The central premise of this application is that the combination of multi-parameter cardiac magnetic resonance (CMR) and advanced genetic manipulations in mice holds considerable potential for unraveling the molecular mechanisms underlying left ventricular (LV) remodeling due to myocardial infarction (MI). Previous work from the Principal Investigator shows that adenosine 2A receptor (A2AR) agonists can reduce infarct size and preserve cardiac function through T-cell mediated pathways. This application proposes to apply multi-parameter CMR to genetically-modified mice to address the hypothesis that related mechanisms may contribute importantly to LV remodeling after reperfused MI. In these studies, a multidisciplinary approach will be used that spans the fields of radiology, cardiology, immunopathology & molecular genetics.
The specific aims are to: 1) Apply multi-parameter CMR to test the hypothesis that adenosine 2A receptor (A2AR) signaling, which will be pharmacologically enhanced or genetically ablated, modifies LV remodeling and regional 3D strain, as well as macrophage activity and recovery of perfusion in the infarct zone. In preliminary studies, our team has shown that global LV remodeling is dramatically reduced by A2AR activation. In this Aim, 3D myocardial mechanics will be assessed by 3D cine DENSE, macrophage infiltration by T1 mapping of Gd-liposomes, regional perfusion by first-pass kinetics and infarct size/location by late gadolinium enhanced (LGE) CMR. These imaging techniques will be applied serially in the settings of both A2AR activation and gene knock-out to define the role of A2AR signaling in the spatiotemporal relationships that exist between these critical parameters. 2) Develop T2 mapping for quantifying myocardial edema and apply it to test the hypothesis that the kinetics of myocardial edema surrounding the infarct zone are modulated by A2AR signaling, both in the settings of LV remodeling and myocardial salvage. The essential role of A2AR signaling as a negative feedback mechanism for resolving inflammation leads us to hypothesize that A2AR agonists curtail both infarct expansion and LV remodeling by mechanisms that should also resolve edema. Here, T2 mapping will be developed and used to serially assess regional edema in mouse models of both LV remodeling (60 min reperfused coronary occlusion) and myocardial salvage (20 min occlusion) to test the hypothesis that edema will resolve more quickly in mice treated with an A2AR agonist. Conversely, post-MI edema should be aggravated in A2AR-/- mice. 3) Apply select combinations of advanced CMR techniques and gene modified mice to determine whether the efficacious A2AR signaling occurs in inflammatory cells or in other cell types. Here, we propose to use bone marrow transplantation to generate chimeric mice where A2AR signaling is selectively abolished in either the cells of the heart or in the inflammatory system. The results of these experiments will not only clarify the relative importance of A2AR signaling in these two tissue compartments, they will guide future studies focused on elucidating the role(s) of these mechanism(s) in curtailing the LV remodeling response.
Ischemic heart disease remains the single leading cause of death in the United States, accounting for fully one out of every five deaths. Myocardial infarction (heart attack) and heart failure account for the vast majority of the morbidity and mortality associated with ischemic heart disease. Over the last twenty years, genetically modified mice have greatly expedited biomedical research aimed at unraveling the role of individual genes in the progression from heart attack to heart failure. During that same period, cardiac magnetic resonance (CMR) imaging has emerged as perhaps the single most versatile tool for the non-invasive evaluation of ischemic heart disease, both in small animal research and in clinical trials. This research project will apply recently developed CMR methods capable of measuring myocardial form, function, perfusion and inflammatory status to elucidate the roles of inflammation and wound healing in the progression from heart attack to heart failure. The results will not only to identify new treatment strategies for the prevention of heart failure, they will aso demonstrate the utility of CMR in making comprehensive assessments of multiple parameters critical to diagnosing the progression of heart failure, thus offering new opportunities for the personalized care of patients that survive large heart attacks.
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