Mavroudis, C; (2015) An investigation into the relationship between platelet activation (platelet monocyte interaction & microparticles), inflammation and microvascular dysfunction in coronary artery disease. Doctoral thesis , UCL (University College London).

Text C. A. MAVROUDIS THESIS[1].pdf Available under License : See the attached licence file. Download (1MB)

Abstract

Introduction Inflammation and platelet activation play a pivotal role in the pathogenesis of acute coronary syndrome (ACS). Mounting evidence indicates that microparticles (MP) are potent pro-coagulant molecules modulating inflammatory processes. Aims The aim of my study was to investigate the intracoronary and systemic microparticle expression in patients with symptomatic coronary heart disease (CHD) and their relationship with markers of inflammation, platelet activation and microvascular dysfunction (MvD). Methods Forty eight patients with CHD (37 with ACS [23 patients with ST segment myocardial infarction (STEMI) and 14 with non-ST segment elevation myocardial infarction (NSTEMI)] and 11 with stable angina (SA) treated with percutaneous coronary intervention (PCI) were recruited. Blood samples were aspirated sequentially from the right atrium (RA) and the coronary (CO) artery (distal to the culprit lesion). AnnexinV+ MP (AnV+MP) from platelet poor plasma were measured using fluorescent monoclonal antibodies and flow cytometry. Markers of inflammation (hs-CRP, IL-6, TNF-α, serum amyloid antigen (SAA) and platelet activation (soluble p-selectin and platelet monocyte aggregates (PMA) were measured using ELISA. MvD was assessed by measuring the index of microvascular resistance (IMR) and coronary wedge pressure (Pw). Results The main novel findings of this study are the demonstration of: 1) differences between MP levels in patients with varying severity of CHD i.e. MP levels were overall higher in those with ACS (more specifically the highest MP levels were observed in the STEMI patients) compared with SA; 2. differential local and systemic AnV+ MP expression in human coronary artery disease; 3. differential local and systemic expression of inflammatory markers in ACS patients; 4. differential local and systemic expression of markers of platelet activation in ACS patients; 5. positive correlation between AnV+MP and markers of inflammation, platelet activation and myocardial necrosis in ACS patients both in the CO and RA; and 6. positive correlation between invasive markers of microvascular dysfunction and PMA in human coronary artery disease. Conclusions High levels of AnV+MP occur in the coronary artery of patients with ACS. Levels of AnV+MP correlate with severity of the ischaemic lesion since higher MPs were detected in the STEMI versus the NSTEMI and SA groups. Markers of platelet activation and inflammation in ACS patients, both at the site of the culprit lesion and in the systemic circulation, strongly correlated with total and cell specific AnV+MP. The interaction between activated platelets and monocytes with endothelial cells and the subsequent formation of AnV+MP and PMA during ACS would be compatible with a direct pathogenic link between inflammatory and prothrombotic pathways in the pathogenesis of ACS and myocardial necrosis. This may suggest a novel role for MPs as effectors of the inflammatory response and cellular injury in ACS. Our observations also support the hypothesis that PMA formation may be important determinants of platelet activation, inflammation and microvascular dysfunction in coronary artery disease. Whether these MP merely reflect the severity of the ischaemic lesion, and/or are active participants in the pathogenesis of ACS now warrants further study, since these could be important, novel therapeutic targets.

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