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

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 B 4 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.

Race‐based and sex‐based differences in bioactive lipid mediators after myocardial infarction

“…19,36 Before troponin markers, leucocyte-directed SPMs are immune responsive polyunsaturated fatty acids-derived biomolecules generated within a narrow time window after the cardiac injury that initiate resolution of inflammation. 20,36 Deficiency of SPMs associated with monocyte/macrophage depletion or in obesogenic ageing leads to non-resolving inflammation. 20,37 Ethyl EPA lowered the risk of MI events, stroke, and overall CV death by 25% in patients with hypertriglyceridaemia in the REDUCE-IT trial and by 19% in the JELIS trial, suggesting preventive therapy.…”

“…Time-dependent cardiac repair in pathogen and risk-free rodents clearly suggests that the timing of the acute inflammatory phase coincides with the beginning of the resolving phase, to the same extent as MI patients biosynthesize resolution molecules within 2.5 h as the onset of initial inflammation post-MI. 20,33,36 Thus, beginning of acute inflammation-resolution programmes the termination of inflammatory response after cardiac injury of acute inflammation programmes the beginning of inflammatory resolution after cardiac injury. 43 A previous report indicates that SPMs levels in atheroma define the stable and unstable milieu, providing the rationale for precise and personalized therapy for atherosclerotic patients.…”

“…Recently published temporal analyses of SPMs at the onset of and at Day 1 and Day 8 post-MI define the differential signatures of 5, 12, and 15 LOX-derived mediators post-MI. 36 The docosapentaenoic acid metabolome is one of the major fatty acids in the plasma lipidome that facilitates biosynthesis of T-series resolvins and reduces the risk of CV disease. 45 Amplified pro-inflammatory markers are signs of an acute inflammatory response, despite detectable levels of HETEs in all samples, limited pro-inflammatory lipid species that noted despite race-based and sex-based differences.…”

“…During this period, prior to troponin (clinical biomarker) release, biosynthesis of inflammatory‐resolving lipid mediators involved in the resolution (safe clearance of inflammation) that limits chronic inflammation . Before troponin markers, leucocyte‐directed SPMs are immune responsive polyunsaturated fatty acids‐derived biomolecules generated within a narrow time window after the cardiac injury that initiate resolution of inflammation . Deficiency of SPMs associated with monocyte/macrophage depletion or in obesogenic ageing leads to non‐resolving inflammation .…”

Use of DAMPs and SAMPs as Therapeutic Targets or Therapeutics: A Note of Caution

“…Plasma concentrations of SAMPs, here SPM profiles, have also been measured using liquid chromatographytandem mass spectrometry (LC-MS) technology [49,50]. Of note, in a recently published evaluation of SPM profiles using an optimized LC-MS method for the detection of SPMs in biological samples, Kutzner et al [51] concluded, "SPMs were generally not detectable/quantifiable in plasma and serum of healthy individuals, while good recovery rates were found in spiked samples.…”