Development and Application of MRI Methods to Assess Coronary Microvascular Disease

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Shah, Soham, Biomedical Engineering - School of Engineering and Applied Science, University of Virginia
Epstein, Frederick, MD-BIOM Biomedical Eng, University of Virginia

Every year, over eight million patients in the US visit the emergency department for angina with the most common cause being myocardial ischemia. Traditionally, treatment for myocardial ischemia has focused on the evaluation of obstructed coronary arteries via angiography for coronary artery disease (CAD). However, a considerable proportion of these patients have a normal coronary angiogram. In presentations of ischemia with no obstructive CAD (NOCAD), current evidence has shown that the primary cause may be coronary microvascular disease (CMD), defined as an impairment to the coronary microcirculation and assessed by an inadequate vasodilatory response to physiological or pharmacological stress. Patients with CMD are at a high risk of major adverse cardiovascular events, and emerging evidence links CMD with NOCAD to heart failure with preserved ejection fraction (HFpEF), the most common form of heart disease in the US. However, the mechanisms underlying CMD are not fully understood, and there are no established treatments for CMD.
Mouse models of heart disease are commonly used to study explore disease processes, mechanisms, and therapies; magnetic resonance imaging (MRI) in mice enables noninvasive and serial assessment of cardiovascular structure, function, and disease. The overall goal of this dissertation is to a) develop MRI methods for the assessment of CMD, and b) use these novel methods along with traditional imaging methods to study the underlying mechanisms and potential therapies for CMD using mouse models of high-fat high-sucrose diet (HFHSD) induced CMD.
Oxidative stress, defined as the imbalance of the generation and biotransformation of reactive oxygen species (ROS), has a potential central role in altering microvascular function and exacerbating CMD. In Specific Aim 1, we developed a dynamic nitroxide-enhanced MRI method for the quantification of cardiovascular oxidative stress to facilitate future investigations of the role of oxidative stress in CMD. The development of the technique is summarized in Chapter 2.
Epicardial adipose tissue (EAT), in pathological conditions, has been described as a transducer metabolic inflammation to the myocardium and coronary microvasculature. Recent studies have linked the EAT fatty acid composition (FAC) to its proinflammatory state. In Specific Aim 2, we developed an accelerated FAC MRI method for the mouse EAT and assessed the role of EAT FAC on HFHSD-induced CMD. The development and assessment of this technique is summarized in Chapter 3.
Lastly, mineralocorticoid receptor (MLR) activation has many downstream mechanisms, including vascular oxidative stress and a proinflammatory EAT, and may contribute to the development of CMD. In Specific Aim 3, we utilized multiparametric preclinical MRI to test the hypotheses that MLR antagonism with eplerenone and cell-specific MLR deletion protects against microvascular impairment in a mouse model of HFHSD-induced CMD. The results of these experiments are summarized in Chapter 4.

PHD (Doctor of Philosophy)
MRI, Coronary Microvascular Disease, Oxidative Stress, Epicardial Adipose Tissue, Mineralocorticoid Receptor, Inducible Nitric Oxide Synthase
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