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Original research
Trimethylamine-N-oxide is associated with cardiovascular mortality and vascular brain lesions in patients with atrial fibrillation
  1. Marco Luciani1,2,
  2. Daniel Müller3,4,
  3. Chiara Vanetta5,
  4. Thamonwan Diteepeng2,
  5. Arnold von Eckardstein3,
  6. Stefanie Aeschbacher6,7,
  7. Nicolas Rodondi8,9,
  8. Giorgio Moschovitis10,
  9. Tobias Reichlin11,
  10. Tim Sinnecker12,13,
  11. Jens Wuerfel13,14,
  12. Leo H Bonati12,15,
  13. Seyed Soheil Saeedi Saravi1,2,
  14. Patricia Chocano-Bedoya8,16,
  15. Michael Coslovsky7,17,
  16. Giovanni G Camici2,
  17. Thomas F Lüscher2,18,19,
  18. Michael Kuehne6,20,
  19. Stefan Osswald6,20,
  20. David Conen21,
  21. Jürg Hans Beer1,2
  22. SWISS-AF Investigators
    1. 1Department of Medicine, Baden Cantonal Hospital, Baden, Switzerland
    2. 2Center for Molecular Cardiology, University of Zurich, Schlieren, Switzerland
    3. 3Institute of Clinical Chemistry, University Hospital Zurich, Zurich, Switzerland
    4. 4Laboratory Medicine, University of Basel, Basel, Switzerland
    5. 5Seminar for Statistics, ETH Zurich, Zurich, Switzerland
    6. 6Cardiovascular Research Institute, University Hospital Basel, Basel, Switzerland
    7. 7Cardiology Division, University Hospital Basel, Basel, Switzerland
    8. 8Institute of Primary Health Care (BIHAM), University of Bern, Bern, Switzerland
    9. 9Department of General Internal Medicine, Inselspital University Hospital Bern, Bern, Switzerland
    10. 10Division of Cardiology, Ospedale Regionale di Lugano-Civico e Italiano, Lugano, Switzerland
    11. 11Department of Cardiology, Inselspital Universitatsspital Bern, Bern, Switzerland
    12. 12Department of Neurology and Stroke Center, University Hospital Basel, Basel, Switzerland
    13. 13Medical Image Analysis Center (MIAC), Basel, Switzerland
    14. 14Department of Biomedical Engineering, University of Basel, Basel, Switzerland
    15. 15Research Department, Reha Rheinfelden, Rheinfelden, Switzerland
    16. 16Population Health Laboratory, University of Fribourg, Fribourg, Switzerland
    17. 17Department of Clinical Research, University Hospital Basel, Basel, Switzerland
    18. 18Department of Cardiology, Royal Brompton and Harefield Hospitals Trust, London, UK
    19. 19National Heart and Lung Institute, Imperial College, London, UK
    20. 20Cardiology Division, University of Basel Hospital, Basel, Switzerland
    21. 21Population Health Research Institute, McMaster University, Hamilton, Ontario, Canada
    1. Correspondence to Professor Jürg Hans Beer, Department of Medicine, Cantonal Hospital of Baden, Baden Cantonal Hospital, Baden, 5404, Switzerland; hansjuerg.beer{at}ksb.ch

    Abstract

    Objective Trimethylamine-N-oxide (TMAO) is a metabolite derived from the microbial processing of dietary phosphatidylcholine and carnitine and the subsequent hepatic oxidation. Due to its prothrombotic and inflammatory mechanisms, we aimed to assess its role in the prediction of adverse events in a susceptible population, namely patients with atrial fibrillation.

    Methods Baseline TMAO plasma levels were measured by liquid chromatography-tandem mass spectrometry in 2379 subjects from the ongoing Swiss Atrial Fibrillation cohort. 1722 underwent brain MRI at baseline. Participants were prospectively followed for 4 years (Q1–Q3: 3.0–5.0) and stratified into baseline TMAO tertiles. Cox proportional hazards and linear and logistic mixed effect models were employed adjusting for risk factors.

    Results Subjects in the highest TMAO tertile were older (75.4±8.1 vs 70.6±8.5 years, p<0.01), had poorer renal function (median glomerular filtration rate: 49.0 mL/min/1.73 m2 (35.6–62.5) vs 67.3 mL/min/1.73 m2 (57.8–78.9), p<0.01), were more likely to have diabetes (26.9% vs 9.1%, p<0.01) and had a higher prevalence of heart failure (37.9% vs 15.8%, p<0.01) compared with patients in the lowest tertile. Oral anticoagulants were taken by 89.1%, 94.0% and 88.2% of participants, respectively (from high to low tertiles). Cox models, adjusting for baseline covariates, showed increased total mortality (HR 1.65, 95% CI 1.17 to 2.32, p<0.01) as well as cardiovascular mortality (HR 1.86, 95% CI 1.21 to 2.88, p<0.01) in the highest compared with the lowest tertile. When present, subjects in the highest tertile had more voluminous, large, non-cortical and cortical infarcts on MRI (log-transformed volumes; exponentiated estimate 1.89, 95% CI 1.11 to 3.21, p=0.02) and a higher chance of small non-cortical infarcts (OR 1.61, 95% CI 1.16 to 2.22, p<0.01).

    Conclusions High levels of TMAO are associated with increased risk of cardiovascular mortality and cerebral infarction in patients with atrial fibrillation.

    Trial registration number NCT02105844.

    • Atrial Fibrillation
    • Magnetic Resonance Angiography
    • Biomarkers
    • Stroke

    Data availability statement

    Data are available upon reasonable request.

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    Data availability statement

    Data are available upon reasonable request.

