A study of the adaptive immune system in coronary thromboaspirate during human acute myocardial infarction

Abstract

Introduction: This thesis aims to characterize the biology of solid and liquid phase coronary thromboaspirate obtained during therapeutic aspiration at primary angioplasty for ST elevation myocardial infarction (STEMI). Methods: We studied coronary thromboaspirate obtained from the coronary artery (CA) in STEMI and focussed on three lines of investigation: • Intracoronary solid phase thrombus was subjected to immunohistochemistry for characterization and quantification of the different leukocyte types and proteins involved in the thrombus. • Resident cell populations in the liquid phase filtrate from the aspirate including platelets and leukocytes along with their subpopulations were analysed by flow cytometry for phenotypic and activation markers. Comparison was made with cells in the peripheral femoral artery (FA) blood. • Paired plasma/serum from the CA filtrate and FA blood were analysed for the presence of autoreactive antibodies and cytotoxic potential. Results: • Leukocytes were heterogeneously distributed in the ex-vivo thrombus. The granulocyte population was predominant and strongly expressed CD11b and vimentin. • The CA aspirate filtrate when compared to the paired FA blood contained significantly more leukocyte-platelet conjugates, more activated platelets, and more Vimentin. • More of the CD4+ T cells in the CA than FA had lost the co-stimulatory molecule CD28 (p<0.00001) and they often expressed effector phenotype marker. • Conversely, the immune-regulatory T cells expressing the FoxP3 were more attenuated in the CA than FA (p<0.00001). • Whilst IgG and IgM antivimentin antibody titres in the CA sera were consistently lower than the titres in FA sera (p<0.001), auto-reactive non-HLA IgM were more prevalent in CA sera. The CA sera had increased potential to induce apoptosis than FA sera when incubated with endothelial cells (p<0.001). Conclusions: • Aspirated intracoronary clot contained granulocytes as the predominant leukocyte component. This investigation of the immune system in the CA during AMI therefore moved on to the adaptive system in the coronary filtrate. • Increased concentrations of pro-inflammatory immune cells and reduced concentrations of immune-modulating cells were observed in the aspirate from the culprit site of CA occlusion when compared with the FA. The presence of T memory cells implies that this subset may have been released from the ruptured coronary plaque and this phenotypic analysis may help clarify the role of the immune system in the pathogenesis of coronary plaque instability. • The higher titres of auto-reactive IGM in the CA than FA sera have the potential to activate the complement system and may contribute to myocardial injury following therapeutic restoration of coronary flow in STEMI.