using k = 3 clusters and including high sensitivity C-reactive protein in the variable set showed high stability (all Jaccard indices >0.75). The three de novo clusters (n = 96, n = 172, n = 33, respectively) adequately captured heterogeneity within the sample and showed different distributions of polygenic risk scores and diabetes complications, that is, cluster 1 was characterized by insulin resistance with high neuropathy prevalence, cluster 2 was defined as age-related diabetes and cluster 3 showed highest risk of genetic and obesity-related diabetes., Conclusion: T2D subphenotyping based on its sample's own clinical characteristics leads to stable categorization and adequately reflects T2D heterogeneity., (Diabetes, Obesity and Metabolism© 2024 The Author(s). Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)
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- 2024
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40. Comparison of exercise training modalities and change in peak oxygen consumption in heart failure with preserved ejection fraction: a secondary analysis of the OptimEx-Clin trial.
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Mueller S, Kabelac M, Fegers-Wustrow I, Winzer EB, Gevaert AB, Beckers P, Haller B, Edelmann F, Christle JW, Haykowsky MJ, Sachdev V, Kitzman DW, Linke A, Adams V, Wisloff U, Pieske B, van Craenenbroeck E, and Halle M
- Abstract
Aims: Exercise training (ET) is an effective therapy in heart failure with preserved ejection fraction (HFpEF), but the influence of different ET characteristics is unclear. We aimed to evaluate the associations between ET frequency, duration, intensity [% heart rate reserve (%HRR)] and estimated energy expenditure (EEE) with the change in peak oxygen consumption (V̇O2) over 3 months of moderate continuous training (MCT, 5×/week) or high-intensity interval training (HIIT, 3×/week) in HFpEF., Methods and Results: ET duration and heart rate (HR) were recorded with a smartphone application. EEE was calculated using the HR data during ET and the individual HR-V̇O2 relationships during cardiopulmonary exercise testing. Differences between groups and associations between ET characteristics and peak V̇O2 change were assessed with linear regression analyses. Peak V̇O2 improved by 9.2 ± 13.2% after MCT and 8.7 ± 15.9% after HIIT (P = 0.67). The average EEE of 1 HIIT session was equivalent to ∼1.42 MCT sessions and when adjusted for EEE, the mean difference between MCT and HIIT was -0.1% (P = 0.98). For both MCT and HIIT, peak V̇O2 change was positively associated with ET frequency (MCT: R2 = 0.103; HIIT: R2 = 0.149) and duration/week (MCT: R2 = 0.120; HIIT: R2 = 0.125; all P < 0.05). Average %HRR was negatively associated with peak V̇O2 change in MCT (R2 = 0.101; P = 0.034), whereas no significant association was found in HIIT (P = 0.234). Multiple regression analyses explained ∼1/3 of the variance in peak V̇O2 change., Conclusion: In HFpEF, isocaloric HIIT and MCT seem to be equally effective over 3 months. Within each mode, increasing ET frequency or duration/week may be more effective to improve peak V̇O2 than increasing ET intensity., Competing Interests: Conflict of interest: Dr Mueller reported personal fees (advisory board) from Bristol Myers Squibb outside the submitted work. Dr Winzer reported grants from Boehringer Ingelheim, and personal fees from Amarin, Amgen, AstraZeneca, Daiichi Sankyo, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, CVRx, Novartis and Pfizer outside the submitted work. Dr Gevaert reported receiving lecture/advisory fees paid to his institution by Abbott, AstraZeneca, Boehringer Ingelheim, Novartis, Johnson and Johnson, and Menarini outside the submitted work. Dr Edelmann reported personal fees from AstraZeneca, Bayer, Berlin Chemie, Boehringer Ingelheim, CVRx, Medtronic, Merck, MSD, Novartis, Pfizer, PharmaCosmos, Resmed, Servier and Vifor Pharma, non-financial support from Novartis, and grants from AstraZeneca, Boehringer Ingelheim, Servier and Thermo Fischer outside the submitted work. Dr Kitzman has been a consultant for AstraZeneca, Pfizer, Corvia Medical, Bayer, Boehringer Ingleheim, NovoNorDisk, Rivus, and St. Luke’s Medical Center; received grant support from US National Institutes of Health (grants U01AG076928; R01AG078153; R01AG045551; R01AG18915; P30AG021332; U24AG059624; and