Because of the alarming rise in obesity, the incidence of Type II Diabetes mellitus (DM) is increasing globally in epidemic proportions. DM is characterized by accelerated atherosclerosis leading to plaque rupture and thrombosis. Several features characterize diabetic atherosclerosis. Of those, inflammation, neovascularization, intraplaque hemorrhage and thrombus are key features that may influence plaque instability, as demonstrated by our group and others. New noninvasive vascular molecular approaches are an exciting wave within diagnostic imaging, and may alter our approach to cardiovascular risk assessment and requirement for early intervention. Diagnostic methods capable of accurately assess these histopathologic correlates of """"""""vulnerability"""""""" are critical in the detection of early vascular complications and enable the evaluation of therapeutic response. Moreover, proof that imaging methodologies are capable of tracking these changes will greatly increase the applicability of noninvasive magnetic resonance imaging (MRI) for epidemiologic studies and clinical trials. Our previous success in studying atherothrombosis in diabetes has been partly facilitated by improvements in fast MR imaging and analysis methodologies for the assessment and characterization of atherothrombotic plaques in human subjects and in animal models. Newer molecular MR imaging methods will lead to the successful study of the structure and activity of the thrombus in the various stages of thrombus """"""""aging"""""""" and to further characterization of atherothrombotic plaques. In this project we propose extending these initial studies to tease out the relative contributions of inflammation, neovascularization, and intraplaque hemorrhage in the DM population. We will assess using """"""""integrated"""""""" multi-modality MRI approach with combined positron emission tomography (PET)and computed tomography (CT) for vessel wall characterization. The overall goals of this project are to validate and test noninvasive imaging (MRI and PET/CT) approaches for the detection of histopathologic correlates of plaque instability in diabetes. To accomplish this overall goal, we will perform key investigations in animal models and humans. In the first part of this project we will target atherosclerosis-induced molecular alterations and resultant histopathologic correlates (inflammatory, neovascularization, and thrombus) using molecular MRI approaches in specific animal models. This will be critical for the evaluation of the efficacy of these new noninvasive methods to detect the progression and regression (""""""""change"""""""") of specific molecular and pathologic alterations seen in diabetes. In the second part of the proposal, we will perform a pilot study for Mount Sinai's current large NIH-funded multicenter clinical trial in patients with diabetes, Future REvascularization Evaluation in patients with Diabetes mellitus: Qptimal management of Multivessel disease (FREEDOM) Trial (HL071988) in which these imaging methods will be implemented in a cohort of DM subjects and matched non-DM patients for the study of atherosclerosis-induced diabetes and progression.
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