Article Text

Download PDFPDF

227 Infarct size in a rat model of acute myocardial infarction is reduced by interleukin-6 trans-signalling blockade using sgp130fc but not an anti-il-6r monoclonal antibody
  1. Marc Jonathan George,
  2. Daniel Stuckey,
  3. Valerie Taylor,
  4. Aroon Hingorani,
  5. Derek Gilroy
  1. University College London


Introduction Interleukin-6 (IL-6) is elevated during acute myocardial infarction (AMI) particularly after reperfusion with primary percutaneous coronary intervention (PPCI). Higher circulating levels of IL-6 and its soluble receptor (sIL-6R) are associated with adverse outcomes post AMI. Therefore while IL-6 is a potential therapeutic target in AMI, animal models employing monoclonal antibodies (MAb) against the IL-6R have failed to demonstrate benefit. We hypothesised that blockade of the pro-inflammatory aspects of IL-6 signalling (trans-signalling) with the sgp130Fc protein in an animal model of AMI would result in reduced infarct size (IS) whereas blockade with a MAb against IL-6R (which blocks both the pro and anti-inflammatory actions of IL-6) would not.

Methods AMI was induced in male Sprague-Dawley rats by occluding the left-anterior descending artery for 50 minutes prior to reperfusion (analogous to PPCI). The model was characterised by measuring the temporal profile of IL-6, sIL-6R and other inflammatory mediators (MCP-1, KC/GRO, IL-1β, TNFα) within the heart tissue and plasma by ELISA at 2, 4, 24, 72, 120 and 168 hours post AMI (n=3–4/group). In addition, infarct progression over time (measured histologically with TTC and Evans Blue dyes and with plasma myoglobin), and leukocyte infiltration (flow-cytometry of cells obtained from heart digests) were measured. In therapeutic experiments rats received either 4 μg/g of a MAb against IL-6R (clone 15A7), 0.5 μg/g of sgp130Fc or vehicle alone given intravenously 1 minute prior to reperfusion (n=7–8/group).

Results IS/Area at risk (AAR) increased from 31.81% at 4 hours to 46.1% at 24 hours (p=0.03), with no further change at 48 hours. Myoglobin peaked at 24 hours. IL-6 levels in the heart were biphasic; a robust early peak at 2–4 hours was followed by a trough at 24 hours, and a more sustained peak between days 3–5. Only the early peak was associated with significantly elevated circulating IL-6. The early peak was temporally associated with infarct progression and neutrophil influx, whereas the second was associated with classical mononcyte infiltration. Other inflammatory mediators followed a similar but less pronounced biphasic pattern. Cardiac and plasma sIL-6R peaked at 24 hours, coinciding with maximal cardiac neutrophil numbers. Based on these data the effect of IL-6 antagonism was assessed at 24 hours. IS/AAR after blockade with anti-IL-6R MAb was unchanged compared with control (46.8% vs 46.1%). However, blockade with sgp130Fc resulted in a substantial reduction in IS/ARR (26.32%, p 0.0004).

Conclusions IL-6 trans-signalling blockade with sgp130Fc but not blockade with an anti-IL-6R MAb reduces IS/AAR in an animal model of AMI with reperfusion. Ongoing experiments seek to understand the mechanisms underpinning this observation and to explore the effects on infarct healing and remodelling.

  • Myocardial Infarction
  • Interleukin-6
  • Inflammation

Statistics from

Request Permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.