COBRE Project 2: Center of Research in Obesity and Cardiovascular Disease

Obesity amongst adults has emerged as a national health crisis in the United States, with afflicted individuals at heightened risk of heart failure (1). The clinical diagnosis of heart failure in obese patients relies upon measurement of reduced global ventricular function via ejection fraction or abrogated longitudinal shortening. While such measurements are easily obtained, intrinsic compensatory mechanisms that preserve cardiac output limit the presence of reduced global function to only the latest stages of heart failure (2). In contrast molecular, cellular, and tissue structure changes occur over the years that precede the loss of global function and contribute equally to cardiovascular mortality in obese patients (1). Specifically, changes in cardiomyocyte metabolism, deposition of fibrotic collagen, constitutive immuno-activation, and progressive microvascular dysfunction in the absence of macrovascular obstruction are all early features of obesity related heart failure and are potentially manageable but remain inadequately understood (1). These responses represent both potential biomarkers for improved risk-stratification and avenues for therapeutic intervention. Over the last decade I have worked to establish powerful MRI methods to measure myocardial calcium cycling (3), function (3, 4), perfusion (5), and fibrosis (6), and for MRI cell tracking (7, 8). More recently, I have developed a novel molecular MRI technique for multiplex in vivo cardiac imaging termed cardioCEST (6). With cardioCEST, multiple molecular targets can be selectively visualized and quantified through the process of chemical exchange saturation transfer (CEST) in a manner analogous to fluorescence microscopy. Specifically, fibrotic substrate, creatine, cells labeled with CEST contrast agents, pH sensitive contrast agents, and even MRI reporter genes can all be imaged non-invasively in a single session and coupled with measurements of tissue structure, function, and perfusion. This unique method can enable in vivo investigation of multiple complex biological processes underlying heart failure in the setting of obesity. Our goals are to use cardioCEST MRI and additional MRI methods to (i) examine reduced cardiac creatine as an early in vivo biomarker of obesity induced heart failure in mice and patients, and (ii) to test the hypothesis that modulation of persistent inflammation can prevent obesity induced heart failure. We are uniquely suited