BACKGROUND: The clinical relevance of cardiac troponin (cTn) elevation in takotsubo syndrome (TTS) remains uncertain. The present study sought to investigate the role of cardiac troponin (cTn) elevations in mortality prediction of patients with Takotsubo syndrome (TTS). METHODS: Patients enrolled in the International Takotsubo (InterTAK) Registry from January 2011 to February 2020 with available data on peak cTn levels were included in the analysis. Peak cTn levels during the index hospitalization were used to define clinically relevant myocardial injury. The threshold at which clinically relevant myocardial injury drives mortality at 1 year was identified using restricted cubic spline analysis. RESULTS: Out of 2'938 patients, 222 (7.6%) patients died during 1-year follow-up. A more than 28.8-fold increase of cTn above the upper reference limit was identified as threshold for clinically relevant myocardial injury. The presence of clinically relevant myocardial injury was significantly associated with an increased risk of mortality at 5 years (adjusted HR 1.58, 95% CI 1.18-2.12, p =.002). Clinically relevant myocardial injury was related to an increased 5-year mortality risk in patients with apical TTS (adjusted HR 1.57, 95% CI 1.21-2.03, p =.001), in presence of physical stressors (adjusted HR 1.60, 95% CI 1.22-2.11, p =.001), and in absence of emotional stressors (adjusted HR 1.49, 95% CI, 1.17-1.89, p =.001). CONCLUSION: This study for the first time determined a troponin threshold for the identification of TTS patients at excess risk of mortality. These findings advance risk stratification in TTS and assist in identifying patients in need for close monitoring and follow-up.

1st Clinic of Internal Medicine Department of Internal Medicine University of Genoa Genoa Italy

1st Department of Cardiology Medical University of Gdansk Gdansk Poland

1st Department of Medicine Faculty of Medicine University Medical Centre Mannheim University of Heidelberg Mannheim Germany

Advanced Heart Failure and Transplantation Center University Medical Center Ljubljana Ljubljana Slovenia

Berlin Institute of Health Berlin Germany

Cardiocenter 3rd Faculty of Medicine Charles University Prague and University Hospital Královské Vinohrady Prague Czech Republic

Center for Cardiology Cardiology 1 University Medical Center Mainz Mainz Germany

Center for Molecular Cardiology Schlieren Campus University of Zurich Zurich Switzerland

Center of Translational and Experimental Cardiology University Hospital Zurich Zurich Switzerland

Centro cardiologico Monzino IRCCS Milan Italy

Christine Kühne Center for Allergy Research and Education Medicine Campus Davos Davos Switzerland

Clinic for Cardiology and Pneumology Georg August University Goettingen Goettingen Germany

Department of Cardiology and Angiology Hannover Medical School Hannover Germany

Department of Cardiology and Cardiac Imaging Center University Hospital of Rangueil Toulouse France

Department of Cardiology and Internal Medicine B University Medicine Greifswald Germany

Department of Cardiology Basil Hetzel Institute Queen Elizabeth Hospital University of Adelaide Adelaide Australia

Department of Cardiology Centro Hospitalar Universitário de São João E P E Porto Portugal

Department of Cardiology Chiba Emergency Medical Center Chiba Japan

Department of Cardiology Christchurch Hospital Christchurch New Zealand

Department of Cardiology Deutsches Herzzentrum der Charité Angiology and Intensive Care Medicine Berlin Germany

Department of Cardiology Heidelberg University Hospital Heidelberg Germany

Department of Cardiology John Radcliffe Hospital Oxford University Hospitals Oxford UK

Department of Cardiology Kantonsspital Frauenfeld Frauenfeld Switzerland

Department of Cardiology Kantonsspital Lucerne Lucerne Switzerland

Department of Cardiology Kantonsspital St Gallen St Gallen Switzerland

Department of Cardiology Kantonsspital Winterthur Winterthur Switzerland

Department of Cardiology King's College Hospital London UK

Department of Cardiology Leiden University Medical Centre Leiden The Netherlands

Department of Cardiology Medical University of Warsaw Warsaw Poland

Department of Cardiology National University Heart Centre Singapore Singapore

Department of Cardiology University Hospital Basel Basel Switzerland

Department of Cardiovascular Diseases Mayo Clinic Rochester Minnesota USA

Department of Cardiovascular Medicine Chiba University Graduate School of Medicine Chiba Japan

