PROJECT ABSTRACT Chronic ischemic heart disease (IHD) is a $10.4-billion-dollar problem that is responsible for 45.1% of deaths attributable to cardiovascular disease. Compared to men, women have a different spectrum of IHD. Current diagnostic tools follow a one-size-fits-all model and are designed to detect a male pattern of IHD. Issues such as breast tissue, obesity, and lung disease render easily accessible tools such as ultrasound or nuclear SPECT imaging more limiting for women. Ischemia with no obstructive coronary disease is more common in women compared to men; symptomatic women face higher rates of major cardiac events than asymptomatic women. Therefore, accurate non-invasive tools that enable characterization of the entire spectrum of IHD and its correlative ischemic burden are crucial for clinical management of women with ischemic symptoms. Invasive interventions are without risks and lack of therapeutics contributes to disability. Myocardial ischemia occurs when there is an imbalance between metabolic demand and blood supply. Although tissue blood supply is affected by both myocardial blood flow (MBF) and myocardial blood volume (MBV), current stress perfusion strategies focus on measuring deficits in MBF, which alone may not reflect all aspects of myocardial ischemia. To better reflect the ischemic burden, we propose an MBV-based, whole-heart, gadolinium-free, non- nephrotoxic, ferumoxytol contrast-enhanced, cardiac magnetic resonance imaging (MRI) stress testing approach that will detect inducible ischemia. We build upon our experience in ferumoxytol-enhanced MRI and add rigor by testing our strategy in pre-clinical models of ischemia; we efficiently translate our approach to the clinic by validating the technique in women with IHD, some of whom require ferumoxytol for therapeutic purposes. Because 2 billion people worldwide have iron deficiency, the dual use of ferumoxytol as a diagnostic and therapeutic agent in the context of stress testing represents one approach to tailoring stress cardiac MRI for women who are frequently iron deficient. Successful completion of our project would result in a gadolinium- free, ferumoxytol-enhanced MRI stress testing approach that can reliably differentiate between normal vs ischemic myocardial tissue and would establish a foundation for development of myocardial stress testing approaches that enable interrogation of both epicardial and microvascular IHD.