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Original article
Effect of interleukin-6 inhibition on coronary microvascular and endothelial function in myocardial infarction
  1. Espen Holte1,2,
  2. Ola Kleveland1,2,
  3. Thor Ueland3,4,5,6,7,
  4. Gabor Kunszt8,
  5. Marte Bratlie4,5,8,
  6. Kaspar Broch6,8,
  7. Annika E Michelsen4,5,
  8. Bjørn Bendz8,
  9. Brage H Amundsen1,2,
  10. Svend Aakhus1,2,
  11. Jan Kristian Damås9,
  12. Lars Gullestad5,8,10,
  13. Pål Aukrust3,4,5,7,11,
  14. Rune Wiseth1,2
  1. 1 Clinic of Cardiology, St Olavs Hospital, Trondheim, Norway
  2. 2 Department of Circulation and Medical Imaging, Norwegian University of Science and Technology NTNU, Trondheim, Norway
  3. 3 K.G. Jebsen Thrombosis Research and Expertise Centre, University of Tromsø, Tromsø, Norway
  4. 4 Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway
  5. 5 Institute of Clinical Medicine, University of Oslo, Oslo, Norway
  6. 6 K.G. Jebsen Cardiac Research Centre, University of Oslo, Oslo, Norway
  7. 7 K.G. Jebsen Centre of Inflammatory Research, University of Oslo, Oslo, Norway
  8. 8 Department of Cardiology, Oslo University Hospital Rikshospitalet, Oslo, Norway
  9. 9 Centre of Molecular Inflammation Research, Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology NTNU, Trondheim, Norway
  10. 10 Center for Heart Failure Research, University of Oslo, Oslo, Norway
  11. 11 Section of Clinical Immunology and Infectious Diseases, Oslo University Hospital Rikshospitalet, Oslo, Norway
  1. Correspondence to Dr Espen Holte, Clinic of Cardiology, St Olavs Hospital, P.B. 3250 Sluppen, Trondheim 7006, Norway; espen.holte{at}ntnu.no

Abstract

Objective Interleukin-6 (IL-6) is a driver of inflammation and associated endothelial cell activation in acute coronary syndromes. We evaluated the effect of the IL-6 receptor antagonist tocilizumab on coronary microvascular function and endothelial dysfunction measured by coronary flow reserve (CFR) and markers of endothelial cell activation in patients with non-ST-elevation myocardial infarction (NSTEMI).

Methods This substudy was part of a two-centre, double-blind, randomised, placebo-controlled trial evaluating the effect of a single dose of tocilizumab in NSTEMI. Markers of endothelial cell activation (vascular cell adhesion molecule (VCAM)-1, intercellular adhesion molecule-1 and von Willebrand factor) were assessed in 117 patients. In 42 of these patients, 20 assigned to placebo and 22 to tocilizumab, we measured CFR. Blood samples were obtained at seven consecutive time points between day 1 and 3. CFR was measured by transthoracic echocardiography during hospitalisation and after 6 months.

Results Tocilizumab did not affect CFR during hospitalisation (tocilizumab: 3.4±0.8 vs placebo: 3.3±1.2, p=0.80). CFR improved significantly in both groups at 6 months. Patients in the tocilizumab group had significantly higher area under the curve for VCAM-1 (median 622 vs 609 ng/mL/hour, tocilizumab and placebo respectively, p=0.003). There were inverse correlations between VCAM-1 and CFR in the placebo (hospitalisation: r=−0.74, p<0.01, 6 months: r=−0.59, p<0.01), but not in the tocilizumab group (hospitalisation: r=0.20, p=0.37, 6 months r=−0.28, p=0.20).

Conclusions Tocilizumab did not affect CFR during hospitalisation or after 6 months. Tocilizumab increased VCAM-1 levels during hospitalisation, but this was not associated with reduced CFR in these patients.

  • Echocardiography
  • Inflammatory markers
  • Acute coronary syndromes
  • Acute myocardial infarction
  • Vascular biology

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Footnotes

  • Contributors EH and OK are joint first authors.

  • Funding South-Eastern Norway Regional Health Authorities, Oslo, Norway.

  • Competing interests LG has participated in an expert meeting sponsored by F. Hoffmann-La Roche AG in 2014. The other authors declare no conflicts of interest.

  • Ethics approval Regional Committee for Medical and Health Research Ethics of South-Eastern Norway.

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

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