Inflammation and Coronary Endothelial Function

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DESCRIPTION (provided by applicant): Despite aggressive current guideline-driven therapies, coronary artery disease (CAD) patients remain at increased risk of cardiovascular events, possibly because conventional treatments do not adequately address some of the inflammatory pathways implicated in the disease. Anti- inflammatory strategies have been associated with lower cardiovascular event rates in individuals with inflammatory autoimmune disease and are appealing in more general CAD populations but are not currently used in practice because of the lack of an established and easily obtained measure of the effect of inflammation on the processes which result in coronary atherosclerosis and because no clinical trial has established whether an anti-inflammatory strategy, per se, alters these processes. Inflammation contributes to the process of coronary endothelial dysfunction which plays a pivotal role in the development, progression, and clinical manifestations of CAD, and is a marker for sub-clinical disease, an independent predictor of adverse cardiovascular events, and a potential target for medical interventions. We recently developed noninvasive, reproducible MRI-based methods to measure CEF. We propose a 2x2 blinded, placebo-controlled trial to test the hypothesis that anti-inflammatory approaches, namely very low dose methotrexate (VLDM), low dose colchicine (LDC) and/or their combination, improve impaired local CEF in stable CAD patients with increased markers of inflammation on conventional cardiovascular medications. The studies will provide novel much- needed mechanistic insight into the potential of anti-inflammatory strategies to reduce coronary endothelial dysfunction, which inflammatory biomarkers herald the CEF response, and whether a heterogeneous coronary response occurs with differential effects in more severely than mildly diseased coronary vessels, suggesting local anti-inflammatory effects. In addition to this novel mechanistic information, the findings with these clinically available drugs will guide the next generation of clinical outcome trials and can be rapidly translated to practice.