U01HL160272), Novartis, AstraZeneca, Bayer, Pfizer, Novo NorDisk, Rivus, and St. Luke’s Medical Center outside the submitted work; and owns stock in Gilead Sciences. Dr Linke reported grant/research support from Edwards Lifesciences and Novartis, consultant fees from Edwards Lifesciences, Boston Scientific, Abiomed, Novartis, Meril, Pfizer, AstraZeneca, Boehringer Ingelheim, Abbott, MSD, Corvia Medical, and Daiichi Sankyo outside the submitted work, and individual stocks/stock options from Transverse Medical, Picardia and Filterlex. Dr Pieske reported institutional grants from AstraZeneca, Bayer Healthcare and Boston Scientific; personal fees for Steering Committee, consulting, and speaker services from Bayer Healthcare, MSD, AstraZeneca, Boehringer Ingelheim, Novartis, Boston Scientific and Abbott outside the submitted work; and holds minor shares in ICTS GmbH (Imaging in Clinical Trials Services). Dr Van Craenenbroeck reported receiving grants from Vifor Pharma outside the submitted work. Dr Halle reported receiving personal fees from Abbott, Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, sanofi-aventis, Novartis, Medical Park (consulting fees and honoraria for lectures) and being the past-president of the European Association of Preventive Cardiology (2020–22) outside the submitted work. No other potential conflicts of interest were reported., (© 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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41. Transcatheter Valve Repair for Tricuspid Regurgitation: 1-Year Results from a Large European Real-World Registry.
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Wild MG, Stolz L, Rosch S, Rudolph F, Goebel B, Köll B, von Stein P, Rottbauer W, Rassaf T, Beucher H, Kraus M, Kassar M, Geisler T, Rück A, Ferreira-Martins J, Toggweiler S, Sagmeister P, Westermann D, Stocker TJ, Weckbach LT, Näbauer M, Settergren M, Dawkins S, Kister T, Praz F, Vorpahl M, Konstandin MH, Lüdike P, Keßler M, Iliadis C, Kalbacher D, Lauten P, Gerçek M, Besler C, Lurz P, and Hausleiter J
- Abstract
Background: Tricuspid valve transcatheter edge-to-edge repair has emerged as a valuable treatment option for patients with severe tricuspid regurgitation (TR)., Objectives: This study aims to investigate the safety and effectiveness of the PASCAL transcatheter valve repair system in treating severe TR in a real-world patient population., Methods: The PASTE (PASCAL for Tricuspid Regurgitation-a European registry) study is an investigator-initiated, multicenter, retrospective, and prospective observational cohort analysis conducted across 16 European heart valve centers including consecutive patients treated with the PASCAL transcatheter valve repair system from February 2019 to November 2023. Echocardiographic assessments were performed at baseline, discharge, and follow-up, and were subjected to centralized analysis., Results: The study included 1,059 high-risk patients (mean age 79 ± 9 years; 53% female; TRI-SCORE risk 23% ± 18%; 87% NYHA functional class III/IV) with multiple comorbidities. Severe or higher graded TR was observed in 96% of patients. Intraprocedural success according to Tricuspid Valve Academic Research Consortium criteria was achieved in 85%, and TR reduced to ≤moderate in 87%. Independent predictors for a postprocedure residual TR of >moderate were coaptation gaps ≥8 mm (OR: 1.67; 95% CI: 1.03-2.72; P = 0.038), tenting height ≥10 mm (OR: 2.18; CI: 1.30-3.65; P = 0.003), the presence of a transvalvular lead (OR: 1.91; 95% CI: 1.19-3.05; P = 0.007), right ventricular dilatation >42 mm (OR: 3.35; 95% CI: 1.37-9.1; P = 0.009) and massive/torrential TR at baseline (OR: 4.59; 95% CI: 2.35-8.96; P < 0.001). At 1 year, 83% of patients showed ≤moderate TR. Significant clinical improvements included enhanced NYHA functional class (66% class I/II vs 17% at baseline; P < 0.001). Patients treated with the first-generation PASCAL system (n = 570) and with the new PASCAL Precision system (n = 489) had similar clinical profiles and TR severity at baseline. However, the Precision cohort showed greater TR reduction to trace/mild (63% vs 49%; P < 0.001), shorter procedure times (median 93 minutes [Q1-Q3: 69-130 minutes] vs 120 minutes [Q1-Q3: 82-165 minutes]; P < 0.001), and higher clinical success rates according to the Tricuspid Valve Academic Research