EBioMedicine (Jun 2022)
Interleukin-6 inhibition in ST-elevation myocardial infarction: Immune cell profile in the randomised ASSAIL-MI trial
- Camilla Huse,
- Anne Kristine Anstensrud,
- Annika E. Michelsen,
- Thor Ueland,
- Kaspar Broch,
- Sindre Woxholt,
- Kuan Yang,
- Kapil Sharma,
- Ingvild Maria Tøllefsen,
- Bjørn Bendz,
- Brage Høyem Amundsen,
- Jan Kristian Damås,
- Erlend Sturle Berg,
- Elisabeth Bjørkelund,
- Ana Quiles-Jiménez,
- Vigdis Bjerkeli,
- Christina Bendz,
- Ola Kleveland,
- Knut Haakon Stensaeth,
- Anders Opdahl,
- Nils-Einar Kløw,
- Geir Øystein Andersen,
- Rune Wiseth,
- Bente Halvorsen,
- Lars Gullestad,
- Ingebjørg Seljeflot,
- Pål Aukrust,
- Liv Osnes,
- Tuva B. Dahl
Affiliations
- Camilla Huse
- Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway; Faculty of Medicine, Institute of Clinical Medicine, University of Oslo, Oslo, Norway
- Anne Kristine Anstensrud
- Department of Cardiology, Oslo University Hospital Rikshospitalet, Oslo, Norway; Faculty of Medicine, Institute of Clinical Medicine, University of Oslo, Oslo, Norway
- Annika E. Michelsen
- Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway; Faculty of Medicine, Institute of Clinical Medicine, University of Oslo, Oslo, Norway
- Thor Ueland
- Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway; K. G. Jebsen Thrombosis Research and Expertise Centre (TREC), The Arctic University of Norway, Tromsø, Norway
- Kaspar Broch
- Department of Cardiology, Oslo University Hospital Rikshospitalet, Oslo, Norway; K. G. Jebsen Cardiac Research Centre and Centre for Heart Failure Research, University of Oslo, Oslo, Norway
- Sindre Woxholt
- Clinic of Cardiology, St. Olav's Hospital, Trondheim University Hospital, Trondheim, Norway; Department of Circulation and Medical Imaging, Norwegian University of Science and Technology (NTNU), Trondheim, Norway
- Kuan Yang
- Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway; Faculty of Medicine, Institute of Clinical Medicine, University of Oslo, Oslo, Norway
- Kapil Sharma
- Department of Cardiology, Oslo University Hospital Ullevål, Oslo, Norway
- Ingvild Maria Tøllefsen
- Department of Cardiology, Oslo University Hospital Ullevål, Oslo, Norway
- Bjørn Bendz
- Department of Cardiology, Oslo University Hospital Rikshospitalet, Oslo, Norway; Faculty of Medicine, Institute of Clinical Medicine, University of Oslo, Oslo, Norway
- Brage Høyem Amundsen
- Clinic of Cardiology, St. Olav's Hospital, Trondheim University Hospital, Trondheim, Norway; Department of Circulation and Medical Imaging, Norwegian University of Science and Technology (NTNU), Trondheim, Norway
- Jan Kristian Damås
- Department of Infectious Disease, St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway; Department of Clinical and Molecular Medicine, Centre of Molecular Inflammation Research, Norwegian University of Science and Technology (NTNU), Trondheim, Norway
- Erlend Sturle Berg
- Department of Cardiology, Oslo University Hospital Rikshospitalet, Oslo, Norway
- Elisabeth Bjørkelund
- Department of Cardiology, Oslo University Hospital Rikshospitalet, Oslo, Norway
- Ana Quiles-Jiménez
- Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway; Faculty of Medicine, Institute of Clinical Medicine, University of Oslo, Oslo, Norway
- Vigdis Bjerkeli
- Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway; Faculty of Medicine, Institute of Clinical Medicine, University of Oslo, Oslo, Norway
- Christina Bendz
- Department of Cardiology, Oslo University Hospital Rikshospitalet, Oslo, Norway
- Ola Kleveland
- Clinic of Cardiology, St. Olav's Hospital, Trondheim University Hospital, Trondheim, Norway; Department of Circulation and Medical Imaging, Norwegian University of Science and Technology (NTNU), Trondheim, Norway
- Knut Haakon Stensaeth
- Department of Circulation and Medical Imaging, Norwegian University of Science and Technology (NTNU), Trondheim, Norway; Department of Radiology and Nuclear Medicine, St. Olav's Hospital, Trondheim University Hospital, Trondheim, Norway