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    Footnotes

    • Collaborators SWISS-AF Investigators. Stefanie Aeschbacher, Chloé Auberson, Steffen Blum, Leo Bonati, Selinda Ceylan, David Conen, Simone Evers- Doerpfeld, Ceylan Eken, Marc Girod, Elisa Hennings, Elena Herber, Vasco Iten, Philipp Krisai, Michael Kühne, Mirko Lischer, Christine Meyer-Zürn, Pascal Meyre, Andreas U. Monsch, Christian Müller, Stefan Osswald, Rebecca Paladini, Anne Springer, Christian Sticherling, Thomas Szucs, Gian Völlmin, Stefan Osswald, Michael Kühne, Drahomir Aujesky, Urs Fischer, Juerg Fuhrer, Laurent Roten, Simon Jung, Heinrich Mattle, Luise Adam, Carole Elodie Aubert, Martin Feller, Axel Loewe, Elisavet Moutzouri, Claudio Schneider, Tanja Flückiger, Cindy Groen, Lukas Ehrsam, Sven Hellrigl, Alexandra Nuoffer, Damiana Rakovic, Nathalie Schwab, Rylana Wenger, Tu Hanh Zarrabi Saffari, Nicolas Rodondi, Tobias Reichlin, Christopher Beynon, Roger Dillier, Michèle Deubelbeiss, Franz Eberli, Christine Franzini, Isabel Juchli, Claudia Liedtke, Samira Murugiah, Jacqueline Nadler, Thayze Obst, Jasmin Roth, Fiona Schlomowitsch, Xiaoye Schneider, Katrin Studerus, Noreen Tynan, Dominik Weishaupt, Andreas Müller, Simone Fontana, Corinne Friedli, Silke Kuest, Karin Scheuch, Denise Hischier, Nicole Bonetti, Alexandra Grau, Jonas Villinger, Eva Laube, Philipp Baumgartner, Mark Filipovic, Marcel Frick, Giulia Montrasio, Stefanie Leuenberger, Franziska Rutz, Jürg-Hans Beer, Angelo Auricchio, Adriana Anesini, Cristina Camporini, Giulio Conte, Maria Luce Caputo, Francois Regoli, Tiziano Moccetti, Roman Brenner, David Altmann, Michaela Gemperle, Peter Ammann, Mathieu Firmann, Sandrine Foucras, Martine Rime, Daniel Hayoz, Benjamin Berte, Virgina Justi, Frauke Kellner-Weldon, Brigitta Mehmann, Sonja Meier, Myriam Roth, Andrea Ruckli-Kaeppeli, Ian Russi, Kai Schmidt, Mabelle Young, Melanie Zbinden, Richard Kobza, Carlo Cereda, Alessandro Cianfoni, Maria Luisa De Perna, Jane Frangi-Kultalahti, Patrizia Assunta Mayer Melchiorre, Anica Pin, Tatiana Terrot, Luisa Vicari, Giorgio Moschovitis, Georg Ehret, Hervé Gallet, Elise Guillermet, Francois Lazeyras, Karl-Olof Lovblad, Patrick Perret, Philippe Tavel, Cheryl Teres, Dipen Shah, Nathalie Lauriers, Marie Méan, Sandrine Salzmann, Jürg Schläpfer, Alessandra Pia Porretta, Andrea Grêt, Jan Novak, Sandra Vitelli, Frank-Peter Stephan, Jane Frangi-Kultalahti, Augusto Gallino, Luisa Vicari, Marcello Di Valentino, Helena Aebersold, Fabienne Foster, Matthias Schwenkglenks, Jens Würfel, Anna Altermatt, Michael Amann, Marco Düring, Petra Huber, Esther Ruberte, Tim Sinnecker, Vanessa Zuber, Michael Coslovsky, Pascal Benkert, Gilles Dutilh, Milica Markovic, Pia Neuschwander, Patrick Simon, Ramun Schmid.

    • Contributors ML and JHB conceived and designed the current substudy and are responsible for the overall content of the manuscript. SA, NR, GM, TR, TS, JW, LHB, PC-B, MC, MK and DC conceived and planned the SWISS-AF study and were responsible for this study in their reference centres and provided additional inputs for improvement of the current substudy and manuscript production. ML, TD, DM and AvE conducted experiments and performed the quality control analysis of LC-MS/MS without having access to clinical data before their release. CV and MC performed the statistical analysis. SSSS, GGC and TFL provided additional conceptual inputs and insights and critically reviewed the manuscript. All authors have reviewed and accepted the current version of the manuscript.

    • Funding The SWISS-AF study is supported by grants from the Swiss National Science Foundation (grant numbers 33CS30_148474, 33CS30_177520, 32473B_176178 and 32003B_197524) and the Swiss Heart Foundation. The present substudy is supported by the Theodor and Ida Herzog-Egli Foundation in association with the University of Zurich.

    • Competing interests ML is supported by Forschungskredit from the University of Zurich (FK-19-043) and received honoraria from Boehringer Ingelheim and Pfizer, outside of the current work. DC received consulting fees from Roche Diagnostics and speaker fees from BMS/Pfizer, both outside of the current work. JHB is supported by the Swiss National Foundation of Science (324730_182328), the Swiss Heart Foundation and Kardio Foundation; he has received grant support and consultation fees through the institution from Bayer, Daiichi Sankyo and Sanofi. TFL has received research and educational funding and in part consulting honoraria from Abbott, Amgen, AstraZeneca, Boehringer Ingelheim, Daiichi Sankyo, Novartis, Servier, Sanofi and Vifor, outside this work. GM has received consultant fees for taking part in the advisory boards from Novartis, Boehringer Ingelheim, Bayer, AstraZeneca and Daiichi Sankyo, all outside of the presented work.

    • Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

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