Consortium at 30 days and 1 year (87% vs 81% [P = 0.021] and 56% vs 50% [P = 0.044], respectively). Higher center experience (≥21 patients/year) resulted in higher intraprocedural and clinical success., Conclusions: The PASCAL system effectively treats severe TR in high-risk patients, offering sustained TR reduction and significant clinical improvements at 1-year follow-up. (PASCAL for Tricuspid Regurgitation-a European registry [PASTE]; NCT05328284)., Competing Interests: Funding Support and Author Disclosures Dr Wild has received speaker fees from Abbott Vascular and Edwards Lifesciences; and has received honoraria for consultancy from IPPMed. Dr Stolz has received speaker honoraria from Edwards Lifesciences. Dr Praz has received travel expenses from Abbott Vascular, Polares Medical, and Edwards Lifesciences. Dr Lüdike has received speaker fees from Edwards Lifesciences. Dr Rassaf has received speaker fees from AstraZeneca, Daiichi-Sankyo, Bayer, Novartis, and Abiomed outside the submitted work. Dr Lurz has received grants from Abbott Vascular, Edwards Lifesciences, and ReCor Medical. Dr Stocker has received speaker honoraria from Edwards Lifesciences; and has served as a consultant for Occlutech International. Dr Kalbacher has received personal fees from Abbott Vascular, Edwards Lifesciences, Medtronic Inc, and Pi-Cardia Ltd. Dr Westermann has received honoraria from Abiomed, Medtronic, and Edwards Lifesciences. Dr Hausleiter has received research support and speaker honoraria from Edwards Lifesciences. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 American College of Cardiology Foundation. All rights reserved.)
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- 2024
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42. Aortic valve calcification volume and prognosis in patients undergoing transcatheter aortic valve implantation.
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Álvarez-Covarrubias HA, Altaner N, Adolf R, Jurisic M, Horban E, Pellegrini C, Duesmann C, Lachmann M, Thilo C, Syryca F, Klos M, Patrick Mayr N, Rheude T, Renker M, Charitos EI, Schunkert H, Kastrati A, Xhepa E, Won-Keun K, and Joner M
- Abstract
Introduction and Objectives: It is unknown whether aortic valve calcium volume, as measured by contrast-enhanced computed tomography angiography (angio-CT), is associated with mortality in patients undergoing transcatheter aortic valve implantation (TAVI). We aimed to confirm that contrast-enhanced aortic valve calcium correlates with noncontrast-enhanced calcium score and provides useful prognostic information in patients undergoing TAVI., Methods: This retrospective observational study included patients from 2 high-volume TAVI centers in Germany, all of whom underwent high-quality angio-CT prior to TAVI. Calcium volume in contrast-enhanced angio-CT was calculated using 3Mensio software (Pie Medical, The Netherlands), while the calcium score from noncontrast-enhanced angio-CT was obtained using the Syngo.via (Siemens Healthineers, Germany) workstation to validate contrast-enhanced angio-CT values. Calcium volume was dichotomized using the median based on to sex-specific values from contrast-enhanced angio-CT, and the risk associated with increased calcium volume was determined using Cox proportional hazard regression analysis., Results: We included 3318 TAVI patients. A good correlation was observed between noncontrast-enhanced and contrast-enhanced angio-CT (r
2 = 0.680; P < .001). The median values for sex-specific contrast-enhanced angio-CT calcium volume were 514 mm3 for women and 1025 mm3 for men. Patients with higher calcium volumes showed lower mortality at 1 year (8.8% vs 12.1%; adjusted hazard ratio [HR], 0.86; 95% confidence interval [95%CI], 0.75-0.98; P = .02) compared with those with lower calcium volumes., Conclusions: Calcium volume in contrast-enhanced angio-CT correlated well with noncontrast-enhanced angio-CT calcium score. Patients with higher calcium volume showed lower mortality at 1 year after TAVI., (Copyright © 2024 Sociedad Española de Cardiología. Published by Elsevier España, S.L.U. All rights reserved.)- Published
- 2024
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43. Characterization of Post Coronary Artery Bypass Grafting Atrial Fibrillation Patterns: Rationale and Design of an Investigator-Initiated Observational Study.