Department of Cardiovascular Medicine Nippon Medical School Tokyo Japan

Department of Intensive Care Medicine University Medical Center Hamburg Eppendorf Hamburg Germany

Department of Internal Medicine 1 Cardiology University Hospital Olomouc Olomouc Czech Republic

Department of Internal Medicine 1 University Hospital Jena Friedrich Schiller University Jena Jena Germany

Department of Internal Medicine 2 Cardiology University of Ulm Medical Center Ulm Germany

Department of Internal Medicine 3 Heart Center University of Cologne Cologne Germany

Department of Internal Medicine Cardiology and Angiology Magdeburg University Magdeburg Germany

Department of Internal Medicine Cardiology Heart Center Leipzig University Hospital Leipzig Germany

Department of Medicine Surgery and Dentistry University of Salerno Salerno Italy

Deutsches Herzzentrum München Technische Universität München Munich Germany

Division of Cardiology A O U San Luigi Gonzaga Orbassano Turin Italy

Division of Cardiology Antonio Cardarelli Hospital Naples Italy

Division of Cardiology Department of Medical Sciences AOU Città della Salute e della Scienza University of Turin Turin Italy

Division of Cardiology Heart and Vascular Center University of Iowa Iowa City Iowa USA

Division of Cardiology Kimitsu Central Hospital Kisarazu Japan

Division of Cardiology Medical University of Graz Graz Austria

Division of Cardiovascular Medicine Department of Medicine College of Medicine University of Florida Gainesville Florida USA

Division of Clinical Cardiology Research Responsible Hospital Department of Medicine and Health Science University of Molise Campobasso Italy

Dorset Heart Centre Royal Bournemouth Hospital Bournemouth UK

DZHK Partner Site Greifswald Greifswald Germany

DZHK Partner Site Hamburg Kiel Luebeck Hamburg Germany

DZHK Partner Site Heidelberg Mannheim Mannheim Germany

DZHK partner site Munich Heart Alliance Munich Germany

Fondazione Policlinico Universitario A Gemelli IRCCS Università Cattolica del Sacro Cuore Rome Italy

Heart and Vascular Centre Bad Bevensen Bad Bevensen Germany

Heart Center Turku University Hospital and University of Turku Turku Finland

Heart Department University Hospital San Giovanni di Dio e Ruggi d'Aragona Salerno Italy

Hochgebirgsklinik Medicine Campus Davos Davos Switzerland

Intensive Coronary Care Unit Moscow City Hospital 1 named after N Pirogov Moscow Russia

IRCCS Ospedale Policlinico San Martino Genoa Italian Cardiovascular Network Genoa Italy

Klinik für Akut und Notfallmedizin St Antonius Hospital gGmbH Akademisches Lehrkrankenhaus der RWTH Aachen Eschweiler Germany

Klinik für Innere Medizin 3 Universitätsklinikum des Saarlandes Homburg Saar Germany

Klinik und Poliklinik für Innere Medizin 2 Universitätsklinikum Regensburg Regensburg Germany

Krankenhaus Maria Hilf Medizinische Klinik Stadtlohn Germany

Local Health Unit n 8 Cardiology Unit Vicenza Italy

Mid German Heart Center Department of Internal Medicine 3 Division of Cardiology Angiology and Intensive Medical Care University Hospital Halle Martin Luther University Halle Wittenberg Halle Germany

Royal Brompton and Harefield Hospitals Trust and Imperial College London UK

Santa Maria University Hospital CHULN Center of Cardiology of the University of Lisbon Lisbon School of Medicine Lisbon Academic Medical Center Lisboa Portugal

Section of Cardiac Electrophysiology Department of Medicine University of California San Francisco San Francisco California USA

Service de Cardiologie Hôpitaux Universitaires de Genève Geneva Switzerland

Structural Interventional Cardiology Careggi University Hospital Florence Italy

TJ Health Partners Heart and Vascular Glasgow Kentucky USA

University Heart Center Department of Cardiology University Hospital Zurich and University of Zurich Zurich Switzerland

University Hospital for Internal Medicine 3 Medical University Innsbruck Innsbruck Austria

University of Southern California Keck School of Medicine Los Angeles California USA

Vascular Physiopathology Unit IRCCS Neuromed Pozzilli Italy

Vincentius Diakonissen Hospital Karlsruhe Germany

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