Non-invasive imaging of reactive oxygen species in reperfusion injury myocardial infarction

Project Summary Coronary heart disease is the leading cause of death worldwide. Patients are treated with clot-busting drugs (thrombolytic therapy) or the artery is reopened with a catheter (percutaneous coronary intervention), but, paradoxically, restoration of blood flow to the heart muscle can cause additional injury that limits the success of these procedures. Reperfusion injury appears to be a cascade of events, initiated by coronary artery extravasation (hemorrhage), culminating in a failure to restore myocardial perfusion and leading to cell death among viable cardiomyocytes in the peri-infarct region. It may be a predictor of long-term adverse clinical outcomes or provide a therapy-modifiable target in patients with myocardial infarction. Imaging methods specific to the molecular mechanisms of reperfusion injury would improve clinical care and our scientific understanding of this disease. We hypothesize that iron is a catalyst for reactive oxygen species production in reperfused myocardial infarction. We propose a series of experiments to investigate the association between iron and reactive oxygen species using iron-sensitive magnetic resonance imaging and positron emission tomography. We will validate these in vivo non-invasive imaging modalities with a battery of pathology, immunohistochemistry, and spectrometry techniques in a large animal model. In Aim 1, we will investigate the association between reactive oxygen species, iron and severity of infarction using MRI and PET. In Aim 2, we will determine the extent of association between imaging markers of reperfusion injury and remodeling of the left ventricle weeks after injury. This study will give a new understanding of the spatiotemporal relationships of reactive oxygen species in the sub-acute and chronic period of myocardial infarction wound healing. This will lead to studies in large animal models and humans that can evaluate therapies targeting imaging biomarkers of reperfusion injury.