- Author
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Herrmann FEM, Jeppsson A, Charitos EI, Dacian D, Brömsen J, Sadoni S, Kirov H, Doenst T, Juchem G, and Hagl C
- Abstract
New-onset postoperative atrial fibrillation (POAF) after cardiac surgery is associated with increased rates of adverse events (including mortality and stroke). Its incidence after coronary artery bypass grafting (CABG) is considered to be approximately 30%, and it is believed to be a transient condition. However, studies investigating POAF after CABG fail to provide appropriate data on incidence and arrhythmia patterns due to the use of intermittent rhythm detection strategies. These methods have a low sensitivity as compared with continuous monitoring. Subsequently, studies using these techniques most likely do not identify all patients with arrhythmia and do not adequately demonstrate the long-term incidence of arrhythmia, which in turn may affect its association with adverse events. The Characterization of Post Coronary Artery Bypass Grafting Atrial Fibrillation Patterns (CABG-AF) study (German Clinical Trials Register Number: DRKS00018887) tests the hypothesis that the incidence of AF in the first 12 months after CABG is significantly underestimated. CABG-AF is an investigator-initiated multicenter, prospective, observational study in which 196 patients with no history of arrhythmia who underwent first-time CABG receive an insertable cardiac monitor for continuous postoperative rhythm monitoring. The primary end point of the study is any episode of AF within the first 12 months after surgery. Secondary end points include AF burden, AF density, and the ratio of silent to symptomatic AF episodes. End points will be investigated by automatic and patient-initiated data transfers from the implanted device, by telephone interview of patients, and by follow-up forms sent to patients by mail. The patients will be followed for a planned follow-up of 3 years. In conclusion, the CABG-AF study will provide information on the true incidence of AF after CABG and on the temporal patterns of the arrhythmia., Competing Interests: Declaration of competing interest Anders Jeppsson discloses personal payments for advisory boards and/or presentations from AstraZeneca, Bayer, Werfen, LFB Biotechnologies, Boehringer-Ingelheim (Ingelheim, Germany), and Novo Nordisk that are unrelated to the present work. Sebastian Sadoni discloses having received payments for work as a proctor for Boston Scientific that are unrelated to the present work. The remaining authors have no competing interests to declare. The graphical abstract and Figure 1 were created using Biorender.com., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)
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- 2024
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44. 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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45. 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
- Abstract
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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46. 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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47. New-generation single-layer PTFE-covered coronary stent for endovascular repair of iatrogenic arterial side-branch injury in non-coronary lesions for the RECOVER (REsults after percutaneous interventions with COVERed stents) Investigators.
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Strauß L, Gibello L, Voll F, Alvarez-Covarrubias HA, Lenz T, Cassese S, Xhepa E, Joner M, Schunkert H, Kastrati A, Ruffino MA, and Kufner S
- Abstract
Background: The incidence of iatrogenic injuries in peripheral arteries is increasing due to the expanding opportunities of managing various cardiovascular diseases by means of percutaneous intervention. Thus, endovascular repair with implantation of covered stent (CS) after vascular injury is gaining importance as an alternative to open surgery. In cases of smaller side-branch injuries, stenting of the main vessel with subsequent exclusion and sealing of the side-branch is associated with unfavourable revascularization rates and unpredictable ischemic complications in the corresponding supply area., Objective: This study reports the procedural and clinical outcomes of patients with iatrogenic vascular side-branch injuries treated with coronary-CS directly at the site of injury., Methods: This is a retrospective, multicentre registry study, including 40 patients with acute iatrogenic injuries of arterial side-branches undergoing implantation of single-layer polytetrafluorethylene (PTFE)-CS at 3 different centres in Europe between June 2014 and June 2023. Endpoints were procedural success, death, target vessel reintervention (TVR), bleeding and the need for surgical conversion., Results: A total of 40 patients underwent implantation of single-layer PTFE-CS in the lower (97.5 %) and the upper limbs (2.5 %). The most common mechanisms were injuries after punctures, caused by needle and/or sheath (80 %), balloon-dilations (7.5 %) and during/after non-cardiac surgery (7.5 %). Procedural success was achieved in all cases (100 %). The rate of in-hospital mortality was 7.5 %. The median duration of hospitalization after the CS procedure was 4 days [2; 5.3]. At a median follow-up of 202.5 days [97.3-711.8], 36 patients (90 %) were alive and main vessel patency was 100 %. There were no cases of TVRs, bleedings or surgical conversions. Access-site related complications occurred in 5 % of all cases., Conclusions: In this study, the use of new-generation single-layer PTFE-covered coronary stents in non-coronary side-branch lesions after iatrogenic arterial injury shows a high technical success rate and favourable clinical efficacy and safety., Competing Interests: Declaration of competing interest MJ reports speaker fees from Biotronik, personal fees from Orbus Neich, grants and personal fees from Boston Scientific, grants and personal fees from Edwards, personal fees from AstraZeneca, personal fees from Recor, grants from Amgen, not related to the current work, HS reports honoraria from AstraZeneca, Bayer Vital, MSD Sharp & Dohme, Novartis, Servier, Sanofi-Aventis, Boehringer Ingelheim, Daiichi Sankyo, Amgen, Pfizer and consulting fees from AstraZeneca, Amgen, MSD Sharp & Dohme, not related to the current work; SK reports speaker and consulting fees from AstraZeneca, Bristol Myers Squibb, and Bentley and speaker fees from Abbott, Boehringer-Ingelheim and Translumina and a research grant from Bentley, all other authors report no conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
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- 2024
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48. Impact of Pulmonary Hypertension on Outcomes after Transcatheter Tricuspid Valve Edge-to-Edge Repair.
