Positron Emission Tomography to Evaluate Cardiac Remodelling After Collagen Hydrogel Therapy

Abstract

Despite the development of therapeutic interventions to prevent mortality following myocardial infarction (MI), there is a significant long-term risk of developing heart failure (HF). Injectable collagen hydrogels have demonstrated considerable promise as a therapeutic solution to reduce adverse ventricle remodeling associated with the development of HF post-MI. Matrix metalloproteinases (MMPs) are proteolytic enzymes involved in the degradation of the structural components of the extracellular matrix (ECM). The activation of MMPs following MI is an essential step in the cardiac repair process. However, uncontrolled enzymatic activity during this time has been associated with the formation of adverse fibrosis. Given the role of the proteases in tissue remodeling, MMPs may be a potential biomarker to predict the development of HF. This thesis work seeks to examine the effect of a novel hydrogel matrix therapy on cardiac tissue post-MI using broad-spectrum MMP-targeted radiotracer, [18F]BR3531. In Study 1, serial positron emission tomography (PET) imaging was performed to elucidate the spatial and temporal binding of [18F]BR351 post-MI using a murine model. Imaging was performed by administering [18F]BR351 at time points corresponding with periods of peak MMP activation post-MI. In vivo PET imaging and in vitro autoradiography demonstrated decreased [18F]BR351 binding in the infarct region. In Study 2, the model was used to evaluate the efficacy of a therapeutic collagen hydrogel to attenuate tissue remodeling. The groups that received the matrix treatment exhibited improved [18F]BR351 uptake in the infarct region. However, conflicting results between in vivo imaging and in vitro autoradiography, and immunohistochemistry using MMP2 and MMP9 indicate that [18F]BR351 may not be suited for MMP imaging in mouse models of MI.