Cardiac Magnetic Resonance Imaging-Guided Therapies for Chronic Hemorrhagic Myocardial Infarction
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Cardiac Magnetic Resonance Imaging-Guided Therapies for Chronic Hemorrhagic Myocardial Infarction


This dissertation aims to evaluate therapies that have the potential to improve the recovery of the left ventricle (LV) following myocardial infarction (MI) burdened with intramyocardial hemorrhage (IMH). Prior studies have shown that hemorrhagic MI results in the deposition of chronic iron in the myocardium, which induces cytotoxic effects as well as impacts the normal function of the microvasculature. In order to characterize the content of intramyocardial iron, T2* magnetic resonance imaging (MRI) was used as the gold standard in non-invasive detection of cardiac iron, and therefore acts as a diagnostic guidance tool informing the efficacy of the therapies. The dissertation may be broken down into three phases, all performed with MRI guidance to elucidate: 1) mechanistic understanding of the microvascular environment in chronic MI subjects; 2) effects of iron chelation therapy via Deferiprone (DFP) administration; and 3) effects of therapeutic hypothermia (TH) induced post reperfusion. The first phase investigated the long-term changes in myocardial perfusion assessed via MRI, in patients with reperfused myocardial infarction and an animal model of ischemia reperfusion (I/R) injury. From animal studies, histology, immunohistochemistry (IHC), and western blotting analysis were performed to elucidate the mechanistic underpinnings of MRI observations. The outcomes of this study led to the discovery that hemorrhagic MI results in reduced myocardial perfusion within hemorrhagic, but not non-hemorrhagic, MI territories. Further, the protein expression investigations enabled the proposal of a mechanistic pathway to examine the role chronic iron deposition plays in the perfusion defects observed in hemorrhagic MI. The subsequent study in a canine model of hemorrhagic MI to remove iron from within chronic infarction regions using the small-molecule iron chelator deferiprone (DFP), is the first to show the potential to abrogate resting perfusion defects observed in the hemorrhagic MI setting. Furthermore, the study showed that the recovery of rest perfusion did not persist following termination of the DFP therapy, indicating the potential need for continuous, or extended, iron chelation in this population to maintain persistent benefits. Lastly, the study showed the potential beneficial impact of DFP therapy on LV remodeling by resulting in reduced end-diastolic mass, suggesting a possible role of iron in LV hypertrophy and diastolic dysfunction. Finally, a study of post-reperfusion localized therapeutic hypothermia was conducted in a pig model to evaluate the potential impact of hypothermia therapy on IMH and chronic iron deposition. This is the first study to show the capability of therapeutic hypothermia to reduce chronic iron deposition in hemorrhagic MI. The results of this study showed that post-reperfusion hypothermia did not impact acute infarct size and did not affect hemorrhage in the acute phase (day 3 post-MI). However, by 1 month hypothermia-treated animals showed significantly reduced T2*-derived iron deposition volume, which held when normalized by infarct size. By 2 months post-MI, absolute T2* values were also indicative of decreased myocardial iron content, with significantly increased T2* values (lower iron content) in hypothermia-treated animals. Furthermore, LV ejection fraction (LVEF) was significantly elevated at 2 months in the hypothermia group, suggesting a positive effect of therapeutic hypothermia on chronic LV function. In summary, this dissertation used animal models of hemorrhagic MI to investigate two promising therapeutic methods for alleviating the adverse remodeling in hemorrhagic MI subjects, showing promising results that will aid the future development of adjunctive clinical therapies for advancing treatment in MI and ischemia reperfusion injury.

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