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Stolz L, Kresoja KP, von Stein J, Fortmeier V, Koell B, Rottbauer W, Kassar M, Goebel B, Denti P, Achouh P, Rassaf T, Barreiro-Perez M, Boekstegers P, Rück A, Doldi PM, Novotny J, Zdanyte M, Adamo M, Vincent F, Lurz P, von Bardeleben RS, Stocker TJ, Weckbach LT, Wild MG, Besler C, Brunner S, Toggweiler S, Grapsa J, Patterson T, Thiele H, Kister T, Tarantini G, Masiero G, De Carlo M, Sticchi A, Konstandin MH, Van Belle E, Metra M, Geisler T, Estévez-Loureiro R, Luedike P, Karam N, Maisano F, Lauten P, Praz F, Kessler M, Kalbacher D, Rudolph V, Iliadis C, Lurz P, Hausleiter J, Pfister R, Baldus S, Gerçek M, Rudolph F, Ludwig S, Pauschinger C, Schneider LM, Felbel D, Salomon C, Lapp H, Puscas T, Berrebi A, Mahabadi AA, Schindhelm F, Caneiro-Queija B, Echarte JC, Schreieck J, Goldschmied A, Pancaldi E, Tomasoni D, Rousse N, Aghezzaf S, Frey N, Kraus M, Westermann D, Rosch S, Arturi F, Panza A, Mazzola M, and Giannini C
- Abstract
Background: Data regarding the association of pulmonary hypertension (PH) and outcomes in patients undergoing transcatheter tricuspid valve edge-to-edge repair (T-TEER) are scarce., Objectives: To 1) investigate the impact of PH on outcomes after T-TEER and 2) to shed further light into the role of pre- and postcapillary PH in patients undergoing T-TEER for relevant tricuspid regurgitation (TR)., Methods: The study included patients from the EuroTR registry (NCT06307262) who underwent T-TEER for relevant TR from 2016 until 2023 with available invasive evaluation of sPAP using right heart catheterization. Study endpoints were procedural TR reduction, improvement in New York Heart Association (NYHA) function class and a combined endpoint of death or heart failure hospitalization (HFH) at two-years., Results: Among a total of 1230 patients (mean age 78.6 ±7.0 years; 51.4% women) increasing systolic pulmonary artery pressure (sPAP) was independently associated with increasing rates of two-year death or HFH (hazard ratio 1.027, 95% confidence interval 1.003-1.052, p=0.030; median survival follow up 343 (114-645) days). No significant survival differences were observed for patients with pre- vs. postcapillary PH. Sensitivity analysis revealed a sPAP value of 46 mmHg as optimized threshold for prediction of death or HFH. Being observed in 526 patients (42.8%), elevated sPAP > 46 mmHg was associated with more severe heart failure symptoms at baseline and follow-up. Importantly, NYHA functional class and TR severity significantly improved irrespective of PH., Conclusion: PH is an important outcome predictor in patients undergoing T-TEER for relevant TR. In contrast to previous studies, no significant differences were observed for patients with pre- and postcapillary PH in terms of survival free from HFH., (Copyright © 2024. Published by Elsevier Inc.)
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- 2024
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49. 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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50. 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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