- Anders Opdahl
- Department of Cardiology, Oslo University Hospital Rikshospitalet, Oslo, Norway
- Nils-Einar Kløw
- Department of Radiology, Oslo University Hospital Ullevål, Oslo, Norway; Faculty of Medicine, Institute of Clinical Medicine, University of Oslo, Oslo, Norway
- Geir Øystein Andersen
- Department of Cardiology, Oslo University Hospital Ullevål, Oslo, Norway; Department of Cardiology, Center for Clinical Heart Research, Oslo University Hospital Ullevål, Oslo, Norway
- Rune Wiseth
- Clinic of Cardiology, St. Olav's Hospital, Trondheim University Hospital, Trondheim, Norway; Department of Circulation and Medical Imaging, Norwegian University of Science and Technology (NTNU), Trondheim, Norway
- Bente Halvorsen
- Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway; Faculty of Medicine, Institute of Clinical Medicine, University of Oslo, Oslo, Norway
- Lars Gullestad
- Department of Cardiology, Oslo University Hospital Rikshospitalet, Oslo, Norway; K. G. Jebsen Cardiac Research Centre and Centre for Heart Failure Research, University of Oslo, Oslo, Norway; Faculty of Medicine, Institute of Clinical Medicine, University of Oslo, Oslo, Norway
- Ingebjørg Seljeflot
- Department of Cardiology, Oslo University Hospital Ullevål, Oslo, Norway; Faculty of Medicine, Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Department of Cardiology, Center for Clinical Heart Research, Oslo University Hospital Ullevål, Oslo, Norway
- Pål Aukrust
- Faculty of Medicine, Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Department of Rheumatology, Dermatology and Infectious Disease, Oslo University Hospital Rikshospitalet, Oslo, Norway
- Liv Osnes
- Department of Immunology, Oslo University Hospital Rikshospitalet, Oslo, Norway
- Tuva B. Dahl
- Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway; Department of Research and Development, Division of Emergencies and Critical Care, Oslo University Hospital, Norway; Corresponding author at: Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, PO Box 4950 Nydalen, Oslo 0424, Norway.
- Journal volume & issue
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Vol. 80
p. 104013
Abstract
Summary: Background: We recently showed that interleukin (IL)-6 inhibition by tocilizumab improves myocardial salvage in ST-elevation myocardial infarction (STEMI). However, the mechanisms for this effect are not clear. Methods: In this exploratory sub-study of the ASSAIL-MI trial, we examined leukocyte differential counts and their relation to myocardial salvage and peak troponin T (TnT) in STEMI patients randomised to tocilizumab (n = 101) or placebo (n = 98). We performed RNA-sequencing on whole blood (n = 40) and T cells (n = 20). B and T cell subpopulations were examined by flow cytometry (n = 69). Findings: (i) STEMI patients had higher neutrophil counts at hospitalisation compared with stable angina patients. (ii) After percutaneous coronary intervention there was a gradual decline in neutrophils, which was significantly more pronounced in the tocilizumab group. (iii) The decrease in neutrophils in the tocilizumab group was associated with improved myocardial salvage and lower peak TnT. (iv) RNA-sequencing suggested that neutrophil function was also attenuated by tocilizumab. (v) B and T cell sub-populations changed only minimally after STEMI with minor effects of tocilizumab, supported as well by RNA-sequencing analyses of T cells. (vi) However, a low CD8+ count was associated with improved myocardial salvage in patients admitted to the hospital > 3 h after symptom onset. Interpretation: Tocilizumab induced a rapid reduction in neutrophils and seemed to attenuate neutrophil function in STEMI patients potentially related to the beneficial effects of tocilizumab on myocardial salvage. Funding: South-Eastern Norway Regional Health Authority (Nos. 2019067, 2017084), the Central Norway Regional Health Authority and Norwegian Research Council (No. 283867).
