Early increase of specialized pro-resolving lipid mediators in patients with ST-elevation myocardial infarction

Linn E Fosshaug; Romain A Colas; Anne K Anstensrud; Ida Gregersen; Ståle Nymo; Ellen L Sagen; Annika Michelsen; Leif E Vinge; Erik Øie; Lars Gullestad; Bente Halvorsen; Trond V Hansen; Pål Aukrust; Jesmond Dalli; Arne Yndestad

doi:10.1016/j.ebiom.2019.07.024

Early increase of specialized pro-resolving lipid mediators in patients with ST-elevation myocardial infarction

EBioMedicine. 2019 Aug:46:264-273. doi: 10.1016/j.ebiom.2019.07.024. Epub 2019 Jul 22.

Authors

Linn E Fosshaug¹, Romain A Colas², Anne K Anstensrud³, Ida Gregersen⁴, Ståle Nymo⁵, Ellen L Sagen⁴, Annika Michelsen⁴, Leif E Vinge⁶, Erik Øie⁷, Lars Gullestad⁸, Bente Halvorsen⁴, Trond V Hansen⁹, Pål Aukrust¹⁰, Jesmond Dalli¹¹, Arne Yndestad¹²

Affiliations

¹ Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway; Department of Medicine, Diakonhjemmet Hospital, Oslo, Norway; Center for Heart Failure Research, Oslo University Hospital, Oslo, Norway; Institute of Clinical Medicine, University of Oslo, Norway. Electronic address: l.e.lillerud@medisin.uio.no.
² William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London, UK.
³ Center for Heart Failure Research, Oslo University Hospital, Oslo, Norway; Institute of Clinical Medicine, University of Oslo, Norway; Department of Cardiology, Oslo University Hospital Rikshospitalet, Oslo, Norway.
⁴ Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway; Institute of Clinical Medicine, University of Oslo, Norway.
⁵ Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway.
⁶ Department of Medicine, Diakonhjemmet Hospital, Oslo, Norway; Center for Heart Failure Research, Oslo University Hospital, Oslo, Norway; Surgical Research, Oslo University Hospital Rikshospitalet, Oslo, Norway.
⁷ Department of Medicine, Diakonhjemmet Hospital, Oslo, Norway; Center for Heart Failure Research, Oslo University Hospital, Oslo, Norway.
⁸ Center for Heart Failure Research, Oslo University Hospital, Oslo, Norway; Institute of Clinical Medicine, University of Oslo, Norway; Department of Cardiology, Oslo University Hospital Rikshospitalet, Oslo, Norway; KG Jebsen Center for Cardiac Research, University of Oslo, Oslo, Norway.
⁹ School of Pharmacy, Department of Pharmaceutical Chemistry, University of Oslo, Oslo, Norway.
¹⁰ Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway; Institute of Clinical Medicine, University of Oslo, Norway; School of Pharmacy, Department of Pharmaceutical Chemistry, University of Oslo, Oslo, Norway; Section of Clinical Immunology and Infectious Diseases, Oslo University Hospital Rikshospitalet, Oslo, Norway.
¹¹ William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London, UK; Centre for Inflammation and Therapeutic Innovation, Queen Mary University of London, London, UK.
¹² Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway; Center for Heart Failure Research, Oslo University Hospital, Oslo, Norway; Institute of Clinical Medicine, University of Oslo, Norway.

Abstract

Background: Termination of acute inflammation is an active process orchestrated by lipid mediators (LM) derived from polyunsaturated fatty acids, referred to as specialized pro-resolving mediators (SPM). These mediators also provide novel therapeutic opportunities for treating inflammatory disease. However, the regulation of these molecules following acute myocardial infarction (MI) remains of interest.

Methods: In this prospective observational study we aimed to profile plasma levels of SPMs in ST-elevation MI (STEMI) patients during the first week following MI. Plasma LM concentrations were measured in patients with STEMI (n = 15) at three time points and compared with stable coronary artery disease (CAD; n = 10) and healthy controls (n = 10).

Findings: Our main findings were: (i) Immediately after onset of MI and before peak troponin T levels, STEMI patients had markedly increased levels of SPMs as compared with healthy controls and stable CAD patients, with levels of these mediators declining during follow-up. (ii) The increase in SPMs primarily reflected an increase in docosapentaenoic acid- and docosahexaenoic acid-derived protectins. (iii) Several individual protectins were correlated with the rapid increase in neutrophil counts, but not with CRP. (iv) A shift in 5-LOX activity from the leukotriene B₄ pathway to the pro-resolving RvTs was observed.

Interpretation: The temporal regulation of SPMs indicates that resolution mechanisms are activated early during STEMI as part of an endogenous mechanism to initiate repair. Thus strategies to boost the activity and/or efficacy of these endogenous mechanisms may represent novel therapeutic opportunities for treatment of patients with MI. FUND: This work was supported by grants from the South-Eastern Norwegian regional health authority, the European Research Council under the European Union's Horizon 2020 research and innovation program, a Sir Henry Dale Fellowship jointly funded by the Wellcome Trust and the Royal Society, and the Barts Charity.

Keywords: Inflammation; Myocardial infarction; Polyunsaturated fatty acids; Resolution; Specialized pro-resolving mediators.

MeSH terms

Aged
Biomarkers
Case-Control Studies
Cytokines / blood
Female
Humans
Inflammation Mediators / blood*
Lipids / blood*
Male
Middle Aged
Myocardial Infarction / blood
Myocardial Infarction / diagnosis
Myocardial Infarction / etiology
Prospective Studies
ST Elevation Myocardial Infarction / blood*
ST Elevation Myocardial Infarction / diagnosis
ST Elevation Myocardial Infarction / etiology

Substances

Biomarkers
Cytokines
Inflammation Mediators
Lipids

Grants and funding

677542/ERC_/European Research Council/International