Heart failure with preserved ejection fraction (HFpEF) is currently being studied intensely as several large trials of drug therapies have failed to benefit patients. Better characterization of these patients is important, and there are open questions regarding microvascular disease and remodeling in the HFpEF population. New MRI methods could be ideal to better characterize and understand HFpEF and its response to treatments. This project seeks to develop, evaluate and apply new MRI methods for high-end perfusion imaging. These methods will estimate endo/epi ratios across the cardiac cycle in free-breathing studies, which will be used along with other new MRI measurements and blood biomarkers to provide new information about microvascular disease. This is of particular value for assessing HFpEF. The aims and methods of this project are to (1) develop and compare new 2D radial simultaneous multi-slice (SMS) and 3D stack-of-stars (SoS) acquisitions and reconstruction methods for quantitative perfusion measurements. (2) To validate the new 2D radial SMS and 3D SoS free- breathing methods in an animal model of HFpEF, and in humans to further characterize the new methods by comparison to a more standard MRI method and to dynamic PET. (3) To use the methods along with fibrosis quantitation and other MRI measures to characterize perfusion and fibrosis changes over time in patients with HFpEF. This will give more insight into non-invasive MRI- based perfusion and fibrosis biomarkers and how they complement other biomarkers and give insight into different subtypes of HFpEF. The relevance to public health is that HFpEF is a leading cause of disability and death and no effective treatment is known. The development and use of accurate and repeatable measurements of perfusion and their combination with fibrosis quantitation will lead to accelerated evaluation of clinical therapies. The project will also provide new tools and knowledge for better management of patients with HFpEF. The proposed approach will be extended to better understand a range of cardiac diseases.