Project 5 - Metabolomic Analysis of Atherothrombosis

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Cardiovascular disease (CVD) is the leading cause of death in individuals with diabetes with rates of acute coronary syndrome (ACS) and total mortality several fold higher in younger adults with versus without type 2 diabetes (T2D). Nevertheless, the mechanisms that impart greater CVD risk in T2D are not well understood and no diabetes-specific CVD treatment regimens have been developed. ACS occurs when intracoronary thrombus obstructs coronary flow to produce myocardial ischemia and is responsible for the majority of irreversible myocardial damage in T2D. Although great advances have been made in diagnosing ACS, all of the current ACS biomarkers measure the result, myocardial necrosis, and not the cause and therapeufic target -atherothrombosis. The ability to identify atherothrombotic-MI at the start of the event, prior to irreversible myocardial necrosis, and quickly disfinguish atherothrombotic from non-atherothrombofic ACS would materially increase the safety and effectiveness of ACS treatment in T2D patients. The long-term goal of this project is to develop a biomarker which differentiates atherothrombotic from non-atherothrombotic Ml in patients with T2D. Such an approach will not only improve diagnostic accuracy but could also potentially identify events at the start of coronary thrombosis, prior to "inevitable" myocardial necrosis, allowing for more prompt and targeted interventions. Hence, using both targeted and unbiased metabolomic approaches, we plan to identify specific biomarkers of atherothrombosis. Our central hypothesis is atherothrombotic events are associated with increased production of metabolites derived from oxidized lipids in the culprit lesion or generated by the atherothrombotic event itself and that measurement of these metabolites will allow for eariy and accurate diagnosis of atherothrombotic Ml is T2D patients.