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Title: MicroRNA release in acute myocardial infarction
Author: Dawkins, Sam
ISNI:       0000 0004 6421 4171
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2016
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Coronary heart disease (CHD) is the single biggest cause of death in the United Kingdom1. Primary percutaneous coronary intervention (primary PCI) has transformed the early treatment of acute myocardial infarction (MI), improving outcome by rapidly re-opening the occluded coronary artery, with a larger mortality benefit and reduced risk compared with thrombolysis. Despite these advances, and even with the optimal treatment, some patients still sustain substantial myocardial damage leading to mortality and morbidity. MicroRNAs (miRs) are short non-coding RNAs with a role in regulating protein synthesis. Some miRs are cardiospecific, can be detected in plasma after a myocardial infarction and show promise as biomarkers and insights into the mechanisms of myocardial injury. In this work, as part of the Oxford Acute MI (OxAMI) Programme, a cohort of patients recruited at the time of ST elevation MI underwent detailed clinical and microRNA analysis at the time of myocardial infarction. This work was validated using separate discovery and validation cohorts. The source of detected miRs was further analysed in an in-vitro endothelial cell culture model and by measuring miRs released into the venous drainage of the heart, the coronary sinus. In the Discovery Cohort, miRs previously shown to be increased in myocardial infarction (e.g. miR-1, -133a, -499) were detectible in plasma after myocardial infarction, and this was confirmed in the validation cohort. Other miRs with a similar relationship were also identified (e.g. miR-30a, -378a, 125b). Microvascular obstruction was found to be associated with increased infarct size and also with release of microRNAs correlating with infarct size suggesting a link between microvascular obstruction and myocardial necrosis. Analysis of paired coronary artery and coronary sinus samples showed that these miRs increased down the myocardial gradient, suggesting myocardial release. The culmination of this work was to use the experimental findings from circulating plasma, cultured endothelial cells and coronary sinus experiments to design a microRNA panel using a blood sample taken six hours after admission to use in a regression model which was more predictive of final infarct size than troponin alone.
Supervisor: Channon, Keith Sponsor: British Heart Foundation
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available