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.