Assessment of Mast Cell Degranulation in Infarcted Myocardium Using Quantitative Multiparametric MRI

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PROJECT SUMMARY The overall objective of the proposed project is to evaluate the effectiveness of a novel pharmacological treatment of myocardial infarction (MI) using quantitative multiparametric magnetic resonance imaging (qMRI). MI is a major cause of death and disability worldwide. Urgent reperfusion of the occluded artery to restore myocardial blood flow is central to the clinical management of acute thrombotic MI (AMI). However, recanalization of the culprit artery may also result in unintended injury by causing microvascular obstruction (MVO), intramyocardial hemorrhage (IMH), and edema during the acute phase. In the setting of chronic MI, iron deposition and fat accumulation (lipomatous metaplasia, LM) are frequently observed in infarcted myocardium. All these biomarkers are strong predictors of major adverse cardiovascular events such as heart failure. To date, however, there have been no effective therapeutic strategies for attenuating either MVO, IMH, chronic iron deposition, or LM post-reperfusion. Mast cells (MC) are derived from blood-borne, multipotent hematopoietic progenitor cells that, once located in tissue, differentiate to a final phenotype under the influence of the local microenvironment. In general, MC exert their physiological and pathological functions by releasing cytoplasmic granules (degranulation) containing a variety of biologically active mediators. Recent experimental studies have shown that hematoma growth, edema expansion and overall neurological damage after cerebral ischemia- reperfusion can be reduced by early treatment with MC stabilizers, which are known to suppress MC degranulation. Equally important, atherosclerosis research over the last two decades has provided strong evidence for MC involvement in foam cell formation and plaque development. Based on these studies, we hypothesized that MC stabilization via the administration of over-the-counter anti-allergy medication loratadine reduces myocardial edema, IMH volume and improves myocardial microcirculation in the acute MI setting; and attenuates LM of infarcted myocardium in the chronic phase. Quantitative cardiovascular MR (qCMR) imaging has been widely used to characterize myocardial ischemia, hemorrhage, edema, inflammation, iron deposition, fat accumulation and other pathological conditions. In this proposal, we aim to validate the effectiveness of MC stabilizer loratadine on structural and functional cardiac remodeling post-pharmacotherapy in a porcine model of MI by temporally following imaging biomarkers of acute and chronic MI using well-established qCMR techniques. Successful completion of the project will provide initial validation that early loratadine intervention has the potential to be a novel therapeutic strategy for prevention of heart failure post-MI as evaluated by our quantitative multiparametric MRI approach.