Myocardial Ischemia Without Obstructive Coronary Artery Disease: Perfusion MRI in Mouse Models

Cardiovascular disease is the leading health disorder in the western world. Recent studies have shown that myocardial ischemia can occur even in the absence of obstructive coronary artery disease (CAD) and this is especially common in patient populations of women, diabetics, patients of metabolic syndrome and obesity. An emerging concept in this realm is abnormal myocardial perfusion reserve as quantified by non-invasive imaging, or the inadequate increase of myocardial blood flow in response to vasodilation. Impaired myocardial perfusion reserve is associated with adverse cardiovascular outcomes even in the absence of obstructive CAD. Furthermore, increased body weight is independently associated with impaired myocardial perfusion reserve. However, molecular mechanisms underlying impaired myocardial perfusion reserve in the absence of obstructive CAD in are still unclear.
Mice are widely used as models to study cardiovascular diseases and research using genetically modified mice has provided tremendous insights into the cellular and molecular mechanisms that underlie many cardiovascular diseases. Currently, no mouse model of ischemia in the absence of obstructive CAD has been established. Thus, it would be extremely useful to develop a mouse model that parallels the human clinical scenario, i.e. a mouse model of non-obstructive inducible myocardial ischemia in order to study causal mechanisms and eventually to develop therapies aimed at improving patient outcomes.
For this dissertation, Specific Aim 1 is to develop improved quantitative perfusion MRI methods for mice to measure myocardial perfusion reserve and to test the hypothesis that these methods can detect impaired myocardial perfusion reserve in mice fed a high-fat diet. Specific Aim 2 is to compare the two perfusion MRI techniques: first-pass contrast enhanced MRI and arterial spin labeling in terms of repeatability and user variability. Specific Aim 3 is to use cardiac MRI to establish the time course of impaired myocardial perfusion reserve and left-ventricular hypertrophy in a mouse model of diet-induced obesity.