ASSESSMENT OF CELLULAR INFLAMMATION FOLLOWING ACUTE MYOCARDIAL INFARCTION Application Of Ultrasmall Superparamagnetic Particles Of Iron Oxide

Background

Coronary atherosclerosis is responsible for the initiation of acute myocardial infarction with plaque rupture leading to acute coronary thrombosis and myocardial infarction. Current treatment in the acute phase involves re-establishing vessel patency by percutaneous coronary intervention supported by anti-thrombotic therapy. Thereafter, statins, angiotensin-converting enzyme inhibitors and beta-blockade all have prognostic benefit but no treatments have been successfully developed to target post-infarction inflammatory pathways.

Necrotic cardiac muscle elicits an inflammatory cascade that serves to clear the infarct of dead cells and matrix debris. Human cardiac muscle has negligible regenerative capacity and ultimately inflammation leads to replacement of damaged tissue with a fibrotic scar. Enhancing reparative mechanisms following the inflammatory reaction to myocardial infarction may reduce cardiomyocyte injury, attenuate adverse remodelling and improve clinical outcome. A better understanding of the early post-infarct healing phase will also facilitate cell therapy strategies to engraft stem cells or stimulate regeneration. In order to achieve this goal, the investigators must better characterise the inflammatory processes that follow infarction and myocardial necrosis in humans.

Inflammatory cell mediated injury and healing in the infarcted myocardium

Neutrophils Inflammation within the infarcted myocardium is associated with induction of endothelial adhesion molecules and enhanced permeability of the microvasculature. Up regulation of chemokines including interleukin (IL)-8 and monocyte chemoattractant protein (MCP)-1 attracts neutrophils and monocytes to the site of injury. Early reperfusion therapy amplifies this inflammatory cell influx and accelerates the healing response through proliferative and maturation phases. Neutrophil adhesion to endothelium of infarcted myocardium occurs within minutes of reperfusion. Ischaemic cardiomyocytes are further injured by adherent neutrophils that release reactive oxygen species and destructive proteases including human neutrophil elastase (HNE) and proteinase 3. HNE has a wide range of substrates including matrix components elastin, fibronectin, and collagen types III and IV. Activated neutrophils also occlude microvessels and increase endothelial permeability contributing to myocardial oedema. Capillary plugging and obstruction by activated neutrophils contributes to failure of microvascular perfusion and increased infarct size within the 'no-reflow' zone. Neutrophil depletion reduces this phenomenon and infarct size following reperfusion in pre-clinical models.