Molecular Imaging of Collagen Turnover in Cardiomyopathy

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Heart failure is a major cause of morbidity and mortality worldwide. Cardiomyopathy, the pathology that underlies most cases of heart failure is often triggered by myocardial injury. This promotes inflammation, fibroblast proliferation and myofibroblast transformation, and ultimately fibrosis, which directly contributes to structural changes that underlie heart failure and its complications. Structural imaging modalities such as magnetic resonance imaging can provide a snapshot of cardiac structure at a given point. However, they do not provide any information on the fibrotic process, which is the target of therapeutic interventions to prevent the progression and promote the regression of fibrosis. Similarly, while several new tracers have been introduced to detect fibrosis by molecular imaging, these agents target mature collagen and cannot distinguish between established disease and ongoing matrix remodeling which accompanies active fibrogenesis and resolution of fibrosis. Therefore, novel non-invasive quantitative tools are needed to characterize fibrosis, detect matrix turnover, select the patients for emerging therapies, track the effect of therapeutic interventions, and improve prognostication. Cardiac fibrosis consists mainly of collagen types I and III. The hallmark of collagen structure is triple helix, a right-handed helix of 3 α-chains formed by repetitive motifs, which self- assemble to form (pro)collagen fibers. During ventricular remodeling, the highly organized mature collagen fibers are degraded by proteases such as matrix metalloproteinases (MMPs) into single stranded α-chains that are not normally present in the extracellular space. Based on the role of collagen turnover in cardiac remodeling and in conjunction with our preliminary data, we hypothesize that the development and regression of fibrosis in ventricular remodeling can be tracked by imaging single stranded collagen. To address this hypothesis, and as a novel approach to imaging cardiac fibrosis, we propose to develop novel radiotracers to target collagen turnover by taking advantage of collagen triple helix self-assembly. This novel class of peptide- based radiotracers is designed with a modular structure and includes a prototype tracer which has yielded promising results in preliminary studies. Here, we seek to further characterize and optimize the lead tracer as needed, and evaluate it for micro single photon computed tomography (SPECT)/computed tomography (CT) imaging in murine models of replacement and interstitial cardiac fibrosis to track fibrosis and its resolution, and to predict ventricular remodeling in comparison with MMP-targeted imaging. Combined these studies will introduce and validate a novel molecular imaging approach with a straightforward path to clinical translation to track fibrosis and its resolution, for not only cardiomyopathy, but also a wide range of other fibrotic disorders.