Inflammation in acute myocardial infarction: the good, the bad and the ugly

Abstract

Convergent experimental and clinical evidence have established the pathophysiological importance of pro-inflammatory pathways in coronary artery disease. Notably, the interest in treating inflammation in patients suffering acute myocardial infarction (AMI) is now expanding from its chronic aspects to the acute setting. Few large outcome trials have proven the benefits of anti-inflammatory therapies on cardiovascular outcomes by targeting the residual inflammatory risk (RIR), i.e. the smouldering ember of low-grade inflammation persisting in the late phase after AMI. However, these studies have also taught us about potential risks of anti-inflammatory therapy after AMI, particularly related to impaired host defence. Recently, numerous smaller-scale trials have addressed the concept of targeting a deleterious flare of excessive inflammation in the early phase after AMI. Targeting different pathways and implementing various treatment regimens, those trials have met with varied degrees of success. Promising results have come from those studies intervening early on the interleukin-1 and -6 pathways. Taking lessons from such past research may inform an optimized approach to target post-AMI inflammation, tailored to spare 'The Good' (repair and defence) while treating 'The Bad' (smouldering RIR) and capturing 'The Ugly' (flaming early burst of excess inflammation in the acute phase). Key constituents of such a strategy may read as follows: select patients with large pro-inflammatory burden (i.e. large AMI); initiate treatment early (e.g. ≤12 h post-AMI); implement a precisely targeted anti-inflammatory agent; follow through with a tapering treatment regimen. This approach warrants testing in rigorous clinical trials.

Keywords: Acute myocardial infarction; Anti-inflammatory therapy; Inflammation; Outcome.

Graphical Abstract

‘The Good’, ‘The Bad’, and ‘The Ugly’: Distinct facets of inflammation in acute myocardial infarction (AMI). The left panel (‘The Good’) shows the role of cytokines, T-cells, NKs, and macrophages in myocardial protection and healing. IL-10 and IL-2 reduce pro-inflammatory signals (e.g. TNFα, MCP-1, IL-8), extracellular matrix remodelling (MMP downregulation), while promoting Treg, Th2, and NK activation with subsequent macrophage polarization towards the M2 phenotype. The mid panel (‘The Bad’) represents the smouldering state of low-grade inflammation persisting in the late phase after AMI. Among the protagonist cellular players responsible for ‘The Bad’ are M1-polarized macrophages, foam cells, and PMNs. Induction of the NLRP3 inflammasome enhances production and secretion of IL-1α, IL-1β with subsequent enhancement of inflammatory signals via IL-6 production. These processes entertain the smouldering embers of inflammation, consequently entailing the residual inflammatory risk (RIR) that negatively affects patient outcome. The right panel focuses on ‘The Ugly’, flaming burst of excess inflammation in the early phase after AMI. PMN activation and monocytes recruitment occur upon plaque rupture and thrombosis that is further increased by NET formation. The ensuing oxidative burst contributes to damage amplification during this early phase. Cytokines which are also present in ‘The Bad’, namely IL-1 and IL-6, show a particularly excessive surge in the early phase after AMI, their damaging characteristics thus potentiated during this phase. AMI, acute myocardial infarction; CRP, C-reactive protein; IL, interleukin; MACE, major adverse cardiovascular events; MCP, monocyte chemoattractant protein; MMP, matrix metalloproteinase; NLRP, NOD-, LRR-, and pyrin domain-containing protein; NET, neutrophil extracellular trap; NK, natural killer cell; PAI1, plasminogen activator inhibitor 1; PMN, polymorphonuclear neutrophil; SAA, serum amyloid A; TIMPS, tissue inhibitors of metalloproteinases; TNF, tumour necrosis factor; Treg, regulatory T-cell.

Figure 1

Putative model for the natural history of ST-segment elevation myocardial infarction vs. non-ST-segment elevation myocardial infarction and the potential effects of percutaneous coronary intervention and anti-inflammatory drugs. Baseline inflammation comprises a chronic level of activity of a patient’s immuno-inflammatory system, determined by traditional cardiovascular risk factors as well as other comorbidities. On top of this chronic inflammation, ST-segment elevation myocardial infarction results in an acute excessive surge of inflammation, both of higher grade and earlier onset compared with non-ST-segment elevation myocardial infarction. Early percutaneous coronary intervention is the gold standard in the treatment of patients with ST-segment elevation myocardial infarction and its beneficial effects on outcome are undisputed. However, percutaneous coronary intervention elicits an additional spike in inflammation caused by local release of inflammatory mediators from balloon and stent expansion, distal microemboli as well as reperfusion injury. Though by far outweighed by the positive aspects of early percutaneous coronary intervention, these effects of reperfusion injury on post-ST-segment elevation myocardial infarction inflammation should not be neglected. Early anti-inflammatory therapy is anticipated to attenuate this early excessive inflammation after ST-segment elevation myocardial infarction. Extending treatment throughout the follow-up period suppresses the residual inflammatory risk (RIR), for which a causal role on patient outcome has been proven. AMI, acute myocardial infarction; hx, history; NSTEMI, non-ST-segment elevation myocardial infarction; PCI, percutaneous coronary intervention; STEMI, ST-segment elevation myocardial infarction.